Controlling the Substitution Pattern of Hexasubstituted Naphthalenes by Aryne/Siloxyfuran Diels–Alder Additions: Regio- and Stereocontrolled Synthesis of Arizonin C1 Analogs

Article abstract of DOI:10.1002/ejoc.201700195

3,4-Dimethoxybenz-1-yne and 2-siloxylated furans without or with a bromine atom at C-3 undergo Diels–Alder reactions with orientational selectivity. Hydrolysis furnished a bromine-free or a bromine-containing naphthalene, respectively. Bromination of the former provided a regioisomer of the latter. Either of the two compounds was processed to give a variety of unnatural naphthoquinonopyrano-γ-lactones. This occurred by a succession of (1) Heck coupling, (2) asymmetric dihydroxylation, (3) oxa-Pictet–Spengler cyclization, and (4) oxidation. The fifteen monomeric naphthoquinonopyrano-γ-lactone structures that we prepared resemble the natural product (–)-arizonin C1 or its C-5 epimer. Accordingly, they represent hexasubstituted naphthalenes likewise. The sixteenth naphthoquinonopyrano-γ-lactone that we synthesized is a kind of dimer. Its moieties are bridged differently than those in naturally occurring naphthoquinonopyrano-γ-lactone dimers.

Full text of DOI:10.1002/ejoc.201700195

A Journal of
Accepted Article
Title: Controlling the Substitution Pattern of Hexasubstituted
Naphthalenes by Aryne/Siloxyfuran Diels-Alder Additions: Regio-
and Stereocontrolled Synthesis of Arizonin C1 Analogs
Authors: Reinhard Brückner, Markus Neumeyer, and Julia Kopp
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
((For Table of Contents:))
Controlling the Substitution Pattern of Hexasubstituted
Naphthalenes by Aryne/Siloxyfuran Diels-Alder Additions:
Regio- and Stereocontrolled Synthesis of Arizonin C1 Analogs
Markus Neumeyer,[a] Julia Kopp,[a] and Reinhard Brückner*[a]
Naphthoquinonopyrano-γ-lactones
10 (−)-arizonin C1 analogs
MeO
MeO
OMe
MeO
OMe
MeO
O
R
iPr3SiO
H
MeO
MeO
H
MeO
MeO
2 steps
4 steps
2 steps
OH
O
+
O
Br
O
O
OMe
OMe
OMe
OMe
O
O
Diels-Alder reaction
with or without
downstream bromination
Heck coupling;
asymmetric
dihydroxylation
oxa-Pictet-
Spengler cycli-
zation; oxidation
O
O
O
R
OH
O
O
+
3 steps
2 steps
MeO
2 steps
MeO
MeO
Br
MeO
Br
iPr3SiO
O
O
MeO
MeO
OMe
MeO
OMe
MeO
O
O
5 (−)-arizonin C1 analogs
Furans with directing power: 3,4-Dimethoxybenz-1-yne and 2-siloxylated furans with or without 3-bromine underwent Diels-
Alder reactions with orientational selectivity. Hydrolysis gave a bromine-containing and a bromine-free naphthalene, respec-
tively. Bromination of the latter provided a regioisomer of the former. In 4 steps, these compounds delivered unnatural naph-
thoquinonopyrano-γ-lactones. They resemble the natural product (−)-arizonin C1 and contain hexasubstituted naphthalene
cores, too.
1
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
Controlling the Substitution Pattern of Hexasubstituted
Naphthalenes by Aryne/Siloxyfuran Diels-Alder Additions:
Regio- and Stereocontrolled Synthesis of Arizonin C1 Analogs
Markus Neumeyer,[a] Julia Kopp,[a] and Reinhard Brückner*[a]
Dedicated to Waldemar Adam at the occasion of his 80th anniversary
Abstract: 3,4-Dimethoxybenz-1-yne and 2-siloxylated furans
without or with a bromine atom at C-3 undergo Diels-Alder reac-
tions with orientational selectivity. Hydrolysis furnished a bro-
mine-free and a bromine-containing naphthalene, respectively.
Bromination of the former provided a regioisomer of the latter.
Either of the two compounds was processed to give a variety of
(+)-frenolicin B (1b[5]), (‒)-arizonin B1 (2[6]), and (‒)-arizonin C1
(3[6]). Considerable efforts were directed towards the total syn-
thesis of these compounds[7] and their congeners.[2] In that con-
text
a
number of C5-epimers,[8,9] naphthoquinonopyrano-γ-
lactones,[10] benzoquinonopyrano-γ-lactones,[11] and carbazole-
unnatural naphthoquinonopyrano-γ-lactones. This occurred by a
succession of (1) Heck coupling, (2) asymmetric dihydroxylation,
(3) oxa-Pictet-Spengler cyclization, and (4) oxidation. The fifteen
5
a) Y. Iwai, A. Kora, Y. Takahashi, T. Hayashi, J. Awaya, R. Masuma, R. Oi-
wa, S. Omura, J. Antibiot. 1978, 31, 959-965 (without the sign of the specific
rotation of the natural product); b) synthetic (+)-deoxyfrenolicin B and “deoxy-
frenolicin B methyl ester of natural origin” were converted into synthetic (+)-
frenolicin B by T. Masquelin, U. Hengartner, J. Streith, Helv. Chim. Acta, 1997,
80, 43-58; natural deoxyfrenolicin B being dextrorotatory (ref.[5a]) the correla-
tions of ref.[5b establish the dextrorotation of natural (+)-frenolicin B (1b).
monomeric naphthoquinonopyrano-
we reached resemble the natural product (
C-5 epimer. Accordingly, they represent hexasubstituted naph-
thalenes likewise. The sixteenth naphthoquinonopyrano- -lac-
tone is a dimer of sorts. Its moieties are bridged differently than
in naturally occurring naphthoquinonopyrano- -lactone dimers.
γ-lactone structures, which
−)-arizonin C1 or its
γ
6
a) J. E. Hochlowski, G. M. Brill, W. W. Andres, S. G. Spanton, J. B. McAl-
pine, J. Antibiot. 1987, 40, 401-407.
γ
7 With respect to the naphthoquinonopyrano-γ-lactone natural products 1- 3 we
are aware of the following total syntheses: (+)-kalafungin (1a): a) K. Tatsuta,
K. Akimoto, M. Annaka, Y. Ohno, M. Kinoshita, Bull. Chem. Soc. Jpn. 1985,
58, 1699-1706; b) J. Antibiot. 1985, 680-682; c) R. A. Fernandes, R. Brückner,
Synlett 2005, 1281-1285; d) C. D. Donner, Tetrahedron Lett. 2007, 48, 8888-
8890; e) R. A. Fernandes, V. P. Chavan, S. V. Mulay A. Manchoju, J. Org.
Chem. 2012, 77, 10455−10460; f) C. D. Donner, Tetrahedron, 2013, 69, 377-
386; total syntheses of (−)-nanaomycin D (ent-1a): g) ref.[7a]; h) ref.[7b]; i) M.
P. Winters, M. Stranberg, H. W. Moore, J. Org. Chem. 1994, 59, 7572-7574; j)
ref.[7c]; k) N. P.S. Hassan, B. J. Naysmith, J. Sperry, M. A. Brimble,
Tetrahedron 2015, 71, 7137-7143; total syntheses of (+)-frenolicin B (1b): l) G.
A. Kraus, J. Li, J. Am. Chem. Soc. 1993, 115, 5859-5860; m) G. A. Kraus, J.
Li, M. S. Gordon, J. H. Jensen, J. Org. Chem. 1995, 60, 1154-1159; n) ref.[5b];
o) R. Brückner, R. A. Fernandes, unpublished results; p) ref.[7e] q) Y. Zhang,
X. Wang, M. Sunkara, Q. Ye, L. V. Ponomereva, Q.-B. She, A. J. Morris, J. S.
Thorson, Org. Lett. 2013, 15, 5566-5569; total synthesis of (‒)-arizonin B1 (2):
r) M. Neumeyer, R. Brückner, Eur. J. Org. Chem. 2017, in the press (DOI:
10.1002/ejoc.201700013); total syntheses of (‒)-arizonin C1 (3): s) M. Mahlau,
R. A. Fernandes, R. Brückner, Eur. J. Org. Chem. 2011, 4765-4772; t) R. A.
Fernandes, S. V. Mulay, V. P. Chavan, Tetrahedron: Asymmetry 2013, 24,
1548-1555; u) ref.[7r].
Natural Naphthoquinonopyrano-γ-lactones
and Synthetic Analogs
The naphthoquinonopyrano-γ-lactone natural products exhibit a
wide array of biological activity such as inhibition of Gram posi-
tive and negative bacteria, fungi, yeasts, and malignant tu-
mors.[1] Not in the least therefore, these compounds have at-
tracted the interest of natural product, synthetic, and medicinal
chemists.[2] Figure 1 shows a selection of monomeric naphtho-
quinonopyrano-γ-lactone natural products: (+)-kalafungin (1a[3]),
its naturally occurring enantiomer (‒)-nanaomycin D (ent-1a[4]),
[a]
Institut für Organische Chemie der Albert-Ludwigs-Universität,
Albertstraße 21, 79104 Freiburg, Germany
E-Mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
http//www.brueckner.uni-freiburg.de
8
a) Syntheses of racemic 5-epi-kalafungin = racemic 5-epi-nanaomycin D (5-
epi-rac-1a) are unknown; syntheses of racemic 5-epi-frenolicin B (5-epi-rac-
1b): b) P. Contant, M. Haess, J. Riegl, M. Scalone, M. Visnick, Synthesis,
1999, 821-828; c) C. D. Donner, Synthesis 2010, 415-420; synthesis of race-
mic 5-epi-arizonin B1 (5-epi-rac-2): d) M. A. Brimble, S. J. Phythian,
Tetrahedron Lett. 1993, 34, 5813-5814; synthesis of racemic 5-epi-arizonin C1
(5-epi-rac-3): e) Ref.[8d].
Supporting Information for this article is provided via a link at the end of
this document.
1 M. A. Brimble, L. J. Duncalf, M. R. Nairn, Nat. Prod. Rep. 1999, 16, 267-281.
2 Reviews: a) M. A. Brimble, M. R. Nairn, H. Prabarahan, Tetrahedron 2000,
56, 1937-1992; b) K. Tatsuta, S. Hosokawa, Chem. Rev. 2005, 105, 4707-
4729; c) Review: K. Tatsuta, S. Hosokawa, Science and Technology of Ad-
vanced Materials, 2006, 7, 397-410; d) J. Sperry, P. Bachu, M. A. Brimble,
Nat. Prod. Rep. 2008, 25, 376-400; e) K. Tatsuta, J. Antibiot. 2013, 66, 107-
129; f) R. A. Fernandes, P. H. Patil, D. A. Chaudhari, Eur. J. Org. Chem. 2016,
5778–5798; g) B. J. Naysmith, P. A. Hume, J. Sperry, M. A. Brimble, Nat.
Prod. Rep. 2017, 34, 25-61.
3 a) M. E. Bergy, J. Antibiot. 1968, 21, 454-457; b) H. Hoeksema, W. C. Krue-
ger, J. Antibiot. 1976, 29, 704-709 [ORD spectrum of O-methyl-(+)-kalafungin
but not of (+)-kalafungin (1a)].
S. Omura, H. Tanaka, Y. Okada, H. Marumo, J. Chem. Soc., Chem.
Commun. 1976, 320-321.
9
Syntheses of enantiomerically pure (−)-5-epi-kalafungin (5-epi-1a) or (+)-5-
epi-nanaomycin D (5-epi-ent-1a): a) Ref.[7c]; b) ref.[7d]; c) ref.[7e]; d) ref.[7f];
syntheses of enantiomerically pure (−)-5-epi-frenolicin B (5-epi-1b): e) ref.[5b];
f) ref.[7o]; g) ref.[7e]; h) ref.[7f]; i) ref.[7q]; synthesis of enantiomerically pure
(+)-5-epi-arizonin B1 (5-epi-2) j) ref.[7r]; synthesis of enantiomerically pure (+)-
5-epi-arizonin C1 (5-epi-3): ref.[7r].
10
For example: a) T. Masquelin, U. Hengartner, J. Streith, Synthesis 1995,
780-786; b) C. Tödter, H. Lackner, Liebigs Ann. 1996, 1385-1394; c) E. J.
Salaski, G. Krishnamurthy, W.-D. Ding, K. Yu, S. S. Insaf, C. Eid, J. Shim, J. I.
Levin, K. Tabei, L. Toral-Barza, W.-G. Zhang, L. A. McDonald, E. Honores, C.
4
2
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
OH
O
R
OH
O
O
Me
OR
O
O
Me
products 1-3.[12] Figure 1 shows most of them (4 - 9). Rac-4a dif-
fers from rac-kalafungin (rac-1a) by its phenyl instead of a me-
thyl substituent.[10a] The kalafungin epimer rac-epi-4a contains a
cis,cis- rather than trans,cis-dihydropyran. Compound rac-4b is
MeO
5
5
5
O
O
O
3a
3a
3a
O
O
O
O
O
O
O
monomethyl
kalafungin
(5-Me-rac-1a).[10a]
Other
5,5-
R = Me: (+)-kalafungin (1a)
Pr: (+)-frenolicin B (1b)
(−)-nanaomycin (ent-1a) R = H: (−)-arizonin B1 (2)
Me: (−)-arizonin C1 (3)
dimethylated naphthoquinonopyrano-γ-lactone analogs are
quinolinequinones: iso-rac-5a, rac-5b-d (R = H, Me, OH), and
rac-5e-h (R = OH, OMe, OBn, and NMe2, respectively).[10b] 7-
Deoxykalafungin (6a, R = Me) was targeted four times[10c-f ] and
analogs 6b-e (R = H, alkyl ≠ methyl, aryl) thereof twice.[10c-d]
Benzoquinonopyrano-γ-lactones with an aryl group (7a-c, Ar = 4-
MeOC6H4, 4-ClC6H4, 2,4,6-(MeO)3C6H4; epi-7d), an acyclic ni-
trogen substituent (8a; epi-8b-c, R = 4-MeC6H4, 4-FC6H4), a
heterocyclic nitrogen substituent (8d; epi-8d-h, substituents too
complex for showing) were studied, too,[11h] as were the carba-
zolequinonopyrano-γ-lactones 9a and epi-9b.[11h]
OH
O
Ph
OH
O
Ph
OH
O
Me Me
5
O
O
O
O
O
O
O
O
O
O
O
O
rac-4a[10a]
rac-epi-4a[10a]
rac-4b[10a]
O
O
O
Me
Me
Me
Me
O
Me
O
Me
O
N
R
R
5
5
5
7
10
N
10
N
O
O
O
O
O
O
O
O
O
iso-rac-5a[10b]
rac-5b-d[10b]
rac-5e-h[10b]
The frenolicin B analogs rac-4a and rac-4b (Figure 1) increased
the drug resistance of Eimeria tenella in vitro as much and by
the same mode of action as the natural product frenolicin B (1b)
[10a]. Some quinolinequinones rac-5 are active against bacteria,
fungi, and tumor cell lines.[10b] Brimble et al. proved 7-
deoxykalafungin 6a (R = Me; synthesis: ref.[10e]) is cytotoxic
against three breast cancer cell lines.[13] (+)-Frenolicin B (1b)
inhibits a serine/threonine kinase implicated in certain malignant
tumors.[14] The deoxykalafungin analogs 6a-e[10d] inhibit the
same kinase by the surmised alkylation of a cysteine thiol
group.[10c] Remarkably, antipode ent-6e is as active as 6e it-
self.[10c] The naphthoquinonopyrano-γ-lactone analogs 7-9
proved cytotoxic against various tumor cell lines.[11h] Altogether,
bioactivity in this class of compounds stretches beyond the
natural products considerably.
O
R
O
Ph
O
Ph
O
Ph
Ar
O
O
O
O
O
O
O
O
O
6a-e[10c-f]
O
O
epi-7d[11h]
7a-c[11h]
O
Ph
O
Ph
O
Ph
O
O
O
O
N
PhN
H
ArN
H
O
O
O
N
O
8d[11h]
O
8a[11h]
O
O
O
epi-8b,c[11h]
O
Me
O
Ph
O
O
Ph
O
Ph
O
O
O
N
H
O
N
H
N
various
O
O
O
O
O
O
O
epi-8d-h[11h]
9a[11h]
epi-9b[11h]
Figure 1. Selected monomeric naphthoquinonopyrano-γ-lactone natural
products: (+)-kalafungin (1a), (+)-frenolicin B (1b), (−)-nanaomycin (ent-
1a), (−)-arizonin B1 (2), and (−)-arizonin C1 (3). Synthetic pyrano-γ-
lactone analogs with trans,cis-substituted dihydropyran moieties: naph-
thoquinonopyrano-γ-lactones (rac-4a, 6a-e), benzoquinonopyrano-γ-
lactones (7a-c-8a,d), and carbazolequinonopyrano-γ-lactones (9a); with
cis,cis-substituted dihydropyran moieties: naphthoquinonopyrano-γ-
lactones (rac-epi-4a) benzoquinonopyrano-γ-lactones (epi-7d, epi-8a,b,d-
h) and the carbazolequinonopyrano-γ-lactone epi-9b; with C-5 dimethyl-
ated diyhdropyran moieties: naphthoquinonopyrano-γ-lactones (rac-4b,
iso-rac-5a, and rac-5b-h).
[11h]
zolequinonopyrano-γ-lactones
were synthesized. They all
Scheme 1. The in-vivo alkylation of nucleophiles, which causes the bio-
are “analogs” of the naphthoquinonopyrano-γ-lactone natural
logical activity of naphthoquinonopyrano-γ-lactones according to ref.[15]
,
exemplified for (+)-kalafungin (1a): a) reduction; b) 1,4-elimination; c) 1,4-
addition [steps (b) and (c) combined represent an SN1-substitution].
Hanna, A. Yamashita, B. Johnson, Z. Li, L. Laakso, D. Powell, T. S. Mansour,
J. Med. Chem. 2009, 52, 2181-2184; d) C. N. Eid, J. Shim, J. Bikker, M. Lin, J.
Org. Chem. 2009, 74, 423-426; e) P. A. Hume, J. Sperry, M. A. Brimble, Org.
Biomol. Chem., 2011, 9, 5423-5430; f) S. Korwar, T. Nguyen, K. C. Ellis,
Bioorg. Med. Chem. Lett. 2014, 24, 271-274.
12 More extensive treatises of the structural space of naphthoquinonopyrano-γ-
lactones: ref.[2].
13
A. M. Heapy, A. V. Patterson, J. B. Smaill, S. M. F. Jamieson, C. P. Guise,
11
Examples of racemic benzoquinonopyrano-γ-lactones: a) ref.[10b]; b) Z. Li,
J. Sperry, P. A. Humea, K. Rathwell, M. A. Brimble, Bioorg. Med. Chem. 2013,
21, 7971-7980.
14 L. Toral-Barza, W.-G. Zhang, X. Huang, L. A. McDonald, E. J. Salaski, L. R.
Barbieri, W.-D. Ding, G. Krishnamurthy, Y. B. Hu, J. Lucas, V. S. Bernan, P.
Cai, J. I. Levin, T. S. Mansour, J. J. Gibbons, R. T. Abraham, K. Yu, Mol. Can-
cer Ther. 2007, 6, 3028-3038.
Y. Gao, Y. Tang, M. Dai, G. Wang, Z. Wang, Z. Yang, Org. Lett. 2008, 10,
3017-3020; c) Y. Cui, H. Jiang, Z. Li, N. Wu, Z. Yang, J. Quan, Org. Lett.
2009, 11, 4628-4631; d) ref.[8c]; examples of enantiomerically pure benzoqui-
nonopyrano-γ-lactones: e) ref.[7i]; f) ref.[7l]; g) ref.[7m]; h) X. Jiang, M. Wang,
S. Song, Y. Xu, Z. Miao, A. Zhang, RSC Advances 2015, 5, 27502-27508.
3
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
The chemical basis of these bioactivities should be the bioreduc-
tive alkylation mechanism of Moore and Czerniak.[15] Scheme 1
exemplifies it for (+)-kalafungin (1a). Step 1 is believed to be an
in-vivo reduction providing the naphthohydroquinone 10. The
lactone moiety ring-opens thereupon, forming quinone methide
11. The latter is a Michael acceptor and therefore acts as an al-
kylating agent of nucleophilic sites in proteins.[15] Supporting evi-
dence for this mode of action stems from reductive thioalkyla-
tions of a naphthoquinonopyrano-γ-lactone described by Brimble
et al.[16] and a pertinent theoretical treatment.[17]
on;[20] oxidation of the naphthohydroquinone (details: below).
This strategy equals one, which we followed in total syntheses of
the naphthoquinonopyrano-γ-lactone natural products (+)-kala-
fungin (1),[7c] (‒)-arizonin B1 (2),[7r] (‒)-arizonin C1 (3),[7s] and (+)-
γ-actinorhodin.[21,22] The difference between the present synthe-
ses and our former ones is how we deemed to prepare the bro-
monaphthalene substrate of the Heck coupling. This is shown at
the bottom of Scheme 2 and discussed in the next paragraph.
Scheme 2 depicts retrosynthetic analyses of the desired „type 1-
analogs“ (at left) and „type-2 analogs“ (at right) of the naphtho-
quinonopyrano-γ-lactone pharmacophore. The former analogs
possess scaffold 13, the latter scaffold 14. The upper half of
Scheme 2 retraces the already-mentioned steps: (1) Heck cou-
plings 19→17 and 20→18; (2) asymmetric dihydroxylations
17→15 and 18→16; (3) oxa-Pictet-Spengler cyclizations / (4)
Ce(IV) oxidations (15 → → 13 and 16 → → 14). The lower half
of Scheme 2 shows how we planned to reach the Heck sub-
strates: after annulating 3,4-dimethoxybenz-1-yne (26) to the 2-
siloxyfurans 27 or 28, respectively. This should occur by tan-
dems of regioselective[23] Diels-Alder reactions (→ tricycles 24[24]
and 25, respectively) and in-situ ring-openings (→ naphthalene
22 and bromonaphthalene 23, respectively). The naphthalene
22 should be (re)protected and brominated regioselectively[25] in
order to reach the Heck substrate 19. The bromonaphthalene 23
should be (re)protected to render the Heck substrate 20 directly.
"type-1 analogs" of ( )-arizonin C1
(plus respective enantiomers):
"type-2 analogs" of ( )-arizonin C1:
OMe O
R
O
R
MeO
O
O
MeO
O
O
O
OMe O
O
O
O
13b-f
14a-e
(plus ent-13a-e)
a
b
c
d
e
f
CF3
F
Br
R
Me
Figure 2. Synthetic naphthoquinonopyrano-γ-lactones reached in the
present study. Compounds 13b-f, their mirror images ent-13b-f, and the
unnatural enantiomer ent-13a (≡ ent-3) of (–)-arizonin C1 (3) – summariz-
able as “type-1 analogs” of (–)-arizonin C1 (3) – are dimethoxylated at
the same positions as their antecessor. Compounds 12a-e – collectively
called “type-2 analogs” of (–)-arizonin C1 (3) – are dimethoxylated at
different positions. In addition to these analogs we synthesized the
dimeric naphthoquinonopyrano-γ-lactone 46 (structure: Scheme 6).
The route delivering the aryne 26 and our desire to add it to the
bromine-containing siloxyfuran 28 (Scheme 2, at bottom) de-
serve two comments. (1) To date this aryne seems to have been
prepared solely by treating the bromotosylate iso-29 with
nBuLi.[26] This induces a Br/Li exchange and subsequent β-
elimination of lithium p-toluenesulfinate. We wanted to proceed
This publication describes the synthesis of a 16-membered li-
brary of arizonin C1-like naphthoquinonopyrano-γ-lactones
(structures: Figure 2). It includes the synthesis of the dimeric
naphthoquinonopyrano-γ-lactone 45 (detailed in Scheme 6).
20
a) Review: E. L. Larghi, T. S. Kaufman, Eur. J. Org. Chem. 2011, 5195-
5231; recent uses in the synthesis of naphthoquinonopyrano-γ-lactones: b)
ref.[7e]; c) R. Bartholomäus, J. Bachmann, C. Mang, L. O. Haustedt, K.
Harms, U. Koert, Eur. J. Org. Chem. 2013, 180-190; d) ref.[7t]; e) S. V. Mulay,
A. Bhowmik, R. A. Fernandes, Eur. J. Org. Chem. 2015, 4931-4938; f) ref.[7r];
g) ref.[22].
Orientationally Complementary
21
a) Correct structure: A. Zeeck, H. Zähner, M. Mardin, Liebigs Ann. Chem.
Aryne/Siloxyfuran Diels-Alder Reactions for
Synthesizing Naphthoquinonopyrano-γ-
lactone Analogs of (−)-Arizonin C1
1974, 1100-1125; b) tautomeric structure: B. Krone, A. Zeeck, Liebigs Ann.
Chem. 1987, 751-758; c) the specific rotation was not determined at a single
wavelength; its value at 589 nm can be interpolated from the ORD spectrum
(P. Christiansen, Ph. D. Thesis, Universität Göttingen, Germany, 1970;
ref.[21b]).
22
Each arizonin C1 analog of Figure 2 or Scheme 6 was prepared
by an identical series of 4 late steps: 1) Heck-coupling;[18] 2)
asymmetric dihydroxylation;[19] 3) oxa-Pictet-Spengler reacti-
Total synthesis: M. Neumeyer, R. Brückner, Angew. Chem. 2017, in the
press (DOI: 10.1002/anie.201611183, DOI: 10.1002/ange.201611183).
23
Diels-Alder reactions of unsymmetric 3-alkoxybenz-1-ynes with 2-
oxygenated furans are likely to deliver two regioisomers but usually one ad-
duct predominates. Therein, the mentioned oxygen substituents are located
close to each other, namely at C-1 and C-8 (naphthalene numbering; refer-
ences: cf. footnote 30 in ref.[7r].). We call this the “proximal” Diels-Alder ad-
duct. In contrast, the mentioned oxygen substituents wind up in a greater dis-
tance from one another in what we call the “distal” Diels-Alder adduct, namely
at C-1 and C-5 (naphthalene numbering).
24 We are aware of a single Diels-Alder reaction between an aryne and the sil-
oxyfuran 27: S. Narayan, W. R. Roush, Org. Lett. 2004, 6, 3789-3792. The
aryne employed there was near-symmetric and reacted without regiocontrol.
15 a) H. W. Moore, Science 1977, 198, 527-532.‒ b) H. W. Moore, R. Czerniak,
Med. Res. Rev. 1981, 1, 249-280.
16
Communication: M. A. Brimble, M. R. Nairn, Tetrahedron Lett. 1998, 39,
4879-4882; full paper: M. A. Brimble, M. R. Nairn, J. Chem. Soc. Perkin Trans.
1, 2000, 317-322.
17 P. A. Hume, M. A. Brimble, J. Reynisson, Aust. J. Chem. 2012, 65, 402-408.
18
a) ref.[10d]; b) Y. Zhang, X. Wang, M. Sunkara, Q. Ye, L. V. Ponomereva,
Q.-B. She, A. J. Morris, J. S. Thorson, Org. Lett. 2013, 15, 5566-5569; c)
.[10f]; d) Y. Zhang, Q. Ye, X. Wang, Q.-B. She, J. S. Thorson, Angew. Chem.
2015, 127, 11371-11374; Angew. Chem. Int. Ed. 2015, 54, 11219-11222; e)
ref.[7r].
25
References of C-6 brominations of 1-substituted 2-oxynaphthalenes: cf.
footnote 27 in ref.[7r].
26
19 Such routes to “Nonracemic γ-Lactones From the Sharpless Asymmetric Di-
hydroxylation of β,γ-Unsaturated Carboxylic Esters” were the topic of a perti-
nent review: M. Neumeyer, R. Brückner, Eur. J. Org. Chem. 2016, 5060-5087.
Preparation of 3,4-dimethoxybenz-1-yne (26) from bromotosylate iso-29: a)
R. G. F. Giles, A. B. Hughes, M. V. Sargent, J. Chem. Soc. Perkin Trans. 1
1991, 1581-1587; b) M. A. Brimble, S. J. Phythian, Tetrahedron Lett. 1993, 34,
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
OMe O
R
O
R
(which is susceptible to a Br/Li exchange with nBuLi in THF at
−78°C[28]). However, nBuLi and an iodotosylate gave an aryne
when 2-bromofuran was present.[29] Likewise, nBuLi effected a
dehydrofluorination providing an aryne in the presence of 3-
bromofuran[30]. This meant that our preparation of the aryne 26
should not jeopardize the Br-containing siloxyfuran 28.
MeO
O
O
14
13
MeO
O
O
O
OMe O
O
O
type-1 analogs of (−)-arizonin C1
(or enantiomers thereof)
type-2 analogs of (−)-arizonin C1
OH
OMe
OMe
3
OMe
OMe OMe
OMe
OH
MeO
R
MeO
Br
O
MeO
Br
MeO
b)
c)
3
MeO
OH
4
15
16
OR
MeO
O
R = H
32[31]
33: R = H
29: R = Ts
26
O
O
OMe
OMe OMe
OMe
30:
d)
a)
O
O
31[31]: R = Br
O
iPr3SiO
O
OMe OMe
MeO
e)
f)
j)
O
O
O
17
18
MeO
34
35[34]
27[34]
OMe
OMe OMe
OMe
Br
MeO
O
MeO
O
Br
Br
g)
h)
i)
Br
O
O
HO
HO
HO
Br
Br
O
38[36]
OMe OMe
iPr3SiO
O
O
36[36]
O
37[36]
X = Br: 19
X = H: 21
MeO
28[37]
20
X
MeO
Br
Scheme 3. Syntheses of the Diels-Alder partners: bromotosylate 29
(preceding the aryne 26), siloxyfurans 27 and 28. Reagents and condi-
tions: a) Br2 (1.0 equiv.), NaOAc (2 equiv.) Fe powder (8 mol-%), AcOH,
room temp., 5 h; 73% (ref.[31]: 70%); b) KOH (1.6 equiv.) Me2SO4
(1.6 equiv.), H2O, 60°C, 1 h; 74% (ref. [31]: 96%); c) mCPBA (1.5 equiv.),
CH2Cl2, reflux, 14 h; aqueous KOH (10%, 4 equiv.), room temp., 3 h;
92%; d) TsCl (1.5 equiv.), NEt3 (1.5 equiv.), CH2Cl2, 0°C → room temp.,
4 d; 85%; e) N,N-dimethylethanolamine (34 mol-%), formic acid (2
equiv.), H2O2 (30% in H2O, 2 equiv.), Na2SO4,, room temp., 16 h; 59%
(ref.[34]: 58%); f) iPr3SiOTf (1.2 equiv.),[35] NEt3 (1.3 equiv.), CH2Cl2, 0°C
→ room temp., 1 h; 98% (ref.[34]: 94%); g) NBS (1.0 equiv.), AIBN (0.6
mol-%), CCl4, reflux, 5 h; h) Br2 (1.2 equiv.), 40°C, 5 h; 42% over the 2
steps (ref.[36]: 35%); i) H2O, reflux, 4 h; 43% (ref.[36]: 31%); j) iPr3SiOTf
(1.2 equiv.),[35] NEt3 (1.4 equiv.), CH2Cl2, 0°C → room temp., 2.5 h; 79%
(ref.[37]: 90%).
OMe
OMe OMe
OH
OMe OSiiPr3
MeO
MeO
1
4
1
22
23
3
4
MeO
MeO
Br
OMe OSiiPr3
OH
OMe OSiiPr3
O4
2
8
1
O1
8
Br
24
25
4
OMe OSiiPr3
OMe
iPr3SiO
4
+
O
3
Our syntheses began with preparing the bromotosylate 29 and
the siloxyfurans 27 and 28, i. e., the precursor and substrates,
respectively, of the mentioned Diels-Alder reactions (Scheme 3).
For reaching the bromotosylate 29, isovanillin (30) was ortho-
brominated following the literature.[31] An O-methylation ensued
first[31] (→ 31), a Dakin oxidation[32] then, and formate hydrolysis
thereafter(→ 33).[33] A tosylation accomplished the bromotosyl-
ate 29 in 42% overall yield.
MeO
3
3
4
MeO
3
Br
+
O
iPr3SiO
OMe
26
27
26
28
ref.[26]
this study
ref.[26]
OMe
OMe
OMe
MeO
OTs
Br
MeO
Br
OTs
MeO
OTs
Br
3
3
3
4
4
4
iso-29
iso-29
29
Scheme 2. Retrosynthetic analysis of arizonin C1 analogs. Type 1-
analogs contain the natural naphthoquinone motif (13, left column), type
2-analogs are “methoxy-reversed” variations thereof (14, right column).
28
a) Br/Li exchange: J. Boukouvalas, J.-X. Wang, O. Marion, B. Ndzi, J. Org.
Chem. 2006, 71, 6670-6673; b) 3-lithiated 2-triisopropylsiloxyfurans (from an
I/Li exchange) undergo no retro-[1.2]-Brook rearrangement at ‒78°C (as
shown by quenching 3-lithio-4-methoxy-2-(triisopropylsiloxy)furan with CD3OD
at −78°C and working up at pH 5.5 to a 3-deuterated butenolide) according to
F. F. Paintner, L. Allmendinger, G. Bauschke, Synlett 2005, 18, 2735-2738.
29 G. E. Morton, A. G. M. Barrett, J. Org. Chem. 2005, 70, 3525-3529.
analogously employing the isomeric bromotosylate 29. It is
easier to make than iso-29.[27] (2) Employing nBuLi for gener-
ating 3,4-dimethoxybenz-1-yne (26) requires that Br/Li exchange
in 29 (or iso-29) is faster than in the 3-bromo-2-siloxyfuran 28
30
R. G. F. Giles, M. V. Sargent, H. Sianipar, J. Chem. Soc., Perkin Trans. 1
1991, 1571-1579.
31 A. K. Sinhababu, R. T. Borchardt, J. Org. Chem. 1983, 48, 2356-2360.
32 First reports: a) H. D. Dakin, Proc. Chem. Soc., London, 1909, 25, 194–195;
b) H. D. Dakin, Am. Chem. J. 1909, 42, 477-498.
5813-5814; c) M. A. Brimble, S. J. Phythian, H. Prabaharan, J. Chem. Soc.
Perkin Trans 1, 1995, 2855-2860.
27 This variation entailed no risk: We prepared the analogous aryne − contain-
ing 3-OBn instead of 3-OMe − from the OBn analog of bromotosylate 29 rather
than from the OBn analog of bromotosylate iso-29 earlier (ref. [7r]).
33
A Dakin oxidation delivering 33 had not been known prior to our study. We
based it on a procedure described by M. Altemöller, T. Gehring, J. Cudaj, J.
Podlech, H. Goesmann, C. Feldmann, A. Rothenberger, Eur. J. Org. Chem.
2009, 2130-2140.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
a)
or b)
or c)
OMe
OMe OSiiPr3
OMe
iPr3SiO
−78°C, we treated a solution of the bromotosylate 29 and 1.5
equiv. of the bromine-free siloxyfuran 27 in THF with nBuLi, like
suggested by related literature reports.[26] This generated the ar-
yne 26. It engaged in a Diels-Alder addition with 27 immediately.
Two orientational isomers resulted, namely mainly the “proxi-
mal”[23] adduct 24 and some “distal”[23] adduct iso-24. An aque-
ous acidic work-up and flash chromatography on silica gel[38]
delivered the respective ring-opening products. These were 62%
of the naphthohydroquinonetriether 22 and, within a 10:90
mixture with iPr3SiOH, 12% of the isomeric triether iso-22. Both
compounds gave the same naphthohydroquinonediether 39 by
desilylation. However, it was better to desilylate the crude
mixture of Diels-Alder adducts 24/iso-24 directly. This gave 39 in
82% yield over the 2 steps. Double O-methylation provided the
naphthohydroquinonetetraether 21 in 79% yield over all 3 steps.
It was brominated with NBS in DMF at room temperature as
regioselectively as found for an analogous compound recently.[7r]
This allowed to isolate the (desired) bromonaphthalene 19 in
84% yield and to separate the (presently undesired) bromonaph-
MeO
Br
MeO
MeO
3
+
+
O
O
O
OTs
OSiiPr3
29
27
24
iso-24
OMe
iPr3SiO
MeO
via
+
O
cont.
cont.
26
27
OMe OH
OMe OSiiPr3
OMe OH
MeO
MeO
MeO
b) cont. without
separated
from
separating 22
from iso-22
OH
OH
OSiiPr3
39
22 (62%)
iso-22 (12%,
10:90 mixture
with iPr3SiOH)
d)
e)
f)
c) cont. without separating 22 from iso-22
OMe OMe
OMe OMe
OMe OMe
4a
4a
MeO
MeO
MeO
Br
g)
OSiiPr3
3
7
7
8
2
8
OTs
X
separated
from
a)
8a
8a
Br
O
+
O
+
O
OMe
OMe
OMe
MeO
Br
MeO
X
MeO
Br
21
19 (84%)
20 (2%)
iPr3SiO
OMe
OMe OSiiPr3
OMe
29
28
25: X = Br
iso-25: X = Br
+
+
Scheme 4. Synthesizing the bromotetramethoxynaphthalene 19 − pre-
ceding our “type 1” arizonin C1 analogs − by an aryne/siloxyfuran Diels-
Alder addition and an ensuing bromination. Reagents and conditions: a)
27 (1.5 equiv.), THF, –78°C; dropwise addition of nBuLi (2.60 M in hex-
ane, 1.0 equiv.), THF, –78°C; 5 min; –78°C → room temp., 45 min; 22:
62%, iso-22: 12% (as a 10:90 mixture with iPr3SiOH); b) same as (a);
cooling to 0°C; addition of Bu4NF (in THF, 1.5 equiv.), 0°C → room
temp., 8 min; 82% over the 2 steps; c) same as (b) but 15 min instead of
8 min; addition of Me2SO4 (10 equiv.) KOH (8 equiv.), Bu4NBr (5 mol-%),
THF/H2O (2:1), 0°C → room temp., 17 h; 79% over the 3 steps; d) Bu4NF
(in THF, 1.5 equiv.), THF, 0°C → room temp., 15 min; 90%; e) same as
(d); 86%; f) Me2SO4 (10 equiv.), KOH (8 equiv.), Bu4NBr (5 mol-%),
THF/H2O (2:1), 0°C → room temp., 17 h; 96%; g) NBS (1.0 equiv.), DMF,
room temp., 16 h; 19: 84%; 20: 2%.
