Establishing Consensus Stereostructures for the Naphthoquinonopyrano-γ-lactone Natural Products (–)-Arizonin B1 and (–)-Arizonin C1 by Total Syntheses. Diastereocontrol of Oxa-Pictet–Spengler Cyclizations by Protective-Group Optimization

Article abstract of DOI:10.1002/ejoc.201700013

Previous total syntheses of arizonin C1 (4) led to opposite assignments of its absolute configuration. Here, we report the fourth total synthesis thereof. In addition, we disclose the first total synthesis of arizonin B1 (3) proceeding differently than via arizonin C1. The stereocenters of the two targets stemmed from an asymmetric dihydroxylation and an ensuing oxa-Pictet–Spengler cyclization. Their configurations were in line with Fernandes' assignments. Protective-group variation in the substrate modulated the diastereoselectivity of the Pictet–Spengler cyclization between 77:23 in favor of a trans disubstitution at C-3a vs. C-5 – used for preparing the natural (–)-arizonins C1 and B1 – and 100:0 in favor of a cis disubstitution – exploited for synthesizing the unnatural (+)-5-epi-arizonins C1 and B1. All naphthalenes of the present study were derived from the (benzyloxy)methoxynaphthalenediol 19. It resulted from a Diels–Alder reaction of the aryne 17a with the siloxyfuran 18a.

Full text of DOI:10.1002/ejoc.201700013

A Journal of
Accepted Article
Title: Consensus Stereostructures for the Naphthoqui-nonopyrano-
gamma-lactone Natural Products (‒)-Arizonin B1 and (‒)-Arizonin
C1. Diastereocontrol of Oxa-Pictet-Spengler Cyclizations
Authors: Reinhard Brückner and Markus Neumeyer
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((For Table of Contents:)) Markus Neumeyer, Reinhard Brückner
Establishing Consensus Stereostructures for the Naphthoqui-
nonopyrano-γ-lactone Natural Products (‒)-Arizonin B1 and (‒)-
Arizonin C1 by Total Syntheses. Diastereocontrol of Oxa-Pictet-
Spengler Cyclizations by Protective Group Optimization
((Short Title)) Total Syntheses of (‒)-Arizonins B1 and C1
Previous total syntheses of the naphthoquinonopyrano-γ-lactone arizonin C1 led to opposite assignments of its absolute con-
figuration. Here we disclose another total synthesis thereof and the first total synthesis of arizonin B1 different than via arizon-
in C1. The respective stereocenters stemmed from an asymmetric dihydroxylation and an ensuing oxa-Pictet-Spengler cy-
clization. The correctness of Fernandes´ configurational assignments of arizonin C1 and B1 was thereby ascertained.
1
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
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Establishing Consensus Stereostructures for the Naphthoqui-
nonopyrano-γ-lactone Natural Products (‒)-Arizonin B1 and (‒)-
Arizonin C1 by Total Syntheses. Diastereocontrol of Oxa-Pictet-
Spengler Cyclizations by Protective Group Optimization
Markus Neumeyer[a] and Reinhard Brückner*[a]
frenolicin B (2[4]). These compounds are pentasubstituted
Abstract: Previous total syntheses of arizonin C1 (4) led to op-
naphthoquinones or naphthalenes.[5] The six arizonins[6] are
“monomeric” naphthoquinonopyrano-γ-lactones from Actino-
posite assignments of its absolute configuration. Here we report the
fourth total synthesis thereof. In addition, we disclose the first total
planes arizonaensis sp. nov. They possess hexasubstituted
synthesis of arizonin B1 (3) proceeding differently than via arizonin
naphthoquinone − or naphthalene[5] − cores. Figure 1 exempli-
C1. The stereocenters of the two targets stemmed from an asym-
fies the structures of four such arizonins:[6d] (1) this report’s tar-
get molecule (‒)-arizonin B1 (3[6a]), a lactone; (2) this report’s
metric dihydroxylation and an ensuing oxa-Pictet-Spengler cycliza-
target molecule (‒)-arizonin C1 (4[6a]), another lactone; (3)-(4)
tion. Their configurations were in line with Fernandes’ assignments.
the related seco-esters (‒)-arizonin B2 (5[6a]) and (‒)-arizonin
Protective group variation in the substrate modulated the diastereo-
C3(!) (6[6a]). Dimeric naphthoquinonopyrano-γ-lactone natural
selectivity of the Pictet-Spengler cyclization between 77:23 in favor
products are inherently more complex. Figure 1 illustrates them
of a trans-disubstitution at C-3a vs. C-5 − used for making the natu-
by (+)-γ-actinorhodin (7[7]); each naphthoquinone – or naphtha-
ral (‒)-arizonins C1 and B1 − and 100:0 in favor of a cis-disub-
lene[5] – moiety thereof is heptasubstituted.
stitution − exploited for making the unnatural (+)-5-epi-arizonins
C1 and B1. All naphthalenes of the present study were derived
The relative configurations of the arizonins were assumed to be
from the (benzyloxy)methoxynaphthalenediol 27. It resulted from a
identical in the entire family because of their common origin.[6a]
Diels-Alder reaction of the aryne 26 with the siloxyfuran 18.
Moreover, their relative configurations were equalled with that
of (+)-kalafungin (1[2]).[6a] This was concluded[6a] from pro-
nounced 1H-NMR shift and H,H coupling constant similarities
Background
between (–)-arizonin B1 (3), (–)-arizonin C1 (4), and the refer-
ence compound (+)-kalafungin (1[2]). I. e., the pyrano-γ-lactone
Naphthoquinonopyrano-γ-lactone natural products have been
subunits are 3a,5trans,3a,11bcis-configured throughout. The latter
reviewed repeatedly with regard to their isolation, structure elu-
insight was corroborated further[6a] by NOE experiments with (–
cidation, biological activity, partial synthesis, and total syn-
)-arizonin B1 (3). In addition, the ORD spectrum of (–)-arizonin
thesis.[1] The top line of Figure 1 exemplifies this familiy of
compounds by the structures of six “monomers” and one “di-
4
mer”. The monomers comprise (+)-kalafungin (1[2]), its naturally
a) Y. Iwai, A. Kora, Y. Takahashi, T. Hayashi, J. Awaya, R. Masuma, R.
D
(ent-1[3]), and (+)-
Oiwa, S. Omura, J. Antibiot. 1978, 31, 959-965 (without the sign of the spe-
occurring antipode (‒)-nanaomycin
cific rotation of natural 2); b) ref.[4a] describes natural (+)-deoxyfrenolicin B,
too; c) according to ref.[14b] synthetic (+)-deoxyfrenolicin B and “deoxy-
frenolicin B methyl ester of natural origin” were converted into synthetic (+)-
frenolicin B; combined with the finding from ref.[4b] this establishes the dex-
trorotation of natural 2.