24: X =
H
iso-24: X = H
+
via
O
MeO
Br
iPr3SiO
OMe
26
cont.
OH
cont.
28
OH
OSiiPr3
X
b)
separated
from
MeO
X
MeO
X
MeO
OMe OH
OMe OSiiPr3
OMe OH
40: X = Br
23: X = Br (48%)
iso-23: X = Br (14%)
+
+
+
iPr3SiOH
+
iso-22: X =
(87:7:6 mixture)
39: X =
H
22: X =
(94:6 mixture)
H
H
c)
d)
e)
The bromine-free siloxyfuran 27 was obtained from furfural.[34]
A
OMe
OMe
Dakin oxidation[32] and hydrolysis provided 59% of the butenolide
39 as reported.[34] O-protection with freshly prepared iPr3SiOTf[35]
delivered 98% of the siloxyfuran 27.[34] The bromine-containing
(triisopropylsiloxy)furan 28 was prepared like the analogous (tri-
methylsiloxy)furan, which we used for synthesizing the carote-
noid butenolide pyrrhoxanthin.[36] I. e., we undertook a Wohl-
Ziegler bromination of crotonic acid as before (→36),[36] added
bromine as before (→37),[36] and lactonized / eliminated in re-
fluxing H2O as before (→39).[36] We then introduced the triiso-
propylsilyl group following another procedure37] (→28).
X
MeO
X
MeO
OMe OMe
OMe OMe
20: X = Br
without
19: X = Br
+
21: X = H
(95:5 mixture)
21: X =
H
Scheme 5. Synthesizing the bromotetramethoxynaphthalene 20 − pre-
ceding our “type 2” arizonin C1 analogs − by an aryne/siloxyfuran Diels-
Alder addition. Reagents and conditions: a) 28 (1.5 equiv.), THF, –78°C;
dropwise addition of nBuLi (in hexane, 1.0 equiv.), THF, –78°C; 5 min; –
78°C → room temp., 45 min; 23: 48%, iso-23: 14%; b) Bu4NF (in THF,
1.1 equiv.), THF, 0°C, 45 min; 29%; c) Na2S2O4 (9 mol-%), Bu4NBr (8
mol-%), KOH (9 equiv.), Me2SO4 (10 equiv.) THF/H2O (2:1), room temp.,
16 h; 85% (25% over the 2 steps); d) Bu4NF (in THF, 1.1 equiv.), THF,
We synthesized the bromotetramethoxy naphthalene 19 almost
without producing the isomer 20 as a waste (Scheme 4). At
34 E. K. Kemppainen, G. Sahoo, A. Valkonen, P. M. Pihko, Org. Lett. 2012, 14,
1086-1089.
35 We prepared iPr3SiOTf from iPr3SiH and TfOH (1.2 equiv.) immediately prior
to use, adopting conditions from: a) A. G. Sancho, X. Wang, B. Sui, D. P.
Curran, Adv. Synth. Cat. 2009, 351, 1035-1040. b) E. J. Corey, H. Cho, C.
Rücker, D. H. Hua, Tetrahedron Lett. 1981, 22, 3455-3458.
room temp., 15 min; addition of KOH (1.4
(10 equiv.), THF/H2O (2:1), 0°C → room temp., 14 h; 25% over the 2
steps; e) same as (d); 72% over the 2 steps.
M in H2O, 7.2 equiv.), Me2SO4
36
J. Burghart, R. Brückner, Angew. Chem. 2008, 120, 7777-7782; Angew.
Chem. Int. Ed. 2008, 47, 7664-7668.
37
J. Boukouvalas, J. X. Wang, O. Marion, B. Ndzi, J. Org. Chem. 2006, 71,
38 W. C. Still, M. Kahn, A. Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
6670-6673.
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
thalene 20 in just 2% yield.[39] The major product (19) was incor-
porated in the type-1 arizonin C models as described after the
next paragraph.
Table 1. Preparing the tetracyclic naphthohydroquinones 43 en route to
“type-1 analogs” of (−)-arizonin C1: (a) Heck coupling; (b) Sharpless dihy-
droxylation / lactonization tandems; (c) oxa-Pictet Spengler cyclizations
OMe OMe
OMe OMe
Scheme 5 shows how the bromonaphthalene 20, a 2% side-
product of the bromination of Scheme 4 (bottom line), was ac-
cessed better. This was in the sequel of a Diels-Alder reaction
between the aryne 26 (generated as in Scheme 4) and the bro-
minated silyoxyfuran 28 (synthesis: Scheme 3). Acidic workup
and separation by flash chromatography on silica gel[38] afforded
48% of the ring-opening product 23 of the “proximal”[23] Diels-
Alder adduct 25 as opposed to 14% of the ring-opening product
iso-23 resulting from the “distal”[23] adduct iso-25. Both com-
pounds were admixed with up to 7 rel-% of the debrominated
analogs 24 and iso-24, respectively. Their presence means that
the Diels-Alder adducts 25 and iso-25 preceding them, already
contained the respective debrominated materials 24 and iso-24.
This indicates that generating the aryne 26 without subjecting
the siloxyfuran 28 to a parallel Br/Li exchange[28a] or the Diels-
Alder adducts 25 and iso-25 to a later Br/Li exchange is a nar-
row balance. Desilylating the ring-opening product 23 and per-
forming a double O-methylation afforded the bromonaphthalene
20. It was a key intermediate for synthesizing our type-2 arizonin
C models. They are presented in the penultimate Section.
MeO
MeO
(86:14 mixture with
trans-configured
Cα=Cβ isomer)
a)
β
γ
α
Br
OMe
OMe
MeO
O
MeO
41
O
17
19
(preparation:
Scheme 4)
b)
c)
OMe OMe
OMe OMe
OH
MeO
MeO
OH
O
O
OMe
OMe
O
O
15
ent-15
(98.5% ee)
(96 % ee)
R
e)
d) or e)
O
42a-e
OMe OMe R
OMe OMe
MeO
MeO
5
5
O
3a
O
3a
O
O
OMe
3a,5trans-43b-e
OMe
ent-3a,5trans-43a-e
O
O
42, 43
Step
Yield
43b-e
3a,5trans : 3a,5cis)
Yield
ent-43b-e
3a,5trans : 3a,5cis)
R
(
(
Elaboration of Bromotetramethoxynaphtha-
lene 19 Into Naphthoquinonopyrano-γ-lac-
tones Dimethoxylated Like (−)-Arizonin C1
a
b
c
d
e
Me
d)
e)
e)
e)
e)
93%
78:22
100:0
100:0
95:5
C6H5
89%
91%
91%
96%
100:0
100:0
100:0
100:0
67%
64%
62%
68%
4-F3C−C6H4
4-F−C6H4
4-Br−C6H4
This Section and the following one detail how we converted the
bromonaphthalene 19 (preparation: Scheme 4) into the naphtho-
hydroquinonopyranolactones 43 (Table 1). Oxidation advanced
them to the corresponding quinones − or type-1 arizonin C1
models − 13 of Table 2.
100:0
Reagents and conditions: a) 41 (3 equiv), Pd2dba3·CHCl3 (2.0 mol-%),
P(tBu)3 (8 mol-%), Cy2NMe (3 equiv.), toluene, reflux, 2 d; 83% (of a
86:14 mixture of 17 with the trans-configured Cα=Cβ isomer); b)
K2OsO2(OH)4 (0.4 mol-%), (DHQ)2PHAL (1.0 mol-%), K3Fe(CN)6
(3 equiv.), K2CO3 (3 equiv.), NaHCO3 (3 equiv.), MeSO2NH2 (1.0 equiv.),
tBuOH/H2O (1:1), room temp., 2 d; 66%, 98.5% ee (ref.[7s]: 71%, 99.2%
ee); c) same as (b), but (DHQD)2PHAL instead of (DHQ)2PHAL; 58%,
96% ee; d) 42a (7.5 equiv.), BF3·OEt2 (10 equiv.), CH2Cl2, 0°C → room
The chemistry of Table 1 begins with a Heck-coupling between
the bromonaphthalene 19 and the butenoate 41 (method:
ref.[18]). It furnished an 86:14 mixture of the deconjugated ester
17 (desired) and the isomeric trans-configured conjugated ester
(undesired). Without separating these compounds we subjected
them to an NaHCO3-buffered[40] asymmetric Sharpless dihydrox-
ylation. Using (DHQ)2PHAL or (DHQD)2PHAL as a chiral auxilia-
ry we obtained the β-hydroxy-γ-lactone 15 with 98.5% ee and its
antipode ent-15 with 96% ee, respectively. I. e., the β,γ-dihydro-
xyesters, formed initially, transesterified under the dihydroxylati-
temp., 30 min; e) 42b-e (3 equiv.), BF3·OEt2 (4 equiv.), CH2Cl2, 0°C
room temp., 30 min.
→
on conditions giving lactones although they implied less base-
catalysis than usually.[19] Next, the lactones 15 and ent-15 were
diversified in a total of nine oxa-Pictet-Spengler cyclizations.[20]
As a reaction partner we employed acetaldehyde (7.5 equiv.)
and four aromatic benzaldehydes (Ar = Ph, 4-F3C-C6H4, 4-F-
C6H4, 4-Br-C6H4; 3.0 equiv.). BF3·OEt2 (10 or 4.0 equiv., respec-
tively) was used as a promotor. Acetaldehyde rendered the
naphthohydroquinonopyranolactone 43a with a modest 3a,5trans-
selectivity. It was isolated as a 78:22 3a,5trans:3a,5cis-mixture,
which was inseparable by flash chromatography on silica gel.[38]
In contrast, the aromatic aldehydes gave the naphthohydroqui-
nonopyranolactones 43b-e – and their enantiomers ent-43b-e –
with 100:0 3a,5trans-selectivity[41] (except ent-43d).
39
The structures 19 and 20 were differentiated as follows. (1) The most de-
shielded aromatic proton in either compound resonates as a dublet. It must be
8-H (numbering: cf. Scheme 4; in 19: δ = 7.74 ppm; in 20: δ = 8.00 ppm) rather
than 7-H for complying with the chemical shift ordering in any naphthalene,
which contains no strongly (de)shielding substituents. (2) In either compound,
the aromatic singlet must be due to the isolated proton between Br and MeO.
This proton would be 3-H in 19 (δ = 6.86 ppm) but 2-H in 20 (δ = 6.78 ppm).
(3) The latter shifts were too similar for inferring whether they originate from 19
or 20. We therefore probed the HMBC spectra (500 MHz / 126 MHz) of these
3
compounds for JC,H-based cross-peaks relating the bridgehead 13C nuclei to
the pair of protons at C-8 and between Br and MeO. The bromonaphthalene
19 displayed two such (!) crosspeaks for 13C-4a (regarding 8-1H and 3-1H) but
zero such (!) crosspeaks for 13C-8a. In contrast, the bromonaphthalene 20
showed one such (!) crosspeak both for 13C-4a (regarding 8-1H) and 13C-8a
(regarding 2-1H). This makes the distinction of 19 and 20 unequivocal.
41
The oxa-Pictet-Spengler products 43b-e and ent-43b-e are 3a,5trans- rather
than 3a,5cis-configured for the following reason: The (at first: alleged) trans-
orientation of 5-Ar and 3a-C implies that the 5-Ar bond and the 3a-H bond are
cis-oriented. Therefore, 5-Ar-Hortho and 3a-H reside close to each other. In the
40
Method: K. P. M. Vanhessche, Z.-M. Wang, K. B. Sharpless, Tetrahedron
Lett. 1994, 35, 3469-3472.
7
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
20
Table 2. Accomplishing nine “type-1 analogs” 13 of (−)-arizonin C1
Table 3. Impurity effects on the specific rotations ([α]D in CHCl3) of en-
antiomerically pure hydroxylactones 15 and ent-15: a caveat regarding
configurational assignments in this field
A Bis(pyrano-γ-lactone) Analog of (−)-Arizonin
C1
The perfect 3a,5trans-selectivites, with which hydroxylactone 15
and the aromatic aldehydes 42b-e oxa-Pictet-Spengler cyclized
(Table 1), manifested itself also when the same lactone and
terephthalaldehyde (42f) oxa-Pictet-Spengler cyclized in the
presence of BF3·OEt2 (Scheme 6). The product structure de-
pended on how many aldehyde groups reacted. The only reac-
tion conditions, which we tested, allowed either course. One al-
dehyde group reacted to give rise to the “simple” oxa-Pictet-
The naphthohydroquinonopyranolactones 43b-e and their oppo-
sitely configured congeners ent-43a-e were oxidized with
(NH4)2Ce(NO3)6 (Table 2). This provided the naphthoquinono-
pyranolactones (−)-13b-e and (+)-ent-13a-e, respectively, in
yields of 61-99%. They all constitute “type 1” arizonin C1 mod-
els. Specifically, oxidation of the 78:22 mixture of 3a,5trans- and
3a,5cis-ent-43a provided a 75:25 mixture of 3a,5trans- and 3a,5cis-
ent-13a. Re-purification by flash chromatography[38] increased
the trans:cis ratio to 90:10. HPLC afforded the naph-
thoquinonopyrano-γ-lactone 3a,5trans-13a analytically pure. It
equals the unnatural enantiomer (+)-ent-13a ≡ (+)-ent-3 of (–)-
arizonin C1. The other “type 1” arizonin C1 models included in
Table 2 had the identical isomeric composition as the respective
precursor.
O
OMe OMe
MeO
OH
+
O
OMe
O
O
O
OMe
O
15 (98.5% ee)
42f
3''a
O
5''
O
a)
OMe
OMe OMe
MeO MeO
MeO MeO
MeO
MeO
a) cont.:
5
O
3a
5
O
3a
+ 15
O
OMe
O
OMe
O
O
3a,5trans-43f
separated from
3a,5trans,3''a,5''trans-44
(32%, pure diastereomer)
b)
(42%, pure diastereomer)
Getting hold of the hydroxylactones 15 and ent-15 by the Sharp-
less dihydroxylations of Table 1, we determined that 15 is (slight-
ly) levorotatory and ent-15 (slightly) dextrorotatory (Table 3, en-
try 1). This contrasts with Fernandes’s report of the opposite
senses of rotation (Table 3, entry 2).[7t] Yet the specimen to
which they assigned the stereostructure ent-15 [“levorotatory”]
and we, too [“dextrorotatory”], delivered (+)-ent-arizonin C1 in
their laboratory (ref.[7t]) as well as in ours (Table 1/Table 2). This
means that they or us published the specific rotation of the
hydroxylactones 15 and ent-15 with the incorrect sign. Accord-
ingly, 15 and ent-15 offer no stereochemical reference point.
c)
O
O
O
O
3''a
5''
O
O
OMe
OMe
MeO
O
OMe O
MeO
MeO
5
5
O
O
3a
3a
O
O
O
O
O
O
( )-3a,5trans,3''a,5''trans-45
(74%, dr = 100:0:0)
( )-3a,5trans-13f
(46%, dr = 100:0)
Scheme 6. Modifying the follow-up chemistry of the hydroxylactone 15 of
Table 1: (a) oxa-Pictet-Spengler cyclizations providing the naphthohydro-
quinones 43 and 44; (b) and (c) oxidation to “type-1 analogs” of (−)-arizo-
nin C1. Reagents and conditions: a) Terephthalaldehyde (0.52-fold molar
amount), BF3·OEt2 (2.06 equiv.), CH2Cl2, 0°C
→ room temp., 30 min;
3a,5trans-43f: 32%; 3a,5trans,3’’a,5’’trans-44: 42%; b) (NH4)2Ce(NO3)6
(2.0 equiv.), MeCN/H2O (1:1), room temp., 30 min; 46%; c)
(NH4)2Ce(NO3)6 (4.0 equiv.), MeCN/H2O (1:1), room temp., 30 min; 74%.
NOESY spectrum (400 and 500 MHz, respectively, CDCl3) this causes 5-Ar-
Hortho to correlate with 3a-H.
8
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
Spengler product 3a,5trans-43f (32% yield), both aldehyde func-
tions reacted to form the “double” oxa-Pictet-Spengler product
3a,5trans,3’’a,5’’trans-44 (42% yield; eluted second to 3a,5trans-43f
from the flash chromatography column[38]). These structures
were distinguished 1H-NMR spectroscopically:
Table 4. Preparing naphthohydroquinone precursors 46 of “type-2 ana-
logs” of (−)-arizonin C1: (a) Heck coupling; (b) Sharpless dihydroxylation /
lactonization tandem; (c) oxa-Pictet Spengler cyclizations
OMe
OMe
a)
• The “simple” oxa-Pictet-Spengler product 3a,5trans-43f
displayed an aldehyde as a 1-proton singlet at δ = 9.99 ppm.
In contrast, 3a,5trans,3’’a,5’’trans-44 did not.
• The “double” oxa-Pictet-Spengler product 3a,5trans,3’’a,5’’trans-
44 displayed the para-phenylene moiety as a 4-proton singlet
at δ = 7.05 ppm. Oppositely, 3a,5trans-43f did not.
• The “double” oxa-Pictet-Spengler product 3a,5trans,3’’a,5’’trans-
44 showed a common set of resonances for the two pyrano-
lactone moieties. This excludes a 3a,5trans,3’’a,5’’cis-configurati-
on but allows for a 3a,5cis,3’’a,5’’cis-configuration.
MeO
MeO
Br
OMe OMe
OMe OMe
MeO
O
MeO
O
18
20
41
b)
R
OMe R
OMe
42a-e
X
5
O
OH
3a
c)
MeO
MeO
O
O
OMe OMe
OMe OMe
O
O
3a,5trans-46a-e
16 (> 99% ee)
• A NOESY experiment analogous to that in footnote[41] was
supportive of 44 being 3a,5trans,3’’a,5’’trans-configured and
incompatible with its being 3a,5cis,3’’a,5’’cis-configured.
42, 46
R
X
Yield
3a,5trans : 3a,5cis
a
Me[a]
O
63%
27%
75%
81:19
fllash chromatogr.
94:6
a
b
c
d
e
Me[a]
C6H5
(OMe)2
52:48
Finishing up, we oxidized the “simple” oxa-Pictet-Spengler prod-
uct 3a,5trans-43f with (NH4)2Ce(NO3)6 (Scheme 6). This gave the
naphthoquinonopyranolactone 13f in 46% yield. It is the tenth
type-1 arizonin C1 analog of our study. The “double” oxa-Pictet-
Spengler product 3a,5trans,3’’a,5’’trans-44 was oxidized with
O
O
O
O
86%
68%
60%
86%
100:0
100:0
100:0
100:0
4-F3C-C6H4
4-F-C6H4
4-Br-C6H4
(NH4)2Ce(NO3)6,
too.
This
provided
the
naphtho-
Reagents and conditions: a) 41 (3 equiv), Pd2dba3·CHCl3 (2.0 mol-%),
P(tBu)3 (8.0 mol-%), Cy2NMe (3 equiv.), toluene, reflux, 2 d; 61% (of a
92:8 mixture of 18 with the trans-configured Cα=Cβ isomer); b)
K2OsO2(OH)4 (0.4 mol-%), (DHQ)2PHAL (1.0 mol-%), K3Fe(CN)6
(3.1 equiv.), K2CO3 (3.2 equiv.), NaHCO3 (3.2 equiv.), MeSO2NH2
(1.0 equiv.), tBuOH/H2O (1:1), room temp., 15 h; 60%, >99% ee; c)
quinonopyranolactone 3a,5trans,3’’a,5’’trans-45 in 74% yield. It con-
stitutes a dimeric arizonin C1 analog of sorts.
Elaboration of Bromotetramethoxynaphtha-
lene 20 Into Naphthoquinonopyrano-γ-lac-
tones Dimethoxylated Unlike (−)-Arizonin C1
RCH=X (3 equiv.), BF3·OEt2 (4 equiv.), CH2Cl2, 0°C
min. [a] RCH=X: 7.5 equiv., BF3·OEt2: 10 equiv.
→ room temp., 30
Table 5. Accomplishing five “type-1 analogs” 13 of (−)-arizonin C1
This Section describes how we processed the bromonaphtha-
lene 20 from Scheme 5 via the naphthohydroquinonopyranolac-
tones 46 (Table 4) to the naphthoquinonopyranolactones 14a-e
,
i. e., type-2 arizonin C1 models (Table 5).
We proceeded as delineated in the previous Section for the
preparation of the type-1 arizonin C1 models 13 and ent-13. I.
e., we started by a Heck-coupling of the bromonaphthalene 20
and methyl but-3-enoate (41; Table 4). The resulting unsaturat-
ed ester 18 (61%, 92:8 mixture with a C=C-shifted isomer) was
Sharpless-dihydroxylated.[40] This led to the lactone 16 in 60%
yield and with >99% ee. Oxa-Pictet-Spengler cyclizations fur-
nished the naphthohydroquinonopyranolactones 46. This oc-
curred with a 81:19 preference for the 3a,5trans-isomer using ac-
etaldehyde (→ 46a) and with 100:0 selectivities using aromatic
aldehydes (→ 46b-e). Oxidation with (NH4)2Ce(NO3)6 afforded
the corresponding naphthoquinonopyranolactones 14a-e (Table
5). This went along with a complete or an almost complete reten-
tion of the 3a,5trans-configuration.
Distinguishing Naphthoquinonopyrano-γ-lac-
tones Dimethoxylated Like or Unlike (−)-Arizo-
nin C1 NMR-Spectroscopically
(−)-Arizonin C1 (3) equals the naphthoquinonopyranolactone
numbered 13a in (Table 6). The type-1 arizonin C1 analogs syn-
thesized in the present study comprise the naphthoquinonopyra-
nolactones 13b-f (Table 6). In addition we synthesized the naph-
thoquinonopyranolactones 14a-f (ibid.). Dubbed type-2 arizonin
9
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
Table 6. Pertinent 13C NMR resonances (recorded at 101 or 126 MHz in CDCl3) for distinguishing the naphthoquinonopyrano-γ-lactones 13a-f and 14a-
e from this work. Where we could not attribute δC-5a and δC-11a individually, they are collected group-wise and separated by a comma.[42]
C1 analogs, the latter are constitutional isomers of the former
compounds. Each pair 13/14 of isomers differs by the orientation
of the A-ring substituents relative to the C-ring substituents (one
of which is the D-ring). We were able to assign each 13C-NMR
shift of the respective A/B/C/D scaffolds a-f nucleus-specifically
– except that we could not differentiate C5a and C-11a unless
the substitution pattern was a. These assignments stem from
analyzing the cross-peaks in HBMC spectra [400 MHz (1H) / 101
MHz (13C) or 500 MHz (1H) / 126 MHz (13C)] in terms of the
underlying JC,H and JC,H couplings.[42] The essence of these
analyses is embedded in the chemical shifts of four quaternary
13C nuclei per compound: the atoms C-6a/C-10a at the A-ring/B-
ring junction (“benzene/quinone junction”) and the atoms C-
5a/C-11a at the B-ring/C-ring junction (“quinone/pyran junction”).
pertinent example is the controversy about where the naphtho-
quinonopyranolactone-C-glycoside medermycin is glycosylat-
ed.[45] In this regard, systematic NMR analyses like that of Table
6 may hold a potential, which has not yet been exploited.
Conclusion
To sum up we have made 15 naphthoquinonopyrano-γ-lactone
analogs dimethoxylated like (13, “type 1” analogs) or unlike (14,
“type 2” analogs) (−)-arizonin C1 (3). Both substitution patterns
were reached from naphthalenes, which emerged from an
orientationally selective Diels-Alder reaction between 3,4-
dimethoxybenz-1-yne and a 2-siloxylated furan. The latter was
bromine-free (27; → → 13) or 3-brominated (28; → → 14). This
allowed to process the respective Diels-Alder product such that
a Heck coupling, an SAD, and an oxa-Pictet-Spengler reaction
2
3
Table 6 shows that the chemical shifts of the four mentioned 13
C
nuclei can be combined pairwise in each compound such that
they seem to become structure-revealing:
established the remaining rings in
fashion.
a regiocomplementary
1)∆δ ≡ δC-6a − δC-10a is a small negative number in type-13
naphthoquinonopyranolactones but a small positive number in
type-14 naphthoquinonopyranolactones.
As numerous naphthoquinonopyrano-γ-lactones have proved bi-
oactive, we had our models 13 and 14 tested in vitro against
B16-melanoma tumor cells.[46] The best potency was observed
for ent-13b (LD50 = 2.9 µM). However, adding the other models
to phosphate-buffered saline (containing 1% DMSO) in amounts
corresponding to concentrations of 3 µM if dissolved completely
did not render solutions but suspensions. This left their cell toxic-
ity unknown.
2)The absolute value of ∆’δ ≡ δC-5a − δC-11a is 11-12 ppm in type-
13 naphthoquinonopyranolactones but 7-8 ppm in type-14
naphthoquinonopyranolactones.
Elucidating the structure of naphthoquinonopyranolactone natu-
ral products often entails localizing substituents in their A-ring
relative to their C-ring/D-ring moiety. This used to be not easy.
Good illustrations are how long it took to prove the location of
the biaryl bond in the dimeric naphthoquinonopyrano-γ-lactone
natural products actinorhodin[43] and γ-actinorhodin.[44] Another
Experimental Section
General Working Technique and Analytic Techniques
Working technique: If not indicated differently, all reactions were carried
out under a nitrogen atmosphere. Reaction flasks were dried in vacuo
42 Details: Experimental Section
43
Structure known except the location of the biaryl bond: a) A. Zeeck, P.
45
Christiansen, Liebigs Ann. Chem. 1969, 724, 172-182; b) P. Christiansen, Ph.
D. Thesis, Universität Göttingen, Germany, 1970; c) biaryl bond localized by
C. P. Gorst-Allman, B. A. M. Rudd, C. Chang, H. G. Floss, J. Org. Chem.
1981, 46, 455-456 in isotopologs gained by biosynthesis.
44 a) 1974: Biaryl bond position inferred from analogy: ref.[21a]; b) 2017: biaryl
bond position proved by NOESY and HMBC experiments with totally synthetic
material: ref.[22].
a) Structure assignment by total synthesis: K. Tatsuta, H. Ozeki, M.
Yamaguchi, M. Tanaka, T. Okui, Tetrahedron Lett. 1990, 31, 5495-5498; b)
structure revision: P.-M. Léo, C. Morin, C. Philouze, Org. Lett. 2002, 4, 2711-
2714; c) revision of the structure revision: G. T. Williamson, L. A. McDonald, L.
R. Barbieri, G. T. Carter, Org. Lett. 2002, 4, 4695-4662.
46
We express our gratitude to Dr. L. O. Haustedt (AnalytiCon Discovery,
Potsdam) for these experiments.
10
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
with a heat gun prior to use. Small amounts of liquids were added with a
syringe through a rubber septum. If solids were suspended, the flask was
evacuated again and flushed with nitrogen prior to addition of the solvent.
If solids were added to a reaction this was carried out in a nitrogen
counter flow. Solvents for reactions: Tetrahydrofuran (THF) and
toluene were distilled over potassium under a nitrogen atmosphere prior
to use. Diethyl ether (Et2O) was distilled over a sodium/potassium alloy
under a nitrogen atmosphere. Dichloromethane (CH2Cl2), acetonitrile
Elmer Paragon 1000 spectrometer for a film of the substance on a NaCl
crystal plate.
General procedure A: Representative (NH4)2Ce(NO3)6 Oxidation to
the Arizonin C1 analog 13b:
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-phenyl-3,3a,5,11b-tetrahydro-
2H-benzo[g]furo[3,2-c]isochromen-2-one (43b, 58.1 mg, 133 µmol) was
(MeCN),
N,N,N’,N’-tetramethylethylenediamine
(TMEDA),
and
triethylamine (NEt3) were distilled over CaH2 and also under a nitrogen
atmosphere. Other solvents and reagents were purchased and – if not
indicated – used without further purification. Organolithium reagents
were stored in a fridge in Schlenk flasks with PTFE screw caps and
PTFE valves. Prior to use, they were titrated using N-pivaloyl-o-
toluidine.[47] Solvents for extraction and flash chromatography [i.e.
methyl tert-butyl ether (tBuOMe), dichloromethane (CH2Cl2), petroleum
ether (PE 30/50), toluene (PhMe), ethyl acetate (EtOAc or EE),
cyclohexane (C6H12 or CH), and diethyl ether (Et2O) were purchased in
technical quality] and distilled using a rotary evaporator to free them from
high boiling fractions. Flash chromatography:[38] Macherey-Nagel silica
gel 60® (230-400 mesh) was used for flash chromatography. All eluents
were distilled prior to use. Chromatography conditions are documented
as following: “[diameter d = y cm height h = x cm, eluent a/eluent b =
va:vb, fraction volume = e mL] furnished the product (Fx-y, yield in g and
%)“ example: “flash chromatography [d = 1.5 cm, h = 12 cm, CH/EE 5:1,
F = 6 mL] furnished the product (F9-13, 26.9 mg, 78%) as a colorless
oil.”. Thin layer chromatography was carried out on Merck silica TLC
plates (silica gel 60 F254). The chromatograms were marked under UV
light and were subsequently stained in one of the three following
solutions: 1. Cer-(IV)-phosphomolybdic acid: Ce(SO4)2 (10 g),
phosphomolybdic acid (20 g), conc. H2SO4 (80 mL), and H2O (1 L). 2.
KMnO4: KMnO4 (2.5 g), K2CO3 (12.5 g), H2O (500 mL). 3. vanillin: vanillin
(2.5 g), acetic acid (50 mL), conc. H2SO4 (16 mL), MeOH (480 mL).
Nuclear magnetic resonance (NMR) spectra were recorded by Dr. M.
Keller, Ms. M. Schonhard, and Mr. F. Reinbold (all Inst. f. Org. Chemie,
suspended in acetonitrile (1.3 mL). At room temperature
a freshly
prepared solution of (NH4)2Ce(NO3)6 (145.8 mg, 266 µmol, 2.0 equiv.) in
H2O (1.3 mL) was added dropwise. The reaction mixture was stirred for
30 min and afterwards diluted with CH2Cl2 (10 mL). The organic phase
was separated and the aqueous phase was extracted with CH2Cl2 (4 ×
8 mL). The combined organic extracts were washed with brine (8 mL)
and dried over Na2SO4. The solvent was removed in vacuo. Flash
chromatography [d = 1.5 cm, h = 10 cm, F = 8 mL; CH/EE 2:1 (F1-13),
CH/EE 1:1 (F14-29),] afforded the title compound [F15-26, Rf (2:1) = 0.2,
53.3 mg, 99%, dr = 100:0] as an orange solid.
(3aR,5R,11bR)-7,8-dimethoxy-5-methyl-3,3a,5,11b-tetrahydro-2H-
benzo[g]furo[3,2-c]isochromene-2,6,11-trione (+)-ent-3a,5trans-13a ≡
(+)-ent-3
Following the General Procedure B (see below) β-hydroxy-γ-lactone 15
(75.0 mg, 0.22 mmol), acetaldehyde (0.09 mL, 0.07 g, 1.65 mmol,
7.5 equiv.) and BF3·OEt2 (0.27 mL, 0.31 g, 2.2 mmol, 10 equiv.) were
reacted in CH2Cl2 (2 mL). Purification by flash chromatography
[d = 1.5 cm, h = 10 cm, F = 8 ml; CH/EE 2:1] afforded a 78:22 mixture of
3a,5trans:3a,5cis-mixture of 43a (F6-14, Rf (2:1) = 0.3, 75.0 mg, 93%,
ds = 78:22). Following the General Procedure A the title compound was
prepared from the 78:22 mixture of 43a (75.0 mg, 0.20 mmol) dissolved
in MeCN (2 mL) and a solution of (NH4)2Ce(NO3)6 (219.0 mg, 0.40 mmol,
2.0 equiv.) in H2O (2 mL). Purification by flash chromatography
[d = 1.5 cm, h = 18 cm, F = 8 mL; CH/EE 1:1] afforded the title compound
[F14-24, Rf (1:1) = 0.25, 58.0 mg, 84%, dr = 75:25] as an orange solid.
An analytical sample was obtained by preparative HPLC [Phenomenex
Luna 5µ C18, 100 Å column, λdetector = 265 nm, MeCN/H2O (50:50), flow
Albert-Ludwigs-Universität Freiburg) on
a Bruker Avance III 500
spectrometer (500 MHz for 1H, 125 MHz for 13C, and 478 MHz for 19F), a
Bruker Avance II 400 spectrometer (400 MHz and 100 MHz for 1H and
13C respectively), a Bruker Avance III 300 spectrometer, and a Bruker
DRX 250 spectrometer (250 MHz for 1H, 63 MHz for 13C). Spectra were
referenced internally by the 1H- and 13C-NMR signals of the solvent
[CDCl3: δCHCl = 7.26 ppm (1H) and δCDCl = 77.10 ppm (13C)]. 1H-NMR
3
3
data are reported as follows: chemical shift (δ in ppm), multiplicity (s for
singlet; d for dublet; t for triplet; m for multiplet; mc for symmetrical
multiplet; br for broad signal), coupling constant(s) (in Hz; J means 3J
couplings unless otherwise noted), integral, and specific assignment. 13C-
NMR data are reported in terms of chemical shift and assignment. For
AB signals the high-field part was named A and the low-field part B.
Elemental analyses (EA) were performed by Ms A. Siegel on a Vario EL
analyzer from Elementar. High resolution mass spectra (HRMS) were
recorded by Dr. J Wörth and C. Warth on a Thermo Exactive mass
spectrometer equipped with an orbitrap analyzer. Ionization methods:
Electron spray ionization (ESI; spray voltage: 2.5-4 kV) or atmospheric
pressure chemical ionization (APCI; spray current: 5 µA). HPLC:
Determinations of the enantiomeric excess (ee) were conducted by Dr.
R. Krieger and A. Schuschkowski, and X. Iwanowa (all Inst. f. Org.
Chemie, Albert-Ludwigs-Universität Freiburg) using a Merck Hitachi
LaChrom (pump: L-7100. UV detector: D-7400, oven: L-7360; columns:
Chiralpak AD-3, AD-H, IA, Chiralcel OD-3, 25 cm, 4.6 mm). Further
details for chiral HPLC are given in the following experimental section.
Optical rotation was measured on a Perkin-Elmer polarimeter 241 or
341 at 589 nm (λ = D, Na-D-lamp) or 546 nm, 436 nm, 365 nm (Hg-
rate = 10 mL/min, tR (ent-3a,5trans-13a) = 14.2 min, tR (ent-3a,5cis-13a) =
15.3 min. Optical rotation of ent-3a,5trans-13a ≡ (+)-ent-3: [α]D
+120.0 (c = 0.28, MeOH). For reference values and complete analytical
data see ref.[7r].
20
=
(3aS,5S,11bS)-7,8-Dimethoxy-5-phenyl-3,3a,5,11b-tetrahydro-2H-
benzo[g]furo[3,2-c]isochromene-2,6,11-trione (13b)
20
20
lamp). [α]λ values were calculated by the following equation: [α]λ
(αexp · 100)/(c · d), where λ is the wavelength, αexp is the experimental
result (given as arithmetic mean of 10 measurements), is the
=
c
concentration [g/100 mL], and d is the length of the cell [dm]. Solvent and
concentration were given in brackets. Melting points were determined in
a Büchi melting point apparatus using open glass capillaries.[48] Boiling
points were measured in the head of the distillation column and are
uncorrected. If no pressure is indicated the distillation was performed
under ambient pressure. IR spectra were obtained on an FT-IR Perkin
Following the General Procedure A the title compound was prepared
from 43b (58.1 mg, 133 µmol) dissolved in MeCN (1.3 mL) and a solution
of (NH4)2Ce(NO3)6 (145.8 mg, 266 µmol, 2.0 equiv.) in H2O (1.3 mL).
Purification by flash chromatography [d = 1.5 cm, h = 10 cm, F = 8 mL;
CH/EE 2:1 (F1-13), CH/EE 1:1 (F14-29)] afforded the title compound
[F15-26, Rf (2:1) = 0.2, 53.3 mg, 99%, dr = 100:0] as an orange solid.