5
“Naphthoquinonopyrano-γ-lactones” contain 1,4-naphthoquinone moieties.
[a]
Dipl.-Chem. Markus Neumeyer, Prof. Dr. Reinhard Brückner
Institut für Organische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstraße 21, 79104 Freiburg
Fax: (+49)761-2036100
Unsubstituted 1,4-naphthoquinone has a higher oxidation state than unsub-
stituted naphthalene. Hence, it seems as if one could – and should – differ-
entiate “naphthoquinones” and “naphthalenes” unambiguously. However,
IUPAC nomenclature does not comply with this. In fact, certain substituted
naphthoquinones are “dihydro(!)naphthalenes”. For instance, (1,4-
naphthoquinone-2-yl)–C(=O)–CH2–O–CH3 is named 2-(2-methoxyacetyl)-
1,4-naphthoquinone while the isomer (1,4-naphthoquinone-2-yl)–C(=O)–O–
CH2–CH3 is 1,4-dioxo-1,4-dihydronaphthalene-2-carboxylic acid ethyl ester.
Accordingly, the present paper does not restrict the notion “naphthalene” to
the strictest meaning but comprises naphthoquinone and naphthazarine (=
5,8-dihydroxy-1,4-naphthoquinone) motifs as well.
E-mail: reinhard.brueckner@organik.uni-freiburg.de
1 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 Advanced
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,
DOI: 10.1002/ejoc.201600544; g) B. J. Naysmith, P. A. Hume, J. Sperry, M.
A. Brimble, Nat. Prod. Rep. 2016, DOI: 10.1039/C6NP00080K.
6
a) J. E. Hochlowski, G. M. Brill, W. W. Andres, S. G. Spanton, J. B.
McAlpine, J. Antibiot. 1987, 40, 401-407; b) the specific rotation of arizonin
B2 (5) is not published in ref.[6a]; c) ref.[6a] lacks NMR data of arizonin B2
(5) and (–)-arizonin C3 (6), which leaves open on which grounds their
relative configurations were published as shown in Figure 1; d) Figure 1
shows neither (–)-arizonin A1 nor (–)-arizonin A2. (–)-Arizonin A1 differs from
(–)-arizonin B1 (3) by swapping OH and OMe, and so does (–)-arizonin A2
vs. (–)-arizonin B2 (5).
2
a) M. E. Bergy, J. Antibiot. 1968, 21, 454-457; b) H. Hoeksema, W. C.
Krueger, J. Antibiot. 1976, 29, 704-709 [ORD spectrum of O-methyl-(+)-
kalafungin but not of (+)-kalafungin (1)].
3
a) S. Omura, H. Tanaka, Y. Okada, H. Marumo, J. Chem. Soc., Chem.
7
Commun. 1976, 320-321; b) ref.[3a]: “The ORD curve of [(–)-nanaomycin D]
shows a negative Cotton effect with a trough [ϕ] –450, at 355 nm and a peak,
[ϕ] +640, at 292 nm (c 0.1, MeOH). The ORD curve of [(+)-kalafungin] is the
exact reverse of this, with a peak at 355 nm and a trough at 292 nm, sug-
gesting that the absolute configuration of nanaomycin D is as in ... the enan-
tiomer of kalafungin.”
a) Correct structure: A. Zeeck, H. Zähner, M. Mardin, Liebigs Ann. Chem.
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.[14b]).
2
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
B1 (3)[8] was compared[6a] with ORD data both of (+)-kalafungin
(1)[2b] and (‒)-nanaomycin D (ent-1).[3b] The inferrence was[6a]
that their absolute configurations are the same.[9]
γ-actinorhodin (7).[19,20] The current paper contributes one syn-
thesis both of (−)-arizonin B1 (3) and (−)-arizonin C1 (4).
The arizonin syntheses accomplished to date can be summa-
rized as follows. In the mid-90s Brimble et al. synthesized ra-
cemic 5-epi-arizonin B1 (rac-5-epi-3),[15] racemic 5-epi-arizonin
C1 (rac-5-epi-4),[15] and racemic arizonin C1 (rac-4).[17] In 2011,
our group presented the first total synthesis of (−)-arizonin
C1.[18] Supposedly it possessed the stereostructure 4 but, in
truth, must have been the mirror image thereof. This became
clear in 2013. Fernandes then was no longer a member of the
earlier team[18a] but a researcher with his own group. He devel-
oped a different approach – and realized that the resulting
structure ent-4 was (+)-arizonin C1![16] Stunned about the dis-
crepancy he had the key intermediate 4 of the earlier ap-
proach[18a] (Scheme 1) processed with AD-mix α (i. e., not, as
published,[18a] with AD-mix β). Carrying the resulting product
through the remainder of our sequence,[18a] they reached (−)-
arizonin C1 (4).[16] This was the same enantiomer, which ac-
cording to our report[18a] stemmed from dihydroxylating the in-
termediate 4 with AD-mix β. Obviously, we, too, must have
converted 4 into (−)-arizonin C1 using AD-mix α. Thus, at some
point we confounded a sample made for reaching the desired
enantiomer 4 with an oppositely configured sample,[18b] which
we carried through the identical sequence of steps for calibrat-
ing our HPLC analyses of the ee’s of the intermediates en
route to 4.
OH
O
R
OH
O
OR
O
7
MeO
5
O
O
O
8
3a
11b
O
O
O
O
O
O
O
O
O
1, R = Me: (+)-kalafungin[2] ent-1: (−)-nanaomycin D[3] 3, R = H: (−)-arizonin B1[6]
2, R = iPr: (+)-frenolicin B[4]
4, R = Me: (−)-arizonin C1[6]
O
OR
O
O
O
OH
O
9
MeO
1
4
O
8
OH
O
3
O
O
O
OR
MeO
OH
O
O
arizonin B2[6]
6, R2 = Me2: (−)-arizonin C3[6]
OH
O
5, R2 = H2:
O
7: (+)-γ-actinorhodin[7]
Figure 1: Representative naphthoquinonopyrano-γ-lactone natural
products: “monomers” (top and bottom left) and a “dimer” (bottom right).
Except the arizonins B2 and C3 these compounds have been synthe-
sized prior to the present study. We describe the first synthesis of (−)-
arizonin B1 (3), which does not proceed via (−)-arizonin C1 (4), and an-
other synthesis of (−)-arizonin C1 (4).
Five of the seven naphthoquinonopyrano-γ-lactone natural
products shown in Figure 1 have been a synthetic target so far:
From our perspective making up for this flaw required de-
signing another arizonin C1 synthesis from scratch. The ac-
cess, which resulted allowed us to reach (−)-arizonin C1 anew.
This confirms its stereostructure as 4, just as deduced by Fer-
nandes.[16] Moreover, our second generation synthesis of (−)-
arizonin C1 was adopted to also making (−)-arizonin B1. The
latter possesses stereostructure 3. This is another confirmation
of Fernandes’ results.[16]
kalafungin (1),[10,11] nanaomycin
D
(ent-1),[12] frenolicin
B
and
(2),[13,14] arizonin B1 (3),[15, 16] arizonin C1 (4),[15,16,17,18]
8
Ref.[6a] neither substantiates this claim by revealing details of the ORD
spectrum of (–)-arizonin B1 (3) nor details the origin of the “ORD spectrum of
(+)-kalafungin” (cf. ref.[2b]!).
9 Considering that both (–)-arizonin B1 (3) and (–)-arizonin C1 (4) are levora-
totary (ref.[6a]) and (+)-kalafungin (1) is dextrorotatory (ref.[2a]) one wonders
whether the absolute configurations should not rather be all opposite (cf. the
respective deliberations in ref.[18a]).
10
a) Total syntheses of rac-kalafungin (rac-1): T. Li, R. H. Ellison, J. Am.
Chem. Soc. 1978, 100, 6263-6265; b) G. A. Kraus, H. Cho, S. Crowley, B.
Roth, H. Sugimoto, S. Prugh, J. Org. Chem. 1983, 48, 3439-3444; c) G. A.
Kraus, J. Li, M. S. Gordon, J. H. Jensen, J. Org. Chem. 1995, 60, 1154-
1159.
11
Total syntheses of (+)-kalafungin (1): a) K. Tatsuta, K. Akimoto, M. Anna-
ka, Y. Ohno, M. Kinoshita, Antibiot. 1985, 680-682; b) K. Tatsuta, K.
Akimoto, M. Annaka, Y. Ohno, M. Kinoshita, Bull. Chem. Soc. Jpn. 1985, 58,
1699-1706; 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.
12
Total syntheses of (–)-nanaomycin D (ent-1): a) Ref.[11a]; b) ref.[11b]; c)
M. P.Winters, M. Stranberg, H. W. Moore, J. Org. Chem. 1994, 59, 7572-
7574; d) ref.[11c]; e) N. P.S. Hassan, B. J. Naysmith, J. Sperry, M. A.
Brimble, Tetrahedron 2015, 71, 7137-7143.
13
Total syntheses of rac-frenolicin B (rac-2): a) A. Ichihara, M. Ubukata, H.
Oikawa, K. Murakami, S. Sakamura, Tetrahedron Lett. 1980, 21, 4469-4472;
b) ref.[10c]; c) P. Contant, M. Haess, J. Riegl, M. Scalone, M. Visnick,
Synthesis, 1999, 821-828; d) ref.[10c]; e) C. D. Donner, Synthesis 2010,
415-420; f) C. D. Donner, M. I. Casana, Tetrahedron Letters 2012, 53, 1105-
1107.
18
a) First synthesis of (–)-arizonin C1 (4): M. Mahlau, R. A. Fernandes, R.
Brückner, Eur. J. Org. Chem. 2011, 4765-4772; b) regrettably, we confoun-
ded the enantiomers at some point. As a consequence thereof ref.[18a] de-
picts (–)-arizonin C1 (4) with the wrong absolute configuration. Fernandes
corrected this mistake in [ref.16], we in footnote 133 of ref.[25].
14 Total syntheses of (+)-frenolicin B (2): a) G. A. Kraus, J. Li, J. Am. Chem.
Soc. 1993, 115, 5859-5860; b) T. Masquelin, U. Hengartner, J. Streith, Helv.
Chim. Acta, 1997, 80, 43-58; c) R. Fernandes, R. Brückner, unpublished; d)
ref.[11e]; e) 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.
15 Syntheses of racemic 5-epi-arizonin B1 (rac-5-epi-3) and of racemic 5-epi-
arizonin C1 (rac-5-epi-4): M. A. Brimble, S. J. Phythian, Tetrahedron Lett.
1993, 34, 5813-5814.
19 Synthetic approaches towards (+)-γ-actinorhodin (7): a) M. A. Brimble, L. J.
Duncalf, S. J. Phythian, Tetrahedron Lett. 1995, 36, 9209-9210; b) M. A.
Brimble, L. J. Duncalf, S. J. Phythian, J. Chem. Soc., Perkin Trans. 1, 1997,
1399-1403; c) M. A. Brimble, L. J. Duncalf, D. Neville, J. Chem. Soc., Perkin
Trans. 1, 1998, 4165-4173; d) M. A. Brimble, F. Issa, Aust. J. Chem. 1999,
52, 1021-1028; e) S. V. Mulay, A. Bhowmik, R. A. Fernandes, Eur. J. Org.
Chem. 2015, 4931-4938; f) S. V. Mulay, R. A. Fernandes, Chem. Eur. J.
2015, 21, 4842-4852.
16
Syntheses of (–)-arizonin C1 (4) and the unnatural antipodes (+)-ent-
arizonin B1 (ent-3) and (+)-ent-arizonin C1 (ent-4): R. A. Fernandes, S. V.
Mulay, V. P. Chavan, Tetrahedron Asym. 2013, 24, 1548-1555.
17 First synthesis of rac-arizonin C1 (rac-4): M. A. Brimble, S. J. Phythian, H.
Prabaharan, J. Chem. Soc. Perkin Trans 1, 1995, 2855-2860.
20
Total synthesis of (+)-γ-actinorhodin (7): M. Neumeyer, R. Brückner,
Angew.
10.1002/ange.201611183.
Chem.
2017,
DOI:
10.1002/anie.201611183,
DOI:
3
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
show how this selectivity can be modified by modifying the pro-
tective groups in the naphthalene moiety.[23]
An Aryne/Furan Diels-Alder Approach to the
Cores of Arizonins B1 and C1
The interconvertibility of arizonin B1 (3) and arizonin C1 (4)
through O-methylation[24] and mono-O-demethylation, respec-
tively, is known.[16] The backward reaction made racemic 5-epi-
arizonin C1 (rac-epi-4) a precursor of 5-epi-arizonin B1 (rac-
epi-3)[15] and, likewise, (+)-arizonin C1 (ent-4) a precursor of
(+)-arizonin B1 (ent-3).[16] In the forward sense, (–)-arizonin B1
(3) may be considered as a precursor of (–)-arizonin C1 (4). In-
deed, in the present study we prepared (–)-arizonin B1 (3) first
and continued to (–)-arizonin C1 (4) by an O-methylation. The
second premise for the current approach to (–)-arizonin C1 (4)
via (–)-arizonin B1 (3) was to establish the absolute configura-
tion of arizonin B1 and C1 by an asymmetric cis,vic-dihydroxy-
lation of a trans-configured β,γ-unsaturated ester 15 (Scheme
1). This kind of transformation suits well for accessing γ-lac-
tones of high ee values.[25] Under the respective dihydroxylati-
on conditions β-hydroxy-γ-lactones form in a single operation
because the initially formed β,γ-dihydroxyesters lactonize spon-
taneously.