Note: The optical antipode ent-13b was synthesized analogously in 61%
47 J. Suffert, J. Org. Chem. 1989, 54, 509-510.
48 The melting points are neither corrected nor uncorrected, as these terms re-
fer to total immersion thermometers. In our laboratory, like in most modern la-
boratories, only partial immersion thermometers are used, which per definition
need no correction for immersion depth, as they are intended to be only par-
tially immersed: G. V. D. Tiers, J. Chem. Educ. 1990, 67, 258-259.
yield (dr = 100:0).− 1H NMR (500.32 MHz, CDCl3):
δ = AB signal (δA =
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
2.63, δB = 2.82, JAB = 17.8 Hz, A signal shows no further splitting, B
signal further split by JB,3a = 5.4 Hz, 3-HA and 3-HB), 3.85 (s, 3H, 7-OMe),
8.0 Hz, 2’-H and 6’-H), 7.63 (br. d, 2H, J3’,2’ = J5’,6’ = 8.0 Hz, 3’-H and 5’-
H), 8.05 (d, 1H, J10,9 = 8.7 Hz, 10-H). 8-OMe was distinguished from 7-
OMe by the occurrence of a cross-peak only for the former but not for the
latter in the following NOESY spectrum (500.32 MHz, CDCl3) that
allowed additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.85 (3-HB) ↔ δ = 5.29 (11b-H, this
cross-peak proves that 3-HB and 11b-H are oriented cis relative to one
another), δ = 3.99 (8-OMe) ↔ δ = 7.27 (9-H), δ = 7.38 (2’-H and 6’-H) ↔
δ = 4.24 (3a-H, this cross-peak proves that the phenyl ring and 3a-H are
oriented cis relative to one another), δ = 7.38 (2’-H and 6’-H) ↔ δ = 6.06
3.98 (s, 3H, 8-OMe), 4.29 (dd, 1H, J3 = 5.2 Hz, J3a,11b = 3.1 Hz, 3a-H),
5.29 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 6.04 (s, 1H, 5-H), 7.22-7.26 (m, 2H,
2’-H and 6’-H), 7.25 (d, 1H, J9,10 = 8.4 Hz, 9-H), 7.34-7.38 (m, 3H, 3’-H,
a,B
4’-H and 5’-H), 8.05 (d, 1H, J10,9
= 8.7 Hz, 10-H). 8-OMe was
distinguished from 7-OMe by the occurrence of a cross-peak only for the
former but not for the latter in the following NOESY spectrum
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.82
(3-HB) ↔ δ = 5.29 (11b-H, this cross-peak proves that 3-HB and 11b-H
are oriented cis relative to one another), δ = 3.98 (8-OMe) ↔ δ = 7.25 (9-
H), δ = 7.22-7.26 (2’-H and 6’-H) ↔ δ = 4.29 (3a-H, this cross-peak
proves that the phenyl ring and 3a-H are oriented cis relative to one
another), δ = 7.22-7.26 (2’-H and 6’-H) ↔ δ = 6.04 (5-H). 13C NMR
(125.81 MHz, CDCl3): δ = 36.70 (C-3), 56.47 (8-OCH3), 61.31 (7-OCH3),
66.98 (C-3a), 69.24 (C-11b), 72.18 (C-5), 116.33 (C-9), 124.86 (C-6a),
125.11 (C-10), 125.52 (C-10a), 128.62 (C-2’ and C-6’), 128.96 (C-3’ and
C-5’), 129.15 (C-4’), 135.48 and 147.57 (C-5a and C-11a), 136.30 (C-1’),
149.81 (C-7), 159.41 (C-8), 174.16 (C-2), 181.32 (C-11), 181.99 (C-6).
An edHSQC spectrum (“short-range C,H COSY”; 125.81/500.32 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 36.70 (C-3) ↔ [δA = 2.63 (3-HA) and δB = 2.82 (3-HB)], δ =
56.47 (8-OCH3) ↔ δ = 3.98 (8-OMe), δ = 61.31 (7-OCH3) ↔ δ = 3.85 (7-
OMe), δ = 66.98 (C-3a) ↔ δ = 4.29 (3a-H), δ = 69.24 (C-11b) ↔ δ = 5.29
(11b-H), δ = 72.18 (C-5) ↔ δ = 6.04 (5-H), δ = 116.33 (C-9) ↔ δ = 7.25
(9-H), δ = 125.11 (C-10) ↔ δ = 8.05 (10-H), δ = 128.62 (C-2’ and C-6’) ↔
δ = 7.22-7.26 (2’-H and 6’-H), δ = 128.96 (C-3’ and C-5’) ↔ δ = 7.34-7.38
(3’-H, 4’-H and 5’-H), δ = 129.15 (C-4’) ↔ δ = 7.34-7.38 (3’-H, 4’-H and
5’-H). An HMBC spectrum (“long-range C,H COSY”; 125.81/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances[δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 124.86
(C-6a) ↔ δ = 8.05 (10-H), δ = 125.52 (C-10a) ↔ δ = 7.25 (9-H), [δ =
135.48 and 147.57 (C-5a and C-11a) ↔ δ = 5.29 (11b-H), δ = 135.48
and 147.57 (C-5a and C-11a) ↔ δ = 6.04 (5-H) could not be assigned
unambiguously], δ = 136.30 (C-1’) ↔ δ = 6.04 (5-H), δ = 136.30 (C-1’) ↔
δ = 7.34-7.38 (3’-H and 5’-H), δ = 149.81 (C-7) ↔ δ = 3.85 (7-OMe), δ =
149.81 (C-7) ↔ δ = 7.25 (9-H), δ = 159.41 (C-8) ↔ δ = 3.98 (8-OMe), δ =
159.41 (C-8) ↔ δ = 7.25 (9-H), δ = 159.41 (C-8) ↔ δ = 8.05 (10-H), δ =
174.16 (C-2) ↔ [δA = 2.63 (3-HA) and δB = 2.82 (3-HB)], δ = 174.16 (C-2)
↔ 4.29(3a-H), δ = 181.32 (C-11) ↔ δ = 5.29 (11b-H), δ = 181.32 (C-11)
↔ δ = 8.05 (10-H), δ = 181.99 (C-6) ↔ δ = 6.04 (5-H). Melting point:
(5-H). 19F NMR (470.72 MHz, CDCl3):
δ
= –62.85 (s, 3F, CF3). 13C NMR
(125.82 MHz, CDCl3): δ = 36.66 (C-3), 56.50 (8-OCH3), 61.31 (7-OCH3),
67.31 (C-3a), 68.95 (C-11b), 71.56 (C-5), 116.51 (C-9), 123.83 (q, 1C,
1JC,F = 272.4 Hz, 4’-CF3), 124.70 (C-6a), 125.26 (C-10), 125.41 (C-10a),
3
125.98 (q, 2C, JC,F = 4.0 Hz, C-3’ and C-5’), 128.98 (C-2’ and C-6’),
2
131.33 (q, 1C, JC,F = 32.7 Hz, C-4’), 135.89 and 146.62 (C-5a and C-
11a), 140.38 (C-1’), 149.92 (C-7), 159.52 (C-8), 173.81 (C-2), 181.07 (C-
11), 182.06 (C-6). An edHSQC spectrum (“short-range C,H COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 36.66 (C-3) ↔ [δA = 2.64 (3-HA) and δB
= 2.85 (3-HB)], δ = 56.50 (8-OCH3) ↔ δ = 3.99 (8-OMe), δ = 61.31 (7-
OCH3) ↔ δ = 3.86 (7-OMe), δ = 67.31 (C-3a) ↔ δ = 4.24 (3a-H), δ =
68.95 (C-11b) ↔ δ = 5.29 (11b-H), δ = 71.56 (C-5) ↔ δ = 6.06 (5-H), δ =
116.51 (C-9) ↔ δ = 7.27 (9-H), δ = 125.26 (C-10) ↔ δ = 8.05 (10-H), δ =
125.98 (C-3’ and C-5’) ↔ δ = 7.63 (3’-H and 5’-H), δ = 128.98 (C-2’ and
C-6’) ↔ δ = 7.38 (2’-H and 6’-H). An HMBC spectrum (“long-range C,H
COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment of all
quaternary 13C atoms through their cross-peaks with the independently
assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via
2 or 4 covalent bonds]: δ = 124.70 (C-6a) ↔ δ = 8.05 (10-H), δ = 125.41
(C-10a) ↔ δ = 7.27 (9-H), δ = 131.33 (C-4’) ↔ δ = 7.38 (2’-H and 6’-H),
[δ = 135.89 and 146.62 (C-5a and C-11a) ↔ δ = 5.29 (11b-H), δ =
135.89 and 146.62 (C-5a and C-11a) ↔ δ = 6.06 (5-H) could not be
assigned unambiguously], δ = 140.38 (C-1’) ↔ δ = 6.06 (5-H), δ = 140.38
(C-1’) ↔ δ = 7.63 (3’-H and 5’-H), δ = 149.92 (C-7) ↔ δ = 3.86 (7-OMe),
δ = 149.92 (C-7) ↔ δ = 7.27 (9-H), δ = 159.52 (C-8) ↔ δ = 3.99 (8-OMe),
δ = 159.52 (C-8) ↔ δ = 7.27 (9-H), δ = 159.52 (C-8) ↔ δ = 8.05 (10-H), δ
= 173.81 (C-2) ↔ [δA = 2.64 (3-HA) and δB = 2.85 (3-HB)], δ = 173.81 (C-
2) ↔ 4.24(3a-H), δ = 181.07 (C-11) ↔ δ = 5.29 (11b-H), δ = 181.07 (C-
11) ↔ δ = 8.05 (10-H), δ = 182.06 (C-6) ↔ δ = 6.06 (5-H). Melting point:
228-234°C (decomposition). Optical rotation of 13c: [α]D20 = –202.7 (c =
20
0.588, CHCl3). Optical rotation of ent-13c: [α]D = +167.8 (c = 0.83,
CHCl3). HRMS (pos. ESI): calcd. for C24H17F3O7Na [M+Na]+
=
20
228-234°C (decomposition). Optical rotation of 13b: [α]D = –260.3 (c
497.08186; found 497.08206 (+0.41 ppm). IR (film): ν = 3345, 2940,
2855, 1785, 1665, 1620, 1575, 1485, 1455, 1415, 1330, 1275, 1230,
1200, 1165, 1125, 1095, 1065, 1020, 1000, 975, 910, 885, 860, 830,
795, 780, 765, 735, 700, 655 cm-1.
20
= 0.49, CHCl3). Optical rotation of ent-13b: [α]D = +275.3 (c = 0.79,
CHCl3). HRMS (pos. ESI): calcd. for C23H18O7Na [M+Na]+ = 429.09447;
found 429.09445 (–0.05 ppm). IR (film): ν = 3060, 2940, 2850, 1785,
1665, 1625, 1575, 1485, 1450, 1400, 1335, 1275, 1230, 1200, 1155,
1095, 1075, 1050, 1015, 995, 970, 945, 905, 885, 845, 820, 795, 765,
735, 700 cm-1.
(3aS,5S,11bS)-7,8-Dimethoxy-5-(4-fluorophenyl)-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromene-2,6,11-trione (13d)
(3aS,5S,11bS)-7,8-Dimethoxy-5-(4-(trifluoromethyl)phenyl)-
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromene-2,6,11-
trione (13c)
Following the General Procedure A the title compound was prepared
from 43d (55.7 mg, 123 µmol) suspended in MeCN (1.2 mL) and a
solution of (NH4)2Ce(NO3)6 (134.4 mg, 245 µmol, 2.0 equiv.) in H2O
(1.2 mL). Purification by flash chromatography [d = 1.5 cm, h = 10 cm,
F = 8 mL; CH/EE 2:1 (F1-13), CH/EE 1:1 (F14-26),] afforded the title
compound [F14-25, Rf (2:1) = 0.2, 38.8 mg, 75%, dr = 100:0] as an
orange solid. Note: The optical antipode ent-13d was synthesized
Following the General Procedure A the title compound was prepared
from 43c (68.6 mg, 136 µmol) suspended in MeCN (1.4 mL) and a
solution of (NH4)2Ce(NO3)6 (149.1 mg, 272 µmol, 2.0 equiv.) in H2O
(1.4 mL). After workup the solvent was removed in vacuo to afford the
title compound (60.6 mg, 94%, dr = 100:0) in pure form as an orange
solid. Note: The optical antipode ent-13c was synthesized analogously in
analogously in 62% yield (dr = 95:5).− 1H NMR (500.32 MHz, CDCl3):
δ =
AB signal (δA = 2.63, δB = 2.84, JAB = 17.9 Hz, A signal shows no further
splitting, B signal further splitted by JB,3a = 5.3 Hz, 3-HA and 3-HB), 3.86
64% yield (dr = 100:0).− 1H NMR (500.32 MHz, CDCl3):
δ = AB signal (δA
(s, 3H, 7-OMe), 3.99 (s, 3H, 8-OMe), 4.24 (dd, 1H, J3a,B = 5.3 Hz, J3a,11b
=
3.1 Hz, 3a-H), 5.28 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 6.01 (s, 1H, 5-H),
7.05 (m, 2H, 3’-H and 5’-H), 7.23 (m, 2H, 2’-H and 6’-H), 7.26 (d, 1H, J9,10
= 2.64, δB = 2.85, JAB = 17.8 Hz, A signal shows no further splitting, B
signal further splitted by JB,3a = 5.3 Hz, 3-HA and 3-HB), 3.86 (s, 3H, 7-
=
8.7 Hz, 9-H), 8.05 (d, 1H, J10,9 = 8.7 Hz, 10-H). 8-OMe was
OMe, exclusion principle), 3.99 (s, 3H, 8-OMe), 4.24 (dd, 1H, J3
=
a,B
distinguished from 7-OMe by the occurrence of a cross-peak only for the
former but not for the latter in the following NOESY spectrum
5.2 Hz, J3a,11b = 3.1 Hz, 3a-H), 5.29 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 6.06
(s, 1H, 5-H), 7.27 (d, 1H, J9,10 = 8.2 Hz, 9-H), 7.38 (br. d, 2H, J2’,3’ = J6’,5’
=
12
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.84
(3-HB) ↔ δ = 5.28 (11b-H, this cross-peak proves that 3-HB and 11b-H
are oriented cis relative to one another), δ = 3.99 (8-OMe) ↔ δ = 7.26 (9-
H), δ = 7.23 (2’-H and 6’-H) ↔ δ = 4.27 (3a-H, this cross-peak proves
that the phenyl ring and 3a-H are oriented cis relative to one another), δ
= 7.23 (2’-H and 6’-H) ↔ δ = 6.01 (5-H). 19F NMR (470.72 MHz, CDCl3):
another), δ = 7.12 (2’-H and 6’-H) ↔ δ = 5.97 (5-H). 13C NMR
(100.61 MHz, CDCl3): δ = 36.66 (C-3), 56.50 (8-OCH3), 61.32 (7-OCH3),
67.10 (C-3a), 69.03 (C-11b), 71.57 (C-5), 116.47 (C-9), 125.17 (C-10),
130.23 (C-2’ and C-6’), 132.17 (C-3’ and C-5’), 123.44 (C-4’), 124.80 (C-
6a), 125.51 (C-10a), 135.51 (C-1’), 135.71 and 146.96 (C-5a and C-11a),
149.93 (C-7), 159.50 (C-8), 173.85 (C-2), 181.14 (C-11), 181.98 (C-6).
An edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 36.66 (C-3) ↔ [δA = 2.63 (3-HA) and δB = 2.83 (3-HB)], δ =
56.50 (8-OCH3) ↔ δ = 3.99 (8-OMe), δ = 61.32 (7-OCH3) ↔ δ = 3.86 (7-
OMe), δ = 67.10 (C-3a) ↔ δ = 4.26 (3a-H), δ = 69.03 (C-11b) ↔ δ = 5.27
(11b-H), δ = 71.57 (C-5) ↔ δ = 5.97 (5-H), δ = 116.47 (C-9) ↔ δ = 7.26
(9-H), δ = 125.17 (C-10) ↔ δ = 8.05 (10-H), δ = 130.23 (C-2’ and C-6’) ↔
δ = 7.12 (2’-H and 6’-H), δ = 132.17 (C-3’ and C-5’) ↔ δ = 7.50 (3’-H and
5’-H). An HMBC spectrum (“long-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 123.44
(C-4’) ↔ δ = 7.12 (2’-H and 6’-H), δ = 123.44 (C-4’) ↔ 7.50 (3’-H and 5’-
H), δ = 124.80 (C-6a) ↔ δ = 8.05 (10-H), δ = 125.51 (C-10a) ↔ δ = 7.26
(9-H), δ = 135.51 (C-1’) ↔ δ = 5.97 (5-H), δ = 135.51 (C-1’) ↔ δ = 7.50
(3’-H and 5’-H), [δ = 135.71 and 146.96 (C-5a and C-11a) ↔ δ = 5.27
(11b-H), δ = 135.71 and 146.96 (C-5a and C-11a) ↔ δ = 5.97 (5-H) could
not be assigned unambiguously], δ = 149.93 (C-7) ↔ δ = 3.85 (7-OMe),
δ = 149.93 (C-7) ↔ δ = 7.26 (9-H), δ = 159.50 (C-8) ↔ δ = 3.99 (8-OMe),
δ = 159.50 (C-8) ↔ δ = 7.26 (9-H), δ = 159.50 (C-8) ↔ δ = 8.05 (10-H), δ
= 173.85 (C-2) ↔ [δA = 2.63 (3-HA) and δB = 2.83 (3-HB)], δ = 173.85 (C-
2) ↔ 4.26(3a-H), δ = 181.14 (C-11) ↔ δ = 5.27 (11b-H), δ = 181.14 (C-
11) ↔ δ = 8.05 (10-H), δ = 181.98 (C-6) ↔ δ = 5.97 (5-H). Melting point:
238-243°C (decomposition). Optical rotation of 13e: [α]D20 = –225.3 (c =
δ
= –112.17 ppm. 13C NMR (125.82 MHz, CDCl3): δ = 36.66 (C-3), 56.49
(8-OCH3), 61.32 (7-OCH3), 66.92 (C-3a), 69.09 (C-11b), 71.44 (C-5),
2
115.99 (d, 2C, JC,F = 21.7 Hz, C-3’ and C-5’), 116.42 (C-9), 125.18 (C-
3
10), 124.80 (C-6a), 125.47 (C-10a), 130.42 (d, 2C, JC,F = 8.7 Hz, C-2’
and C-6’), 132.34 (d, 1C, JC,F = 3.4 Hz, C-1’), 135.57 and 147.26 (C-5a
4
and C-11a), 149.86 (C-7), 159.47 (C-8), 163.08 (d, 1C, 1JC,F = 247.5 Hz,
C-4’), 173.99 (C-2), 181.22 (C-11), 181.99 (C-6). An edHSQC spectrum
(“short-range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the
assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
36.66 (C-3) ↔ [δA = 2.63 (3-HA) and δB = 2.84 (3-HB)], δ = 56.49 (8-
OCH3) ↔ δ = 3.99 (8-OMe), δ = 61.32 (7-OCH3) ↔ δ = 3.86 (7-OMe), δ =
66.92 (C-3a) ↔ δ = 4.27 (3a-H), δ = 69.09 (C-11b) ↔ δ = 5.28 (11b-H), δ
= 71.44 (C-5) ↔ δ = 6.01 (5-H), δ = 115.99 (C-3’ and C-5’) ↔ δ = 7.05
(3’-H and 5’-H), δ = 116.42 (C-9) ↔ δ = 7.26 (9-H), δ = 125.18 (C-10) ↔
δ = 8.05 (10-H), δ = 130.42 (C-2’ and C-6’) ↔ δ = 7.23 (2’-H and 6’-H).
An HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 124.80
(C-6a) ↔ δ = 8.05 (10-H), δ = 125.47 (C-10a) ↔ δ = 7.26 (9-H), δ =
132.34 (C-1’) ↔ δ = 6.01 (5-H), δ = 132.34 (C-1’) ↔ δ = 7.05 (3’-H and
5’-H), [δ = 135.57 and 147.26 (C-5a and C-11a) ↔ δ = 5.28 (11b-H), δ =
135.57 and 147.26 (C-5a and C-11a) ↔ δ = 6.01 (5-H) could not be
assigned unambiguously], δ = 149.86 (C-7) ↔ δ = 3.86 (7-OMe), δ =
149.86 (C-7) ↔ δ = 7.26 (9-H), δ = 159.47 (C-8) ↔ δ = 3.99 (8-OMe), δ =
159.47 (C-8) ↔ δ = 7.26 (9-H), δ = 159.47 (C-8) ↔ δ = 8.05 (10-H), δ =
173.99 (C-2) ↔ [δA = 2.63 (3-HA) and δB = 2.84 (3-HB)], δ = 173.99 (C-2)
↔ 4.27(3a-H), δ = 181.22 (C-11) ↔ δ = 5.28 (11b-H), δ = 181.22 (C-11)
↔ δ = 8.05 (10-H), δ = 181.99 (C-6) ↔ δ = 6.01 (5-H). Melting point:
20
0.41, CHCl3). Optical rotation of ent-13e: [α]D = +229.7 (c = 0.48,
CHCl3). HRMS (pos. ESI): Calcd. for C23H1779BrO7Na [M+Na]+
=
507.00499; found 507.00497 (–0.02 ppm) and calcd. for C23H1781BrO7Na
[M+Na]+ = 509.00294; found 507.00296 (+0.04 ppm). IR (film): ν = 2940,
2845, 1785, 1665, 1575, 1485, 1450, 1400, 1335, 1275, 1230, 1195,
1150, 1095, 1075, 1050, 1010, 1000, 975, 945, 910, 885, 855, 825, 790,
730, 695 cm-1.
20
231-232°C (decomposition). Optical rotation of 11d: [α]D = –206.7 (c
= 0.388, CHCl3). Optical rotation of ent-13d: [α]D20 = +171.0 (c = 0.41,
CHCl3). HRMS (pos. ESI): Calcd. for C23H17FO7Na [M+Na]+ = 447.08505;
found 447.08508 (+0.07 ppm). IR (film): ν = 2935, 2850, 1785, 1665,
1605, 1575, 1510, 1485, 1455, 1405, 1335, 1275, 1230, 1200, 1155,
1090, 1080, 1050, 1000, 975, 945, 910, 885, 855, 840, 795, 685 cm-1.
4-((3aS,5S,11bS)-7,8-Dimethoxy-2,6,11-trioxo-3,3a,5,6,11,11b-
hexahydro-2H-benzo[g]furo[3,2-c]isochromen-5-yl)benzaldehyde
(13f)
(3aS,5S,11bS)-7,8-Dimethoxy-5-(4-bromoophenyl)-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromene-2,6,11-trione (13e)
Following the General Procedure A the title compound was prepared
from 43f (14.5 mg, 31.2 µmol) suspended in MeCN (1 mL) and a solution
of (NH4)2Ce(NO3)6 (34.2 mg, 62.4 µmol, 2.0 equiv.) in H2O (1 mL).
Purification by flash chromatography (d = 1.5 cm, h = 10 cm, F = 8 mL;
CH/EE 3:2) afforded the title compound [F12-17, Rf (3:2) = 0.2, 6.3 mg,
Following the General Procedure A the title compound was prepared
from 43e (71.0 mg, 138 µmol) suspended in MeCN (1.4 mL) and a
solution of (NH4)2Ce(NO3)6 (151.3 mg, 276 µmol, 2.0 equiv.) in H2O
(1.4 mL). Purification by flash chromatography (d = 1.5 cm, h = 12 cm,
F = 8 mL; CH/EE 2:1) afforded the title compound [F16-25, Rf (2:1) = 0.2,
59.0 mg, 88%, dr = 100:0] as an orange solid. Note: The optical antipode
ent-13e was synthesized analogously in 89% yield (dr = 100:0).− 1H
46%, dr = 100:0] as an orange solid.− 1H NMR (500.32 MHz, CDCl3):
δ =
AB signal (δA = 2.65, δB = 2.85, JAB = 17.8 Hz, A signal shows no further
splitting, B signal further split by JB,3’a = 5.3 Hz, 3’-HA and 3’-HB), 3.86 (s,
3H, 7’-OMe), 3.99 (s, 3H, 8’-OMe), 4.24 (dd, 1H, J3’a,B = 5.3 Hz, J3’a,11’b
=
3.1 Hz, 3’a-H), 5.30 (d, 1H, J11’b,3’a = 3.1 Hz, 11’b-H), 6.07 (s, 1H, 5’-H),
7.27 (d, 1H, J9’,10’ = 8.7 Hz, 9’-H), 7.43 (mc, 2H, 3-H and 5-H), 7.89 (mc,
2H, 2-H, and 6-H), 8.06 (d, 1H, J10’,9’ = 8.6 Hz, 10’-H), 10.02 (s, 1H, 1-
CHO). 8-OMe was distinguished from 7-OMe by the occurrence of a
cross-peak only for the former but not for the latter in the following
NOESY spectrum (500.32 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of crosspeaks [δ(1H) ↔
δ(1H)]: δ = 2.85 (3’-HB) ↔ δ = 5.30 (11’b-H, this cross-peak proves that
3’-HB and 11’b-H are oriented cis relative to one another), δ = 3.99 (8’-
OMe) ↔ δ = 7.27 (9’-H), δ = 7.43 (3-H and 5-H) ↔ δ = 4.24 (3’a-H, this
cross-peak proves that the phenyl ring and 3’a-H are oriented cis relative
to one another), δ = 7.43 (3-H and 5-H) ↔ δ = 6.07 (5’-H), δ = 7.89 (2-H
and 6-H) ↔ δ = 10.02 (1-CHO). 13C NMR (125.82 MHz, CDCl3): δ =
36.69 (C-3’), 56.51 (8’-OCH3), 61.32 (7’-OCH3), 67.41 (C-3’a), 68.95 (C-
11’b), 71.73 (C-5’), 116.52 (C-9’), 124.71 (C-6’a), 125.28 (C-10’), 125.42
(C-10’a), 129.27 (C-3 and C-5), 130.23 (C-2 and C-6), 135.86 and
NMR (400.13 MHz, CDCl3):
δ = AB signal (δA = 2.63, δB = 2.83, JAB =
17.8 Hz, A signal shows no further splitting, B signal further split by JB,3a
= 5.3 Hz, 3-HA and 3-HB), 3.86 (s, 3H, 7-OMe), 3.99 (s, 3H, 8-OMe), 4.26
(dd, 1H, J3
= 5.3 Hz, J3a,11b = 3.1 Hz, 3a-H), 5.27 (d, 1H, J11b,3a =
a,B
3.1 Hz, 11b-H), 5.97 (s, 1H, 5-H), 7.12 (m, 2H, 2’-H and 6’-H), 7.26 (d,
1H, J9,10 = 8.7 Hz, 9-H), 7.50 (m, 2H, 3’-H and 5’-H), 8.05 (d, 1H, J10,9
=
8.6 Hz, 10-H). 8-OMe was distinguished from 7-OMe by the occurrence
of a cross-peak only for the former but not for the latter in the following
NOESY spectrum (400.13 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of crosspeaks [δ(1H) ↔
δ(1H)]: δB = 2.83 (3-HB) ↔ δ = 5.27 (11b-H, this cross-peak proves that 3-
HB and 11b-H are oriented cis relative to one another), δ = 3.99 (8-OMe)
↔ δ = 7.26 (9-H), δ = 7.12 (2’-H and 6’-H) ↔ δ = 4.26 (3a-H, this cross-
peak proves that the phenyl ring and 3a-H are oriented cis relative to one
13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
146.60 (C-5’a and C-11’a), 136.74 (C-1), 142.86 (C-4), 149.92 (C-7’),
159.52 (C-8’), 173.79 (C-2’), 181.06 (C-11’), 182.07 (C-6’), 191.52 (1-
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 124.92
CHO).
An
edHSQC
spectrum
(“short-range
C,H
COSY”;
(C-10a) ↔ δ = 7.94 (7-H), δ = 125.56 (C-6a) ↔ δ = 7.21 (8-H),
125.82/500.32 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 36.69 (C-3’) ↔ [δA = 2.65 (3’-HA) and δB
= 2.85 (3’-HB)], δ = 56.51 (8’-OCH3) ↔ δ = 3.99 (8’-OMe), δ = 61.32 (7’-
OCH3) ↔ δ = 3.86 (7’-OMe), δ = 67.41 (C-3’a) ↔ δ = 4.24 (3’a-H), δ =
68.95 (C-11’b) ↔ δ = 5.30 (11’b-H), δ = 71.73 (C-5’) ↔ δ = 6.07 (5’-H), δ
= 116.52 (C-9’) ↔ δ = 7.27 (9’-H), δ = 125.28 (C-10’) ↔ δ = 8.06 (10’-H),
δ = 129.27 (C-3 and C-5) ↔ δ = 7.43 (3-H and 5-H), δ = 130.23 (C-2 and
C-6) ↔ δ = 7.89 (2-H and 6-H), δ = 191.52 (1-CHO) ↔ δ = 10.02 (1-
δ = 135.26 (C-11a) ↔ δ = 5.03(5-H), δ = 135.26 (C-11a) ↔ δ = 5.30
(11b-H), δ = 148.29 (C-5a) ↔ δ = 1.53 (5-CH3), δ = 148.29 (C-5a) ↔
δ = 5.03 (5-H), δ = 148.29 (C-5a) ↔ δ = 5.30 (11b-H), δ = 149.79 (C-10)
↔ δ = 3.94 (10-OMe), δ = 149.79 (C-10) ↔ δ = 7.21 (8-H), δ = 149.79
(C-10)
↔ δ = 7.94 (7-H), δ = 159.63 (C-9) ↔ δ = 3.99 (9-OMe),
δ = 159.63 (C-9) ↔ δ = 7.21 (8-H), δ = 159.63 (C-9) ↔ δ = 7.94 (7-H),
δ = 174.26 (C-2) ↔ δA = 2.68 (3-HA), δ = 174.26 (C-2) ↔ δB = 2.96 (3-
HB), δ = 174.26 (C-2) ↔ δ = 4.66 (3a-H), δ = 181.57 (C-11) ↔ δ = 5.30
(11b-H), δ = 182.08 (C-6)
↔
δ = 7.94 (7-H). Optical rotation:
[α]D20 = −122.7 (c = 0.410, CHCl3). HRMS (pos. ESI): Calcd. for C18H16O7
[M+Na]+ = 367.07882; found 367.07907 (+0.67 ppm). IR (film): ν = 2925,
2850, 1785, 1740, 1665, 1645, 1575, 1485, 1460, 1415, 1395, 1370,
1335, 1270, 1235, 1200, 1155, 1125, 1085, 1060, 1050, 1005, 995, 950,
900, 850 cm-1.
CHO).
An
HMBC
spectrum
(“long-range
C,H
COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 124.71 (C-6’a) ↔ δ = 8.06 (10’-H), δ = 125.42 (C-
10’a) ↔ δ = 7.27 (9’-H), [δ = 135.86 and 146.60 (C-5’a and C-11’a) ↔ δ
= 5.30 (11’b-H), δ = 135.86 and 146.60 (C-5’a and C-11’a) ↔ δ = 6.07
(5’-H) could not be assigned unambiguously], δ = 136.74 (C-1) ↔ δ =
7.43 (3-H and 5-H), δ = 136.74 (C-1) ↔ δ = 10.02 (1-CHO), δ = 142.86
(C-4) ↔ δ = 6.07 (5’-H), δ = 142.86 (C-4) ↔ δ = 7.89 (2-H and 6-H), δ =
149.92 (C-7’) ↔ δ = 3.86 (7’-OMe), δ = 149.92 (C-7’) ↔ δ = 7.27 (9’-H), δ
= 159.52 (C-8’) ↔ δ = 3.99 (8’-OMe), δ = 159.52 (C-8’) ↔ δ = 7.27 (9’-H),
δ = 159.52 (C-8’) ↔ δ = 8.06 (10’-H), δ = 173.79 (C-2’) ↔ [δA = 2.65 (3’-
HA) and δB = 2.85 (3’-HB)], δ = 173.79 (C-2’) ↔ 4.24 (3’a-H), δ = 181.06
(C-11’) ↔ δ = 8.06 (10’-H), δ = 182.07 (C-6’) ↔ δ = 6.07 (5’-H). Optical
rotation: [α]D20 = –193.6 (c = 0.58, CHCl3). HRMS (pos. ESI): Calcd. for
C24H18O8Na [M+Na]+ = 457.08939; found 457.08929 (–0.21 ppm). IR
(film): ν = 2925, 2850, 1785, 1705, 1665, 1610, 1575, 1485, 1460, 1410,
1335, 1275, 1230, 1155, 1075, 1055, 1005, 975, 910, 825 cm-1.
(3aS,5S,11bS)-5-Phenyl-9,10-dimethoxy-3,3a-dihydro-2H-
benzo[g]furo[3,2-c] isochromen-2,6,11(5H,11bH)-trione (14b)
Following the General Procedure A the title compound was prepared
from 46b (23.4 mg, 53.6 µmol) dissolved in MeCN (4 mL) and a solution
of (NH4)2Ce(NO3)6 (59.1 mg, 108 µmol, 2.0 equiv.) in H2O (2 mL).
Purification by flash chromatography [d = 1 cm, h = 12 cm, F = 8 mL;
CH/EE 2:1 (F1-16)] afforded the pure product [F5-10, Rf (2:1) = 0.20,
(3aS,5S,11bS)-9,10-Dimethoxy-5-methyl-3,3a-dihydro-2H-
benzo[g]furo[3,2-c] isochromen-2,6,11(5H,11bH)-trione (14a)
17.6 mg, 80%, dr
= 94:6] as a yellow oil To separate the two
diastereomers, the obtained product was completely dissolved in CH2Cl2
(2 mL) and heptane (1.5 mL) was added. CH2Cl2 was allowed to slowly
vaporize over 3 d. The solvent was removed with a pipet to furnish 14b
as a yellow oil (12.0 mg, 55%).− 1H-NMR (400.13 MHz, CDCl3): δ = AB
signal (δA = 2.63 and δB = 2.84, JAB = 17.8 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.3 Hz, 3-HA and 3-HB), 3.97 (s,
3H, 10-OMe), 3.99 (s, 3H, 9-OMe), 4.30 (dd, 1H, J3a,B = 5.3 Hz,
J3a,11b = 3.1 Hz, 3a-H), 5.32 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 6.00 (s, 1H,
5-H), 7.21 (d, 1H, J8,7 = 8.8 Hz, 8-H), 7.21-7.26 (m, 2H, 2’-H and 6’-H),
7.34-7.38 (m, 3H, 3’-H, 4’-H and 5’-H), 7.89 (d, 1H, J7,8 = 8.6 Hz, 7-H). 9-
OMe was distinguished from 10-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 2.84
(3-HB) ↔ δ = 5.32 (11b-H, this cross-peak proves that 3-HB and 11b-H
are oriented cis relative to one another), δ = 7.21-7.26 (2’-H and 6’-H) ↔
δ = 4.30 (3a-H, this cross-peak proves that the phenyl ring and 3a-H are
oriented cis relative to one another), δ = 7.21-7.26 (2’-H and 6’-H) ↔
Following the General Procedure A the title compound was prepared
from 46a (8.2 mg, 22 µmol) dissolved in MeCN (1 mL) and a solution of
(NH4)2Ce(NO3)6 (24.1 mg, 44.0 µmol, 2.0 equiv.) in H2O (1 mL).
Purification by flash chromatography [d = 1 cm, h = 13 cm, F = 8 mL;
CH/EE 1:1 (F1-13)] afforded the title compound [F4-8, Rf (1:1) = 0.30,
5.1 mg, 68%, dr = 97:3] as an orange solid].− 1H-NMR (500.32 MHz,
CDCl3, spectrum contains resonances of grease at δ = 0.85 and 1.25
ppm): δ = 1.53 (d, 3H, J5-CH ,5 = 6:9 Hz, 5-CH3), AB signal (δA = 2.68 and
3
δB = 2.96, JAB = 17.7 Hz, A signal shows no further splitting, B signal
further split by JB,3a = 5.2 Hz, 3-HA and 3-HB), 3.94 (s, 3H, 10-OMe), 3.99
(s, 3H, 9-OMe), 4.66 (dd, 1H, J3a,B = 5.2 Hz, J3a,11b = 3.0 Hz, 3a-H), 5.03
(q, 1H, J5,5-CH = 6.9 Hz, 5-H), 5.30 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 7.21
3
δ = 6.00 (5-H), δ = 3.99 (9-OMe)
↔
δ = 7.21 (8-H). 13C-NMR
(d, 1H, J7,8 = 8.6 Hz, 7-H), 7.94 (d, 1H, J8,7 = 8.6 Hz, 8-H). 9-OMe was
distinguished from 10-OMe by the occurrence of a cross-peak only for
the former but not for the latter in the following NOESY spectrum (500.32
MHz, CDCl3) that allowed additional assignments of 1H resonances by
the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.96 (3-HB) ↔
δ = 5.30 (11b-H, this cross-peak proves that 3-HB and 11b-H are oriented
cis relative to one another), δ = 1.53 (5-CH3) ↔ δ = 4.66 (3a-H, this
cross-peak proves that 5-CH3 and 3a-H are oriented cis relative to one
another), δ = 3.99 (9-OMe) ↔ δ = 7.21 (8-H). 13C-NMR (125.81 MHz,
CDCl3, spectrum contains a resonance of grease at δ = 29.79 ppm):
δ = 18.59 (5-CH3), 37.10 (C-3), 56.47 (9-OCH3), 61.49 (10-OCH3), 66.58
(C-5), 66.65 (C-3a), 69.00 (C-11b), 115.95 (C-8), 124.86 (C-7), 124.92
(C-10a), 125.56 (C-6a), 135.26 (C-11a), 148.29 (C-5a), 149.79 (C-10),
159.63 (C-9), 174.26 (C-2), 181.57 (C-11), 182.08 (C-6). An edHSQC
spectrum (“short-range C,H COSY”; 125.81/500.32 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
(100.61 MHz, CDCl3): δ = 36.74 (C-3), 56.50 (9-OCH3), 61.52 (10-OCH3),
67.19 (C-3a), 69.20 (C-11b), 71.94 (C-5), 116.10 (C-8), 125.09 (C-7),
125.09 (C-10a), 125.41 (C-6a), 128.59 (C-2’ and C-6’), 128.96 (C-3’ and
C-5’), 129.16 (C-4’), 136.37 (C-1ˈ), 137.54 and 145.31 (C-5a and C-11a),
149.94 (C-10), 159.75 (C-9), 174.15 (C-2), 181.43 (C-11), 181.73 (C-6).
An edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 36.74 (C-3) ↔ δA = 2.63 and δB = 2.84 (3-HA and 3-HB),
δ = 56.50 (9-OCH3)
↔ δ = 3.99 (9-OMe), δ = 61.52 (10-OCH3) ↔
δ = 3.97 (10-OMe), δ = 67.19 (C-3a) ↔ δ = 4.30 (3a-H), δ = 69.20 (C-
11b) ↔ δ = 5.32 (11b-H), δ = 71.94 (C-5) ↔ δ = 6.00 (5-H), δ = 116.10
(C-8) ↔ δ = 7.21 (8-H), δ = 125.09 (C-7) ↔ δ = 7.89 (7-H), δ = 128.59
(C-2’ and C-6’) ↔ δ = 7.21-7.26 (2’-H and 6’-H), δ = 128.96 (C-3’ and C-
5’) ↔ δ = 7.34-7.38 (3’-H, 4’-H and 5’-H), δ = 129.16 (C-4’) ↔ δ = 7.34-
7.38 (3’-H, 4’-H and 5’-H). An HMBC spectrum (“long-range C,H COSY”;
with the independently assigned 1H resonances [δ(13C)
↔
δ(1H)]:
100.61/400.13 MHz, CDCl3) allowed the assignment of all quaternary 13
C
δ = 18.59 (5-CH3) ↔ δ = 1.53 (5-CH3), δ = 37.10 (C-3) ↔ δA = 2.68 and
δB = 2.96 (3-HA and 3-HB), δ = 56.47 (9-OCH3) ↔ δ = 3.99 (9-OMe),
δ = 61.49 (10-OCH3) ↔ δ = 3.94 (10-OMe), δ = 66.58 (C-5) ↔ δ = 5.03
(5-H), δ = 66.65 (C-3a) ↔ δ = 4.66 (3a-H), δ = 69.00 (C-11b) ↔ δ = 5.30
(11b-H), δ = 115.95 (C-8) ↔ δ = 7.21 (8-H), δ = 124.86 (C-7) ↔ δ = 7.94
(7-H). An HMBC spectrum (“long-range C,H COSY”; 125.81/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 125.09 (C-10a) ↔ δ = 7.89 (7-H), δ = 125.41 (C-6a)
↔ δ = 7.21 (8-H), δ = 136.37 (C-1ˈ) ↔ δ = 6.00 (5-H), δ = 136.37 (C-1ˈ)
↔ δ = 7.34-7.38 (3’-H, 4’-H and 5’-H), [δ = 137.54 and 145.31 (C-5a and
C-11a) ↔ δ = 5.32 (11b-H), δ = 137.54 and 145.31 (C-5a and C-11a) ↔
14
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
δ = 6.00 (5-H) could not be assigned unambiguously], δ = 149.94 (C-10)
↔ δ = 3.97 (10-OMe), δ = 149.94 (C-10) ↔ δ = 7.21 (8-H), δ = 159.75
(C-9) ↔ δ = 3.99 (9-OMe), δ = 159.75 (C-9) ↔ δ = 7.21 (8-H), δ = 159.75
(C-9) ↔ δ = 7.89 (7-H), δ = 174.15 (C-2) ↔ δA = 2.63 (3-HA), δ = 174.15
(C-2) ↔ δB = 2.84 (3-HB), δ = 174.15 (C-2) ↔ δ = 4.30 (3a-H), δ = 181.43
δ = 173.83 (C-2) ↔ δ = 4.24 (3a-H), δ = 181.19 (C-11) ↔ δ = 5.33 (11b-
H), δ = 181.74 (C-6) ↔ δ = 6.02 (5-H), δ = 181.74 (C-6) ↔ δ = 7.89 (7-
H). Melting point: Oil. Optical rotation: [α]D20 = −62.1 (c = 0.527,
CHCl3). HRMS (pos. APCl): Calcd. for C24H17F3O7 [M+H]+ = 475.09991;
found 475.09976 (−0.32 ppm). IR (film): ν = 2930, 2855, 1785, 1665,
1650, 1620, 1575, 1485, 1455, 1415, 1330, 1275, 1230, 1200, 110,
1125, 1095, 1030, 1020, 1000, 950, 905, 840 cm-1.
(C-11)
↔ δ = 5.32 (11b-H), δ = 181.73 (C-6) ↔ δ = 6.30 (5-H),
δ = 181.73 (C-6) ↔ δ = 7.89 (7-H). Melting point: Oil. Optical rotation:
[α]D20 = −75.8 (c = 0.530, CHCl3). HRMS (pos. ESI): Calcd. for C23H18O7
[M+Na]+ = 429.09447; found 429.09464 (+0.38 ppm). IR (film): ν = 2925,
2850, 1785, 1665, 1645, 1575, 1485, 1455, 1415, 1395, 1335, 1275,
1230, 1200, 1155, 1090, 1055, 1025, 1000, 970, 950, 925, 900 cm-1.
(3aS,5S,11bS)-9,10-Dimethoxy-5-(4-fluorophenyl)-3,3a-dihydro-2H-
benzo[g]furo [3,2-c]isochromene-2,6-11(5H,11bH)-trione (14d)
(3aS,5S,11bS)-9,10-Dimethoxy-5-(4-(trifluoromethyl)phenyl)-3,3a-
dihydro-2H-benzo[g]furo[3,2-c]isochromene-2,6-11(5H,11bH)-trione
(14c)
Following the General Procedure A the title compound was prepared
from 46d (31.1 mg, 68.4 µmol) dissolved in MeCN (3 mL) and a solution
of (NH4)2Ce(NO3)6 (75.0 mg, 137 µmol, 2.0 equiv.) in H2O (2 mL).
Purification by flash chromatography [d = 1 cm, h = 12.5 cm, F = 8 mL;
CH/EE 2:1 (F1-16)] afforded the pure product [F5-12, Rf (2:1) = 0.20,
20.2 mg, 70%] as a yellow oil.− 1H-NMR (500.32 MHz, CDCl3): δ = AB
signal (δA = 2.64 and δB = 2.86, JAB = 17.8 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.3 Hz, 3-HA and 3-HB), 3.97 (s,
3H, 10-OMe), 4.00 (s, 3H, 9-OMe), 4.27 (dd, 1H, J3a,B = 5.3 Hz,
J3a,11b = 3.1 Hz, 3a-H), 5.32 (d, 1H, J11b,3a = 3.1 Hz, 11b-H), 5.97 (s, 1H,
5-H), 7.06 (mc, 2H, 3ˈ-H and 5ˈ-H), 7.22 (d, 1H, J8,7 = 8.7 Hz, 8-H), 7.22
(mc, 2H, 2ˈ-H and 6ˈ-H), 7.89 (d, 1H, J7,8 = 8.7 Hz, 7-H). 9-OMe was
distinguished from 10-OMe by the occurrence of a cross-peak only for
the former but not for the latter in the following NOESY spectrum (500.32
MHz, CDCl3) that allowed additional assignments of 1H resonances by
the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.86 (3-HB) ↔
δ = 5.33 (11b-H, this cross-peak proves that 3-HB and 11b-H are oriented
cis relative to one another), δ = 7.22 (2ˈ-H and 6ˈ-H) ↔ δ = 4.27 (3a-H,
this cross-peak proves that the phenyl ring and 3a-H are oriented cis
relative to one another), δ = 7.22 (2ˈ-H and 6ˈ-H) ↔ δ = 5.97 (5-H),
Following the General Procedure A the title compound was prepared
from 46c (21.8 mg, 43.2 µmol) dissolved in MeCN (3 mL) and a solution
of (NH4)2Ce(NO3)6 (47.4 mg, 86.5 µmol, 2.0 equiv.) in H2O (2 mL).
Purification by flash chromatography [d = 1 cm, h = 13.5 cm, F = 8 mL;
CH/EE 3:1 (F1-10), 2:1 (F11-20)] afforded the pure product (F10-16,
Rf (2:1) = 0.25, 17.6 mg, 93%) as a yellow oil.− 1H-NMR (500.32 MHz,
CDCl3): δ = AB signal (δA = 2.65 and δB = 2.86, JAB = 17.8 Hz, A signal
shows no further splitting, B signal further split by JB,3a = 5.3 Hz, 3-HA and
3-HB), 3.98 (s, 3H, 10-OMe), 4.00 (s, 3H, 9-OMe), 4.24 (dd, 1H,
J3a,B = 5.3 Hz, J3a,11b = 3.1 Hz, 3a-H), 5.33 (d, 1H, J11b,3a = 3.1 Hz, 11b-
H), 6.02 (s, 1H, 5-H), 7.23 (d, 1H, J7,8 = 8.7 Hz, 8-H), 7.38 (br,d, 2H,
J2 ˈ = J6 ˈ = 8.5 Hz, 2ˈ-H and 6ˈ-H), 7.64 (br,d, 2H, J3 ˈ = J5 ˈ = 8.5 Hz,
ˈ
,3
ˈ
,5
ˈ
,2
ˈ,6
3ˈ-H and 6ˈ-H), 7.91 (d, 1H, J8,7 = 8.5 Hz, 7-H). 9-OMe was distinguished
from 10-OMe by the occurrence of a cross-peak only for the former but
not for the latter in the following NOESY spectrum (500.32 MHz, CDCl3)
that allowed additional assignments of 1H resonances by the occurrence
of crosspeaks (500.32 MHz, CDCl3) [δ(1H) ↔ δ(1H)]: δB = 2.86 (3-HB) ↔
δ = 5.33 (11b-H, this cross-peak proves that 3-HB and 11b-H are oriented
cis relative to one another), δ = 7.38 (2ˈ-H and 6ˈ-H) ↔ δ = 4.24 (3a-H,
this cross-peak proves that the phenyl ring and 3a-H are oriented cis
relative to one another), δ = 7.38 (2ˈ-H and 6ˈ-H) ↔ δ = 6.02 (5-H),
δ = 4.00 (9-OMe)
↔
δ = 7.89 (8-H). 19F-NMR (470.72 MHz, 1H-
decoupled, CDCl3): δ = −112.12 ppm. 13C-NMR (125.82 MHz, CDCl3):
δ = 36.71 (C-3), 56.51 (9-OCH3), 61.53 (10-OCH3), 67.12 (C-3a), 69.05
2
(C-11b), 71.18 (C-5), 115.98 (d, 2C, JC,F = 21.7 Hz, C-3ˈ and C-5ˈ),
116.11 (C-8), 125.04(C-10a), 125.15 (C-7), 125.27 (C-6a), 130.40 (d, 2C,
4
3JC,F = 8.4 Hz, C-2ˈ and C-6ˈ), 132.34 (d, 1C, JC,F = 3.4 Hz, C-1ˈ),
δ = 4.00 (9-OMe)
↔
δ = 7.23 (8-H). 19F-NMR (470.72 MHz, 1H-
137.58 and 145.02 (C-5a and C-11a), 149.95 (C-10), 159.82 (C-9),
1
decoupled, CDCl3): δ = −62.83 ppm. 13C-NMR (125.82 MHz, CDCl3):
δ = 36.71 (C-3), 56.54 (9-OCH3), 61.55 (10-OCH3), 67.52 (C-3a), 68.91
163.07 (d, 1C, JC,F = 249.2 Hz, C-4ˈ), 174.04 (C-2), 181.34 (C-11),
181.70 (C-6). An edHSQC spectrum (“short-range C,H COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 36.71 (C-3) ↔ δA = 2.64 and δB = 2.86
(3-HA and 3-HB), δ = 56.51 (9-OCH3) ↔ δ = 4.00 (9-OMe), δ = 61.53 (10-
OCH3) ↔ δ = 3.97 (10-OMe), δ = 67.12 (C-3a) ↔ δ = 4.27 (3a-H),
δ = 69.05 (C-11b) ↔ δ = 5.32 (11b-H), δ = 71.18 (C-5) ↔ δ = 5.97 (5-H),
1
(C-11b), 71.28 (C-5), 116.16 (C-8), 123.83 (q, 1C, JC,F = 272.5 Hz, 4ˈ-
CF3), 125.03(C-10a), 125.17 (C-6a), 125.21 (C-7), 125.97 (q, 2C,
3JC,F = 3.7 Hz, C-3ˈ and C-5ˈ), 128.96 (C-2ˈ and C-6ˈ), 131.36 (q, 1C,
2JC,F = 32.8 Hz, C-4ˈ), 137.89 (C-5a), 144.43 (C-11a), 140.39 (C-1ˈ),
150.05 (C-10), 159.94 (C-9), 173.83 (C-2), 181.19 (C-11), 181.74 (C-6).
An edHSQC spectrum (“short-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 36.71 (C-3) ↔ δA = 2.68 and δB = 2.85 (3-HA and 3-HB),
2
δ = 115.98 (d, 2C, JC,F = 21.7 Hz, C-3ˈ and C-5ˈ) ↔ δ = 7.06 (3ˈ-H and
5ˈ-H), δ = 116.11 (C-8) ↔ 7.22 (8-H), δ = 125.15 (C-7) ↔ 7.89 (7-H),
δ = 130.40 (d, 2C, 3JC,F = 8.4 Hz, C-2ˈ and C-6ˈ) ↔ δ = 7.22 (2ˈ-H and 6ˈ-
H). An HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ = 56.54 (9-OCH3)
↔ δ = 4.00 (9-OMe), δ = 61.55 (10-OCH3) ↔
δ = 3.98 (10-OMe), δ = 67.52 (C-3a) ↔ δ = 4.24 (3a-H), δ = 68.91 (C-
11b) ↔ δ = 5.33 (11b-H), δ = 71.28 (C-5) ↔ δ = 6.02 (5-H), δ = 116.16
(C-8) ↔ δ = 7.23 (8-H), δ = 125.21 (C-7) ↔ δ = 7.91 (7-H), δ = 125.97 (q,
2C, 3JC,F = 3.7 Hz, C-3ˈ and C-5ˈ) ↔ δ = 7.64 (3ˈ-H and 5ˈ-H), δ = 128.96
(C-2ˈ and C-6ˈ) ↔ 7.38 (2ˈ-H and 6ˈ-H). An HMBC spectrum (“long-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all quaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-
peaks linked via 2 or 4 covalent bonds]: δ = 125.03(C-10a) ↔ δ = 7.91(7-
δ(1H); in grey: cross-peaks linked via
2 or 4 covalent bonds]:
δ = 125.04(C-10a) ↔ δ = 7.89 (7-H), δ = 125.27 (C-6a) ↔ δ = 7.22 (8-H),
4
δ = 132.34 (d, 1C, JC,F = 3.4 Hz, C-1ˈ) ↔ δ = 7.09 (3ˈ-H and 5ˈ-H),
4
δ = 132.34 (d, 1C, JC,F = 3.4 Hz, C-1ˈ) ↔ δ = 7.22 (2ˈ-H and 6ˈ-H),
[δ = 137.58 and 145.02 (C-5a and C-11a)
↔ δ = 5.32 (11b-H),
δ = δ = 137.58 and 145.02 (C-5a and C-11a) ↔ δ = 5.97 (5-H) could not
be assigned unambiguously], δ = 149.95 (C-10) ↔ δ = 3.97 (10-OMe),
δ = 149.95 (C-10) ↔ δ = 7.22 (8-H), δ = 149.95 (C-10) ↔ δ = 7.89 (7-H),
δ = 159.82 (C-9) ↔ δ = 4.00 (9-OMe), δ = 159.82 (C-9) ↔ δ = 7.22 (8-H),
H), δ = 125.17 (C-6a)
↔
δ = 7.23 (8-H), δ = 131.36 (q, 1C,
2JC,F = 32.8 Hz, C-4ˈ) ↔ δ = 7.38 (2ˈ-H and 6ˈ-H), [δ = 137.89 and 144.43
(C-5a and C-11a) ↔ δ = 5.33 (11b-H), δ = 137.89 and 144.43 (C-5a and
1
δ = 159.82 (C-9) ↔ δ = 7.89 (7-H), δ = 163.07 (d, 1C, JC,F = 249.2 Hz,
1
C-4ˈ) ↔ δ = 7.09 (3ˈ-H and 5ˈ-H), δ = 163.07 (d, 1C, JC,F = 249.2 Hz, C-
C-11a)
↔ δ = 6.02 (5-H) could not be assigned unambiguously],
4ˈ) ↔ δ = 7.22 (2ˈ-H and 6ˈ-H), δ = 174.04 (C-2) ↔ δA = 2.64 (3-HA),
δ = 174.04 (C-2) ↔ δB = 2.86 (3-HB), δ = 174.04 (C-2) ↔ δ = 4.27 (3a-H),
δ = 181.34 (C-11) ↔ δ = 5.32 (11b-H), δ = 181.70 (C-6) ↔ δ = 5.97 (5-
H), δ = 181.70 (C-6) ↔ δ = 7.89 (7-H). Melting point: Oil. Optical
rotation: [α]D20 = −64.8 (c = 0.707, CHCl3). HRMS (pos. APCl): Calcd. for
C23H17FO7 [M+H]+ = 425.10311; found 425.10291 (−0.48 ppm). IR (film):
δ = 140.39 (C-1ˈ) ↔ δ = 7.64 (3ˈ-H and 5ˈ-H), δ = 140.39 (C-1ˈ) ↔
δ = 6.02 (5-H), δ = 150.05 (C-10) ↔ δ = 3.98 (10-OMe), δ = 150.05 (C-
10) ↔ δ = 7.23 (8-H), δ = 159.94 (C-9) ↔ δ = 4.00 (9-OMe), δ = 159.94
(C-9) ↔ δ = 7.23 (8-H), δ = 159.94 (C-9) ↔ δ = 7.91 (7-H), δ = 173.83
(C-2)
↔ ↔
δA = 2.65 (3-HA), δ = 173.83 (C-2) δB = 2.86 (3-HB),
15
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
ν = 2930, 2850, 1785, 1665, 1645, 1605, 1575, 1510, 1485, 1455, 1415,
1335, 1275, 1230, 1200, 1155, 1095, 1060, 1030, 1015, 1000, 975, 905,
840 cm-1.
(4S,5S)-4-Hydroxy-5-(1,4,5,6-tetramethoxynaphthalen-2-
yl)dihydrofuran-2(3H)-one (15)
(3aS,5S,11bS)-9,10-Dimethoxy-5-(4-bromophenyl)-3,3a-dihydro-2H-
benzo[g]furo[3,2-c]isochromene-2,6-11(5H,11bH)-trione (14e)
A
86:14
isomeric
mixture
of
(E)-methyl
4-(1,4,5,6-
tetramethoxynaphthalen-2-yl)but-3-enoate (17) and its α,β-unsaturated
carboxylic ester isomer (iso-17) (70.0 mg, 0.20 mmol) and (DHQ)2PHAL
(1.6 mg, 2.1 µmol, 1.0 mol-%) were dissolved in t-BuOH (2 mL).
K3Fe(CN)6 (0.20 g, 0.60 mmol, 3.0 equiv.), K2CO3 (82.9 mg, 0.60 mmol,
3.0 equiv.), NaHCO3 (50.4 mg, 0.60 mmol, 3.0 equiv.) and Me2SO2NH2
(19.0 mg, 0.20 mmol, 1.0 equiv.) were dissolved in H2O (1.8 mL). The
aqueous solution was added to the vigorously stirred organic reaction
mixture. A solution of K2OsO2(OH)4 (0.3 mg, 0.8 µmol, 0.4 mol-%) in H2O
(0.2 mL) was added in one portion to initiate the reaction. The reaction
was vigorously stirred for 2 d. Afterwards it was quenched by the addition
of solid Na2SO3 (0.20 g) and stirred for 30 min. EtOAc (10 mL) was
added and the organic phase was separated. The aqueous phase was
extracted with EtOAc (5 × 5 mL) and the combined organic extracts were
washed with aqueous KOH solution (1 M, 2 × 5 mL) and brine (10 mL)
and dried over Na2SO4. The solvent was evaporated in vacuo and the
residue was purified by flash chromatography (d = 3 cm, h = 12 cm,
F = 25 mL; CH/EE 1:1) to obtain the product [46.1 mg, 66% relative to
the total of the substrate mixture = 77% relative to the fraction of 17
(ref.[7s]: 71% relative to the total of the substrate mixture = 79% relative to
the fraction of the β,γ-unsaturated ester in the substrate mixture)] as a
white solid.− 1H NMR (500.32 MHz, CDCl3): δ = 2.34 (br. s, 1H, 4-OH),
AB signal (δA = 2.76, δB = 2.95, JAB = 17.6 Hz, A signal shows no further
splitting, B signal further split by JB,4 = 5.4 Hz, 3-HA and 3-HB), 3.81 (s,
3H, 5’-OMe), 3.85 (s, 3H, 1’-OMe), 3.94 (s, 3H, 4’-OMe), 3.97 (s, 3H, 6’-
Following the General Procedure A the title compound was prepared
from 46e (24.2 mg, 47.0 µmol) dissolved in MeCN (2 mL) and a solution
of (NH4)2Ce(NO3)6 (52.1 mg, 95.0 µmol, 2.0 equiv.) in H2O (2 mL).
Purification by flash chromatography [d = 1 cm, h = 14 cm, F = 8 mL;
CH/EE 3:1 (F1-11), 2:1 (F12-28)] afforded the product [F11-24,
Rf (2:1) = 0.20, 20.5 mg, 90%] as a yellow oil and as a 95:5 mixture of
the two diastereomers.− 1H-NMR (400.13 MHz, CDCl3): δ = AB signal
(δA = 2.63, δB = 2.85, JAB = 17.8 Hz, A signal shows no further splitting, B
signal further split by JB,3a = 5.3 Hz, 3-HA and 3-HB), 3.97 (s, 3H, 10-
OMe), 4.00 (s, 3H, 9-OMe), 4.26 (dd, 1H, J3a,B = 5.3 Hz, J3a,11b = 3.0 Hz,
3a-H), 5.31 (d, 1H, J11b,3a = 3.0 Hz, 11b-H), 5.93 (s, 1H, 5-H), 7.12 (mc,
2H, 2ˈ-H and 6ˈ-H), 7.22 (d, 1H, J8,7 = 8.7 Hz, 8-H), 7.50 (mc, 2H, 3ˈ-H
and 5ˈ-H), 7.89 (d, 1H, J7,8 = 8.6 Hz, 7-H). 9-OMe was distinguished from
10-OMe by the occurrence of a cross-peak only for the former but not for
the latter in the following NOESY spectrum (400.13 MHz, CDCl3) that
allowed additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.85 (3-HB) ↔ δ = 5.31 (11b-H, this
cross-peak proves that 3-HB and 11b-H are oriented cis relative to one
another), δ = 4.26 (3a-H) ↔ δ = 5.31 (11b-H), δ = 7.12 (2ˈ-H and 6ˈ-H) ↔
δ = 4.26 (3a-H, this cross-peak proves that the phenyl ring and 3a-H are
oriented cis relative to one another), δ = 7.12 (2ˈ-H and 6ˈ-H) ↔ δ = 5.93
(5-H), δ = 4.00 (9-OMe) ↔ δ = 7.22 (8-H). 13C-NMR (100.63 MHz,
CDCl3): δ = 36.71 (C-3), 56.52 (9-OCH3), 61.53 (10-OCH3), 67.30 (C-3a),
69.00 (C-11b), 71.30 (C-5), 116.15 (C-8), 123.46 (C-4ˈ), 125.07 (C-10a),
125.14 (C-7), 125.28 (C-6a), 130.21 (C-2ˈ and C-6ˈ), 132.16 (C-3ˈ and C-
5ˈ), 135.50 (C-1ˈ), 137.71 and 144.74 (C-5a and C-11a), 150.02 (C-10),
159.87 (C-9), 173.93 (C-2), 181.27 (C-11), 181.68 (C-6). An edHSQC
spectrum (“short-range C,H COSY”; 100.63/400.13 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
OMe), 4.82 (dd, 1H, J4 = 5.0 Hz, J4,5 = 3.8 Hz, J4,4-OH = 1.3 Hz, 4-H),
,B
5.83 (d, 1H, J5,4 = 3.8 Hz, 5-H), 6.83 (s, 1H, 3’-H), 7.25 (d, 1H, J7’,8’
=
9.2 Hz, 7’-H), 7.66 (d, 1H, J8’,7’ = 9.3 Hz, 8’-H). 1’-OMe, 4’-OMe and 8’-
OMe were distinguished from 5’-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 2.34
(4-OH) ↔ δ = 4.82 (4-H), δB = 2.95 (3-HB) ↔ δ = 5.83 (5-H, this cross-
peak proves that 3-HB and 5-H are oriented cis relative to one another), δ
= 3.85 (1’-OMe) ↔ δ = 5.83 (5-H), δ = 3.85 (1’-OMe) ↔ δ = 7.66 (8’-H), δ
= 3.94 (4’-OMe) ↔ δ = 6.83 (3’-H), δ = 3.97 (6’-OMe) ↔ δ = 7.25 (7’-H),
δ = 6.83 (3’-H) ↔ δ = 5.83 (5-H). 13C NMR (125.82 MHz, CDCl3): δ =
38.43 (C-3), 56.72 (4’-OCH3), 57.21 (6’-OCH3), 61.87 (5’-OCH3), 62.37
(1’-OCH3), 70.03 (C-4), 81.79 (C-5), 104.24 (C-3’), 115.86 (C-7’), 118.70
(C-8’), 119.46 (C-2’), 122.91 (C-4’a), 125.18 (C-8’a), 144.85 (C-5’),
146.53 (C-1’), 151.09 (C-6’), 152.71 (C-4’), 175.67 (C-2). An edHSQC
spectrum (“short-range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
38.43 (C-3) ↔ [δA = 2.76 (3-HA) and δB = 2.95 (3-HB)], δ = 56.72 (4’-
OCH3) ↔ δ = 3.94 (4’-OMe), δ = 57.21 (6’-OCH3) ↔ δ = 3.96 (6’-OMe), δ
= 61.87 (5’-OCH3) ↔ δ = 3.81 (5’-OMe), δ = 62.37 (1’-OCH3) ↔ δ = 3.85
(1’-OMe), δ = 70.03 (C-4) ↔ δ = 4.82 (4-H), δ = 81.79 (C-5) ↔ δ = 5.83
(5-H), δ = 104.24 (C-3’) ↔ δ = 6.83 (3’-H), δ = 115.86 (C-7’) ↔ δ = 7.25
(7’-H), δ = 118.70 (C-8’) ↔ δ = 7.66 (8’-H). An HMBC spectrum (“long-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all quaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-
peaks linked via 2 or 4 covalent bonds]: δ = 119.46 (C-2’) ↔ δ = 5.83 (5-
H), δ = 119.46 (C-2’) ↔ δ = 6.83 (3’-H), δ = 122.91 (C-4’a) ↔ δ = 6.83
(3’-H), δ = 122.91 (C-4’a) ↔ δ = 7.66 (8’-H), δ = 125.18 (C-8’a) ↔ δ =
7.25 (7’-H), δ = 144.85 (C-5’) ↔ δ = 3.81 (5’-OMe), δ = 144.85 (C-5’) ↔ δ
= 7.25 (7’-H), δ = 146.53 (C-1’) ↔ δ = 3.85 (1’-OMe), δ = 146.53 (C-1’) ↔
δ = 6.83 (3’-H), 146.53 (C-1’) ↔ δ = 7.66 (8’-H), δ = 151.09 (C-6’) ↔ δ =
3.97 (6’-OMe), δ = 151.09 (C-6’) ↔ δ = 7.25 (7’-H), δ = 151.09 (C-6’) ↔ δ
with the independently assigned 1H resonances [δ(13C)
↔
δ(1H)]:
δ = 36.71 (C-3) ↔ δA = 2.63 and δB = 2.85 (3-HA and 3-HB), δ = 56.52 (9-
OCH3) ↔ δ = 4.00 (9-OMe), δ = 61.53 (10-OCH3) ↔ δ = 3.97 (10-OMe),
δ = 67.30 (C-3a) ↔ δ = 4.26 (3a-H), δ = 69.00 (C-11b) ↔ δ = 5.31 (11b-
H), δ = 71.30 (C-5) ↔ δ = 5.93 (5-H), δ = 116.15 (C-8) ↔ 7.22 (8-H),
δ = 125.14 (C-7) ↔ 7.89 (7-H), δ = 130.21 (C-2ˈ and C-6ˈ) ↔ δ = 7.12
(2ˈ-H and 6ˈ-H), δ = 132.16 (C-3ˈ and C-5ˈ) ↔ δ = 7.50 (3ˈ-H and 5ˈ-H).
An HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 123.46
(C-4ˈ) ↔ δ = 7.12 (2ˈ-H and 6ˈ-H), δ = 123.46 (C-4ˈ) ↔ δ = 7.50 (3ˈ-H
and 5ˈ-H), δ = 125.07 (C-10a) ↔ δ = 7.89 (7-H), δ = 125.28 (C-6a) ↔
δ = 7.22 (8-H), δ = 135.50 (C-1ˈ) ↔ δ = 5.93 (5-H), δ = 135.50 (C-1ˈ) ↔
δ = 7.50 (3ˈ-H and 5ˈ-H), [δ = 137.71 and 144.74 (C-5a and C-11a) ↔
δ = 5.31 (11b-H), δ = 137.71 and 144.74 (C-5a and C-11a) ↔ δ = 5.93
(5-H) could not be assigned unambiguously], δ = 150.02 (C-10) ↔
δ = 3.97 (10-OMe), δ = 150.02 (C-10) ↔ δ = 7.22 (8-H), δ = 159.87 (C-9)
↔ δ = 4.00 (9-OMe), δ = 159.87 (C-9) ↔ δ = 7.22 (8-H), δ = 159.87 (C-9)
↔ δ = 7.89 (7-H), δ = 173.93 (C-2) ↔ δA = 2.63 (3-HA), δ = 173.93 (C-2)
↔ δB = 2.85 (3-HB), δ = 173.93 (C-2) ↔ δ = 4.26 (3a-H), δ = 181.27 (C-
11) ↔ δ = 5.31 (11b-H), δ = 181.68 (C-6) ↔ δ = 5.93 (5-H), δ = 181.68
(C-6) ↔ δ = 7.89 (7-H). Melting point: Oil. HRMS (pos. APCl): Calcd. for
C23H17BrO7 [M+H]+ = 485.02304; found 485.02310 (+0.12 ppm), calcd.
for C23H1781BrO7 [M+H]+ = 487.02100; found 487.02087 (−0.25 ppm). IR
(film): ν = 2925, 2850, 1785, 1735, 1665, 1645,1575, 1485, 1460, 1405,
1380, 1335, 1275, 1230, 1200, 1155, 1095, 1060, 1030, 1010, 975, 950,
905, 885 cm-1.
16
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
= 7.66 (8’-H), δ = 152.71 (C-4’) ↔ δ = 3.94 (4’-OMe), δ = 152.71 (C-4’) ↔
↔ δ(1H)]: δ = 38.33 (C-3) ↔ δA = 2.76 and δB = 2.95 (3-HA and 3-HB),
δ = 56.04 (4`-OCH3) ↔ δ = 3.98 (4`-OMe), δ = 56.70 (7`-OCH3) ↔
δ = 6.83 (3’-H), δ = 175.67 (C-2) ↔ [δA = 2.76 (3-HA) and δB = 2.95 (3-
HB)]. Melting point: 74°C (decomp.). Optical rotation of 15: [α]D
=
=
δ = 4.01 (7`-OMe), δ = 62.05 (8`-OCH3) ↔ δ = 3.87 (8`-OMe), δ = 62.86
(1`-OCH3) ↔ δ = 3.86 (1`-OMe), δ = 70.12 (C-4) ↔ δ = 4.89 (4-H),
δ = 82.19 (C-5) ↔ δ = 5.96 (5-H), δ = 100.10 (C-3`) ↔ δ = 6.75 (3`-H),
δ = 114.13 (C-6`) ↔ δ = 7.31 (6`-H), δ = 119.62 (C-5`) ↔ δ = 8.08 (5`-H).
An HMBC spectrum (“long-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 123.44
(C-2`) ↔ δ = 5.96 (5-H), δ = 123.44 (C-2`) ↔ δ = 6.75 (3`-H), δ = 123.55
(C-4`a)↔ δ = 7.31 (6`-H), δ = 123.86 (C-8`a)↔ δ = 8.08 (5`-H),
δ = 142.50 (C-8`)↔ δ = 3.87 (8`-OMe), δ = 142.50 (C-8`)↔ δ = 7.31 (6`-
H), δ = 145.23 (C-1`)↔ δ = 3.86 (1`-OMe), δ = 145.23 (C-1`)↔ δ = 5.96
(5-H), δ = 145.23 (C-1`)↔ δ = 6.75 (3`-H), δ = 151.37 (C-7`)↔ δ = 4.01
(7`-OMe), δ = 151.37 (C-7`)↔ δ = 7.31 (6`-H), δ = 151.37 (C-7`)↔
δ = 8.08 (5`-H), δ = 152.51 (C-4`)↔ δ = 3.98 (4`-OMe), δ = 152.51 (C-
4`)↔ δ = 6.75 (3`-H), δ = 152.51 (C-4`)↔ δ = 8.08 (5`-H), δ = 175.56 (C-
2) ↔ δA = 2.76 (3-HA), δ = 175.56 (C-2) ↔ δB = 2.95 (3-HB), δ = 175.56
(C-2) ↔ δ = 4.89 (4-H). Melting point: 167-168°C. Optical rotation of
22: [α]D20 = +36.4 (c = 0.623, CHCl3). HRMS (pos. ESI): Calcd. for
C18H20O7 [M+Na]+ = 371.11012; found 371.11017 (+0.12 ppm). IR (film):
ν = 2940, 2845, 1775, 1660, 1620, 1600, 1515, 1460, 1450, 1420, 1365,
1325, 1275, 1245, 1215, 1195, 1160, 1135, 1100, 1075, 1055, 1030,
1000, 975, 915, 895, 850, 820, 790, 735, 700, 665 cm-1. Enantiomeric
excess of 22: > 99.5% ee. The ee was determined by chiral HPLC [AD-
20
‒5.2 (c = 1.04, CHCl3) and [α]D20 = ‒5.5 (c = 0.45, CHCl3) {ref.[7s]: [α]D
20
‒3.5 (c = 0.46, CHCl3); ref.[7t]: [α]D25 = +5.2 (c = 0.4, CHCl3)}. HRMS (neg.
APCI): Calcd. for C18H20O7Cl [M+Cl]– = 383.09042; found: 383.09042
(+0.31 ppm). Enantiomeric excess of 15: 98.5% ee (ref.[7s]: 99.2% ee).
The ee was determined by chiral HPLC (OD-H, heptane/EtOH = 60:40, λ
= 230 nm, flow: 0.7 mL/min, tR(ent-15) = 10.55 min, tR(15) = 12.71 min).
To develop a separation method for chiral HPLC a mixture of both
enantiomers was measured (OD-H, heptane/EtOH = 60:40, λ = 230 nm,
flow: 0.7 mL/min, tR(ent-15) = 10.14 min, tR(15) = 12.66 min). The optical
antipode ent-15 was synthesized analogously by using the
(DHQD)2PHAL-ligand in the Sharpless asymmetric dihydroxylation
procedure. Yield: 58% (67% relative to the amount of 15). Optical
rotation of ent-15: [α]D20 = +2.3 (c = 0.96, CHCl3) and [α]D20 = +3.1 (c =
0.45, CHCl3) {ref.[ 7t]: [α]D25 ‒4.6 (c = 0.5, CHCl3)}. Enantiomeric excess
of ent-15: 96% ee. The ee was determined by chiral HPLC (OD-H,
heptane/EtOH = 60:40, λ = 230 nm, flow: 0.7 mL/min, tR(ent-15) =
10.37 min, tR(15) = 12.94 min).
(4S,5S)-4-Hydroxy-5-(1,4,7,8-tetramethoxynaphthalen-2-yl)dihydro-
furan-2(3H)-one (16)
3,
heptane/EtOH = 40:60,
λ = 230 nm,
flow:
1.0 mL/min;
tR
(22) = 4.33 min, tR (ent-22) not detected]. To develop a separation
method for chiral HPLC a mixture of both enantiomers was measured
[AD-3, heptane/EtOH = 40:60, λ = 230 nm, flow: 1.0 mL/min; tR
(22) = 4.34 min, tR (ent-22) = 7.81 min]. The optical antipode ent-22
was synthesized analogously by using the (DHQD)2PHAL-ligand in the
Sharpless asymmetric dihydroxylation procedure. Optical rotation of
ent-22: [α]D20 = −48.2 (c = 0.330, CHCl3).
A 92:8 isomeric mixture of (E)-methyl 4-(1,4,5,6-tetramethoxynaphthalen-
2-yl)but-3-enoate (18) and its α,β-unsaturated carboxylic ester isomer
iso-18 (343.1 mg, 0.991 mmol) and (DHQ)2PHAL (7.8 mg, 10 µmol, 1.0
mol-%) were dissolved in tBuOH (10 mL). K3Fe(CN)6 (1.00 g, 3.04 mmol,
3.06 equiv.), K2CO3 (0.44 g, 3.17 mmol, 3.20 equiv.), NaHCO3 (267 mg,
3.21 mmol, 3.24 equiv.) and Me2SO2NH2 (103.3 mg, 1.076 mmol,
1.09 equiv.) were dissolved in H2O (8 mL) and added dropwise to the
vigorously stirred reaction mixture. K2OsO2(OH)4 (1.6 mg, 4.3 µmol, 0.4
mol-%) was dissolved in H2O (2 mL) and equally added to the solution.