Scheme 1. Top (white background): Sketch of the first synthesis of (−)-
arizonin C1 by our group.[18a] If we had performed the asymmetric dihy-
droxylation as published,[18a] i. e., using AD-mix β, we would have ob-
tained the mirror images of the structures 9 and 4 shown here. Hind-
sight[18b] made clear that we used AD-mix α. Therefore, we must have
obtained the molecules 9 and 4 depicted here. Fernandes re-synthe-
sized 8 and deliberately dihydroxylated it with AD-mix α.[16] He thereby
obtained 9 first and 4 in the sequel.[16] Bottom (grey background):
Sketch of the first synthesis of (+)-arizonin C1 (ent-4) by Fernandes´
group.[16]
The arizonin C1 syntheses of ourselves[18a] (Scheme 1, at top)
and Fernandes et al.[16] (Scheme 1, at bottom) share one key
feature and differ with respect to a second one. The common
feature is establishing a pentasubstituted naphthalene by de-
novo syntheses of the aromatic nucleus[21] by Dötz reactions
between the Fischer carbene 11 and the alkynes 10[18a] or
12.[16] The major difference between the arizonin C1 syntheses
of Scheme 1 is the origin of the configurational homogeneity. In
our approach,[18a] it stems from a highly enantioselective Sharp-
less dihydroxylation, in Fernandes’ synthesis[16] from the incor-
poration of
D-glucono-δ-lactone (13). Last but not least, both
Scheme 2. Tracing back (–)-arizonin C1 (4) to arizonin (–)-B1 (3) retro-
synthetically and simplifying the latter towards a de-novo synthesis of
tetraoxygenated naphthalenes 16 by the Diels-Alder reaction of a 3,4-
dioxygenated aryne 17 with a 2-oxygenated furan 18.− PG-PG’’’ = pro-
tective groups
syntheses of Scheme 1 encountered the same selectivity prob-
lem: the methylated stereocenter of the dihydropyran moiety
formed no better than with ds[22] = 67:33[18a] and 73:27[16], re-
spectively. The syntheses, which we disclose in the following
Starting from the mentioned presuppositions we continued our
retrosynthetic analysis of (–)-arizonin C1 (4) – and arizonin B1
(3) – beyond the unsaturated ester 15 as shown in Scheme 2.
Such esters are often reached by Heck coupling an aryl halide
21 De-novo approaches to naphthalenes continue sparking synthetic interest.
Selected recent examples: a) F. Wagner, K. Harms, U. Koert, Org. Lett.
2015, 17, 5670-5673; b) L. S. Kocsis, H. N. Kagalwala, S. Mutto, B. Godugu,
S. Bernhard, D. J. Tantillo, K. M. Brummond, J. Org. Chem. 2015, 80,
11686-11698; c) T. A. Unzner, A. S. Grossmann, T. Magauer, Angew.
Chem. 2016, 128, 9915-9919; Angew. Chem. Int. Ed. 2016, 55, 9763-9767;
d) H. Takikawa, A. Nishii, K. Suzuki, Synthesis 2016, 48, 3331-3338; e) our
approach in Scheme 4.
22
We distinguish the terms „ds“ and „d.r.“ rather than use them as syno-
nyms. „Diastereoselectivity“ (ds) characterizes the selectivity, with which a
stereogenic step generates a crude mixture of diastereomers. A „diastereo-
meric ratio“ (d.r.) describes the compositions of chromatographed or recrys-
tallized materials. In follow-up steps, the d.r. values of whatever substrate/-
product pair may vary: to the extent, with which the respective purification
procedure depletes or enriches the minor diastereomer. These variations do
not alter, of course, the „diastereoselectivity“ of the preceding diastereogenic
step.
23
We surmise that the responsible factor is a „steric relay effect“. It exerted
diasterocontrol in a total synthesis (ref.[20]) of γ-actinorhodin (7).
24
Related O-methylations succeeded with natural (+)-kalafungin (1; ref.[2b])
or with a precursor of racemic arizonin C1 (rac-4; ref.17]).
25 Nonracemic γ-lactone syntheses based on the asymmetric dihydroxylation
of such esters were reviewed recently: M. Neumeyer, R. Brückner, Eur. J.
Org. Chem. 2016, 5060-5087.
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
to an alkyl but-3-enoate.[26] This approach defined type-14
naphthyl halides as desirable precursors. While not described
in the literature they looked accessible by brominating[27] or io-
dinating[28] type-16 naphthalenes. An attractive way of getting
hold of such substrates seemed to be the Diels-Alder reaction
of an aryne 17 oxygenated at C-3 and C-4 (PG’’ being a pro-
tective group) with a furan[29] oxygenated at C-2[30] (PG’’’ being
another protective group). Eventually, we interpreted the aryne
17 as 3-(benzyloxy)-4-methoxybenz-1-yne (17a;[31] formula:
Scheme 3) and the furan 18 as 2-(triisopropylsiloxy)furan
(18a;[32] formula: Scheme 3).
26
a) C. N. Eid, J. Shim, J. Bikker, M. Lin, J. Org. Chem. 2009, 74, 423-426;
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) S. Korwar, T.
Nguyen, K. C. Ellis, Bioorg. Med. Chem. Lett. 2014, 14, 271-274; 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.
Scheme 3. Starting material synthesis for this study’s de-novo prepara-
tion of type-16 naphthalenes. Striving for Diels-Alder reactions between
3,4-dioxygenated arynes 17 and 2-oxygenated furans 18, we started by
synthesizing the bromotosylate 23 as a precursor of aryne 17a and the
(triisopropylsiloxy)furan 18a as the corresponding diene. Reagents and
conditions: a) Br2 (1.0 equiv.), NaOAc (2.0 equiv.) Fe powder (8.0 mol-
%), HOAc, room temp., 5 h; 73% (ref.[33]: 70%); b) K2CO3 (3.0 equiv.),
BnCl (1.5 equiv.), EtOH, reflux,
mCPBA (1.5 equiv.), CH2Cl2, reflux, 14 h; aq. workup; aq. KOH (10%,
4.0 equiv.), room temp., 3 h; 94%; d) TsCl (1.5 equiv.), NEt3 (1.5
27
1-Substituted 2-oxygenated naphthalenes are brominated at C-6, i. e.,
“opposite” to the oxygen-containing substituent at C-2. Recent examples: a)
C. Fehér, B. Urbán, L. Ürge, F. Darvas, J. Bakos, R. Skoda-Földes,
Tetrahedron 2011, 67, 6327-6333; b) L. Feng, Y. Wang, F. Liang, M. Xu, X.