The reaction mixture was vigorously stirred for 15 h. Afterwards the
reaction mixture was carefully quenched by adding solid sodium sulfite
(0.99 g). The aqueous phase was extracted with EE (5 × 30 mL) and the
(E)-Methyl 4-(1,4,5,6-tetramethoxynaphthalen-2-yl)but-3-enoate (17)
and
(E)-Methyl
4-(5-(tert-butoxycarbonyloxy)-1,4,6-
trimethoxynaphthalen-2-yl)but-2-enoate (iso-17)[49]
combined organic extracts were washed with aqueous NaOH (1 M, 2 ×
30 mL) and brine (30 mL) and dried over Na2SO4. The solvent was
evaporated in vacuo and the residue was purified by flash
chromatography [d = 3.5 cm, h = 13 cm, F = 20 mL; CH/EE 1:1 (F1-43)]
to obtain a fraction containing impurities (Rf (1:1) = 0.25, F21-24 and 25-
40, 205.3 mg, 60%).− 1H-NMR (400.13 MHz, CDCl3): δ = 1.68 (br.s, 1H,
4-OH), AB signal [δA = 2.76 and δB = 2.95, JAB = 17.7 Hz, additionally
splitted by JB,4 = 5.5 Hz and JA,4 = 0.9 Hz, 3-HA and 3-HB], 3.86 (s, 3H, 1`-
OMe), 3.87 (s, 3H, 8`-OMe), 3.98 (s, 3H, 4`-OMe), 4.01 (s, 3H, 7`-OMe),
4.89 (ddd, 1H, J4,B = 5.4 Hz , J4,5 = 3.8 Hz, J4,A = 0.8 Hz, 4-H), 5.96 (d,
1H, J5,4 = 3.7 Hz, 5-H), 6.75 (s, 1H, 3`-H), 7.31 (d, 1H, J6`,5` = 9.3 Hz, 6`-
H), 8.08 (d, 1H, J5`,6` = 9.3 Hz, 5`-H). 1`-OMe, 4`-OMe and 7`-OMe were
distinguished from 8`-OMe by the occurrence of a cross-peak only for the
former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3), that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.68
(4-OH) ↔ δ = 4.89 (4-H), δB = 2.95 (3-HB) ↔ δ = 5.96 (5-H, this cross-
peak proves that 3-HB and 5-H are oriented cis relative to one another),
δ = 3.86 (1`-OMe) ↔ δ = 5.96 (5-H), δ = 3.98 (4`-OMe) ↔ δ = 6.75 (3`-
H), δ = 4.02 (7`-OMe) ↔ δ = 7.31 (6`-H). 13C-NMR (100.63 MHz, CDCl3):
δ = 38.33 (C-3), 56.04 (4`-OCH3), 56.70 (7`-OCH3), 62.05 (8`-OCH3),
62.86 (1`-OCH3), 70.12 (C-4), 82.19 (C-5), 100.10 (C-3`), 114.13 (C-6`),
119.62 (C-5`), 123.44 (C-2`), 123.55 (C-4`a), 123.86 (C-8`a), 142.50 (C-
8`), 145.23 (C-1`), 151.37 (C-7`), 152.51 (C-4`), 175.56 (C-2). An
edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
2-Bromo-1,4,5,6-tetramethoxynaphthalene (19, 1.00 g, 3.06 mmol) and
Pd2dba3·CHCl3 (63.2 mg, 0.06 mmol, 2.0 mol-%) were dissolved in
freshly distilled toluene (30 mL). P(tBu)3 (49.6 mg, 0.24 mmol, 8.0 mol-%)
was weighed out in a glove box and afterwards dissolved in freshly
distilled toluene (2mL). The latter solution was transferred to the reaction
mixture. N,N-dicyclohexylmethylamine (1.97 mL, 1.79 g, 9.17 mmol,
3.0 equiv.) and methyl 2-vinylacetate (0.98 mL, 0.92 g, 9.17 mmol,
3.0 equiv) were added at room temperature. The reaction mixture was
refluxed for 2 d. The mixture was allowed to cool to room temperature
and CH2Cl2 (40 mL) was added. The organic phase was washed with
aqueous HCl (1M, 2 × 30 mL) and brine (30 ml) and dried over Na2SO4.
The solvent was removed in vacuo and the oily residue was purified by
flash chromatography (d = 4 cm, h = 15 cm, F = 50 mL; CH/EE 5:1) to
obtain the product (0.88 g, 83%) as a yellow-brownish oil.− NMR
characterization of 17: 1H NMR (400.13 MHz, CDCl3): δ = 3.35 (dd, 2H,
4
J2,3 = 7.2 Hz, J2,4 = 1.5 Hz, 2-H2), 3.74 (s, 3H, 1-OMe), 3.84 (s, 3H, 1’-
OMe), 3.88 (s, 3H, 5’-OMe), 3.98 (s, 3H, 6’-OMe), 3.99 (s, 3H, 4’-OMe),
6.35 (dt, 1H, J3,4 = 16.0 Hz, J3,2 = 7.2 Hz, 3-H), 6.90 (s, 1H, 3’-H), 6.93
49
Note: This reaction needs to entirely be performed under inert gas. Every
fluid reagent has to be degassed (freeze & pump technique) prior to use. It is
mandatory to freshly distill toluene over potassium prior to use. P(tBu)3 has to
be weighed out in a glove box.
17
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
(dt, 1H, J4,3 = 16.0 Hz, 4J4,2 = 1.5 Hz, 4-H), 7.28 (d, 1H, J7’,8’ = 9.2 Hz, 7’-
H), 7.84 (d, 1H, J8’,7’ = 9.2 Hz, 8‘-H). 1’-OMe, 4’-OMe and 6’-OMe were
distinguished from 5’-OMe by the occurrence of a cross-peak only for the
former but not for the latter in the following NOESY spectrum (400.13
MHz, CDCl3) that allowed additional assignments of 1H resonances by
the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.84 (1’-OMe) ↔ δ =
6.93 (4-H), δ = 3.84 (1’-OMe) ↔ δ = 7.84 (8’-H), δ = 3.99 (4’-OMe) ↔ δ =
6.90 (3’-H), δ = 3.98 (6’-OMe) ↔ δ = 7.28 (7’-H). 13C NMR (100.61 MHz,
CDCl3): δ = 38.71 (C-2), 52.01 (1-OCH3), 56.96 (4’-OCH3), 57.26 (6’-
OCH3), 61.87 (5’-OCH3), 62.51 (1’-OCH3), 103.82 (C-3’), 115.70 (C-7’),
119.18 (C-8’), 121.96 (C-3), 127.81 (C-4), 126.21 (C-8’a), 144.94 (C-5’),
147.51 (C-1’), 150.93 (C-6’), 152.37 (C-4’), 172.23 (C-1). An edHSQC
spectrum (“short-range C,H COSY”; 100.61/400.13 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
38.71 (C-2) ↔ δ = 3.35 (2-H2), δ = 52.01 (1-OCH3) ↔ δ = 3.74 (1-OMe),
δ = 56.96 (4’-OCH3) ↔ δ = 3.99 (4’-OMe), δ = 57.26 (6’-OCH3) ↔ δ =
3.98 (6’-OMe), δ = 61.87 (5’-OCH3) ↔ δ = 3.88 (5’-OMe), δ = 62.51 (1’-
OCH3) ↔ δ = 3.84 (1’-OMe), δ = 103.82 (C-3’) ↔ δ = 6.90 (3’-H), δ =
115.70 (C-7’) ↔ δ = 7.28 (7’-H), δ = 119.18 (C-8’) ↔ δ = 7.84 (8’-H), δ =
121.96 (C-3) ↔ δ = 6.35 (3-H), δ = 127.81 (C-4) ↔ δ = 6.93 (4-H). An
HMBC spectrum (“long-range C,H COSY”; 100.61/400.13 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]: [δ = 122.59 and
122.73 (C-2’ and C-4’a) ↔ δ = 6.90 (3’-H) and δ = 7.84 (8’-H) could not
be assigned unambiguously], δ = 126.21 (C-8’a) ↔ δ = 7.28 (7’-H), δ =
144.94 (C-5’) ↔ δ = 3.88 (5’-OMe), δ = 144.94 (C-5’) ↔ δ = 7.28 (7’-H), δ
= 147.51 (C-1’) ↔ δ = 3.84 (1’-OMe), δ = 147.51 (C-1’) ↔ δ = 6.90 (3’-H),
δ = 147.51 (C-1’) ↔ δ = 7.84 (8’-H), δ = 150.93 (C-6’) ↔ δ = 3.98 (6’-
OMe), δ = 150.93 (C-6’) ↔ δ = 7.28 (7’-H), δ = 150.93 (C-6’) ↔ δ = 7.84
(8’-H), δ = 152.37 (C-4’) ↔ δ = 3.99 (4’-OMe), δ = 152.37 (C-4’) ↔ δ =
6.90 (3’-H), δ = 172.23 (C-1) ↔ δ = 3.35 (2-H2), δ = 172.23 (C-1) ↔ δ =
3.75 (1-OMe). NMR analysis of iso-17: 1H NMR (400.13 MHz, CDCl3): δ
Combined yield: 212.2 mg, 61%.− NMR analysis of 18: 1H-NMR
(400.13 MHz, CDCl3): δ = 3.37 (dd, 2H, J2,3 = 7.1 Hz, J2,4 = 1.5 Hz, 2-H2),
3.75 (s, 3H, 1-OMe), 3.80 (s, 3H, 1`-OMe), 3.88 (s, 3H, 8`-OMe), 3.99 (s,
3H, 7`-OMe), 3.99 (s, 3H, 4`-OMe), 6.36 (dt, 1H, J3,4 = 16.1 Hz,
J3,2 = 7.1 Hz, 3-H), 6.78 (s, 1H, 3`-H), 7.10 (dt, 1H, J4,3 = 16.0 Hz,
J4,2 = 1.6 Hz, 4-H), 7.22 (d, 1H, J6`,5` = 9.3 Hz, 6`-H), 8.00 (d, 1H,
J5`,6` = 9.2 Hz, 5`-H). 1’-OMe, 4’-OMe and 7’-OMe were distinguished
from 8’-OMe by the occurrence of a cross-peak only for the former but
not for the latter in the following NOESY spectrum (400.13 MHz, CDCl3)
that allowed additional assignments of 1H resonances by the occurrence
of cross-peaks [δ(1H) ↔ δ(1H)]: [δ(1H) ↔ δ(1H)]: δ = 3.99 (7`-OMe) ↔ δ =
7.22 (6`-H), δ = 3.37 (2-H2) ↔ δ = 7.10 (4-H), δ = 3.80 (1`-OMe) ↔ δ =
7.10 (4-H), δ = 3.99 (4`-OMe) ↔ δ = 6.78 (3`-H), δ = 6.36 (3-H) ↔ δ =
6.78 (3`-H). 13C-NMR (100.61 MHz, CDCl3): δ = 38.75 (C-2), 52.00 (1-
OCH3), 55.75 and 56.63 (4`-OCH3 and 7`-OCH3), 62.05 (8`-OCH3), 62.89
(1`-OCH3), 98.81 (C-3`), 113.31 (C-6`), 119.21 (C-5`), 122.43 (C-3),
123.39 (C-4`a), 124.58 (C-8`a), 126.63 (C-2`), 128.44 (C-4), 143.11 (C-
8`), 146.08 (C-1`), 151.33 (C-7`), 152.00 (C-4`), 172.30 (C-1). An
edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 38.75 (C-2) ↔ δ =, 3.37 (2-H2), δ = 52.00 (1-OCH3) ↔ δ =
3.75 (1-OMe), [δ = 55.75 and 56.63 (4`-OCH3 and 7`-OCH3) ↔ δ = 3.99
(4`-OMe) and δ = 3.99 (7`-OMe) could not be assigned unambiguously],
δ = 62.05 (8`-OCH3) ↔ δ = 3.80 (8`-OMe), δ = 62.89 (1`-OCH3) ↔ δ =
3.88 (1`-OMe), δ = 98.81 (C-3`) ↔ δ = 6.78 (3`-H), δ = 113.31 (C-6`) ↔ δ
= 7.22 (6`-H), δ = 119.21 (C-5`) ↔ δ = 8.00 (5`-H), δ = 122.43 (C-3) ↔ δ
= 6.36 (3-H), δ = 128.44 (C-4) ↔ δ = 7.10 (4-H). An HMBC spectrum
(“long-range C,H COSY”; 100.61/400.13 MHz, CDCl3) allowed the
assignment of all quaternary 13C atoms through their cross-peaks with
the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey:
cross-peaks linked via 2 or 4 covalent bonds]: δ = 123.39 (C-4`a) ↔ δ =
6.78 (3`-H), δ = 123.39 (C-4`a) ↔ δ = 7.22 (6`-H), δ = 124.58 (C-8`a) ↔
δ = 8.00 (5`-H), δ = 126.63 (C-2`) ↔ δ = 6.36 (3-H), δ = 143.11 (C-8`) ↔
δ = 3.88 (8`-OMe), δ = 143.11 (C-8`) ↔ δ = 7.22 (6`-H), δ = 143.11 (C-8`)
↔ δ = 8.00 (5`-H), δ = 146.08 (C-1`) ↔ δ = 3.80 (1`-OMe), δ = 146.08
(C-1`) ↔ δ = 6.78 (3`-H), δ = 151.33 (C-7`) ↔ δ = 3.99 (7`-OMe), δ =
151.33 (C-7`) ↔ δ = 7.22 (6`-H), δ = 151.33 (C-7`) ↔ δ = 8.00 (5`-H), δ =
152.00 (C-4`) ↔ δ = 3.99 (4`-OMe), δ = 152.00 (C-4`) ↔ δ = 6.78 (3`-H),
δ = 152.00 (C-4`) ↔ δ = 8.00 (5`-H), δ = 172.30 (C-1) ↔ δ = 3.37 (2-H2),
δ = 172.30 (C-1) ↔ δ = 3.75 (1-OMe), δ = 172.30 (C-1) ↔ δ = 6.36 (3-H).
NMR analysis of iso-18: 1H-NMR (400.13 MHz, CDCl3): δ = 3.65 (dd, 2H,
4
= 3.66 (dd, 2H, J4,3 = 6.3 Hz, J4,2 = 1.8 Hz, 4-H2), 3.71, 3.83, 3.88, 3.94
and 3.98 (5×s, 5×3H, 1-OMe, 1’-OMe, 4’-OMe, 5’-OMe and 6’-OMe), 5.86
4
(dt, 1H, J2,3 = 15.7 Hz, J2,4 = 1.7 Hz, 2-H), 6.54 (s, 1H, 3’-H), 7.17 (dt,
1H, J3,2 = 15.5 Hz, J3,4 = 6.5 Hz, 3-H), 7.31 (d, 1H, J7’,8’ = 9.0 Hz, 7’-H),
7.81 (d, 1H, J8’,7’ = 9.2 Hz, 8‘-H).
(E)-Methyl 4-(1,4,7,8-tetramethoxynaphthalen-2-yl)but-3-enoate (18)
and (E)-Methyl 4-(1,4,7,8-tetramethoxynaphthalen-2-yl)but-2-enoate
(iso-18)[49]
J
4,3 = 6.4 Hz, J4,2 = 1.8 Hz), 3.71, 3.79, 3.88, 3.93, 4.00 (s, 5 × OMe, 1-
OMe, 1`-OMe, 4`-OMe, 7`-OMe, 8`-OMe), 5.87 (dt, 1H, J2,3 = 15.5 Hz,
J2,4 = 1.8 Hz, 2-H), 6.40 (s, 1H, 3`-H), 7.20 (dt, 1H, J3,2 = 15.6 Hz,
J3,4 = 6.5 Hz, 3-H), 7.17 (d, 1H, J6`,5` = 9.2 Hz, 6`-H), 8.02 (d, 1H,
J5`,6` = 9.3 Hz, 5`-H). Melting point: Oil. Elemental analysis: Calculated:
C: 65.88%, H: 6.40%; found: C: 65.58%, H: 6.04%; deviation: C: 0.30%,
H: 0.36%. HRMS (pos. ESI): Calcd. for C19H22O6 [M+Na]+ = 369.13086;
found 369.13123 (+0.99 ppm). IR (film): ν = 2930, 2855, 1785, 1665,
1650, 1620, 1575, 1485, 1455, 1415, 1330, 1295, 1275, 1230, 1200,
1160, 1125, 1095, 1065, 1030, 1020, 1000, 905 cm-1.
3-Bromo-1,4,5,6-tetramethoxynaphthalene (20, 328 mg, 1.00 mmol) and
Pd2dba3 (22.1 mg, 0.02 mmol, 2.0 mol-%) were dissolved in toluene
(8mL). P(tBu)3 (16.8 mg, 0.08 mmol, 8 mol-%) was dissolved in toluene
(2mL) and and transferred into the reaction mixture. N,N-
dicyclohexylmethylamine (0.65 mL, 587 mg, 3.00 mmol, 3.0 equiv.) and
methyl but-3-enoate (0.32 mL, 301 mg, 3.01 mmol, 3.0 equiv) were
added dropwise at room temperature. The reaction mixture was refluxed
for 2 d. The reaction was allowed to cool to room temperature and diluted
2-Bromo-1,4,5,6-tetramethoxynaphthalene (19) and 2-Bromo-1,4,7,8-
tetramethoxynaphthalene (20)
with EE (15 mL). Afterwards it was washed with HCl (1M, 3 × 10 mL) and
dried over Na2SO4. The solvent was evaporated in vacuo and the residue
was purified by flash chromatography [d = 3.5 cm, h = 13 cm, F = 20 mL;
CH/EE 5:1 (F1-23), 3:1 (F24-43)] to obtain the product (F25-30,
Rf (5:1) = 0.20, 131.9 mg) as a pale-yellow oil and as 92:8 mixture with
iso-18, as well as a second fraction containing impurities (F21-24 and
F31). This second fraction was purified again by flash chromatography
[d = 2.5 cm, h = 13 cm, F = 20 mL; CH/EE 5:1 (F1-26)], to obtain the
product (F10-15, Rf (5:1) = 0.20, 80.3 mg) as a 91:9 mixture with iso-18.
Under
a nitrogen atmosphere 1,2,5,8-tetramethoxynaphthalene (27,
1.36 g, 5.47 mmol) was dissolved in dry DMF (22 mL). Solid N-
Bromosuccinimide (0.98 g, 5.51 mmol, 1.0 equiv.) was added in one
portion and the solution was stirred at room temperature for 16 h. Silica
gel was added and the solvent was removed in vacuo (60°C, 15 mbar,
~15 min, room temp., 1 mbar, ~15 min). Flash chromatography (d = 5,
18
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
h = 12 cm, F = 50 ml; CH/EE 9:1) afforded the minor product 20 (F6-9,
38.0 mg, 2%) and the major product 19 (F10-18, 1.51 g, 84%) as a
yellow solid.− Analysis of the major product 19: 1H NMR (500.32 MHz,
CDCl3): 3.87 (s, 3H, 5-OMe), 3.92 (s, 3H, 1-OMe), 3.95 (s, 3H, 4-OMe),
3.98 (s, 3H, 6-OMe), 6.86 (s, 1H, 3-H), 7.32 (d, 1H, J7,8 = 9.2 Hz, 7-H),
7.74 (d, 1H, J8,7 = 9.2 Hz, 8-H). 1-OMe, 4-OMe and 6-OMe were
distinguished from 5-OMe by the occurrence of a cross-peak only for the
former but not for the latter in the following NOESY spectrum (500.32
MHz, CDCl3) that allowed additional assignments of 1H resonances by
the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.92 (1-OMe) ↔ δ =
7.74 (8-H), δ = 3.95 (4-OMe) ↔ δ = 6.86 (3-H), δ = 3.98 (6-OMe) ↔ δ =
7.32 (7-H). 13C NMR (125.82 MHz, CDCl3): δ = 56.89 (4-OCH3), 57.18 (6-
OCH3), 61.40 (1-OCH3), 61.91 (5-OCH3), 110.25 (C-3), 116.13 (C-7),
118.86 (C-8), 109.39 (C-2), 121.99 (C-4a), 126.21 (C-8a), 144.93 (C-5),
147.02 (C-1), 150.01 (C-6), 152.65 (C-4). An edHSQC spectrum (“short-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 56.89 (4-
OCH3) ↔ δ = 3.95 (4-OMe), δ = 57.18 (6-OCH3) ↔ δ = 3.98 (6-OMe), δ =
61.40 (1-OCH3) ↔ δ = 3.92 (1-OMe), δ = 61.91 (5-OCH3) ↔ δ = 3.89 (5-
OMe), δ = 110.25 (C-3) ↔ δ = 6.86 (3-H), δ = 116.13 (C-7) ↔ δ = 7.32
(7-H), δ = 118.86 (C-8) ↔ δ = 7.74 (8-H). An HMBC spectrum (“long-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all quaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-
peaks linked via 2 or 4 covalent bonds]: δ = 109.39 (C-2) ↔ δ = 6.86 (3-
H), δ = 109.39 (C-2) ↔ δ = 7.74 (8-H), δ = 121.99 (C-4a) ↔ δ = 6.86 (3-
H), δ = 121.99 (C-4a) ↔ δ = 7.74 (8-H), δ = 126.21 (C-8a) ↔ δ = 6.86 (3-
H), δ = 126.21 (C-8a) ↔ δ = 7.32 (7-H), δ = 144.93 (C-5) ↔ δ = 3.87 (5-
OMe), δ = 144.93 (C-5) ↔ δ = 6.86 (3-H), δ = 144.93 (C-5) ↔ δ = 7.32
(7-H), δ = 144.93 (C-5) ↔ δ = 7.74 (8-H), δ = 147.02 (C-1) ↔ δ = 3.92 (1-
OMe), δ = 147.02 (C-1) ↔ δ = 6.86 (3-H), δ = 147.02 (C-1) ↔ δ = 7.74
(8-H), δ = 150.01 (C-6) ↔ δ = 3.98 (6-OMe), δ = 150.01 (C-6) ↔ δ = 7.32
(7-H), δ = 150.01 (C-6) ↔ δ = 7.74 (8-H), δ = 152.65 (C-4) ↔ δ = 3.95 (4-
OMe), δ = 152.65 (C-4) ↔ δ = 6.86 (3-H), δ = 152.65 (C-4) ↔ δ = 7.74
(8-H). Melting point: 53°C. Elemental analysis: Calculated: C: 51.40%,
H: 4.62%; found: C: 51.44%, H: 4.67%, deviation: C: 0.04%, H: 0.05%.
HRMS (pos. ESI): Calcd. for C14H1679BrO4: [M+H]+ = 327.02265; found:
327.02274 (+0.27 ppm); calcd. for C14H1679BrO4: [M+NH4]+ = 344.04920;
found: 344.04935 (+0.44 ppm). IR (film): ν = 2955, 2935, 2835, 1585,
1575, 1510, 1465, 1375, 1365, 1315, 1275, 1245, 1130, 1075, 1035,
1005, 975, 920, 815, 790 cm-1. Analysis of the minor product 20: 1H NMR
(400.13 MHz, CDCl3): 3.88 (s, 3H, 1-OMe), 3.89 (s, 3H, 8-OMe), 3.94 (s,
(3-H), δ = 151.57 (C-7) ↔ δ = 3.99 (7-OMe), δ = 151.57 (C-7) ↔ δ = 7.26
(6-H), δ = 151.57 (C-7) ↔ δ = 8.00 (5-H), δ = 152.17 (C-4) ↔ δ = 3.94 (4-
OMe), δ = 152.17 (C-4) ↔ δ = 6.78 (3-H). Melting point: 68-71°C.
Elemental analysis: Calculated: C: 51.40%, H: 4.62%; found: C:
51.33%, H: 4.65%; deviation: C: 0.07%, H: 0.03%. HRMS (pos. ESI):
Calcd. for C14H1579BrO4Na: [M+Na]+ = 349.00459; found: 349.00476
(+0.48 ppm). IR (film): ν = 2995, 2960, 2935, 2835, 1610, 1595, 1515,
1460, 1450, 1410, 1370, 1325, 1275, 1240, 1210, 1190, 1180, 1130,
1060, 1005, 980, 925, 880, 815, 795, 760, 725, 715, 680, 665 cm-1.
Alternative Preparation of 19 from iso-23: 3-Bromo-7,8-dimethoxy-4-
(triisopropylsilyloxy)naphthalen-1-ol (iso-23, 132.0 mg, 0.289 mmol) was
dissolved in THF (3 mL) and Bu4NF (1.0
M in THF, 0.30 mL, 0.30 mmol,
1.10 equiv.) was added dropwise at 0°C and the solution was allowed to
warm up to room temperature for 15 min. KOH (85 w-%, 136.6 g,
2.069 mmol, 7.16 equiv.) was dissolved in H2O (1.5 mL, degassed with
N2) and the solution was transferred dropwise at 0°C. Me2SO4 (0.30 mL,
0.36 g, 2.89 mmol, 10.0 equiv.) was added dropwise at 0°C and the
solution was allowed to warm to room temperature and stirred for 16 h.
Afterwards the reaction mixture was carefully quenched by adding conc.
NH3 (2 mL) and the solution was stirred for 30 min. THF was removed
under reduced pressure and the aqueous phase was extracted with EE
(4 × 10 mL). The combined organic extracts were washed with brine
(10 mL) and dried over Na2SO4. The solvent was evaporated in vacuo
and the residue was purified by flash chromatography [d = 2 cm,
h = 14 cm, F = 20 mL; CH/EE 5:1 (F1-17)] to obtain the pure product [F5-
7, Rf (5:1) = 0.25, 68.1 mg, 72%] as pale-yellow solid.
Alternative Preparation of 20 from 23:
3-Bromo-5,6-dimethoxy-4-(triisopropylsilyloxy)naphthalen-1-ol
2.28 g, 5.01 mmol) was dissolved in THF (50 mL), tetrabutylammonium
fluoride (1.0 in THF, 5.5 mL, 5.5 mmol, 1.1 equiv.) was added dropwise
at 0°C and the solution was stirred at room temperature for 45 min.
Afterwards the mixture was quenched with aqueous HCl (1 , 10 mL,
(23,
M
M
10 mmol, 2.0 equiv.) and stirred for 15 min. EE (150 mL) was added, the
organic phase was separated and the aqueous phase was extracted with
EE (4 × 50 mL). The combined organic extracts were washed with
aqueous CaCl2 (5%, 50 mL) and brine (50 mL) and dried over Na2SO4.
The solvent was evaporated in vacuo and the residue was purified by
flash chromatography [d = 7.5 cm, h = 12 cm, F = 100 mL; CH/EE 3:1
(contained 1% formic acid, F1-24), 1:1 (contained 2% formic acid, F25-
34)] to obtain the desilylated product (F12-20, Rf (3:1) = 0.20, 427.5 mg,
29%) as a pale-yellow oil that was used in the following step without
further purification. Crude 2-bromo-7,8-dimethoxynaphthalene-1,4-diol
(387.5 mg, 1.295 mmol), sodium dithionite (22.1 mg, 0.13 mmol, 9.0 mol-
%), Bu4NBr (35.0 mg, 0.11 mmol, 8.0 mol-%) and KOH (85 w-%, 796 mg,
12.1 mmol, 9.3 equiv) were dissolved in THF (8.7 mL) and H2O (4.3 mL)
at 0°C. Dimethyl sulfate (1.23 mL, 1.64 g, 13.0 mmol, 10.0 equiv.) was
added dropwise at 0°C and the solution was stirred at room temperature
for 16 h. Afterwards the reaction mixture was carefully quenched by
adding conc. NH3 (10 mL). After stirring for 45 min, the organic phase
was separated and the aqueous phase was extracted with EE
(5 × 10 mL). The combined organic extracts were washed with brine
(10 mL) and dried over Na2SO4. The solvent was evaporated in vacuo
and the residue was purified by flash chromatography [d = 3 cm,
h = 12 cm, F = 20 mL; CH/EE 9:1 (F1-16), 5:1 (F17-28)] to obtain the
pure product [F6-15, Rf (5:1) = 0.50, 358.1 mg, 85% (25% over these 2
steps)] as a white solid.
3H, 4-OMe), 3.99 (s, 3H, 7-OMe), 6.78 (s, 1H, 3-H), 7.26 (d, 1H, J6,5
=
9.2 Hz, 6-H), 8.00 (d, 1H, J5,6 = 9.2 Hz, 5-H). 4-OMe and 7-OMe were
distinguished from 1-OMe and 8-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.94
(4-OMe) ↔ δ = 6.78 (3-H), δ = 3.99 (7-OMe) ↔ δ = 7.26 (6-H). 13C NMR
(100.61 MHz, CDCl3): δ = 55.96 (4-OCH3), 56.60 (7-OCH3), 61.87 (1-
OCH3), 62.09 (8-OCH3), 106.39 (C-3), 113.56 (C-6), 119.50 (C-5),
109.39 (C-2), 121.61 (C-4a), 125.02 (C-8a), 142.28 (C-8), 145.37 (C-1),
151.57 (C-7), 152.17 (C-4). An edHSQC spectrum (“short-range C,H
COSY”; 100.61/400.13 MHz, CDCl3) allowed the assignment of all
nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 55.96 (4-
OCH3) ↔ δ = 3.94 (4-OMe), δ = 56.60 (7-OCH3) ↔ δ = 3.99 (7-OMe), δ =
61.87 (1-OCH3) ↔ δ = 3.88 (1-OMe), δ = 62.09 (8-OCH3) ↔ δ = 3.89 (8-
OMe), δ = 106.39 (C-3) ↔ δ = 6.78 (3-H), δ = 113.56 (C-6) ↔ δ = 7.26
(6-H), δ = 119.50 (C-5) ↔ δ = 8.00 (5-H). An HMBC spectrum (“long-
range C,H COSY”; 100.61/400.13 MHz, CDCl3) allowed the assignment
of all quaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-
peaks linked via 2 or 4 covalent bonds]: δ = 109.39 (C-2) ↔ δ = 6.78 (3-
H), δ = 121.61 (C-4a) ↔ δ = 6.78 (3-H), δ = 121.61 (C-4a) ↔ δ = 7.26 (6-
H), δ = 125.02 (C-8a) ↔ δ = 8.00 (5-H), δ = 142.28 (C-8) ↔ δ = 3.89 (8-
OMe), δ = 142.28 (C-8) ↔ δ = 7.26 (6-H), δ = 142.28 (C-8) ↔ δ = 8.00
(5-H), δ = 145.37 (C-1) ↔ δ = 3.88 (1-OMe), δ = 145.37 (C-1) ↔ δ = 6.78
1,2,5,8-Tetramethoxynaphthalene (21)
19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
One-pot
procedure
from
2-bromo-3,4-dimethoxyphenyl
4-
0.98 g, 4.45 mmol,) and Bu4NBr (72 mg, 0.23mmol, 5.0 mol-%) were
suspended in freshly distilled THF (30 ml) under N2 atmosphere. At 0°C a
solution of KOH [85%, technical grade, 2.35g (≙2.00 g), 35.6 mmol,
8.0 equiv.] in degassed H2O (15 ml) was added dropwise. The
methylation reaction was started by the dropwise addition of Me2SO4
(4.22 ml, 5.61 g, 44.5 mmol, 10 equiv.) at 0°C. The ice-bath was
removed and the reaction mixture was stirred for 14 h at room
temperature. The reaction was quenched with conc. ammonium
hydroxide solution (5 ml) and stirred for 1.5 h at room temperature.
CH2Cl2 (20 ml) was added, the organic phase was separated and the
aqueous phase was extracted with CH2Cl2 (3 × 20 ml). The combined
organic extracts were washed with brine (20 ml) and dried over Na2SO4.
The solvent was removed in vacuo. Flash chromatography (d = 4 cm,
h = 12 cm, F = 50 mL; CH/EE 3:1) afforded the title compound [F4-7, Rf
(3:1) = 0.5, 1.06 g, 96%] as a pale-yellow solid.
methylbenzenesulfonate (29): 2-Bromo-3,4-dimethoxyphenyl 4-
methylbenzenesulfonate (29, 5.81 g, 15.0 mmol) and (furan-2-
yloxy)triisopropylsilane (27, 5.40 g, 22.5 mmol, 1.5 equiv.) were dissolved
in freshly distilled THF (40 ml).[50] At –78°C nBuLi (2.37
M in hexane,
6.33 ml, 15.0 mmol, 1.0 equiv.) was added dropwise and the solution
was stirred at this temperature for 5 min. Afterwards the cooling bath was
removed and by continuous stirring the reaction was allowed to warm to
room temperature for 45 min. The solution was cooled to 0°C and TBAF
(1
M in THF, 22.5 ml, 22.5 mmol, 1.5 equiv.) was added dropwise. The
ice-bath was removed and the reaction mixture was stirred at room
temperature for 15 min. Solid nBu4NBr (0.24 g, 0.75mmol, 5.0 mol-%)
was added, the mixture was cooled to 0°C and a solution of KOH [85%,
technical grade, 7.92 g, (≙6.73 g), 120 mmol, 8.0 equiv.] in degassed
H2O (20 ml) was added dropwise. The methylation reaction was started
by the dropwise addition of Me2SO4 (14.23 ml, 18.92 g, 150 mmol, 10
equiv.) at 0°C. The ice-bath was removed and the reaction mixture was
stirred for 17 h at room temperature. The reaction was quenched with
conc. ammonium hydroxide solution (12 ml) and stirred for 1.5 h at room
temperature. The organic phase was separated and the aqueous phase
was extracted with CH2Cl2 (3 × 50 ml). The combined organic extracts
were washed with brine (50 ml) and dried over Na2SO4. The solvent was
removed in vacuo. Flash chromatography [d = 5 cm, h = 12 cm, F = 100
ml; CH/EE 5:1 (F1-12), CH/EE 3:1 (F13-27)] afforded the title compound
(F14-21, Rf (5:1) = 0.15, Rf (3:1) = 0.5, 2.95 g, 79%) as a pale-yellow
solid.– 1H NMR (500.32 MHz, CDCl3): 3.89 (s, 3H, 1-OMe), 3.93 (s, 3H,
5-OMe), 3.94 (s, 3H, 8-OMe), 3.98 (s, 3H, 2-OMe), AB signal (δA = 6.57,
δB = 6.76, JAB = 8.4 Hz, A and B signal show no further splitting, 6-H and
7-H), 7.27 (d, 1H, J3,4 = 9.2 Hz, 3-H), 8.02 (d, 1H, J4,3 = 9.2 Hz, 4-H). 2-
OMe, 5-OMe and 8-OMe were distinguished from 1-OMe by the
occurrence of cross-peaks only for the former but not for the latter in the
following NOESY spectrum (500.32 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of cross-peaks [δ(1H)
↔ δ(1H)]: δ = 3.93 (5-OMe) ↔ δA = 6.57 (6-H), δ = 3.93 (5-OMe) ↔ δ =
8.02 (4-H), δ = 3.94 (8-OMe) ↔ δB = 6.76 (7-H), δ = 3.98 (2-OMe) ↔ δ =
7.28 (3-H). 13C NMR (125.82 MHz, CDCl3): δ = 55.74 (8-OCH3), 57.13 (2-
OCH3), 57.58 (5-OCH3), 61.86 (1-OCH3), 101.52 (C-6), 107.58 (C-7),
114.53 (C-3), 118.81 (C-4), 122.71 (C-8a), 123.56 (C-4a), 144.02 (C-1),
149.72 and 149.97 (C-5 and C-8), 150.94 (C-2). An edHSQC spectrum
(“short-range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the
assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
55.74 (8-OCH3) ↔ δ = 3.94 (8-OMe), δ = 57.13 (2-OCH3) ↔ δ = 3.98 (2-
OMe), δ = 57.58 (5-OCH3) ↔ δ = 3.93 (5-OMe), δ = 61.86 (1-OCH3) ↔ δ
= 3.89 (1-OMe), δ = 101.52 (C-6) ↔ δA = 6.57 (6-H), δ = 107.58 (C-7) ↔
δB = 6.76 (7-H), δ = 114.53 (C-3) ↔ δ = 7.27 (3-H), δ = 118.81 (C-4) ↔ δ
5,6-Dimethoxy-4-[(triisopropylsilyl)oxy]naphthalen-1-ol (22) and 7,8-
Dimethoxy-4-((triisopropylsilyl)oxy)naphthalen-1-ol (iso-22)
2-bromo-3,4-dimethoxyphenyl 4-methylbenzenesulfonate (29, 3.10 g,
8.0 mmol) and (furan-2-yloxy)triisopropylsilane (27, 2.89 g, 12.0 mmol,
1.5 equiv.) were dissolved in freshly distilled THF (16 ml).[50] At –78°C
nBuLi (2.60
M in hexane, 3.1 ml, 8.0 mmol, 1.0 equiv.) was added
dropwise and the solution was stirred at this temperature for 5 min.
Afterwards the cooling bath was removed and by continuous stirring the
reaction was allowed to warm to room temperature for 45 min. The
reaction was quenched with aqueous HCl (1 M, 12 ml) and stirred for
5 min at room temperature. CH2Cl2 (30 ml) was added and the organic
phase was separated. The aqueous phase was extracted with CH2Cl2 (3
× 50 ml). The combined organic extracts were washed with brine (30 ml)
and dried over Na2SO4. The solvent was removed in vacuo. Flash
chromatography [d = 5 cm, h = 15 cm, F = 100 ml; CH/EE 9:1] afforded
the minor isomer iso-22 [F6-8, 1.05 g of a 10:90 mixture with iPr3SiOH (≙
0.20 g, 7% of pure iso-22)] and in a second fraction the major isomer 22
(F9-17, 1.87 g, 62%) as a dark green oil.– Analysis of 22: 1H NMR
(400.13 MHz, CDCl3):
δ
=
1.12 {d, 18H, Jsilyl-CH,silyl-CH3 = 7.4 Hz, 4-
OSi[CH(CH3)2]3}, 1.39
{sept, 3H, Jsilyl-CH ,silyl-CH = 7.5 Hz, 4-
3
OSi[CH(CH3)2]3}, 3.85 (s, 3H, 5-OMe), 3.98 (s, 3H, 6-OMe), 4.95 (br. s,
1H, 1-OH), AB signal (δA = 6.50, δB = 6.64, JAB = 8.1 Hz, A and B signal
show no further splitting, 2-H and 3-H), 7.27 (d, 1H, J7,8 = 9.3 Hz, 7-H),
7.93 (d, 1H, J8,7 = 9.3 Hz, 8-H). 6-OMe was distinguished from 5-OMe by
the occurrence of a cross-peak only for the former but not for the latter in
the following NOESY spectrum (400.13 MHz, CDCl3) that allowed
additional assignments of 1H resonances by the occurrence of cross-
peaks [δ(1H) ↔ δ(1H)]: δ = 3.98 (6-OMe) ↔ δ = 7.27 (7-H), δ = 4.95 (1-
OH) ↔ δ = 7.93 (8-H), δB = 6.64 (3-H) ↔ δ = 4.95 (1-OH), δB = 6.64 (3-
H) ↔ δ = 1.12 {4-OSi[CH(CH3)2]3}, δB = 6.64 (3-H) ↔ δ = 1.39 {4-
=
8.02 (4-H). An HMBC spectrum (“long-range C,H COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 122.71 (C-8a) ↔ δB = 6.76 (7-H),, δ = 122.71 (C-8a)
↔ δ = 8.02 (4-H), δ = 123.56 (C-4a) ↔ δA = 6.57 (6-H), δ = 123.56 (C-
4a) ↔ δ = 7.27 (3-H), δ = 144.02 (C-1) ↔ δ = 3.89 (1-OMe), δ = 144.02
(C-1) ↔ δ = 6.76 (7-H), δ = 144.02 (C-1) ↔ δ = 7.27 (3-H), δ = 144.02
(C-1) ↔ δ = 8.02 (4-H), [δ = 149.72 and 149.97 (C-5 and C-8) ↔ δ = 3.93
and 3.94 (5-OMe and 8-OMe), δ = 149.72 and 149.97 (C-5 and C-8) ↔ δ
= 6.57 (6-H), δ = 149.72 and 149.97 (C-5 and C-8) ↔ δ = 6.76 (7-H) and
δ = 149.72 and 149.97 (C-5 and C-8) ↔ δ = 8.02 (4-H) could not be
assigned unambiguously.], δ = 150.94 (C-2) ↔ δ = 3.98 (2-OMe), δ =
150.94 (C-2) ↔ δ = 7.27 (3-H), δ = 150.94 (C-2) ↔ δ = 8.02 (4-H).