Wang, Tetrahedron, 2011, 67, 3175-3180; c) J.-K. Ou-Yang, Y.-Y. Zhang,
M.-L. He, J.-T. Li, X. Li, X.-L. Zhao, C.-H. Wang, Y. Yu, De-X. Wang, L. Xu,
H.-B. Yang, Org. Lett. 2014, 16, 664-667; d) J. Yadav, G. R. Stanton, X. Fan,
J. R. Robinson, E. J. Schelter, P. J. Walsh, M. A. Pericas, Chem. Eur. J.
2014, 20, 7122-7127; e) J. M. Wieting, T. J. Fisher, A. G. Schafer, M. D.
Visco, J. C. Gallucci, A. E. Mattson, Eur. J. Org. Chem. 2015, 525-533; f) Y.
Zhao V. Snieckus, Org. Lett. 2015, 17, 4674-4677.
1 : quant.); c)
d; 98% (ref.[34]
equiv.), CH2Cl2, 0°C
→
room temp., 16 h; 99%; e) N,N-
dimethylethanolamine (34 mol-%.), formic acid (2.0 equiv.), H2O2 (30%
in H2O, 2.0 equiv.), Na2SO4, room temp., 16 h; 59% (ref.[37]: 58%); f)
iPr3SiOTf[38] (1.2 equiv.), NEt3 (1.3 equiv.), CH2Cl2, 0°C → room temp.,
1 h; 98% (ref.[37]: 94%).
28
1-Substituted 2-oxygenated naphthalenes are iodinated at C-6, i. e., “op-
posite” to the oxygen-containing substituent at C-2, e. g.: a) ref.[27a]; b) T.
Kamei, H. Shibaguchi, M. Sako, K. Toribatake, T. Shimada, Tetrahedron
Lett. 2012, 53, 3894-3896.
29
Diels-Alder reactions of arynes with furans devoid of an oxygen-
Giles et al. generated the aryne 17b from the bromotosylate 26
by a Br/Li exchange reaction and an ensuing β-elimination of
lithium para-toluenesulfinate (Scheme 3, bottom right).[30c] In
the bromotosylate 23, which we forsaw as a precursor of the
differently protected aryne 17a, the positions of Br and OTs
were swapped. This made the bromotosylate 23 accessible in
fewer steps – namely four (Scheme 3, top) – than a benzyl
analog of the bromotosylate 26. Step 1 was the bromination of
isovanillin (19) giving 2-bromoisovanillin (20[33]). Step 2 was an
O-benzylation (→ aldehyde 21[34]). Step 3 was a Dakin oxidati-
on.[35] It turned the last-mentioned aldehyde into the phenol 22
−via a formate, which was hydrolyzed in situ.[36] Step 4, a tosyl-
ation, accomplished the bromotosylate 23 in 67% overall yield.
The (triisopropylsiloxy)furan (18a) was gained from furfural (24)
by Pihko’s 2-step synthesis (Scheme 3, bottom left).[37] Step 1
was a Dakin-type oxidation. In-situ hydrolysis of the initially
formed formate and a subsequent tautomerization gave 59% of
the butenolide 24. Treatment of this compound with freshly pre-
pared iPr3SiOTf[38] provided 98% of the siloxyfuran 18a.
substituent at C-2 render oxo-bridged 1,4-dihydronaphthalenes {=
[2,3]benzo-(7-oxabicyclo[2.2.1]hepta-2,5-dienes)}. They were carried on to
naphth-1-ols by acidic hydrolyses. First example: a) G. Wittig, L. Pohmer,
Angew. Chem. 1955, 13, 348-348. b) G. Wittig, L. Pohmer, Chem. Ber. 1956,
89, 1334-1351; other early examples: c) E. Wolthuis, B. Bossenbroek, G.
DeWall, E. Geels, A. Leegwater, J. Org. Chem. 1963, 28, 148-152; d) M.
Nakata, M. Kinoshita, Tetrahedron Lett. 1984, 25, 1373-1376; e) K. Jung, M.
Koreeda, J. Org. Chem. 1989, 54, 5667-5675; f) ref.[15] (used for making a
naphthoquinonopyrano-γ-lactone); g) ref.[17] (used for making a naphthoqui-
nonopyrano-γ-lactone); h) M. A. Brimble, L. J. Duncalf, S. J. Phythian,
Tetrahedron Lett. 1995, 36, 9209-9210 (used for making a naphthoquinono-
pyrano-γ-lactone).
30
Diels-Alder reactions of 3-oxygenated arynes with 2-oxygenated furans
give oxa-bridged 1,4-dihydronaphthalenes {= [2,3]benzo-(7-oxabicyclo-
[2.2.1]hepta-2,5-dienes)} with “orientational selectivity” (notion: ref.[40]; de-
tails: ref.[30]). These compounds inevitably hydrolyze during aqueous work-
up and deliver mono-O-protected naphthohydroquinones thereby. Orientati-
onal selectivity starting from a 3,4-benzannulated lithium furan-2-olate: a) C.
A. Townsend, S. G. Davis, S. B. Christensen, J. C. Link, C. P. Lewis, J. Am.
Chem. Soc. 1981, 103, 6885-6888; orientational selectivity starting from 2-
acetoxyfuran: b) R. G. F. Giles, M. V. Sargent, H. Sianipar, J. Chem. Soc.
Perkin Trans 1 1991, 1571-1579; orientational selectivities starting from 2-
methoxyfuran: c) R. G. F. Giles, A. B. Hughes, M. V. Sargent, J. Chem. Soc.
Perkin Trans. 1 1991, 1581-1587; d) T. Matsumoto, T. Hosoya, M. Katsuki,
K. Suzuki, Tetrahedron Lett. 1991, 32, 6735-6736; e) T. Matsumoto, T.
Hosoya, K. Suzuki, J. Am. Chem. Soc. 1992, 114, 3568-3570; f) ref.[15]; g)
T. Hosoya, E. Takashi, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 1994,
116, 1004-1015; h) ref.[17]; i) M. A. Brimble, L. J. Duncalf, S. J. Phythian, J.
Chem. Soc., Perkin Trans. 1 1997, 1399-1403 (used for making a naphtho-
quinonopyrano-γ-lactone); j) S. Futagami, Y. Ohashi, K. Imura, T. Hosoya, K.
Ohmori, T. Matsumoto, K. Suzuki, Tetrahedron Lett. 2000, 41, 1063-1067; k)
M. A. Brimble, M. Y. H. Lai, Org. Biomol. Chem. 2003, 1, 2084-2095 (used
for making a naphthoquinonopyrano-γ-lactone); orientational selectivity start-
ing from a trisubstituted 2-ethoxyfuran: l) D. J. Pollart, B. Rickborn, J. Org.
Chem. 1987, 52, 792-798; orientational selectivity starting from 2-(tert-
butyldimethylsiloxy)furan: m) T. Matsumoto, H. Yamaguchi, M. Tanabe, Y.
Yasui, K. Suzuki, Tetrahedron 1995, 51, 7347-7360.
32
The only example of a Diels-Alder reaction of an aryne, albeit symmetric,
and 2-(triisopropylsiloxy)furan (18a), of which we are aware, is by S.
Narayan, W. R. Roush, Org. Lett. 2004, 6, 3789-3792.
33 A. K. Sinhababu, R. T. Borchardt, J. Org. Chem. 1983, 48, 2356-2360.
34
B. Cheng, S. Zhang, L. Zhu, J. Zhang, Q. Li, A. Shan, L. He, Synthesis
2009, 41, 2501-2504.
35
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.
36 A Dakin oxidation delivering 22 was unknown. We performed it by a proce-
dure of M. Altemöller, T. Gehring, J. Cudaj, J. Podlech, H. Goesmann, C.
Feldmann, A. Rothenberger, Eur. J. Org. Chem. 2009, 2130-2140.
31 Aryne 17a had not been described in the literature whereas aryne 17b had
{a) ref.[30c]; b) ref.[15]; c) ref.[17]}. However, if we had converted the latter to
a type-16 naphthalene by following the approach of Scheme 2 we would
have reached (–)-arizonin C1 (4) first and, by demethylation, (–)-arizonin B1
(3) thereafter. However, we targeted (–)-arizonin B1 (3) first and, by
deprotection and O-methylation, (–)-arizonin C1 (4) thereafter. This is why
we’d rather employ the aryne 17a.
37
E. K. Kemppainen, G. Sahoo, A. Valkonen, P. M. Pihko, Org. Lett. 2012,
14, 1086-1089.
38 We prepared iPr3SiOTf from iPr3SiH and TfOH (1.2 equiv.) directly prior to
use, adopting conditions from two sources: 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.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
bound Boc group provided the carbonate 16c. It was our first
type-16 substrate to react with NBS/DMF as expected.[27] The
bromonaphthalene 14c resulted in 94% yield as a single iso-
mer, i. e., without a trace of the regioisomer iso-14c.[41]
OBn OMe
OH OMe
OBocOMe
MeO
MeO
MeO
a)
b)
OMe
OMe
OMe
16a
16b
16c
(preparation: Scheme 4)
c)
OBocOMe
MeO
OBocOMe
8a
MeO
MeO
d)
8
7
2
3
5
4
4a
Br
Br
OMe
OMe
MeO
30
O
15c
14c
without
MeO
O
e)
OBocOMe
MeO
OBocOMe
8a
OH
8
6
2
3
Scheme 4. The aryne / furan Diels-Alder reaction delivering the naphthalene
core of the arizonins of this study. Reagents and conditions: a1) 18a
(1.5 equiv.), THF, –78°C; dropwise addition of BuLi (in hexane, 1.0 equiv.),
THF, –78°C; 5 min; –78°C → room temp., 45 min; a2) cooling to 0°C; addi-
tion of Bu4NF (in THF, 1.5 equiv.), 0°C → room temp., 8 min; 85%; b)
Me2SO4 (10 equiv.) KOH (8 equiv.), Bu4NBr (5.0 mol-%), THF/H2O (2:1), 0°C
→ room temp., 14 h; 75%.
5
4
4a
O
OMe
OMe
31
f)
iso-14c
O
O
OH OMe
OBocOMe
MeO
MeO
5
O
O
3a
With the bromotosylate 23 and the furan 18a in our hands
(Scheme 3), we dissolved a mixture thereof in THF and added
1.0 equiv. BuLi at –78°C.[39] This must have generated the ar-
yne 17a and therefrom mainly the Diels-Alder adduct 27 (“prox-
imal” orientational isomer[40]) and subordinately the Diels-Alder
adduct iso-27 (“distal” orientational isomer[40]) (Scheme 4). This
course of events followed from isolating, after hydrolyzing the
crude product with aq. HCl, 62% of the naphthol 28 (as a 50:50
mixture with iPr3SiOH) and 12% of the isomeric naphthol iso-28
(as a 78:22 mixture with iPr3SiOH). This is the result of an iden-
tical orientational preference as in all previously studied Diels-
Alder reactions between 3-oxygenated arynes and 2-oxygena-
ted furans.[30] When we treated the crude mixture of naphthols
28 and iso-28 with a THF solution of tetrabutylammonium fluo-
ride, it converged to 85% of one uncontaminated naphthohy-
droquinone 29. Double O-methylation afforded the correspond-
ing per-ether 16a in 75% yield.
O
O
OMe
33
OMe
O
32 (ds = 77:23)
flash chro-
matography
g)
h)
BocO
O
MeO
O
O
(dr = 100:0)
26 : 74
O
O
OMe O
OH
O
34
MeO
MeO
O
O
j)
i)
O
O
O
O
O
O
4 [( )-arizonin C1]
3 [( )-arizonin B1]
Scheme 5. Total syntheses of (–)-arizonin B1 (3) and (–)-arizonin C1 (4).