Melting point: 64°C. Elemental analysis: Calculated: C: 67.73%, H:
6.50%; found: C: 67.64%, H: 6.30%; deviation: C: 0.09%, H: 0.20%.
HRMS (pos. ESI): Calcd. for C14H17O4: [M+H]+ = 249.11214; found:
249.11230 (+0.68 ppm). IR (film): ν = 2935, 2835, 1620, 1600, 1465,
1450, 1425, 1410, 1360, 1275, 1260, 1080, 1050, 1010, 815, 805, 790,
730 cm-1.
OSi[CH(CH3)2]3}. 13C NMR (100.61 MHz, CDCl3):
δ = 13.55 {4-
OSi[CH(CH3)2]3}, 18.03 {4-OSi[CH(CH3)2]3}, 56.83 (6-OCH3), 62.11 (5-
OCH3), 106.33 (C-2), 113.96 (C-7), 114.07 (C-3), 118.55 (C-8), 122.74
(C-8a), 123.95 (C-4a), 144.36 (C-5), 145.37 (C-1), 145.77 (C-4), 150.31
(C-6).
An
edHSQC
spectrum
(“short-range
C,H
COSY”;
100.61/400.13 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 13.55 {4-OSi[CH(CH3)2]3} ↔ δ = 1.39
{4-OSi[CH(CH3)2]3}, δ = 18.03 {4-OSi[CH(CH3)2]3} ↔ δ = 1.17 {4-
OSi[CH(CH3)2]3}, δ = 56.83 (6-OCH3) ↔ δ = 3.98 (6-OMe), δ = 62.11 (5-
OCH3) ↔ δ = 3.85 (5-OMe), δ = 106.33 (C-2) ↔ δA = 6.50 (2-H), δ =
Preparation of 21 from 5,6-Dimethoxynaphthalene-1,4-diol (39): In a
100 ml round-bottomed flask 5,6-dimethoxynaphthalene-1,4-diol (39,
50
It is absolutely neccessary, that 2-bromo-3,4-dimethoxyphenyl 4-
methylbenzenesulfonate (29) is entirely dissolved at room temperature.
20
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
113.96 (C-7) ↔ δ = 7.27 (7-H), δ = 114.07 (C-3) ↔ δB = 6.64 (3-H), δ =
118.55 (C-8) ↔ δ = 7.93 (8-H). An HMBC spectrum (“long-range C,H
COSY”; 100.61/400.13 MHz, CDCl3) allowed the assignment of all
quaternary 13C atoms through their cross-peaks with the independently
assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via
2 or 4 covalent bonds]: δ = 122.74 (C-8a) ↔ δA = 6.50 (2-H), δ = 122.74
(C-8a) ↔ δ = 7.27 (7-H), δ = 123.95 (C-4a) ↔ δB = 6.64 (3-H), δ =
123.95 (C-4a) ↔ δ = 7.93 (8-H), δ = 144.36 (C-5) ↔ δ = 3.85 (5-OMe), δ
= 144.36 (C-5) ↔ δ = 7.27 (7-H), δ = 145.37 (C-1) ↔ δA = 6.50 (2-H),
145.37 (C-1) ↔ δB = 6.64 (3-H), δ = 145.37 (C-1) ↔ δ = 7.93 (8-H), δ =
145.77 (C-4) ↔ δA = 6.50 (2-H), δ = 145.77 (C-4) ↔ δB = 6.64 (3-H), δ =
150.31 (C-6) ↔ δ = 3.98 (6-OMe), δ = 150.31 (C-6) ↔ δ = 7.27 (7-H), δ =
150.31 (C-6) ↔ δ = 7.93 (8-H). Melting point: Oil. Elemental analysis:
Calculated: C: 66.98%, H: 8.57%; found: C: 67.02%, H: 8.13%; deviation:
(4- Si[CH(CH3)2]3), δ = 18.39 (4-OSi[CH(CH3)2]3)
OSi[CH(CH3)2]3), δ = 57.11 (6-OCH3) ↔ δ = 3.99 (6-OMe), δ = 62.16 (5-
OCH3) δ = 3.74 (5-OMe), δ = 111.38 (C-2) δ = 6.82 (2-H),
↔
δ = 1.03 (4-
↔
↔
δ = 114.33 (C-7) ↔ δ = 7.26 (7-H), δ = 118.70 (C-8) ↔ δ = 7.87 (8-H). An
HMBC spectrum (“long-range C,H COSY”; 100.61/400.13 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 110.96 (C-3) ↔
δ = 6.82 (2-H), δ = 121.75 (C-8a) ↔ δ = 6.82 (2-H), δ = 121.75 (C-8a) ↔
δ = 7.26 (7-H), δ = 124.99 (C-4a) ↔ δ = 7.87 (8-H), δ = 142.88 (C-4) ↔
δ = 6.82 (2-H), δ = 144.07 (C-5) ↔ δ = 3.74 (5-OMe), δ = 144.07 (C-5) ↔
δ = 7.26 (7-H), δ = 145.70 (C-1) ↔ δ = 6.82 (2-H), δ = 145.70 (C-1) ↔
δ = 7.87 (8-H), δ = 150.65 (C-6) ↔ δ = 3.99 (6-OMe), δ = 150.65 (C-6) ↔
δ = 7.26 (7-H), δ = 150.65 (C-6) ↔ δ = 7.87 (8-H). Melting point: 152-
154°C. Elemental analysis: Calculated: C: 55.38%, H: 6.86%; found: C:
55.00%, H: 6.43%; deviation: C: 0.38%, H: 0.43%. HRMS (neg. ESI):
Calcd. for C21H3179BrO4Si [M−H]− = 453.11022; found 453.11108 (+1.90
ppm), calcd. for C21H3181BrO4Si [M−H]− = 455.10818; found 455.10907
(+1.97 ppm). IR (film): ν = 2945, 2895, 2865, 1680, 1650, 1575, 1490,
1465, 1455, 1440, 1415, 1385, 1335, 1280, 1255, 1215, 1190 1170,
1140, 1115, 1050, 1015, 920, 885, 830, 750, 720, 680 cm-1. An analytical
sample of iso-23 was prepared as follows: iso-23 was purified again by
flash chromatography [d = 1.5 cm, h = 14 cm, F = 8 mL; PE/CH2Cl2 3:1
(F1-21), 1:1 (F22-44)], to obtain the product (F28-33, Rf (PE/CH2Cl2
3:1) = 0.20, 16.4 mg, 7%) as a light-brown oil. 1H-NMR (400.13 MHz,
C:
0.04%, H: 0.44%. HRMS (pos. APCI): Calcd. for C21H33O4Si:
[M+H]+ = 377.21426; found: 377.21436 (+0.25 ppm). IR (film): ν = 3430,
2945, 2890, 2845, 2345 1620, 1595, 1520, 1460, 1425, 1385, 1350,
1270, 1165, 1145, 1095, 1055, 1010, 930, 880, 840, 810, 790, 735, 700,
680 cm-1. iso-22 could not be freed from its byproduct iPr3SiOH and
therefore was not characterized.
3-Bromo-5,6-dimethoxy-4-(triisopropylsilyloxy)naphthalen-1-ol (23)
and 3-Bromo-7,8-dimethoxy-4-(triisopropylsilyloxy)naphthalen-1-ol
(iso-23)
CDCl3): δ = 1.12 (d, 18-H, J4-OSi[CH(C
OSi[CH(CH3)2]3), 1.49 (sept, 3H, J4-OSi[C
3 2 3 = 7.6 Hz, 4-
H
)
]
,4-OSi[C
H(CH
)
]
3
2 3
2 3 = 7.6 Hz, 4-
H
(CH
)
]
,4-OSi[CH(C
H
)
]
3
OSi[CH(CH3)2]3), 3.99 (s, 3H, 7-OMe), 4.06 3(s2,33H, 8-OMe), 6.93 (s, 1H,
2-H), 7.24 (d, 1H, J6,5 = 9.3 Hz, 6-H), 7.84 (d, 1H, J5,6 = 9.3 Hz, 5-H), 9.32
(s, 1H, 1-OH). 8-OMe was distinguished from 7-OMe by the occurrence
of a cross-peak only for the former but not for the latter in the following
NOESY spectrum (400.13 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of crosspeaks [δ(1H) ↔
δ(1H)]: δ = 7.23 (6-H) ↔ δ = 3.98 (7-OMe), δ = 7.84 (5-H) ↔ δ = 1.12 (4-
OSi[CH(CH3)2]3), δ = 7.84 (5-H) ↔ δ = 1.49 (4-OSi[CH(CH3)2]3), δ = 9.32
(1-OH) ↔ δ = 4.06 (8-OMe). 13C-NMR (100.61 MHz, CDCl3): δ = 14.49
(4-OSi[CH(CH3)2]3), 18.18 (4-OSi[CH(CH3)2]3), 56.73 (7-OCH3), 62.18 (8-
OCH3), 107.54 (C-3), 114.19 (C-2), 114.57 (C-6), 118.28 (C-8a), 120.45
(C-5), 125.52 (C-4a), 142.66 (C-4), 142.93(C-8), 147.50 (C-1), 147.81
(C-7). An edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13
MHz, CDCl3) allowed the assignment of all nonquaternary 13C atoms
through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 14.49 (4-OSi[CH(CH3)2]3) ↔ δ = 1.49
2-Bromo-3,4-dimethoxy-((1-methylphenylsulfonyl)oxy)benzene
194.9 mg, 0.510 mmol) and 3-bromo-2-(triisopropylsilyloxy)furan (28,
250.9 g, 0.786 mmol, 1.56 equiv.) were dissolved in THF (2 mL) and the
(29,
solution was cooled to −78°C. Then nBuLi (2.34
M in hexane, 0.21 mL,
0.49 mmol, 0.98 equiv.) was added dropwise and the reaction mixture
was allowed to warm to room temperature and stirred for 45 min.
Aqueous HCl (1M, 5 mL) was added, the mixture was stirred over a
period of 20 min and the organic phase was separated. The aqueous
phase was extracted with EE (4 × 10 mL), the combined organic extracts
were washed with brine (10 mL) and dried over Na2SO4. The solvent was
removed in vacuo and the residue was purified by flash chromatography
[d = 3 cm, h = 17 cm, F = 20 mL; CH/EE 95:5 (1-16), 9:1 (17-30), 5:1 (30-
40)], to obtain iso-23 [F7-11, Rf (9:1) = 0.30, 33.7 mg] as a 93:7 mixture
with triisopropylsilyl alcohol. This corresponds to 97 w-% of iso-23
(32.7 mg, 14%). Another fraction furnished 23 (F18-26, Rf (9:1) = 0.10,
108.8 mg, 48%) as a 94:6 mixture with debrominated product. An
analytical sample of 23 was prepared as follows: The obtained product
was completely dissolved in CH2Cl2 (7 mL) and heptane (3 mL) was
added. CH2Cl2 was removed under reduced pressure and the solution
was cooled to 0°C. The heptane phase was removed with a pipet and the
yellow oil (23) was dried in vacuo. 1H-NMR (400.13 MHz, CDCl3):
(4- Si[CH(CH3)2]3), δ = 18.18 (4-OSi[CH(CH3)2]3)
OSi[CH(CH3)2]3), δ = 56.73 (7-OCH3) ↔ δ = 3.99 (7-OMe), δ = 62.18 (8-
OCH3) δ = 4.06 (8-OMe), δ = 114.19 (C-2) δ = 6.93 (2-H),
↔
δ = 1.12 (4-
↔
↔
δ = 114.57 (C-6) ↔ δ = 7.24 (6-H), δ = 120.45 (C-5) ↔ δ = 7.84 (5-H). An
HMBC spectrum (“long-range C,H COSY”; 100.61/400.13 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]:δ = 107.54 (C-3) ↔
δ = 6.93 (2-H), δ = 107.54 (C-3) ↔ δ = 9.32 (1-OH), δ = 114.19 (C-2) ↔
δ = 9.32 (1-OH), δ = 118.28 (C-8a) ↔ δ = 6.93 (2-H), δ = 118.28 (C-8a)
↔ δ = 7.84 (5-H), δ = 118.28 (C-8a) ↔ δ = 9.32 (1-OH), δ = 125.52 (C-
4a) ↔ δ = 7.24 (6-H), δ = 142.66 (C-4) ↔ δ = 6.93 (2-H), δ = 142.66 (C-
4) ↔ δ = 7.84 (5-H), δ = 142.93(C-8) ↔ δ = 4.06 (8-OMe), δ = 142.93(C-
8) ↔ δ = 7.24 (6-H), δ = 147.50 (C-1) ↔ δ = 6.93 (2-H), δ = 147.50 (C-1)
↔ δ = 9.32 (1-OH), δ = 147.81 (C-7) ↔ δ = 3.99 (7-OMe), δ = 147.81 (C-
7) ↔ δ = 7.24 (6-H), δ = 147.81 (C-7) ↔ δ = 7.84 (5-H). Melting point:
Oil. HRMS (pos. ESI): Calcd. for C21H3179BrO4Si [M+H]+ = 455.12478;
δ = 1.03
(d,
18-H,
J4-OSi[CH(C
3 2 3 = 7.6 Hz,
4-
H
)
]
,4-OSi[CH(CH
) ]
3
2 3
OSi[CH(CH3)2]3), 1.56 (sept, 3H, J4-OSi[C
2 3 = 7.6 Hz, 4-
]
H(CH
)
]
,4-OSi[CH(C
H
)
3
OSi[CH(CH3)2]3), 3.74 (s, 3H, 5-OMe), 3.99 3(s2,33H, 6-OMe), 5.12 (s, 1H,
1-OH), 6.82 (s, 1H, 2-H), 7.26 (d, 1H, J7,8 = 9.2 Hz, 7-H), 7.87 (d, 1H,
J8,7 = 9.3 Hz, 8-H). 6-OMe was distinguished from 5-OMe by the
occurrence of a cross-peak only for the former but not for the latter in the
following NOESY spectrum (400.13 MHz, CDCl3) [δ(1H) ↔ δ(1H)]:
δ = 3.99 (6-OMe) ↔ δ = 7.26 (7-H). 13C-NMR (100.61 MHz, CDCl3):
δ = 14.33 (4-OSi[CH(CH3)2]3), 18.39 (4-OSi[CH(CH3)2]3), 57.11 (6-OCH3),
62.16 (5-OCH3), 110.96 (C-3), 111.38 (C-2), 114.33 (C-7), 118.70 (C-8),
121.75 (C-8a), 124.99 (C-4a), 142.88 (C-4), 144.07 (C-5), 145.70 (C-1),
150.65 (C-6). An edHSQC spectrum (“short-range C,H COSY”;
100.61/400.13 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 14.33 (4-OSi[CH(CH3)2]3) ↔ δ = 1.56
found 455.12476 (−0.04 ppm), calcd. for C21H3181BrO4Si [M+H]+
=
457.12273; found 457.12268 (−0.10 ppm). IR (film): ν = 2945, 2895,
2865, 1665, 1610, 1575, 1505, 1485, 1465, 1435, 1415, 1390, 1350,
1270, 1220, 1200, 1165, 1145, 1110, 1055, 1015, 945, 920, 885, 845,
825, 810, 785, 765, 680 cm-1.
21
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
[(3-bromofuran-2-yl)oxy]triisopropylsilane (28)
CH3) ↔ δ = 2.44 (4’- CH3), δ = 56.36 (4-OCH3) ↔ δ = 3.86 (4-OMe), δ =
60.68 (3-OCH3) ↔ δ = 3.79 (3-OMe), δ = 110.94 (C-5) ↔ δA = 6.82 (5-H),
δ = 118.85 (C-6) ↔ δB = 7.09 (6-H), δ = 128.85 (C-2’ and C-6’) ↔ δ =
7.76-7.79 (2’-H and 6’-H), δ = 129.78 (C-3’ and C-5’) ↔ δ = 7.29-7.32 (3’-
H
and 5’-H). An HMBC spectrum (“long-range C,H COSY”;
100.61/400.13 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 113.41 (C-2) ↔ δA = 6.82 (5-H), δ = 113.41 (C-2) ↔
δB = 7.09 (6-H), δ = 132.88 (C-1’) ↔ δ = 7.29-7.32 (3’-H and 5’-H), δ =
140.92 (C-1) ↔ δA = 6.82 (5-H), δ = 140.92 (C-1) ↔ δB = 7.09 (6-H), δ =
145.64 (C-4’) ↔ δ = 2.44 (4’- CH3), δ = 145.64 (C-4’) ↔ δ = 7.76-7.79 (2’-
H and 6’-H), δ = 147.55 (C-3) ↔ δ = 3.79 (3-OMe), δ = 147.55 (C-3) ↔
δA = 6.82 (5-H), δ = 152.42 (C-4) ↔ δA = 6.82 (5-H), δ = 152.42 (C-4) ↔
δB = 7.09 (6-H), δ = 152.42 (C-4) ↔ δ = 3.86 (4-OMe). Melting point:
99-100°C. Elemental analysis: Calculated: C: 46.52%, H: 3.90%, S:
8.28%; found: C: 46.41%, H: 3.88%, S: 8.28%; deviation: C: 0.11%, H:
0.02%, S: 0.00%. IR (film): ν = 3005, 2970, 2940, 2840, 1595, 1585,
1480, 1450, 1435, 1405, 1375, 1300, 1270, 1240, 1210, 1190, 1175,
1140, 1120, 1095, 1035, 945, 835, 815, 785, 755, 715, 685, 665 cm-1.
According to a general procedure for the preparation of silyltriflates
(ref.[35]) triisopropylsilane (44.0 mL, 34.0 g, 215 mmol) was suspended in
a 100 mL Schlenk flask and trifluoromethanesulfonic acid (21.0 mL, 35.6
g, 237 mmol, 1.10 equiv.) was added dropwise at 0°C. The solution was
stirred for 1 h at 0°C, allowed to warm to room temperature and stirred
for further 17 h. The crude product was used in the following step without
further purification. 3-Bromofuran-2(5H)-one (38, 29.2 g, 179 mmol) was
dissolved in CH2Cl2 (200 mL). iPr3SiOTf (57.8 mL, 65.8 g, 215 mmol,
1.20 equiv.) was transferred via cannula into this solution at 0°C and
NEt3 (34.5 mL, 25.2 g, 249 mmol, 1.40 equiv.) was added at 0°C to
initiate the reaction. The ice-bath was removed and the solution was
stirred for 2.5 h at room temperature. Afterwards the mixture was
quenched with saturated aqueous NaHCO3 (200 mL). The organic phase
was separated and the aqueous phase was extracted with
dichloromethane (3 × 100 mL). The combined organic extracts were
washed with brine (100 mL) and dried over Na2SO4. The solvent was
removed in vacuo and the residue was purified by flash chromatography
[d = 8.5 cm, h = 12 cm, F = 100 mL; PE/CH2Cl2 90:10 containing 1%
NEt3 (F1-20)], to obtain the pure product [F8-15, Rf (PE/CH2Cl2 90:10,
containing 1% NEt3) = 0.8, 47.16 g, 79%; ref.[37]: 90%, Lit.34:54%) as a
yellow liquid.− 1H-NMR (300.13 MHz, CDCl3, product contained 5 w-%
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (31)
CH2Cl2): δ = 1.11 {d, 18H, Jsilyl-CH
= 7.0 Hz, 2-OSi[CH(CH3)2]3},
,silyl-CH
3
1.20-1.38 {m, 3H, 2-OSi[CH(CH3)2]3}, 6.27 (d, 1H, J5,4 = 2.4 Hz, 5-H),
6.79 (d, 1H, J4,5 = 2.4 Hz, 4-H).
Isovanillin (30) (50.0 g, 329 mmol), anhydrous sodium acetate (54.2 g,
658 mmol, 2.0 equiv.) and iron powder (1.47 g, 26.3 mmol, 8.0 mol%)
were suspended in glacial acetic acid (300 mL). At room temperature a
solution of bromine (16.8 mL, 52.5 g, 329 mmol, 1.0 equiv.) in glacial
acetic acid (70 mL) was added dropwise over a period of 20 min. The
reaction mixture was stirred at room temperature for 5 h (KPG stirrer)
and afterwards poured into ice-cold water (2 L). The precipitate was
filtered and washed with ice-cold water (3 × 200 mL) and dried in vacuo
at 60°C (drying pistol, KOH) for 6 h and at room temperature for 3 d
(p < 1 mbar). The product 2-bromo-3-hydroxy-4-methoxybenzaldehyde
(31) (55.50 g, 73%; Lit.[31]: 70%) was received as a white-brown solid.–
1H NMR (300.07 MHz, DMSO-d6): δ = 3.91 (s, 3H, 4-OMe), 7.12 (d, 1H,
J5,6 = 6.9 Hz, 5-H), 7.39 (d, 1H, J6,5 = 7.0 Hz, 6-H), 9.87 (br. s, 1H, 3-OH),
10.09 (s, 1H, 1-CHO).
2-Bromo-3,4-dimethoxyphenyl 4-Methylbenzenesulfonate (29)
2-Bromo-3,4-dimethoxyphenol (33,13.99 g, 60.01 mmol) and TsCl
(17.20 g, 90.01 mmol, 1.50 equiv.) were dissolved in CH2Cl2 (100 mL).
The solution was cooled to 0°C and NEt3 (12.5 mL, 9.13 g, 90.0 mmol,
1.50 equiv.) was added successively. After stirring for 4 d at room
temperature, the reaction mixture was diluted with CH2Cl2 (200 mL),
washed with saturated aqueous NaHCO3 (2 × 100 mL), H2O (100 mL)
and brine (100 mL) and dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified by flash chromatography [d = 8.5 cm,
h = 10 cm, F = 100 mL; CH/EE 5:1 (F1-11), 3:1 (F12-44), 1:1 (F45-55),
1:3 (F55-75)] to obtain the title compound (F21-64, Rf, 3:1 = 0.27, 22.58 g)
as a 96:4 mixture with TsCl. A second flash chromatography [d = 8.5 cm,
h = 12 cm, F = 100 mL; CH:EE 5:1 (F1-16), 3:1 (F17-36), 1:1 (F37-56)]
furnished the product (F19-45, Rf, 3:1 = 0.30, 19.88 g, 85%) as a white
solid.– 1H-NMR (400.13 MHz, CDCl3): δ = 2.44 (s, 3H, 4`-CH3), 3.79 (s,
3H, 3-OMe), 3.86 (s, 3H, 4-OMe), AB signal [δA = 6.82 and δB = 7.09,
JAB = 9.1 Hz, A and B signal show no further splitting, 5-H and 6-H], 7.29-
7.32 (m, 2H, 3`-H and 5`-H), 7.76-7.79 (m, 2H, 2`-H and 6`-H) ppm. 4-
OMe was distinguished from 3-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.86
(4-OMe) ↔ δA = 6.82 (5-H), δ = 7.29-7.32 (3`-H and 5`-H) ↔ δ = 2.44 (4’-
CH3). 13C NMR (100.61 MHz, CDCl3): δ = 21.81 (4’-CH3), 56.36 (4-
OCH3), 60.68 (3-OCH3), 110.94 (C-5), 118.85 (C-6), 128.85 (C-2’ and C-
6’), 129.78 (C-3’ and C-5’), 113.41 (C-2), 132.88 (C-1’), 140.92 (C-1),
145.64 (C-1’), 147.55 (C-3), 152.42 (C-4). An edHSQC spectrum (“short-
range C,H COSY”; 100.61/400.13 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 21.81 (4’-
2-Bromo-3,4-dimethoxybenzaldehyde (32)
2-Bromoisovanillin (31, 16.00 g, 69.25 mmol) and KOH (85w-%, 7.31 g,
111 mmol, 1.60 equiv.) were dissolved in H2O (100 mL). After heating the
mixture to 60°C, dimethyl sulfate (10.5 mL, 14.0 g, 111 mmol,
1.60 equiv.) was added dropwise over a period of 30 min and the
reaction mixture was stirred at 60°C for 30 min (KPG-stirrer). After
cooling to room temperature, the suspension was filtered (Büchner
funnel) and the precipitate was subsequently washed with aqueous
NaOH (1 M, 2×50 mL) and H2O (2 × 50 mL). The solid was dissolved in
CH2Cl2 (300 mL), washed with brine (100 mL) and dried over Na2SO4.
The solvent was removed in vacuo and the title compound was received
as light-brown solid (12.51 g, 74%; (Lit.[31]: 96%) and used in the
following step without further purification.– 1H-NMR (300.13 MHz,
CDCl3): δ = 3.90 (s, 3H, 3-OMe*), 3.97 (s, 3H, 4-OMe*), 6.97 (d, 1H,
J6,5 = 8.7 Hz, 6-H), 7.75 (d, 1H, J5,6 = 8.7 Hz, 5-H), 10.27 (s, 1H, 1-CHO)
ppm. *Assignment interchangeable.
22
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
2-Bromo-3,4-dimethoxyphenol (33)
steps. For initiation of the reaction: 117 mg, 0.71 mmol, 0.20 mol%. After
50 min (102 mg, 0.62 mmol, 0.17 mol-%) and after 1h 45 min (131 mg,
0.80 mmol, 0.23 mol%). The reaction mixture was refluxed for 3.5 h. After
cooling to room temperature, the mixture was stored in a refrigerator
overnight. The resulting precipitate was filtered and bromine (22.0 mL,
68.6 g, 428 mmol, 1.23 equiv.) was added dropwise to the filtrate. The
solution was stirred at 40°C for 5 hours and kept at room temperature
overnight. Afterwards the reaction mixture was carefully quenched by
slow addition of saturated aqueous NaHSO3 (100 mL). A violent reaction
was observed. The organic phase was separated dried over NaSO4 and
kept at room temperature overnight. The crystallized product was filtered
off and dried in vacuo (batch 1: 4.28 g). The solvent of the filtrate was
evaporated in vacuo to furnish a yellow-brown oil (batch 2: 42.58 g).
Combined yield: 46.86 g, 41% (ref.[36]: 35%) over the two steps. The
product was used in the following step without further purification.− 1H-
NMR (300.13 MHz, CDCl3; raw material, additional resonances at
δ = 1.91, 4.40 ppm): δ = AB signal [δA = 3.93 and δB = 4.15,
JAB = 11.9 Hz, additionally splitted by JA,3 = 2.7 Hz and JB,3 = 3.7 Hz, 4-
H2], 4.60 (ddd, J3,2 = 10.5 Hz, J3,B = 3.7 Hz, J3,A = 2.8 Hz, 3-H), 4.67 (d,
J2,3 = 10.5 Hz, 2-H), 11.37 (br. s., CO2H).
2-Bromo-3,4-dimethoxybenzaldehyde (32, 12.46 g, 50.84 mmol) and
mCPBA [77%, 17.55g (≙ 13.15 g), 76.26 mmol, 1.5 equiv.] were
dissolved in CH2Cl2 (250 mL) and the mixture was refluxed for 20 h. After
cooling to room temperature saturated aqueous Na2SO3 solution
(100 mL) was added and the mixture was stirred vigorously for 10 min.
The aqueous phase was separated and the organic phase was
subsequently washed with saturated aqueous NaHCO3 solution
(3×100 mL) and brine (100 mL) and dried over Na2SO4. The solvent was
removed in vacuo and the oily residue was taken up in aqueous KOH
(10% in H2O, 120 mL, 4.0 equiv., degassed with N2). After vigorous
stirring at room temperature for 3 h, the reaction mixture was acidified
with conc. HCl (25 mL) to pH 1. CH2Cl2 (300 mL) was added and the
solution was vigorously stirred for 5 min. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2 (2 ×
100 mL). The combined organic extracts were washed with brine
(100 mL) and dried over Na2SO4. The solvent was removed in vacuo.
The title compound (10.89 g, 92%) was obtained as a colorless solid.–
1H-NMR (400.13 MHz, CDCl3): δ = 3.83 (s, 3H, 4-OMe), 3.88 (s, 3H, 3-
OMe), 5.22 (s, 1H, 1-OH), AB signal (δA = 6.75 and δB = 6.82,
JAB = 9.0 Hz, A and B signal show no further splitting, 6-H and 5-H). 4-
OMe was distinguished from 3-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.83
(4-OMe) ↔ δB = 6.82 (5-H). 13C-NMR (100.63 MHz, CDCl3): δ = 57.02 (4-
OMe), 60.75 (3-OMe), 106.82 (C-2), 110.04 (C-6), 113.40 (C-5), 146.97,
147.32 and 147.38 (C-1, C-3 and C-4). An edHSQC spectrum (“short-
range C,H COSY”; 100.63/400.13 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 57.11 (4-
OCH3) ↔ δ = 3.84 (4-OMe), δ = 60.75 (3-OCH3) ↔ δ = 3.88 (3-OMe), δ =
110.04 (C-6) ↔ δA = 6.75 (6-H), δ = 113.40 (C-5) ↔ δB = 6.82 (5-H). An
HMBC spectrum (“long-range C,H COSY”; 100.63/400.13 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 106.82 (C-2) ↔ δ
= 5.22 (1-OH), δ = 106.82 (C-2) ↔ δA = 6.75 (6-H), δ = 106.82 (C-2) ↔
δB = 6.82 (5-H). δ = 146.97, 147.32 and 147.38 (C-1, C-3 and C-4) could
not be assigned unambiguously. Melting point: 98-99°C (ref.[51]: 103-
104°C, ref.[52]:113-115°C). Elemental analysis: Calculated: C: 41.23%,
H: 3.89%; found: C: 41.11%, H: 3.80%; deviation: C: 0.12%, H: 0.09%.
HRMS (neg. ESI): Calcd. for C8H979BrO3 [M−H]− = 230.96623; found
230.96631 (+0.34 ppm), calcd. for C8H981BrO3 [M−H]− = 232.96418;
found 232.96426 (+0.34 ppm). IR (film): ν = 3005, 2975, 2945, 2925,
2850, 2830, 1495, 1460, 1425, 1320, 1305, 1270, 1230, 1170, 1140,
1035, 950, 820, 795, 750, 730 cm-1.
3-Bromofuran-2-one (38)
rac-2,3,4-Tribromobutyric acid (rac-37) (46.86 g, 144.3 mmol) was
suspended in H2O (150ꢀmL) and heated to reflux under vigourous stirring
for 4h 20 min. The aqueous phase was adjusted to pH 7 with an aqueous
solution of Na2CO3 (2 M, 80 mL). The mixture was extracted with TBME
(3 × 180 mL), washed with brine (140 mL) and dried over Na2SO4. The
solvent was removed in vacuo and the title compound (10.00 g, 43%;
ref.[36]: 31%) received as light brown solid.− 1H-NMR (300.13 MHz,
CDCl3): δ = 4.85 (d, 2H, J5,4 = 2.0 Hz, 5-H2), 7.61 (t, 1H, J4,5 = 1.9 Hz, 4-
H) ppm.
5,6-Dimethoxynaphthalene-1,4-diol (39)
One-pot
procedure
from
2-bromo-3,4-dimethoxyphenyl
4-
methylbenzenesulfonate (29)]: 2-Bromo-3,4-dimethoxyphenyl 4-
methylbenzenesulfonate (29, 3.87 g, 10.0 mmol) and (furan-2-
yloxy)triisopropylsilane (27, 3.60 g, 15.0 mmol, 1.5 equiv.) were dissolved
in freshly distilled THF (20 mL).[50] At –78°C nBuLi (2.56
M in hexane,
3.91 mL, 10.0 mmol, 1.0 equiv.) was added dropwise and the solution
was stirred at this temperature for 5 min. Afterwards the cooling bath was
removed and by continuous stirring the reaction was allowed to warm to
room temperature for 45 min. The solution was cooled to 0°C and TBAF
rac-2,3,4-Tribromobutyric Acid (rac-37)
(1
M in THF, 15 mL, 15 mmol, 1.5 equiv.) was added dropwise. The ice-
bath was removed and the reaction mixture was stirred at room
temperature for 8 min. The reaction was quenched with aqueous HCl
(1 M, 25 mL) and stirred for 5 min at room temperature. CH2Cl2 (25 mL)
was added and the organic phase was separated. The aqueous phase
was extracted with CH2Cl2 (3 × 30 mL). The combined organic extracts
were washed with brine (25 mL) and dried over Na2SO4. The solvent was
removed in vacuo. Flash chromatography [d = 5 cm, h = 12 cm, F = 100
mL; CH/EE 3:1 (F1-20), CH/EE 1:1 (F21-45)] afforded the title compound
(F10-40, 1.81 g, 82%) as a yellow-orange solid.– 1H NMR (500.32 MHz,
CDCl3): δ = 3.93 (s, 3H, 5-OMe), 3.94 (s, 3H, 6-OMe), 5.09 (br. s, 1H, 1-
OH), AB signal (δA = 6.60, δB = 6.68, JAB = 8.1 Hz, A and B signal show
no further splitting, 3-H and 2-H), 7.25 (d, 1H, J7,8 = 9.3 Hz, 7-H), 7.94 (d,
1H, J8,7 = 9.3 Hz, 8-H), 9.23 (s, 1H, 4-OH). A NOESY spectrum (500.32
Crotonic acid (30.02 g, 348.7 mmol) and NBS (62.16 g, 349.2 mmol,
1.00 equiv.) were suspended in CCl4 (240 mL). The solution was heated
to reflux and AIBN (350 mg, 2.13 mmol, 0.6 mol%) was added in three
51
T. Katoh, M. Nakatani, S. Shikita, R. Sampe, A. Ishiwata, O. Ohmori, M.
Nakamura, S. Terashima, Org. Lett. 2001, 3, 2701-2704.
52 H. A. Anderson, R. H. Thomson, J. Chem. Soc., C 1967, 2152-2155.
23
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3) allowed additional assignments of 1H resonances by the
occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δ = 3.99 (6-OMe) ↔ δ = 7.25
(7-H), δ = 4.07 (5-OMe) ↔ δ = 9.23 (4-OH). 13C NMR (125.82 MHz,
CDCl3): δ = 56.87 (6-OCH3), 62.12 (5-OCH3), 107.82 (C-3), 109.48 (C-2),
114.31 (C-7), 119.67 (C-8), 118.87 (C-4a), 121.88 (C-8a), 142.80 (C-5),
144.15 (C-1), 147.05 (C-4), 148.06 (C-6). An edHSQC spectrum (“short-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 56.87 (6-
OCH3) ↔ δ = 3.99 (6-OMe), δ = 62.12 (5-OCH3) ↔ δ = 4.07 (5-OMe), δ =
107.82 (C-3) ↔ δA = 6.60 (3-H), δ = 109.48 (C-2) ↔ δB = 6.67 (2-H), δ =
114.31 (C-7) ↔ δ = 7.25 (7-H), δ = 119.67 (C-8) ↔ δ = 7.94 (8-H). An
HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 118.87 (C-4a) ↔
δB = 6.67 (2-H), δ = 118.87 (C-4a) ↔ δ = 7.94 (8-H), δ = 118.87 (C-4a)
↔ δ = 9.23 (4-OH), δ = 121.88 (C-8a) ↔ δA = 6.60 (3-H),, δ = 121.88 (C-
8a) ↔ δ = 7.25 (7-H), δ = 142.80 (C-5) ↔ δ = 4.07 (5-OMe), δ = 142.80
(C-5) ↔ δ = 7.25 (7-H), δ = 142.80 (C-5) ↔ δ = 7.94 (8-H), δ = 144.15
(C-1) ↔ δA = 6.60 (3-H), δ = 144.15 (C-1) ↔ δB = 6.67 (2-H), δ = 147.05
(C-4) ↔ δA = 6.60 (3-H), δ = 147.05 (C-4) ↔ δB = 6.67 (2-H), δ = 147.05
(C-4) ↔ δ = 9.23 (4-OH), δ = 148.06 (C-6) ↔ δ = 3.99 (6-OMe), δ =
148.06 (C-6) ↔ δ = 7.25 (7-H), δ = 148.06 (C-6) ↔ δ = 7.94 (8-H).
Melting point: 119°C. Elemental analysis: Calculated: C: 65.45%, H:
5.49%; found: C: 65.43%, H: 5.45%; deviation: C: 0.02%, H: 0.04%.
HRMS (pos. ESI, 70 eV, file: nebrb48s_hr2): Calcd. for C12H10O4Na:
[M+Na]+ = 241.04713; found: 241.04720 (+0.27 ppm). IR (film): ν =
3320, 3010, 2935, 2830, 1635, 1610, 1590, 1525, 1465, 1435, 1405,
1370, 1355, 1315, 1270, 1230, 1205, 1175, 1140, 1090, 1035, 995, 870,
805, 780, 750, 690, 665 cm-1.
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-phenyl-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (43b)
Following the General Procedure B the title compound was prepared
from β-hydroxy-γ-lactone 15 (52.3 mg, 0.15 mmol), benzaldehyde
(45.9 µL, 47.8 mg, 0.45 mmol, 3.0 equiv.) and BF3·OEt2 (76.0 µL,
85.2 mg, 0.60 mmol, 4.0 equiv.). Purification by flash chromatography
[d = 1.5 cm, h = 12 cm, F = 8 ml; CH/EE 3:1 (F1-10), CH/EE 2:1 (F11-
26)] afforded the title compound (F10-18, Rf (3:1) = 0.1, Rf (2:1) = 0.4,
58.1 mg, 89%, ds = 100:0) as a colorless oil.− Note: The optical antipode
ent-43b was synthesized analogously from ent-15 in 67% yield
(ds = 100:0).− 1H NMR (400.13 MHz, CDCl3):
δ = AB signal (δA = 2.66, δB
= 2.83, JAB = 17.7 Hz, A signal shows no further splitting, B signal further
split by JB,3a = 5.1 Hz, 3-HA and 3-HB), 3.52 (s, 3H, 6-OMe), 3.81 (s, 3H,
7-OMe, exclusion principle), 4.03 (s, 3H, 8-OMe), 4.12 (s, 3H, 11-OMe),
4.31 (dd, 1H, J3 = 5.1 Hz, J3a,11b = 2.9 Hz, 3a-H), 5.57 (d, 1H, J11b,3a
=
a,B
2.9 Hz, 11b-H), 6.41 (s, 1H, 5-H), 7.10-7.15 (m, 2H, 2’-H and 6’-H), 7.26-
7.31 (m, 3H, 3’-H, 4’-H and 5’-H), 7.39 (d, 1H, J9,10 = 9.3 Hz, 9-H), 7.98
(d, 1H, J10,9
= 9.3 Hz, 10-H). 6-OMe, 8-OMe and 11-OMe were
distinguished from 7-OMe by the occurrence of cross-peaks only for the
former but not for the latter in the following NOESY spectrum
(400.13 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δB = 2.83
(3-HB) ↔ δ = 5.57 (11b-H this cross-peak proves that 3-HB and 11b-H are
oriented cis relative to one another), δ = 3.52 (6-OMe) ↔ δ = 6.41 (5-H),
δ = 4.03 (8-OMe) ↔ δ = 7.39 (9-H), δ = 4.12 (11-OMe) ↔ δ = 5.57 (11b-
H), δ = 4.12 (11-OMe) ↔ δ = 7.98 (10-H), δ = 7.10-7.15 (2’-H and 6’-H)
↔ δ = 4.31 (3a-H, this cross-peak proves that the phenyl ring and 3a-H
are oriented cis relative to one another), δ = 7.10-7.15 (2’-H and 6’-H) ↔
δ = 6.41 (5-H). 13C NMR (100.61 MHz, CDCl3): δ = 37.55 (C-3), 56.82 (8-
OCH3), 62.25 (7-OCH3), 62.40 (6-OCH3), 64.43 (11-OCH3), 66.83 (C-3a),
72.47 (C-11b), 73.26 (C-5), 114.88 (C-9), 116.91 and 125.56 (C-5a and
C-11a could not be assigned unambiguously), 120.08 (C-10), 125.06 and
125.26 (C-6a and C-10a could not be assigned unambiguously), 128.39
(C-4’), 128.45 (C-3’ and C-5’), 128.89 (C-2’ and C-6’), 139.64 (C-1’),
143.12 (C-7), 147.13 (C-6), 151.48 (C-8), 153.65 (C-11), 175.28 (C-2).
An edHSQC spectrum (“short-range C,H COSY”; 100.61/400.13 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 37.55 (C-3) ↔ [δA = 2.66 (3-HA) and δB = 2.83 (3-HB)], δ =
56.82 (8-OCH3) ↔ δ = 4.03 (8-OMe), δ = 62.25 (7-OCH3) ↔ δ = 3.81 (7-
OMe), δ = 62.40 (6-OCH3) ↔ δ = 3.52 (6-OMe), δ = 64.43 (11-OCH3) ↔
δ = 4.12 (11-OMe), δ = 66.83 (C-3a) ↔ δ = 4.31 (3a-H), δ = 72.47 (C-
11b) ↔ δ = 5.57 (11b-H), δ = 73.26 (C-5) ↔ δ = 6.41 (5-H), δ = 114.88
(C-9) ↔ δ = 7.39 (9-H), δ = 120.08 (C-10) ↔ δ = 7.98 (10-H), δ = 128.39
(C-4’) ↔ δ = 7.26-7.31 (3’-H, 4’-H and 5’-H), δ = 128.45 (C-3’ and C-5’)
↔ δ = 7.26-7.31 (3’-H, 4’-H and 5’-H), δ = 128.89 (C-2’ and C-6’) ↔ δ =
7.10-7.15 (2’-H and 6’-H). An HMBC spectrum (“long-range C,H COSY”;
Alternative Preparation from 22 or iso-22: 5,6-dimethoxy-4-
((triisopropylsilyl)oxy)naphthalen-1-ol (22, 1.41 g, 3.74 mmol) was
suspended in freshly distilled THF (15 ml) and TBAF (1 M in THF, 3.8 ml,
3.8 mmol, 1.0 equiv.) was added dropwise at room temperature. The
reaction mixture was stirred for 15 min at room temperature. Afterwards
the reaction was quenched with HCl (1 M, 10 ml) and the organic phase
was separated. The aqueous phase was extracted with CH2Cl2 (3 ×
30 ml). The combined organic extracts were washed with aqueous CaCl2
(10%, 30 ml) and dried over Na2SO4. The solvent was removed in vacuo.
Flash chromatography [d = 4 cm, h = 12 cm, F = 50 ml; CH/EE 3:1 (F1-
11), CH/EE 1:1 (F12-25)] afforded the title compound (F5-18, 0.74 g,
90%) as a yellow-orange solid. Note: In an analogous procedure the
isomer 7,8-dimethoxy-4-((triisopropylsilyl)oxy)naphthalen-1-ol [iso-22, as
a 10:90 mixture with iPr3SiOH, 1.04 g (≙0.20 g, 0.53 mmol of pure iso-
22)] was desilylated to furnish the title compound (0.10 g, 86%) as a
yellow-orange solid.
General Procedure B: Representative oxa-Pictet Spengler
Cyclization of β-Hydroxy-γ-lactone 15 and Benzaldehyde to
Dihydropyran 43b.
(4S,5S)-4-Hydroxy-5-(1,4,5,6-tetramethoxynaphthalen-2-yl)dihydrofuran-
2(3H)-one (15, 52.3 mg, 0.15 mmol) was suspended in CH2Cl2 (1.5 ml).
At 0°C benzaldehyde (45.9 µl, 47.8 mg, 0.45 mmol, 3.0 equiv.) was
added and the reaction was started by the addition of BF3·OEt2 (76.0 µl,
85.2 mg, 0.60 mmol, 4.0 equiv.). Afterwards the ice-bath was removed.
The reaction mixture was allowed to warm to room temperature and
stirred for 30 min. Afterwards the reaction mixture was quenched by the
addition of aqueous saturated NaHCO3 (2 ml) and stirred for 5 min. The
organic phase was separated and the aqueous phase was extracted with
CH2Cl2 (3× 8ml). The combined organic extracts were washed with brine
(8 ml) and dried over Na2SO4. The solvent was removed in vacuo. Flash
chromatography [d = 1.5 cm, h = 12 cm, F = 8 ml; CH/EE 3:1 (F1-10),
CH/EE 2:1 (F11-26)] afforded 43b (F10-18, Rf (3:1) = 0.1, Rf (2:1) = 0.4,
58.1 mg, 89%, ds = 100:0) as a colorless oil.
100.61/400.13 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 116.91 and 125.56 (C-5a and C-11a) ↔ δ = 5.56
(11b-H), δ = 116.91 and 125.56 (C-5a and C-11a) ↔ δ = 6.41 (5-H), δ =
125.06 and 125.26 (C-6a and C-10a) ↔ δ = 7.36 and 7.98 (9-H and 10-
H), δ = 139.64 (C-1’) ↔ δ = 6.41 (5-H), δ = 139.64 (C-1’) ↔ δ = 7.26-7.31
(3’-H and 5’H), δ = 143.12 (C-7) ↔ δ = 3.81 (7-OMe), δ = 143.12 (C-7) ↔
δ = 7.39 (9-H), δ = 143.12 (C-7) ↔ δ = 7.98 (10-H), δ = 147.13 (C-6) ↔ δ
= 3.52 (6-OMe), δ = 147.13 (C-6) ↔ δ = 6.41 (5-H), δ = 151.48 (C-8) ↔ δ
= 4.03 (8-OMe), δ = 151.48 (C-8) ↔ δ = 7.39 (9-H), δ = 151.48 (C-8) ↔ δ
= 7.98 (10-H), δ = 153.65 (C-11) ↔ δ = 4.12 (11-OMe), δ = 153.65 (C-
11) ↔ δ = 5.57 (11b-H), δ = 153.65 (C-11) ↔ δ = 7.98 (10-H), δ = 175.28
24
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
(C-2) ↔ [δA = 2.66 (3-HA) and δB = 2.83 (3-HB)], δ = 175.28 (C-2) ↔
10a) ↔ δ = 7.41 (9-H), δ = 125.05 and 125.33 (C-6a and C-10a) ↔ δ =
7.99 (10-H) could not be assigned unambiguously], δ = 143.00 (C-7) ↔ δ
= 3.81 (7-OMe), δ = 143.00 (C-7) ↔ δ = 7.41 (9-H), δ = 143.00 (C-7) ↔ δ
= 7.99 (10-H), δ = 143.36 (C-1’) ↔ δ = 6.40 (5-H), δ = 143.36 (C-1’) ↔ δ
= 7.56 (3’-H and 5’H), δ = 147.17 (C-6) ↔ δ = 3.61 (6-OMe), δ = 147.17
(C-6) ↔ δ = 6.40 (5-H), δ = 151.63 (C-8) ↔ δ = 4.04 (8-OMe), δ = 151.63
(C-8) ↔ δ = 7.41 (9-H), δ = 151.63 (C-8) ↔ δ = 7.99 (10-H), δ = 153.90
(C-11) ↔ δ = 4.12 (11-OMe), δ = 153.90 (C-11) ↔ δ = 5.56 (11b-H), δ =
153.90 (C-11) ↔ δ = 7.99 (10-H), δ = 175.04 (C-2) ↔ [δA = 2.68 (3-HA)
and δB = 2.85 (3-HB)], δ = 175.04 (C-2) ↔ 4.22 (3a-H). Melting point:
20
4.31(3a-H). Melting point: Oil. Optical rotation of 43b: [α]D = –437.2
(c = 1.162, CHCl3). Optical rotation of ent-43b: [
0.686, CHCl3). HRMS (pos. APCI): Calcd. for C25H25O7 [M+H]+
437.15948; found 437.15961 (0.29 ppm). IR (film): ν = 2940, 2845, 1780,
1665, 1615, 1600, 1505, 1455, 1425, 1405, 1360, 1335, 1275, 1200,
1155, 1110, 1065, 1045, 990, 955, 905, 885, 845, 805, 735, 700 cm-1.
20
α
]
= +411.5 (c =
D
=
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-(4-(trifluoromethyl)phenyl)-
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (43c)
20
68-72°C. Optical rotation of 43c: [α]D = –354.8 (c = 1.372, CHCl3).
20
Optical rotation of ent-43c: [
α
]
= +308.8 (c = 0.96, CHCl3). HRMS
505.14686; found
D
(pos. APCI): Calcd. for C26H24O7F3 [M+H]+
=
505.14658 (–0.57 ppm). IR (film): ν = 2945, 2845, 1785, 1665, 1620,
1580, 1460, 1415, 1365, 1325, 1275, 1200, 1165, 1065, 1015, 995, 905,
885, 830, 780, 735, 700 cm-1.
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-(4-fluorophenyl)-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (43d)
F
Following the General Procedure B the title compound was prepared
4'
5'
3'
2'
from
β-hydroxy-γ-lactone
15
(52.3 mg,
0.15 mmol),
4-
(trifluoromethyl)benzaldehyde (61.5 µL, 78.4 mg, 0.45 mmol, 3.0 equiv.)
and BF3·OEt2 (76.0 µL, 85.2 mg, 0.60 mmol, 4.0 equiv.). Purification by
flash chromatography [d = 1.5 cm, h = 12 cm, F = 8 mL; CH/EE 3:1 (F1-
11), CH/EE 2:1 (F12-30)] afforded the title compound (F13-19, Rf
(3:1) = 0.1, Rf (2:1) = 0.5, 68.6 mg, 91%, ds = 100:0) as a colorless oil.−
Note: The optical antipode ent-43c was synthesized analogously from
MeO MeO6'
1'
7
6
8
MeO
5
O
6a
5a
3a
10a
11b
11a
9
3
11
10
2
O
OMe
O
ent-15 in 70% yield (ds = 100:0). − 1H NMR (500.32 MHz, CDCl3):
δ = AB
signal (δA = 2.68, δB = 2.85, JAB = 17.6 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.1 Hz, 3-HA and 3-HB), 3.61 (s,
3H, 6-OMe), 3.81 (s, 3H, 7-OMe), 4.04 (s, 3H, 8-OMe), 4.12 (s, 3H, 11-
Following the General Procedure B the title compound was prepared
from β-hydroxy-γ-lactone 15 (52.3 mg, 0.15 mmol), 4-fluorobenzaldehyde
(48.1 µL, 55.8 mg, 0.45 mmol, 3.0 equiv.) and BF3·OEt2 (76.0 µL,
85.2 mg, 0.60 mmol, 4.0 equiv.). Purification by flash chromatography
[d = 1.5 cm, h = 12 cm, F = 8 mL; CH/EE 3:1 (F1-12), CH/EE 2:1 (F13-
28)] afforded the title compound (F14-21, Rf (3:1) = 0.1, Rf (2:1) = 0.5,
62.2 mg, 91%, ds = 100:0) as a colorless oil.– Note: The optical antipode
OMe), 4.22 (dd, 1H, J3 = 5.1 Hz, J3a,11b = 2.8 Hz, 3a-H), 5.56 (d, 1H,
a,B
J11b,3a = 2.8 Hz, 11b-H), 6.40 (s, 1H, 5-H), 7.26 (br. d, 2H, J2’,3’ = J6’,5’
=
8.0 Hz, 2’-H and 6’-H), 7.41 (d, 1H, J9,10 = 9.3 Hz, 9-H), 7.56 (br. d, 2H,
J3’,2’ = J5’,6’ = 8.0 Hz, 3’-H and 5’-H), 7.99 (d, 1H, J10,9 = 9.3 Hz, 10-H). 6-
OMe, 8-OMe and 11-OMe were distinguished from 7-OMe by the
occurrence of cross-peaks only for the former but not for the latter in the
following NOESY spectrum (500.32 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of cross-peaks [δ(1H)
↔ δ(1H)]: δ = 3.61 (6-OMe) ↔ δ = 6.40 (5-H), δ = 4.04 (8-OMe) ↔ δ =
7.41 (9-H), δ = 4.12 (11-OMe) ↔ δ = 5.56 (11b-H), δ = 4.12 (11-OMe) ↔
δ = 7.99 (10-H). δ = 7.26 (2’-H and 6’-H) ↔ δ = 4.22 (3a-H, this cross-
peak proves that the phenyl ring and 3a-H are oriented cis relative to one
ent-43d was synthesized analogously from ent-15 in 62% yield
1
(ds = 95:5).– H NMR (500.32 MHz, CDCl3):
δ = AB signal (δA = 2.66, δB
= 2.85, JAB = 17.7 Hz, A signal shows no further splitting, B signal further
split by JB,3a = 5.2 Hz, 3-HA and 3-HB), 3.55 (s, 3H, 6-OMe), 3.80 (s, 3H,
7-OMe), 4.03 (s, 3H, 8-OMe), 4.12 (s, 3H, 11-OMe), 4.28 (dd, 1H, J3
=
a,B
5.1 Hz, J3a,11b = 2.9 Hz, 3a-H), 5.57 (d, 1H, J11b,3a = 2.9 Hz, 11b-H), 6.37
(s, 1H, 5-H), 6.98 (mc, 2H, 3’-H and 5’-H), 7.09 (mc, 2H, 2’-H and 6’-H),
7.39 (d, 1H, J9,10 = 9.3 Hz, 9-H), 7.98 (d, 1H, J10,9 = 9.3 Hz, 10-H). 6-
OMe, 8-OMe and 11-OMe were distinguished from 7-OMe by the
occurrence of cross-peaks only for the former but not for the latter in the
following NOESY spectrum (500.32 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of cross-peaks [δ(1H)
↔ δ(1H)]: δB = 2.85 (3-HB) ↔ δ = 5.57 (11b-H, this cross-peak proves
that 3-HB and 11b-H are oriented cis relative to one another), δ = 3.60 (6-
OMe) ↔ δ = 4.28 (3a-H), δ = 3.60 (6-OMe) ↔ δ = 6.37 (5-H), δ = 4.03 (8-
OMe) ↔ δ = 7.39 (9-H), δ = 4.12 (11-OMe) ↔ δ = 5.57 (11b-H), δ = 4.12
(11-OMe) ↔ δ = 7.98 (10-H), δ = 7.09 (2’-H and 6’-H) ↔ δ = 4.28 (3a-H,
this cross-peak proves that the phenyl ring and 3a-H are oriented cis
another). 19F NMR (470.77 MHz, CDCl3):
δ
= –62.64 (s, 3F, CF3). 13C
NMR (125.82 MHz, CDCl3): δ = 37.53 (C-3), 56.77 (8-OCH3), 62.25 (7-
OCH3), 62.49 (6-OCH3), 64.47 (11-OCH3), 67.22 (C-3a), 72.18 (C-11b),
72.57 (C-5), 115.03 (C-9), 116.46 and 124.37 (C-5a and C-11a), 120.15
(C-10), 124.01 (q, 1C, 1JC,F = 272.0 Hz, 4’-CF3), 125.05 and 125.33 (C-6a
3
and C-10a), 125.45 (q, 2C, JC,F = 3.6 Hz, C-3’ and C-5’), 129.01 (C-2’
2
and C-6’), 130.58 (q, 1C, JC,F = 32.4 Hz, C-4’), 143.00 (C-7), 143.36 (C-
1’), 147.17 (C-6), 151.63 (C-8), 153.90 (C-11), 175.04 (C-2). An edHSQC
spectrum (“short-range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
37.53 (C-3) ↔ [δA = 2.68 (3-HA) and δB = 2.85 (3-HB)], δ = 56.77 (8-
OCH3) ↔ δ = 4.04 (8-OMe), δ = 62.25 (7-OCH3) ↔ δ = 3.81 (7-OMe), δ =
62.49 (6-OCH3) ↔ δ = 3.61 (6-OMe), δ = 64.47 (11-OCH3) ↔ δ = 4.12
(11-OMe), δ = 67.22 (C-3a) ↔ δ = 4.22 (3a-H), δ = 72.18 (C-11b) ↔ δ =
5.56 (11b-H), δ = 72.57 (C-5) ↔ δ = 6.40 (5-H), δ = 115.03 (C-9) ↔ δ =
7.41 (9-H), δ = 120.15 (C-10) ↔ δ = 7.99 (10-H), δ = 125.45 (C-3’ and C-
5’) ↔ δ = 7.56 (3’-H and 5’-H), δ = 129.01 (C-2’ and C-6’) ↔ δ = 7.26 (2’-
relative to one another), δ = 7.09 (2’-H and 6’-H) ↔ δ = 5.57 (11b-H). 19
NMR (470.77 MHz, CDCl3):
–113.63 (s, 1F, 4’-F). 13C NMR
F
δ
=
(125.82 MHz, CDCl3): δ = 37.51 (C-3), 56.76 (8-OCH3), 62.24 (7-OCH3),
62.45 (6-OCH3), 64.45 (11-OCH3), 66.76 (C-3a), 72.32 (C-11b), 72.49
(C-5), 114.88 (C-9), 116.63, 125.03, 125.22 and 125.24 (C-5a, C-6a, C-
10a and C-11a could not be assigned unambiguously), 120.10 (C-10),
2
115.35 (d, 2C, JC,F = 21.5 Hz, C-3’ and C-5’), 130.50 (d, 2C,
3JC,F = 8.4 Hz, C-2’ and C-6’), 135.47 (d, 1C, 4JC,F = 3.2 Hz, C-1’), 142.99
(C-7), 147.05 (C-6), 151.52 (C-8), 153.73 (C-11), 162.64 (d, 1C,
1JC,F = 247.5 Hz, C-4’), 175.21 (C-2). An edHSQC spectrum (“short-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 37.51 (C-3)
↔ [δA = 2.66 (3-HA) and δB = 2.85 (3-HB)], δ = 56.76 (8-OCH3) ↔ δ =
4.03 (8-OMe), δ = 62.24 (7-OCH3) ↔ δ = 3.80 (7-OMe), δ = 62.45 (6-
H
and 6’-H). An HMBC spectrum (“long-range C,H COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: [δ = 116.46 and 124.37 (C-5a and C-11a) ↔ δ = 5.56
(11b-H), δ = 116.46 and 124.37 (C-5a and C-11a) ↔ δ = 6.40 (5-H) could
not be assigned unambiguously], [δ = 125.05 and 125.33 (C-6a and C-
25
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
OCH3) ↔ δ = 3.55 (6-OMe), δ = 64.45 (11-OCH3) ↔ δ = 4.12 (11-OMe),
δ = 66.76 (C-3a) ↔ δ = 4.28 (3a-H), δ = 72.32 (C-11b) ↔ δ = 5.57 (11b-
H), δ = 72.49 (C-5) ↔ δ = 6.37 (5-H), δ = 114.88 (C-9) ↔ δ = 7.39 (9-H),
δ = 120.10 (C-10) ↔ δ = 7.98 (10-H), δ = 115.35 (C-3’ and C-5’) ↔ δ =
6.98 (3’-H and 5’-H), δ = 130.50 (C-2’ and C-6’) ↔ δ = 7.09 (2’-H and 6’-
H). An HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 135.47
(C-1’) ↔ δ = 6.37 (5-H), δ = 135.47 (C-1’) ↔ δ = 6.98 (3’-H and 5’H), δ =
142.99 (C-7) ↔ δ = 3.80 (7-OMe), δ = 142.99 (C-7) ↔ δ = 7.39 (9-H), δ =
147.05 (C-6) ↔ δ = 3.55 (6-OMe), δ = 147.05 (C-6) ↔ δ = 6.37 (5-H), δ =
151.52 (C-8) ↔ δ = 4.03 (8-OMe), δ = 151.52 (C-8) ↔ δ = 7.98 (10-H), δ
= 153.73 (C-11) ↔ δ = 4.12 (11-OMe), δ = 153.73 (C-11) ↔ δ = 7.98 (10-
H), δ = 162.64 (C-4’) ↔ δ = 6.98 (3’-H and 5’H), δ = 162.64 (C-4’) ↔ δ =
7.09 (2’-H and 6’H), δ = 175.21 (C-2) ↔ [δA = 2.66 (3-HA) and δB = 2.85
(3-HB)], δ = 175.21 (C-2) ↔ 4.28 (3a-H). Melting point: 76-77°C. Optical
with the independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ =
37.53 (C-3) ↔ [δA = 2.66 (3-HA) and δB = 2.84 (3-HB)], δ = 56.82 (8-
OCH3) ↔ δ = 4.03 (8-OMe), δ = 62.25 (7-OCH3) ↔ δ = 3.81 (7-OMe), δ =
62.49 (6-OCH3) ↔ δ = 3.58 (6-OMe), δ = 64.47 (11-OCH3) ↔ δ = 4.12
(11-OMe), δ = 66.97 (C-3a) ↔ δ = 4.26 (3a-H), δ = 72.27 (C-11b) ↔ δ =
5.55 (11b-H), δ = 72.60 (C-5) ↔ δ = 6.34 (5-H), δ = 115.04 (C-9) ↔ δ =
7.40 (9-H), δ = 120.12 (C-10) ↔ δ = 7.98 (10-H), δ = 130.46 (C-2’ and C-
6’) ↔ δ = 6.98-7.02 (2’-H and 6’-H), δ = 131.64 (C-3’ and C-5’) ↔ δ =
7.40-7.44 (3’-H and 5’-H). An HMBC spectrum (“long-range C,H COSY”;
100.63/400.13 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: [δ = 116.63 and 124.83 (C-5a and C-11a) ↔ δ = 5.55
(11b-H), δ = 116.63 and 124.83 (C-5a and C-11a) ↔ δ = 6.34 (5-H) could
not be assigned unambiguously] , δ = 122.54 (C-4’) ↔ δ = 6.98-7.02 (2’-
H and 6’-H), δ = 122.54 (C-4’) ↔ 7.40-7.44 (3’-H and 5’-H), δ = 125.07
(C-6a) ↔ δ = 7.98 (10-H), δ = 125.33 (C-10a) ↔ δ = 7.40 (9-H), δ =
138.67 (C-1’) ↔ δ = 6.34 (5-H), δ = 138.67 (C-1’) ↔ δ = 7.40-7.44 (3’-H
and 5’H), δ = 143.10 (C-7) ↔ δ = 3.81 (7-OMe), δ = 143.10 (C-7) ↔ δ =
7.40 (9-H), δ = 143.10 (C-7) ↔ δ = 7.98 (10-H), δ = 147.14 (C-6) ↔ δ =
3.58 (6-OMe), δ = 147.14 (C-6) ↔ δ = 6.34 (5-H), δ = 151.59 (C-8) ↔ δ =
4.03 (8-OMe), δ = 151.59 (C-8) ↔ δ = 7.40 (9-H), δ = 151.59 (C-8) ↔ δ =
7.98 (10-H), δ = 153.81 (C-11) ↔ δ = 4.12 (11-OMe), δ = 153.81 (C-11)
↔ δ = 5.55 (11b-H), δ = 153.81 (C-11) ↔ δ = 7.98 (10-H), δ = 175.09 (C-
2) ↔ [δA = 2.66 (3-HA) and δB = 2.84 (3-HB)], δ = 175.09 (C-2) ↔ 4.26
(3a-H). Melting point: 70-73°C. Optical rotation of 43e: [α]D20 = –311.8
20
rotation of 43d: [α]D = –336.7 (c = 1.39, CHCl3). Optical rotation of
ent-43d: [α]D20 = +333.2 (c = 0.73, CHCl3). HRMS (pos. APCI): Calcd. for
C25H24O7F [M+H]+ = 455.15006; found 455.14978 (–0.61 ppm). IR (film):
ν = 3365, 3055, 2985, 2945, 2845, 2305, 1775, 1665, 1625, 1605, 1575,
1510, 1460, 1415, 1360, 1335, 1275, 1225, 1200, 1155, 1080, 1050,
1000, 910, 885, 835, 800, 730, 705 cm-1.
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-(4-bromophenyl)-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (43e)
20
(c = 1.484, CHCl3). Optical rotation of ent-43e: [α]D = +360.4 (c =
0.74, CHCl3). HRMS (pos. ESI): Calcd. for C25H2379BrO7Na [M+Na]+
=
Br
4'
537.05194; found 537.05164 (–0.56 ppm) and calcd. for C25H2381BrO7Na
[M+Na]+ = 539.04989; found 539.04950 (–0.72 ppm). IR (film): ν = 2935,
2840, 1780, 1615, 1600, 1505, 1485, 1465, 1450, 1425, 1380, 1360,
1335, 1275, 1250, 1200, 1150, 1130, 1100, 1070, 1050, 1010, 990, 905,
885, 850, 820, 730 cm-1.
5'
3'
2'
MeO MeO6'
1'
7
6
8
MeO
5
O
6a
10a
5a
3a
11b
11a
9
3
11
10
2
O
OMe
(3aS,3a'S,5S,5'S,11bS,11b'S)-5,5'-(1,4-Phenylene)bis(6,7,8,11-
tetramethoxy-3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-
O
c]isochromen-2-one)
Tetramethoxy-2-oxo-3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-
c]isochromen-5-yl}benzaldehyde (43f)
(44)
and
4-{(3aS,5S,11bS)-6,7,8,11-
Following the General Procedure B the title compound was prepared
from β-hydroxy-γ-lactone 15 (52.3 mg, 0.15 mmol), 4-
bromobenzaldehyde (82.3 mg, 0.45 mmol, 3.0 equiv.) and BF3·OEt2
(76.0 µL, 85.2 mg, 0.60 mmol, 4.0 equiv.). Purification by flash
chromatography [d = 1.5 cm, h = 12 cm, F = 8 mL; CH/EE 3:1 (F1-11),
CH/EE 2:1 (F12-29)] afforded the title compound (F9-17, Rf (3:1) = 0.1,
Rf (2:1) = 0.5, 74.2 mg, 96%, ds = 100:0) as a colorless solid.– Note: The
optical antipode ent-43e was synthesized analogously from ent-15 in
68% yield (ds = 100:0).– 1H NMR (400.13 MHz, CDCl3):
δ = AB signal (δA
= 2.66, δB = 2.84, JAB = 17.6 Hz, A signal shows no further splitting, B
signal further split by JB,3a = 5.1 Hz, 3-HA and 3-HB), 3.58 (s, 3H, 6-OMe),
3.81 (s, 3H, 7-OMe), 4.03 (s, 3H, 8-OMe), 4.12 (s, 3H, 11-OMe), 4.26
(dd, 1H, J3
= 5.1 Hz, J3a,11b = 2.8 Hz, 3a-H), 5.55 (d, 1H, J11b,3a =
a,B
2.9 Hz, 11b-H), 6.34 (s, 1H, 5-H), 6.98-7.02 (m, 2H, 2’-H and 6’-H), 7.40
(d, 1H, J9,10 = 9.4 Hz, 9-H), 7.40-7.44 (m, 2H, 3’-H and 5’-H), 7.98 (d, 1H,
J10,9 = 9.2 Hz, 10-H). 6-OMe, 8-OMe and 11-OMe were distinguished
from 7-OMe by the occurrence of cross-peaks only for the former but not
for the latter in the following NOESY spectrum (400.13 MHz, CDCl3) that
allowed additional assignments of 1H resonances by the occurrence of
cross-peaks [δ(1H) ↔ δ(1H)]: δ = 2.84 (3-HB) δ = 5.55 (11b-H, this cross-
peak proves that 3-HB and 11b-H are oriented cis relative to one
another), δ = 3.58 (6-OMe) ↔ δ = 6.34 (5-H), δ = 4.03 (8-OMe) ↔ δ =
7.40 (9-H), δ = 4.12 (11-OMe) ↔ δ = 7.99 (10-H), δ = 7.26 (2’-H and 6’-
H) ↔ δ = 4.22 (3a-H, this cross-peak proves that the phenyl ring and 3a-
H are oriented cis relative to one another), δ = 7.26 (2’-H and 6’-H) ↔ δ
=6.34 (5-H). 13C NMR (100.63 MHz, CDCl3): δ = 37.53 (C-3), 56.82 (8-
OCH3), 62.25 (7-OCH3), 62.49 (6-OCH3), 64.47 (11-OCH3), 66.97 (C-3a),
72.27 (C-11b), 72.60 (C-5), 115.04 (C-9), 116.63 and 124.83 (C-5a and
C-11a), 120.12 (C-10), 122.54 (C-4’), 125.07 (C-6a), 125.33 (C-10a),
130.46 (C-2’ and C-6’), 131.64 (C-3’ and C-5’), 138.67 (C-1’), 143.10 (C-
7), 147.14 (C-6), 151.59 (C-8), 153.81 (C-11), 175.09 (C-2). An edHSQC
spectrum (“short-range C,H COSY”; 100.63/400.13 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
(4S,5S)-4-Hydroxy-5-(1,4,5,6-tetramethoxynaphthalen-2-yl)dihydrofuran-
2(3H)-one (15, 33.8 mg, 97.0 µmol) and terephthaldehyde (6.7 mg,
50 µmol, 0.52 equiv.) were suspended in CH2Cl2 (1.0 mL). At 0°C the
reaction was started by the addition of BF3·OEt2 (25.3 µL, 28.4 mg,
0.20 mmol, 2.06 equiv.). Afterwards the ice-bath was removed. The
reaction mixture was allowed to warm to room temperature and stirred for
30 min. Afterwards the reaction mixture was quenched by the addition of
H2O (3 mL) and stirred for 5 min. The organic phase was separated and
the aqueous phase was extracted with CH2Cl2 (3 × 5mL). The combined
organic extracts were washed with brine (5 mL) and dried over Na2SO4.
The solvent was removed in vacuo. Flash chromatography [d = 1.5 cm,
h = 10 cm, F = 8 mL; CH/EE 2:1 (F1-11), CH/EE 1:1 (F12-26), CH/EE 1:3
(F27-46)] afforded the aldehyde 43f (F9-16, Rf (1:1) = 0.4, 14.5 mg, 32%,
ds = 100:0) as a colorless oil and the dimeric compound 40 (F20-38, Rf
(1:1) = 0.2, 16.2 mg, 42%, ds = 100:0) as a colorless oil.– Analysis of
26
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
1
dimer 44: H NMR (500.32 MHz, CDCl3):
δ
= AB signal (δA = 2.65, δB
=
↔ δ = 8.00 (10’-H), δ = 7.32 (3-H and 5-H) ↔ δ = 4.24 (3’a-H, this cross-
peak proves that the phenyl ring and 3a-H are oriented cis relative to one
another), δ = 7.32 (3-H and 5-H) ↔ δ = 6.41 (5’-H), δ = 7.82 (2-H and 6-
H) ↔ δ = 9.99 (1-CHO). 13C NMR (100.61 MHz, CDCl3): δ = 37.57 (C-3’),
56.82 (8’-OCH3), 62.24 (7’-OCH3), 62.46 (6’-OCH3), 64.49 (11’-OCH3),
67.33 (C-3’a), 72.19 (C-11’b), 72.82 (C-5’), 115.14 (C-9’), 116.48 and
124.39 (C-5’a and C-11’a), 120.16 (C-10’), 125.09 (C-6’a), 125.40 (C-
10’a), 129.38 (C-3 and C-5), 129.83 (C-2 and C-6), 136.36 (C-1), 143.08
(C-7’), 146.21 (C-4), 147.23 (C-6’), 151.66 (C-8’), 153.92 (C-11’), 174.97
(C-2’), 191.68 (1-CHO). An edHSQC spectrum (“short-range C,H COSY”;
100.61/400.13 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 37.57 (C-3’) ↔ [δA = 2.68 (3’-HA) and δB
= 2.85 (3’-HB)], δ = 56.82 (8’-OCH3) ↔ δ = 4.04 (8’-OMe), δ = 62.24 (7’-
OCH3) ↔ δ = 3.81 (7’-OMe), δ = 62.46 (6’-OCH3) ↔ δ = 3.60 (6’-OMe), δ
= 64.49 (11’-OCH3) ↔ δ = 4.13 (11’-OMe), δ = 67.33 (C-3’a) ↔ δ = 4.24
(3’a-H), δ = 72.19 (C-11’b) ↔ δ = 5.57 (11’b-H), δ = 72.82 (C-5’) ↔ δ =
6.41 (5’-H), δ = 115.14 (C-9’) ↔ δ = 7.41 (9’-H), δ = 120.16 (C-10’) ↔ δ =
8.00 (10’-H), δ = 129.38 (C-3 and C-5) ↔ δ = 7.32 (3-H and 5-H), δ =
129.83 (C-2 and C-6) ↔ δ = 7.82 (2-H and 6-H), δ = 191.68 (1-CHO) ↔
2.83, JAB = 17.7 Hz, A signal shows no further splitting, B signal further
split by JB,3a = 5.2 Hz, 2×3-HA and 2×3-HB), 3.53 (s, 2×3H, 2×6-OMe),
3.79 (s, 2×3H, 2×7-OMe), 4.02 (s, 2×3H, 2×8-OMe), 4.09 (s, 2×3H, 2×11-
OMe), 4.28 (dd, 2×1H, J3 = 5.0 Hz, J3a,11b = 2.9 Hz, 2×3a-H), 5.53 (d,
2×1H, J11b,3a = 2.9 Hz, 2×11b-H), 6.34 (s, 2×1H, 2×5-H), 7.05 (br. s, 4H,
2’-H, 3’-H, 5’-H and 6’-H), 7.37 (d, 2×1H, J9,10 = 9.3 Hz, 2×9-H), 7.95 (d,
a,B
2×1H, J10,9
= 9.3 Hz, 2×10-H). 6-OMe, 8-OMe and 11-OMe were
distinguished from 7-OMe by the occurrence of cross-peaks only for the
former but not for the latter in the following NOESY spectrum
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of cross-peaks [δ(1H) ↔ δ(1H)]: δA = 2.83
(3-HB) ↔ δ = 5.53 (11b-H, this cross-peak proves that 3-HB and 11b-H
are oriented cis relative to one another), δ = 3.53 (6-OMe) ↔ δ = 6.34 (5-
H), δ = 3.53 (6-OMe) ↔ δ = 7.05 (2’-H, 3’-H, 5’-H and 6’-H), δ = 4.02 (8-
OMe) ↔ δ = 7.37 (9-H), δ = 4.09 (11-OMe) ↔ δ = 5.53 (11b-H), δ = 4.09
(11-OMe) ↔ δ = 7.95 (10-H), δ = 7.05 (2’-H, 3’-H, 5’-H and 6’-H) ↔ δ =
4.28 (3a-H, this cross-peak proves that the phenyl ring and both 3a-H are
oriented cis relative to one another). 13C NMR (125.82 MHz, CDCl3): δ =
37.59 (2×C-3), 56.78 (2×8-OCH3), 62.23 (2×7-OCH3), 62.38 (2×6-OCH3),
64.44 (2×11-OCH3), 66.96 (2×C-3a), 72.34 (2×C-11b), 72.75 (2×C-5),
114.88 (2×C-9), 116.59 and 125.19 (2×C-5a and 2×C-11a), 120.09 (2×C-
10), 124.96 (2×C-6a), 125.19 (2×C-10a), 128.74 (C-2’, C-3’, C-5’ and C-
6’), 139.55 (C-1’ and C-4’), 142.97 (2×C-7), 147.05 (2×C-6), 151.50 (2×C-
8), 153.72 (2×C-11), 175.18 (2×C-2). An edHSQC spectrum (“short-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 37.59 (C-3)
↔ [δA = 2.65 (3-HA) and δB = 2.83 (3-HB)], δ = 56.78 (8-OCH3) ↔ δ =
4.02 (8-OMe), δ = 62.23 (7-OCH3) ↔ δ = 3.79 (7-OMe), δ = 62.38 (6-
OCH3) ↔ δ = 3.53 (6-OMe), δ = 64.44 (11-OCH3) ↔ δ = 4.09 (11-OMe),
δ = 66.96 (C-3a) ↔ δ = 4.28 (3a-H), δ = 72.34 (C-11b) ↔ δ = 5.53 (11b-
H), δ = 72.75 (C-5) ↔ δ = 6.34 (5-H), δ = 114.88 (C-9) ↔ δ = 7.37 (9-H),
δ = 120.09 (C-10) ↔ δ = 7.95 (10-H), δ = 128.74 (C-2’, C-3’, C-5’ and C-
6’) ↔ δ = 7.05 (2’-H, 3’-H, 5’-H and 6’-H). An HMBC spectrum (“long-
range C,H COSY”; 125.82/500.32 MHz, CDCl3) allowed the assignment
of all quaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H); in grey: cross-
peaks linked via 2 or 4 covalent bonds]: [δ = 116.59 and 125.19 (C-5a
and C-11a) ↔ δ = 5.53 (11b-H), δ = 116.59 and 125.19 (C-5a and C-
11a) ↔ δ = 6.34 (5-H) could not be assigned unambiguously], δ = 124.96
(C-6a) ↔ δ = 7.95 (10-H), δ = 125.19 (C-10a) ↔ δ = 7.37 (9-H), δ =
139.55 (C-1’ and C-4’) ↔ δ = 6.34 (5-H), δ = 139.55 (C-1’ and C-4’) ↔ δ
= 7.05 (2’-H, 3’-H, 5’-H and 6’-H), δ = 142.97 (C-7) ↔ δ = 3.79 (7-OMe),
δ = 142.97 (C-7) ↔ δ = 7.37 (9-H), δ = 142.97 (C-7) ↔ δ = 7.95 (10-H), δ
= 147.05 (C-6) ↔ δ = 3.53 (6-OMe), δ = 147.05 (C-6) ↔ δ = 6.34 (5-H), δ
= 151.50 (C-8) ↔ δ = 4.02 (8-OMe), δ = 151.50 (C-8) ↔ δ = 7.37 (9-H), δ
= 151.50 (C-8) ↔ δ = 7.95 (10-H), δ = 153.72 (C-11) ↔ δ = 4.09 (11-
δ
= 9.99 (1-CHO). An HMBC spectrum (“long-range C,H COSY”;
100.61/400.13 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: [δ = 116.48 and 124.39 (C-5’a and C-11’a) ↔ δ = 5.57
(11’b-H), δ = 116.48 and 124.39 (C-5’a and C-11’a) ↔ δ = 6.41 (5’-H)
could not be assigned unambiguously], δ = 125.09 (C-6’a) ↔ δ = 8.00
(10’-H), δ = 125.40 (C-10’a) ↔ δ = 7.41 (9’-H), δ = 136.36 (C-1) ↔ δ =
7.32 (3-H and 5-H), δ = 136.36 (C-1) ↔ δ = 9.99 (1-CHO), δ = 143.08 (C-
7’) ↔ δ = 3.81 (7’-OMe), δ = 143.08 (C-7’) ↔ δ = 7.41 (9’-H), δ = 143.08
(C-7’) ↔ δ = 8.00 (10’-H), δ = 146.21 (C-4) ↔ δ = 6.41 (5’-H), δ = 146.21
(C-4) ↔ δ = 7.82 (2-H and 6-H), δ = 147.23 (C-6’) ↔ δ = 3.60 (6’-OMe), δ
= 147.23 (C-6’) ↔ δ = 6.41 (5’-H), δ = 151.66 (C-8’) ↔ δ = 4.04 (8’-OMe),
δ = 151.66 (C-8’) ↔ δ = 7.41 (9’-H), δ = 151.66 (C-8’) ↔ δ = 8.00 (10’-H),
δ = 153.92 (C-11’) ↔ δ = 4.13 (11’-OMe), δ = 153.92 (C-11’) ↔ δ = 5.57
(11’b-H), δ = 153.92 (C-11’) ↔ δ = 8.00 (10’-H), δ = 174.97 (C-2’) ↔ [δA
= 2.68 (3’-HA) and δB = 2.85 (3’-HB)], δ = 174.97 (C-2’) ↔ 4.24 (3’a-H).