Reagents and conditions: a) H2, Pd (10 w-% on C, 1.5 mol-%), EtOAc, room
temp., 16 h; 100%; b) Boc2O (2.0 equiv.), NEt3 (2.0 equiv.), DMAP (10 mol-
%), CH2Cl2, 0°C
→ room temp., 16 h; 93%; c) NBS (1.0 equiv.), DMF, room
temp., 16 h; 94%; d) 30 (3.0 equiv), Pd2dba3·CHCl3 (2.0 mol-%), P(tBu)3
(8.0 mol-%), Cy2NMe (3.0 equiv.), toluene, reflux, 2 d; 82% of a 87:13 mix-
ture of 15c with the trans-configured α,β-unsaturated isomer; e)
K2OsO2(OH)4 (0.4 mol-%), (DHQ)2PHAL (1.0 mol-%), K3Fe(CN)6 (3.0 equiv.),
K2CO3 (3.0 equiv.), NaHCO3 (3.0 equiv.), MeSO2NH2 (1.0 equiv.),
tBuOH/H2O (2:1), room temp., 2 d; 60% (98.6% ee); f) acetaldehyde
(7.5 equiv.), BF3·OEt2 (10 equiv.), CH2Cl2, 0°C → room temp., 30 min; 75%
(ds = 77:23) and by re-purification thereof 51% (dr = 100:0); g) Boc2O
Synthetic (–)-Arizonin B1, Synthetic (–)-Arizo-
nin C1, Synthetic (+)-5-epi-Arizonin B1, and
Synthetic (+)-5-epi-Arizonin C1
NBS in DMF brominates 2-iodo-1,4,5,8-tetramethoxynaphtha-
lene with perfect regioselectivity.[20] This suggested to bromin-
ate the naphthalene tetraether 16a likewise. However, this
compound decomposed. The same occurred when we treated
the corresponding triether 16b – obtained from 16a hydro-
genolytically (Scheme 5) – with NBS in DMF. Introducing an O-
41 NMR-analyses in CDCl3 solution proved that we had obtained bromonaph-
thalene 14c rather than its isomer iso-14c as follows: The 1H-NMR spectrum
(500 MHz) depicts an aromatic d (Jortho = 9.3 Hz) as far down-field as
7.96 ppm that it must be 4-H. Accordingly, the other aromatic d ( = 7.35
ppm) is due to 3-H. Whether these locants reside in structure 14c or struc-
ture iso-14c remains open. In this regard, the aromatic s at = 6.86 ppm is
δ =
39
δ
These conditions resemble conditions for making another aryne for a
Diels-Alder reaction with 2-methoxyfuran: ref.[15].
40
δ
Any Diels-Alder reaction between an unsymmetric dienophile and an un-
of no help, either: it may be caused by 7-H of structure 14c or by 6-H of
structure iso-14c. Distinguishing features: (1) In an HMBC spectrum (500
MHz / 126 MHz) 3-1H showed a cross-peak to exactly 1 “bridgehead” 13C nu-
symmetric diene may lead to “orientational isomers”. The favored “orienta-
tional isomer” obtained from a dienophile with an electron-withdrawing group
at C-1 and from diene oxygenated at C-1 is often called an “ortho”-adduct.
Analogously, the respective disfavored “orientational isomer” would be a
“meta”-adduct. In the case at hand, the orientationally isomeric Diels-Alder
adducts from 3-oxygenated benz-1-ynes and 2-oxygenated furans have no
established designations. The respectivé favored “orientational isomer” is a
1,4-dihydronaphthalene, which is dioxygenated at C-1 and monooxygenated
at C-8, i. e., at a close-by position. Accordingly, this isomer may be called the
cleus (in 14c and in iso-14c explicable by 3J3-H,C-4a
, δC-4a being 125.61 ppm).
The same “bridgehead” 13C nucleus showed no cross-peak to the aromatic
singlet at 6.88 ppm (in 14c explicable because JC-4a,7-H would be 4JC,H; in iso-
3
14c inexplicable because JC-4a,6-H would be JC,H). (2) In the same HMBC
spectrum (500 MHz / 126 MHz) 4-1H displayed a cross-peak to exactly 1
3
“bridgehead” 13C nucleus (in 14c and in iso-14c explicable by J4-H,C-8a
,
δC-8a
“proximal”-adduct. The disfavored “orientational isomer” is
a
1,1,5-
being 120.87 ppm). The same “bridgehead” 13C nucleus displayed a cross-
peak to the aromatic singlet at 6.86 ppm (in 14c explicable because JC-8a,7-H
would be 3JC,H; in iso-14c inexplicable because JC-8a,6-H would be 4JC,H).
triioxygenated naphhtalene. We refer to it as a “distal” product throughout the
remainder of the text.
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
Table 1. Specific rotations (589 nm) in methanol of both enantiomers of
arizonin B1 (3) and arizonin C1 (4) published elsewhere or measured
here.
(2.0 equiv.), NEt3 (2.0 equiv.), DMAP (10 mol-%), CH2Cl2, 0°C → room
temp., 16 h; 85%; h) (NH4)2Ce(NO3)6 (2.0 equiv.), MeCN/H2O (1:1), room
temp., 20 min; 39% 34 separated from 14% 3; i) CF3CO2H/CH2Cl2 (1:1),
room temp., 30 min; quant.; j) MeI (20 equiv.), Ag2O (14 equiv.), CH2Cl2,
room temp., 18 h; 34% 4.
OH
O
OH
O
MeO
MeO
O
O
The bromonaphthalene 14c and methyl but-3-enoate (30) un-
derwent a Heck-copuling in 82% yield (Scheme 5). It delivered
a 87:13 mixture of the trans-isomers of the β,γ-unsaturated es-
ter 15c and the isomeric α,β-unsaturated ester.[26] An asym-
metric Sharpless dihydroxylation of this mixture in the presence
of NaHCO3 (“buffered conditions[42]) furnished the hydroxy-
lactone 31 (60% yield, 98.6% ee[43]).
O
O
O
O
O
O
Entry
3 [( )-arizonin B1]
ent-3 [( )-arizonin B1]
1
2
natural[6a]
Fernandes et al.[18a]
53.0 (c = 0.112)
137.0 (c = 0.108)
168.0 (c = 0.024)
88.9 (c = 0.011)
The dihydropyran ring was annulated to the last-mentioned
compound by what is often called an “oxa-Pictet-Spengler re-
action[44]”. It is a variant of the “classical Pictet-Spengler reac-
tion[45]”, i. e., an intramolecular Mannich reaction wherein an
electron-rich aromatic is the nucleophile. In a classical Pictet-
Spengler reaction the electrophile is an iminium-ion. However,
it is an carboxoxonium-ion in oxa-Pictet-Spengler reactions. In
Scheme 5, this carboxonium-ion was generated from the hy-
droxylactone 31, acetaldehyde, and BF3·OEt2. Nucleophilic at-
tack by the electron-rich aromatic completed the oxa-Pictet-
Spengler reaction. It provided a 77:23 mixture of tetracyclic di-
astereomers possessing a 3a,5trans- and 3a,5cis-configuration,
respectively. Re-purification by flash-chromatography on sili-
cagel[46] rendered 51% of the pure diastereomer 3a,5trans-32.[47]
It was deprived of the Boc group of its antecessor 31, contain-
ing a phenolic proton instead [δ = 8.64 ppm (s), 400 MHz,
CDCl3]. This leaves open, however, whether Boc loss preced-
ed dihydropyran formation or ensued.