Melting point: Oil. Optical rotation: [α]D20 = –318.5 (c = 0.483, CHCl3).
HRMS (pos. APCI): calcd. for C26H25O8 [M+H]+ = 465.15439; found
465.15408 (–0.66 ppm). IR (film): ν = 2940, 2845, 1785, 1700, 1665,
1605, 1575, 1505, 1455, 1425, 1360, 1335, 1275, 1205, 1155, 1085,
1065, 1050, 990, 905, 885 840, 810, 735 cm-1.
(3aS,3a'S,5S,5'S,11bS,11b'S)-5,5'-(1,4-Phenylene)bis(7,8-dimethoxy-
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromene-2,6,11-
trione) (45)
OMe), δ = 153.72 (C-11) ↔ δ = 7.95 (10-H), δ = 175.18 (C-2) ↔ [δA
=
2.65 (3-HA) and δB = 2.83 (3-HB)], δ = 175.18 (C-2) ↔ 4.28 (3a-H).
Melting point: Oil. Optical rotation: [α]D20 = –474.3 (c = 0.527, CHCl3).
HRMS (pos. ESI): Calcd. for C44H43O14 [M+H]+ = 795.26473; found
795.26398 (–0.95 ppm). IR (film): ν = 2935, 1780, 1615, 1600, 1510,
1465, 1450, 1425, 1400, 1380, 1360, 1335, 1275, 1200, 1155, 1130,
1105, 1085, 1065, 1050, 1020, 990, 955, 920, 905, 885, 815, 805, 735,
700 cm-1.– Analysis of 43f: 1H NMR (400.13 MHz, CDCl3):
δ = AB signal
(δA = 2.68, δB = 2.85, JAB = 17.6 Hz, A signal shows no further splitting, B
signal further split by JB,3’a = 5.0 Hz, 3’-HA and 3’-HB), 3.60 (s, 3H, 6’-
OMe), 3.81 (s, 3H, 7’-OMe, exclusion principle), 4.04 (s, 3H, 8’-OMe),
4.13 (s, 3H, 11’-OMe), 4.24 (dd, 1H, J3’a,B = 5.0 Hz, J3’a,11’b = 2.8 Hz, 3’a-
H), 5.57 (d, 1H, J11’b,3’a = 2.8 Hz, 11’b-H), 6.41 (s, 1H, 5’-H), 7.32 (mc, 2H,
3-H and 5-H), 7.41 (d, 1H, J9’,10’ = 9.4 Hz, 9’-H), 7.82 (mc, 2H, 2-H, and 6-
H), 8.00 (d, 1H, J10’,9’ = 9.2 Hz, 10’-H), 9.99 (s, 1H, 1-CHO). 6’-OMe, 8’-
OMe and 11’-OMe were distinguished from 7’-OMe by the occurrence of
cross-peaks only for the former but not for the latter in the following
NOESY spectrum (400.13 MHz, CDCl3) that allowed additional
assignments of 1H resonances by the occurrence of cross-peaks [δ(1H)
↔ δ(1H)]: δ = 3.60 (6’-OMe) ↔ δ = 6.41 (5’-H), δ = 4.04 (8’-OMe) ↔ δ =
7.41 (9’-H), δ = 4.13 (11’-OMe) ↔ δ = 5.57 (11’b-H), δ = 4.13 (11’-OMe)
Following the General Procedure A the title compound was prepared
from 44 (15.8 mg, 19.9 µmol) suspended in MeCN (1 mL) and a solution
of (NH4)2Ce(NO3)6 (43.6 mg, 79.6 µmol, 4.0 equiv.) in H2O (1 mL).
Purification by flash chromatography (d = 1.5 cm, h = 10 cm, F = 8 mL;
CH/EE 1:1) afforded the title compound [F15-26, Rf (1:1) = 0.2, 10.8 mg,
74%, dr = 100:0] as an orange solid.− 1H NMR (500.32 MHz, CDCl3):
δ =
AB signal (δA = 2.62, δB = 2.83, JAB = 17.9 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.3 Hz, 2×3-HA and 2×3-HB), 3.86
(s, 2×3H, 2×7-OMe), 3.98 (s, 2×3H, 2×8-OMe), 4.26 (dd, 2×1H, J3
=
a,B
5.2 Hz, J3a,11b = 3.1 Hz, 2×3a-H), 5.23 (d, 2×1H, J11b,3a = 3.1 Hz, 2×11b-
27
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
2.7 Hz, 3a-H), 5.32 (q, 1H, J5,5-CH3 = 6.8 Hz, 5-H), 5.62 (d, 1H,
H), 6.01 (s, 2×1H, 2×5-H), 7.24 (br. s, 4H, 2’-H, 3’-H, 5’-H and 6’-H), 7.24
(d, 2×1H, J9,10 = 8.7 Hz, 2×9-H), 8.02 (d, 2×1H, J10,9 = 8.9 Hz, 2×10-H). 8-
OMe was distinguished from 7-OMe by the occurrence of a cross-peak
only for the former but not for the latter in the following NOESY spectrum
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.83
(3-HB) ↔ δ = 5.23 (11b-H, this cross-peak proves that 3-HB and 11b-H
are oriented cis relative to one another), δ = 3.98 (8-OMe) ↔ δ = 7.24 (9-
H), δ = 7.24 (2’-H, 3’-H, 5’-H and 6’-H) ↔ δ = 4.26 (3a-H, this cross-peak
proves that the phenyl ring and 3a-H are oriented cis relative to one
another), δ = 7.24 (2’-H, 3’-H, 5’-H and 6’-H) ↔ δ = 6.01 (5-H). 13C NMR
(125.82 MHz, CDCl3): δ = 36.63 (2×C-3), 56.48 (2×8-OCH3), 61.30 (2×7-
OCH3), 67.15 (2×C-3a), 69.01 (2×C-11b), 71.60 (2×C-5), 116.45 (2×C-9),
124.21 (2×C-6a), 125.21 (2×C-10), 125.39 (2×C-10a), 129.11 (C-2’, C-3’,
C-5’ and C-6’), 135.66 and 147.09 (2×C-5a and 2×C-11a), 137.28 (C-1’
and C-4’), 149.77 (2×C-7), 159.42 (2×C-8), 173.97 (2×C-2), 181.13 (2×C-
11), 182.04 (2×C-6). An edHSQC spectrum (“short-range C,H COSY”;
125.82/500.32 MHz, CDCl3) allowed the assignment of all nonquaternary
13C atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H)]: δ = 36.63 (C-3) ↔ [δA = 2.65 (3-HA) and δB
= 2.83 (3-HB)], δ = 56.48 (8-OCH3) ↔ δ = 3.98 (8-OMe), δ = 61.30 (7-
OCH3) ↔ δ = 3.86 (7-OMe), δ = 67.15 (C-3a) ↔ δ = 4.26 (3a-H), δ =
69.01 (C-11b) ↔ δ = 5.23 (11b-H), δ = 71.60 (C-5) ↔ δ = 6.01 (5-H), δ =
116.45 (C-9) ↔ δ = 7.24 (9-H), δ = 125.21 (C-10) ↔ δ = 8.02 (10-H), δ =
129.11 (C-2’, C-3’, C-5’ and C-6’) ↔ δ = 7.24 (2’-H, 3’-H, 5’-H and 6’-H).
An HMBC spectrum (“long-range C,H COSY”; 125.82/500.32 MHz,
CDCl3) allowed the assignment of all quaternary 13C atoms through their
cross-peaks with the independently assigned 1H resonances [δ(13C) ↔
δ(1H); in grey: cross-peaks linked via 2 or 4 covalent bonds]: δ = 124.21
(C-6a) ↔ δ = 8.02 (10-H), δ = 125.39 (C-10a) ↔ δ = 7.24 (9-H), [δ =
135.66 and 147.09 (C-5a and C-11a) ↔ δ = 5.23 (11b-H), δ = 135.66
and 147.09 (C-5a and C-11a) ↔ δ = 6.01 (5-H), δ = 137.28 (C-1’ and C-
4’) ↔ δ = 6.01 (5-H), δ = 137.28 (C-1’ and C-4’) ↔ δ = 7.24 (2’-H, 3’-H,
5’-H and 6’-H), δ = 149.77 (C-7) ↔ δ = 3.86 (7-OMe), δ = 149.77 (C-7) ↔
δ = 7.24 (9-H), δ = 159.42 (C-8) ↔ δ = 3.98 (8-OMe), δ = 159.42 (C-8) ↔
δ = 7.24 (9-H), δ = 159.42 (C-8) ↔ δ = 8.02 (10-H), δ = 173.97 (C-2) ↔
[δA = 2.62 (3-HA) and δB = 2.83 (3-HB)], δ = 173.97 (C-2) ↔ 4.26 (3a-H).
δ = 181.13 (C-11) ↔ δ = 8.02 (10-H), δ = 182.04 (C-6) ↔ δ = 6.01 (5-H).
J11b,3a = 2.6 Hz, 11b-H), 7.39 (d, 1H, J8,7 = 9.2 Hz, 8-H), 7.84 (d, 1H,
J7,8 = 9.2 Hz, 7-H). 6-OMe, 9-OMe and 11-OMe were distinguished from
10-OMe by the occurrence of a cross-peak only for the former but not for
the latter in the following NOESY spectrum (500.32 MHz, CDCl3) that
allowed additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.55 (5-CH3) ↔ δ = 4.74 (3a-H, this
cross-peak proves that 5-CH3 and 3a-H are oriented cis relative to one
another), δ = 3.91 (6-OMe) ↔ δ = 5.32 (5-H), δ = 3.91 (6-OMe) ↔
δ = 7.84 (7-H), δ = 4.02 (9-OMe) ↔ δ = 7.39 (8-H), δ = 4.00 (11-OMe) ↔
δ = 5.62 (11b-H). 13C-NMR (125.81 MHz, CDCl3): δ = 19.86 (5-CH3),
38.07 (C-3), 56.88 (9-OCH3), 61.92 (6-OCH3), 62.14 (10-OCH3), 64.60
(11-OCH3), 66.54 (C-3a), 67.77 (C-5), 72.40 (C-11b), 115.90 or 115.91
(C-8)*, 119.09 (C-11a), 119.16 (C-7), 123.73 (C-10a), 125.57 (C-5a),
126.25 (C-6a), 143.44 (C-10), 147.14 (C-6), 150.51 (C-9), 152.55 or
152.59 (C-11)*, 175.50 (C-2). *Assignment to the appropriate
diastereomer impossible. An edHSQC spectrum (“short-range C,H,
COSY”; 125.81/500.32 MHz, CDCl3) allowed the assignment of all
nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 19.86 (5-
CH3) ↔ δ = 1.55 (5-CH3), δ = 38.07 (C-3) ↔ δA = 2.71 and δB = 2.98 (3-
HA and 3-HB), δ = 56.88 (9-OCH3) ↔ δ = 4.02 (9-OMe), δ = 61.92 (6-
OCH3) ↔ δ = 3.91 (6-OMe), δ = 62.14 (10-OCH3) ↔ δ = 3.89 (10-OMe),
δ = 64.60 (11-OCH3) ↔ δ = 4.00 (11-OMe), δ = 66.54 (C-3a) ↔ δ = 4.74
(3a-H), δ = 67.77 (C-5) ↔ δ = 5.32 (5-H), δ = 72.40 (C-11b) ↔ δ = 5.62
(11b-H), δ = 115.90 or 115.91 (C-8) *↔ δ = 7.39 (8-H), δ = 119.16 (C-7)
↔
δ = 7.84 (7-H). An HMBC spectrum (“long-range C,H COSY”;
125.81/500.32 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 119.09 (C-11a) ↔ δ = 5.32 (5-H), δ = 119.09 (C-
11a)
↔ δ = 5.62 (11b-H), δ = 123.73 (C-10a) ↔ δ = 7.84 (7-H),
δ = 125.57 (C-5a) ↔ δ = 1.55 (5-CH3), δ = 125.57 (C-5a) ↔ δ = 5.32 (5-
H), δ = 125.57 (C-5a) ↔ δ = 5.62 (11b-H), δ = 126.25 (C-6a) ↔ δ = 7.39
(8-H), δ = 143.44 (C-10) ↔ δ = 3.89 (10-OMe), δ = 143.44 (C-10) ↔
δ = 7.39 (8-H), δ = 147.14 (C-6) ↔ δ = 3.91 (6-OMe), δ = 147.14 (C-6) ↔
δ = 5.32 (5-H), δ = 147.14 (C-6) ↔ δ = 7.84 (7-H), δ = 150.51 (C-9) ↔
δ = 4.02 (9-OMe), δ = 150.51 (C-9) ↔ δ = 7.39 (8-H), δ = 150.51 (C-9) ↔
δ = 7.84 (7-H), δ = 152.55 or 152.59 (C-11)* ↔ δ = 4.00 (11-OMe),
δ = 152.55 or 152.59 (C-11)* ↔ δ = 5.62 (11b-H), δ = 175.50 (C-2) ↔ δA
= 2.71 (3-HA), δ = 175.50 (C-2) ↔ δB = 2.98 (3-HB), δ = 175.50 (C-2) ↔
δ = 4.74 (3a-H) .– NMR analysis of 5-epi-46a: 1H-NMR (500.32 MHz,
20
Optical rotation: [α]D = –303.0 (c = 0.3, CHCl3). HRMS (pos. ESI):
Calcd. for C40H30O14Na [M+Na]+ = 757.15278; found 757.15216 (–
0.81 ppm). IR (film): ν = 2935, 2850, 1785, 1665, 1575, 1485, 1455,
1400, 1335, 1275, 1230, 1200, 1155, 1095, 1080, 1050, 1020, 1000,
975, 945, 910, 885, 820, 680 cm-1.
CDCl3): δ = 1.73 (d, 3H, J5-CH ,5 = 6.3 Hz, 5-CH3), AB signal (δA = 2.77
3
and δB = 2.91, JAB = 17.3 Hz, A signal shows no further splitting, B signal
further splitted by JB,3a = 4.5 Hz, 3-HA and 3-HB), 3.80 (s, 3H, 6-OMe),
3.91 (s, 3H, 10-OMe), 4.01 (s, 3H, 9-OMe), 4.02 (s, 3H, 11-OMe), 4.38
(dd, 1H, J3a,B = 4.3 Hz, J3a,11b = 2.4 Hz, 3a-H), 5.01 (q, 1H, J5,5-
(3aS,5S,11bS)-6,7,8,11-Tetramethoxy-5-methyl-3,3a,5,11b-
tetrahydro2H-benzo[g]furo[3,2-c]isochomen-2-one
(46a)
and
(3aS,5R,11bS)-6,7,8,11-Tetramethoxy-5-methyl-3,3a,5,11b-
tetrahydro2H-benzo[g]furo[3,2-c]isochomen-2-one (5-epi-46a)
3 = 6.3 Hz, 5-H), 5.61 (d, 1H, J11b,3a = 2.3 Hz, 11b-H), 7.39 (d, 1H,
CH
J8,7 = 9.2 Hz, 8-H), 7.89 (d, 1H, J7,8 = 9.2 Hz, 7-H). 6-OMe, 9-OMe and
11-OMe were distinguished from 10-OMe by the occurrence of a cross-
peak only for the former but not for the latter in the following NOESY
spectrum (500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 5.01
(5-H) ↔ δ = 4.38 (3a-H, this cross-peak proves that 5-H and 3a-H are
oriented cis relative to one another), δ = 3.80 (6-OMe) ↔ δ = 5.01 (5-H),
δ = 3.80 (6-OMe) ↔ δ = 7.89 (7-H), δ = 4.01 (9-OMe) ↔ δ = 7.39 (8-H),
δ = 4.02 (11-OMe) ↔ δ = 5.61 (11b-H). 13C-NMR (125.81 MHz, CDCl3):
δ = 21.52 (5-CH3), 38.43 (C-3), 56.84 (9-OCH3), 61.04 (6-OCH3), 62.14
(10-OCH3), 64.73 (11-OCH3), 70.12 (C-5), 72.07 (C-3a), 73.56 (C-11b),
115.90 or 115.91 (C-8) *, 119.29 (C-7), 120.31 (C-11a), 123.86 (C-10a),
125.76 (C-5a) 126.70 (C-6a) 143.24 (C-10) 148.46 (C-6) 150.65 (C-9),
152.55 or 152.59 (C-11)*, 175.68 (C-2). *Assignment to the appropriate
diastereomer impossible. An edHSQC spectrum (“short-range C,H,
COSY”; 125.81/500.32 MHz, CDCl3) allowed the assignment of all
nonquaternary 13C atoms through their cross-peaks with the
independently assigned 1H resonances [δ(13C) ↔ δ(1H)]: δ = 21.52 (5-
CH3) ↔ δ = 1.73 (5-CH3), δ = 38.43 (C-3) ↔ δA = 2.77 and δB = 2.91 (3-
HA and 3-HB), δ = 56.84 (9-OCH3) ↔ δ = 4.02 (9-OMe), δ = 61.04 (6-
OCH3) ↔ δ = 3.80 (6-OMe), δ = 62.14 (10-OCH3) ↔ δ = 3.91 (10-OMe),
δ = 64.73 (11-OCH3) ↔ δ = 4.01 (11-OMe), δ = 70.12 (C-5) ↔ δ = 5.01
(5-H), δ = 72.07 (C-3a) ↔ δ = 4.38 (3a-H), δ = 73.56 (C-11b) ↔ δ = 5.61
(11b-H), δ = 115.90 or 115.91 (C-8) *↔ δ = 7.39 (8-H), δ = 119.29 (C-7)
Procedure 1) Following the General Procedure B the title compound
was prepared from β-hydroxy-γ-lactone 16 (38.1 mg, 109 µmol),
acetaldehyde (50 µL, 39 mg, 0.89 mmol, 8.0 equiv.) and BF3·OEt2
(140 µL, 161 mg, 1.13 mmol, 10 equiv.). Purification by flash
chromatography [d = 1.5 cm, h = 13.5 cm, F = 8 mL; CH/EE 2:1 (F1-20),
1:1 (21-30)] afforded the title compounds [F9-11, Rf (CH/EE 1:1) = 0.50,
11.1 mg, 27%, dr = 96:4] as a pale-yellow oil as well as a second fraction
[F12-19, 14.7 mg, 36%, dr = 69:31]. Combined yield: 25.8 mg, 63%, ds =
81:19. Procedure 2) Following the General Procedure B the title
compound was prepared from β-hydroxy-γ-lactone 16 (19.7 mg,
56.6 µmol), acetaldehyde dimethyl acetal (48 µL, 41 mg, 0.45 mmol,
8.0 equiv.)and BF3·OEt2 (70 µL, 81 mg, 0.57 mmol, 10 equiv.).
Purification by flash chromatography [d = 1.5 cm, h = 13 cm, F = 8 mL;
CH2Cl2/TBME 20:1 (F1-28), 9:1 (29-36)] afforded the title compounds
[F9-15, Rf (CH2Cl2/TBME 20:1) = 0.50, 16.0 mg, 75%] as a pale-yellow
oil and as a 52:48 diastereomeric mixture of 46a and 5-epi-46a.– NMR
analysis of 46a: 1H-NMR (500.32 MHz, CDCl3): δ = 1.55 (d, 3H, J5-
↔
δ = 7.89 (7-H). An HMBC spectrum (“long-range C,H COSY”;
125.81/500.32 MHz, CDCl3) allowed the assignment of all quaternary 13
C
atoms through their cross-peaks with the independently assigned 1H
resonances [δ(13C) ↔ δ(1H); in grey: cross-peaks linked via 2 or 4
covalent bonds]: δ = 120.31 (C-11a) ↔ δ = 5.01 (5-H), δ = 120.31 (C-
,5 = 6.8 Hz, 5-CH3), AB signal [δA = 2.71 and δB = 2.98, JAB = 17.4 Hz,
CH
3
A signal shows no further splitting, B signal further split by JB,3a = 4.9 Hz,
3-HA and 3-HB), 3.89 (s, 3H, 10-OMe), 3.91 (s, 3H, 6-OMe), 4.00 (s, 3H,
11a)
↔ δ = 5.61 (11b-H), δ = 123.86 (C-10a) ↔ δ = 7.89 (7-H),
11-OMe), 4.02 (s, 3H, 9-OMe), 4.74 (dd, 1H, J3a,B = 4.9 Hz, J3a,11b
=
δ = 125.76 (C-5a) ↔ δ = 1.73 (5-CH3), δ = 125.76 (C-5a) ↔ δ = 5.01 (5-
28
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10.1002/ejoc.201700195
European Journal of Organic Chemistry
FULL PAPER
H), δ = 125.76 (C-5a) ↔ δ = 5.61 (11b-H), δ = 126.70 (C-6a) ↔ δ = 7.39
(8-H), δ = 143.24 (C-10) ↔ δ = 3.91 (10-OMe), δ = 143.24 (C-10) ↔
δ = 7.39 (8-H), δ = 148.46 (C-6) ↔ δ = 3.80 (6-OMe), δ = 148.46 (C-6) ↔
δ = 5.01 (5-H), δ = 148.46 (C-6) ↔ δ = 7.89 (7-H), δ = 150.65 (C-9) ↔
δ = 4.01 (9-OMe), δ = 150.65 (C-9) ↔ δ = 7.39 (8-H), δ = 150.65 (C-9) ↔
δ = 7.89 (7-H), δ = 152.55 or 152.59 (C-11)* ↔ δ = 4.02 (11-OMe),
δ = 152.55 or 152.59 (C-11)* ↔ δ = 5.61 (11b-H), δ = 175.68 (C-2) ↔ δA
= 2.77 (3-HA), δ = 175.68 (C-2) ↔ δB = 2.91 (3-HB), δ = 175.68 (C-2) ↔
δ = 4.38 (3a-H). Melting point: Oil. HRMS (pos. ESI): Calcd. for
C20H22O7 [M+H]+ = 375.14383; found 375.14389 (+0.16 ppm).
δ = 124.26 (C-10a) ↔ δ = 7.81 (7-H), δ = 126.02 (C-6a) ↔ δ = 7.41 (8-
H), δ = 139.22 (C-1’) ↔ δ = 6.30 (5-H), δ = 139.22 (C-1’) ↔ δ = 7.28-7.35
(3’-H, 4’-H and 5’-H), δ = 143.53 (C-10) ↔ δ = 3.95 (10-OMe), δ = 143.53
(C-10) ↔ δ = 7.41 (8-H), δ = 143.53 (C-10) ↔ δ = 7.84 (7-H), δ = 148.11
(C-6) ↔ δ = 3.67 (6-OMe), δ = 148.11 (C-6) ↔ δ = 6.30 (5-H), δ = 148.11
(C-6) ↔ δ = 7.84 (7-H), δ = 150.78 (C-9) ↔ δ = 4.03 (9-OMe), δ = 150.78
(C-9) ↔ δ = 7.41 (8-H), δ = 150.78 (C-9) ↔ δ = 7.84 (7-H), δ = 152.66
(C-11) ↔ δ = 4.05 (11-OMe), δ = 152.66 (C-11) ↔ δ = 5.61 (11b-H),
δ = 175.38 (C-2) ↔ δA = 2.66 (3-HA), δ = 175.38 (C-2) ↔ δB = 2.84 (3-
HB), δ = 175.38 (C-2) ↔ δ = 4.33 (3a-H). Melting point: Oil. Optical
rotation: [α]D20 = −311.7 (c = 0.870, CHCl3). HRMS (pos. ESI): Calcd. for
C25H24O7 [M+NH4]+ = 454.18603; found 454.18570 (−0.72 ppm). IR
(film): ν = 2930, 2845, 1780, 1615, 1595, 1505, 1495, 1465, 1450, 1425,
1410, 1365, 1340, 1295, 1275, 1225, 1200, 1155, 1130, 1110, 1085,
1065, 1050, 1040, 990, 950, 915, 905, 885, 810, 735, 700 cm-1.
(3aS,5S,11bS)-5-Phenyl-6,9,10,11-tetramethoxy-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (46b)
(3aS,5S,11bS)-6,9,10,11-Tetramethoxy-5-(4-(trifluoromethyl)phenyl)-
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,
2-c]isochromen-2-one
(46c)
Following the General Procedure B the title compound was prepared
from β-hydroxy-γ-lactone 16 (30.0 mg, 86.1 µmol), benzaldehyde (27 µL,
27 mg, 0.26 mmol, 3.0 equiv.) and BF3·OEt2 (42 µL, 49 mg, 0.34 mmol,
4.0 equiv.). Purification by flash chromatography [d = 1.5 cm,
h = 13.5 cm, F = 8 mL; CH/EE 3:1 (F1-18), 1:1 (19-24)] afforded the pure
product [F11-21, Rf (1:1) = 0.65, 32.2 mg, 86%, ds = 100:0] as yellow
oil.– 1H-NMR (500.32 MHz, CDCl3, spectrum contains water with br. s at
δ = 1.57 ppm and grease with resonances at δ = 0.85 and 1.25 ppm): AB
signal (δA = 2.66 and δB = 2.84, JAB = 17.6 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.0 Hz, 3-HA` and 3-HB), 3.67 (s,
3H, 6-OMe), 3.95 (s, 3H, 10-OMe), 4.03 (s, 3H, 9-OMe), 4.05 (s, 3H, 11-
OMe), 4.33 (dd, 1H, J3a,B = 5.0 Hz, J3a,11b = 2.8 Hz, 3a-H), 5.61 (d, 1H,
J11b,3a = 2.8 Hz, 11b-H), 6.30 (s, 1H, 5-H), 7.10-7.15 (m, 2H, 2’-H and 6’-
H), 7.28-7.32 (m, 3H, 3’-H, 4’-H and 5’-H), 7.41 (d, 1H, J8,7 = 9.3 Hz, 8-
H), 7.84 (d, 1H, J7,8 = 9.3 Hz, 7-H). 6-OMe, 9-OMe and 11-OMe were
distinguished from 10-OMe by the occurrence of a cross-peak only for
the former but not for the latter in the following NOESY spectrum
(500.32 MHz, CDCl3) that allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 2.84
(3-HB) ↔ δ = 5.61 (11b-H, this cross-peak proves that the 3-HB and 11b-
H are oriented cis relative to one another), δ = 7.10-7.15 (2’-H and 6’-H)
↔ δ = 4.33 (3a-H, this cross-peak proves that the phenyl ring and 3a-H
are oriented cis relative to one another), δ = 7.10-7.15 (2’-H and 6’-H) ↔
δ = 6.30 (5-H), δ = 3.67 (6-OMe) ↔ δ = 6.30 (5-H), δ = 3.67 (6-OMe) ↔
δ = 7.84 (7-H), δ = 4.03 (9-OMe) ↔ δ = 7.41 (8-H), δ = 4.05 (11-OMe) ↔
δ = 5.61 (11b-H). 13C-NMR (125.81 MHz, CDCl3): δ = 37.68 (C-3), 56.89
(9-OCH3), 61.88 (6-OCH3), 62.22 (10-OCH3), 64.75 (11-OCH3), 67.19 (C-
3a), 72.65 (C-11b), 72.98 (C-5), 115.92 (C-8), 119.48 (C-7), 120.27 and
121.81 (C-5a and C-11a), 124.26 (C-10a), 126.02 (C-6a), 128.46 and
128.53 (C-3’, C-4’ and C-5’), 128.72 (C-2’ and C-6’), 139.22 (C-1’),
143.53 (C-10), 148.11 (C-6), 150.78 (C-9), 152.66 (C-11),175.38 (C-2).
An edHSQC spectrum (“short-range C,H COSY”; 125.81/500.32 MHz,
CDCl3) allowed the assignment of all nonquaternary 13C atoms through
their cross-peaks with the independently assigned 1H resonances [δ(13C)
↔ δ(1H)]: δ = 37.68 (C-3) ↔ δA = 2.66 and δB = 2.84 (3-HA and 3-HB),
δ = 56.89 (9-OCH3) ↔ δ = 4.03 (9-OMe), δ = 61.88 (6-OCH3) ↔ δ = 3.67
(6-OMe), δ = 62.22 (10-OCH3) ↔ δ = 3.95 (10-OMe), δ = 64.75 (11-
OCH3) ↔ δ = 4.05 (11-OMe), δ = 67.19 (C-3a) ↔ δ = 4.33 (3a-H),
δ = 72.65 (C-11b) ↔ δ = 5.61 (11b-H), δ = 72.98 (C-5) ↔ δ = 6.30 (5-H),
δ = 115.92 (C-8) ↔ δ = 7.41 (8-H), δ = 119.48 (C-7) ↔ δ = 7.84 (7-H),
δ = 128.46 and 128.53 (C-3’, C-4’ and C-5’) ↔ δ = 7.28-7.35 (3’-H, 4’-H
and 5’-H), δ = 128.72 (C-2’ and C-6’) ↔ δ = 7.10-7.15 (2’-H and 6’-H). An
HMBC spectrum (“long-range C,H COSY”; 125.81/500.32 MHz, CDCl3)
allowed the assignment of all quaternary 13C atoms through their cross-
peaks with the independently assigned 1H resonances [δ(13C) ↔ δ(1H); in
grey: cross-peaks linked via 2 or 4 covalent bonds]: [δ = 120.27 and
121.81 (C-5a and C-11a) ↔ δ = 5.61 (11b-H), δ = 120.27 and 121.81 (C-
5a and C-11a) ↔ δ = 6.30 (5-H) could not be assigned unambiguously],
Following the General Procedure B the title compound was prepared
from β-hydroxy-γ-lactone 16 (28.2 mg, 81.0 µmol), 4-
(trifluoromethyl)benzaldehyde (33 µL, 42 mg, 0.24 mmol, 3.0 equiv.) and
BF3·OEt2 (41 µL, 46 mg, 0.32 mmol, 4.0 equiv.). Purification by flash
chromatography [d = 1.5 cm, h = 13.5 cm, F = 8 mL; CH/EE 5:1 (F1-12),
3:1 (13-34)] afforded the pure title compound [F16-20, Rf (2:1) = 0.40,
24.1 mg, 60%] as a colorless oil.– 1H-NMR (500.32 MHz, CDCl3): δ = AB
signal (δA = 2.68 and δB = 2.86, JAB = 17.6 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 5.0 Hz, 3-HA and 3-HB), 3.75 (s,
3H, 6-OMe), 3.95 (s, 3H, 10-OMe), 4.04 (s, 3H, 9-OMe), 4.05 (s, 3H, 11-
OMe), 4.25 (dd, 1H, J3a,B = 4.9 Hz, J3a,11b = 2.7 Hz, 3a-H), 5.60 (d, 1H,
J11b,3a = 2.7 Hz, 11b-H), 6.30 (s, 1H, 5-H), 7.26 (br.d, 2H,
J3 ˈ = J5 ˈ = 7.9 Hz, 2ˈ-H and 6ˈ-H), 7.43 (d, 1H, J8,7 = 9.3 Hz, 8-H), 7.56
ˈ
,2
ˈ,6
(br.d, 2H, J2 ˈ = J6 ˈ = 8.1 Hz, 3ˈ-H and 5ˈ-H), 7.85 (d, 1H, J7,8 = 9.3 Hz,
ˈ
,3
ˈ,5
7-H). 6-OMe, 9-OMe and 11-OMe were distinguished from 10-OMe by
the occurrence of a cross-peak only for the former but not for the latter in
the following NOESY spectrum (500.32 MHz, CDCl3) that allowed
additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 2.86 (3-HB) ↔ δ = 5.60 (11b-H, this
cross-peak proves that the 3-HB and 11b-H are oriented cis relative to
one another), δ = 7.26 (2ˈ-H and 6ˈ-H) ↔ δ = 4.25 (3a-H, this cross-peak
proves that the phenyl ring and 3a-H are oriented cis relative to one
another), δ = 7.26 (2ˈ-H and 6ˈ-H) ↔ δ = 6.30 (5-H), δ = 3.75 (6-OMe) ↔
δ = 6.30 (5-H), δ = 3.75 (6-OMe) ↔ δ = 7.85 (7-H), δ = 4.04 (9-OMe) ↔
δ = 7.43 (8-H), δ = 4.05 (11-OMe)
↔
δ = 5.60 (11b-H). 19F-NMR
(470.77 MHz, CDCl3): δ = −62.68 (s, 3F, CF3). 13C-NMR (125.81 MHz,
CDCl3): δ = 36.67 (C-3), 56.88 (9-OCH3), 61.98 (6-OCH3), 62.21 (10-
OCH3), 64.80 (11-OCH3), 67.59 (C-3a), 72.35 and 72.37 (C-5 and C-
11b), 116.10 (C-8), 119.46 (C-7), 119.87 and 120.66 (C-5a and C-11a),
124.00 (q, 1C.1JC,F = 272.2 Hz, CF3), 124.51 (C-10a), 125.53 (q,
2C.3JC,F = 3.6 Hz, C-3ˈ and C-5ˈ), 125.90 (C-6a), 128.91 (C-2ˈ and C-6ˈ),
130.63 (q, 1C.2JC,F = 32.5 Hz, C-4ˈ), 143.11 (C-1ˈ), 143.58 (C-10),
148.19 (C-6), 151.01 (C-9), 152.94 (C-11), 175.08 (C-2). An edHSQC
spectrum (“short-range C,H COSY”; 125.81/500.32 MHz, CDCl3) allowed
the assignment of all nonquaternary 13C atoms through their cross-peaks
with the independently assigned 1H resonances [δ(13C)
↔
δ(1H)]:
δ = 36.67 (C-3) ↔ δA = 2.68 and δB = 2.86 (3-HA and 3-HB), δ = 56.88 (9-
OCH3) ↔ δ = 4.04 (9-OMe), δ = 61.98 (6-OCH3) ↔ δ = 3.75 (6-OMe),
δ = 62.21 (10-OCH3) ↔ δ = 3.95 (10-OMe), δ = 64.80 (11-OCH3) ↔
δ = 4.05 (11-OMe), δ = 67.59 (C-3a) ↔ δ = 4.25 (3a-H), [δ = 72.35 and
29
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