166.6 (c = 0.108 in CHCl3)
169.7 (c = 0.097)
3
this work
OMe O
OMe O
MeO
MeO
O
O
O
O
O
O
O
O
Entry
4 [( )-arizonin C1]
ent-4 [( )-arizonin C1]
4
5
natural[6a]
Brückner et al.[16]
Fernandes et al.[18a]
84.3 (c = 1.017)
86.5 (c = 0.7)
6
72.4 (c = 0.84)
79.2 (c = 0.7)
76.6 (c = 0.35)
75.3 (c = 0.7)
88.2 (c = 0.25)
77.2 (c = 0.1)
68.0 (c = 0.01)
93.9 (c = 0.04)
112.0 (c = 0.01)
7
this work
159.2 (c = 0.34)
142.2 (c = 0.085)
Completing the arizonin B1 synthesis of Scheme 5 seemed to
require no more than a (NH4)2Ce(NO3)6 oxidation of compound
3a,5trans-32. Establishing the naphthoquinone motif thereby
was a mandatory step in any previous arizonin[16,17,18] or 5-epi-
arizonin synthesis.[15] However, substrate 3a,5trans-32 decom-
posed when treated with (NH4)2Ce(NO3)6. Suspecting the free
OH group as responsible, we protected it with a Boc group.
Our synthetic arizonins were levorotatory – like the respective
natural products[6a] (Table 1, entries 1 and 4). However, the ab-
solute values of the specific rotations of our synthetic arizonins
and the natural products differed markedly. For instance, the
absolute value [α]D of our synthetic (–)-arizonin B1 [(–)-3]
(Table 1, entry 3) was more than 3 times that of natural (–)-3
(Table 1, entry 1[6a]). Similarly, the absolute value [α]D of our
synthetic (–)-arizonin C1 [(–)-4] (Table 1, entry 7) was almost
twice that of natural (–)-4 (Table 1, entry 4[6a]). Moreover, our
newly obtained (–)-arizonin C1 [(–)-4] did not dissolve in MeOH
in higher concentrations than about c = 0.35. Therefore, we
could not confirm the respective rotation, which we had report-
ed in 2011 (Table 1, entry 5[18a]). It should be recalled that Fer-
nandes’ synthetic arizonins (+)-ent-3, (+)-ent-4, and [(–)-4 also
differed more non-negligibly from their natural role models re-
garding [α]D values (Table 1, entries 2,[16] 6[16]). They even
seemed to show a concentration dependency.[16] Be this as un-
satisfying as it may, the data of Table 1 reveal a 1:1 correlation
between the sign of the specific rotation and the absolute con-
figuration. Accordingly, the levorotation of this work´s synthetic
samples of (–)-arizonin B1 [(–)-3] and (–)-arizonin C1 [(–)-4]
proves their (3aS,5S,11bS) rather than (3aR,5R,11bR) configu-
rations – and thereby the identical configurations of the respec-
tive natural products.
The
resulting
carbonate
33
was
oxidizable
with
(NH4)2Ce(NO3)6. This gave the Boc-protected naphthoquinone
34 in 39% yield and the Boc-free naphthoquinone 3, i. e.(–)-
arizonin B1 [(–)-3] in 14% yield. The Boc-protected naphtho-
quinone 34 and trifluoroacetic acid delivered a second crop of
(–)-arizonin B1 [(–)-3] in quantitative yield. Its O-methylation
with MeI/Ag2O provided synthetic (–)-arizonin C1 [(–)-4] in 34%
yield.
42
Method: K. P. M. Vanhessche, Z.-M. Wang, K. B. Sharpless, Tetrahedron
Lett. 1994, 35, 3469-3472.
43 This ee was determined by chiral HPLC (details: “Experimental Section”).
44
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.[11e]; c) R. Bartholomäus, J. Bachmann, C. Mang, L. O. Haustedt, K.
Harms, U. Koert, Eur. J. Org. Chem. 2013, 180-190; d) ref.[19e]; e) ref. [20].
45 First report: A. Pictet, T. Spengler, Ber. dtsch. Chem. Ges. 1911, 44, 2030-
2036.
46 W. C. Still, M. Kahn, A. Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
47
The trans-orientation of 5-CH3 and 3a-C in the dihydropyran moiety of
tetracycle 3a,5trans-32 implies a cis-orientation of 5-CH3 and 3a-H. The latter
followed from the occurrence of a respective cross-peak in the NOESY
spectrum.
7
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
OH OMe
OPiv OMe
OPiv OMe
dicated at the beginning of this paragraph, oxidations of com-
pound 36 with (NH4)2Ce(NO3)6 failed. Obtaining a complex mix-
ture of products, we tried to depivaloylate it under acidic and
under basic conditions but got no identifiable material either.[52]
MeO
MeO
MeO
a)
b)
Br
OMe
OMe
OMe
16b
16d
14d
(preparation: Scheme 5)
OBn OSiiPr3
OH OSiiPr3
O
O
c)
without
MeO
MeO
MeO
b)
c)
MeO
O
OPiv OMe
30
MeO
Br
OR
OMe
OMe
OPiv OMe
MeO
OPiv OMe
28: R = H (prepara-
tion: Scheme 4)
16f: R = Me
16g
16h
MeO
a)
OMe
OH
d)
d)
iso-14d
O
OMe
OMe
O
O
O
O
MeO
O
O
35 (97% ee;
15d
MeO
MeO
MeO
e)
at room temp. 55:45 mix-
ture of 1H-NMR rotamers)
e)
Br
Br
OMe
O
OMe
O
MeO
O
15h
14h
MeO
O
30
f)
without
OPiv OMe
MeO
OPiv O
MeO
O
O
5
5
O
O
f)
MeO
3 [( )-ari-
zonin B1]
OH
3a
3a
O
O
OMe
36
O
O
O
37
O
OMe
OMe
38
iso-14h
(pure diastereomer;
at room temp. 85:15 mix-
ture of 1H-NMR rotamers)
[= O-pivaloyl-( )-arizonin B1]
O
g) or h)
O
O
OH
O
O
OMe O
MeO
MeO
MeO
5
Scheme 6. Approaching (−)-arizonin B1 – in vain – with our most 3a,5trans-
selective oxa-Pictet-Spengler cyclization. Reagents and conditions: a)
Pivaloyl chloride (1.2 equiv.), NEt3 (2.4 equiv.), DMAP (5 mol-%), CH2Cl2,
5
5
O
O
O
3a
O
O
O
OMe
O
0°C
→ room temp., 16 h; 97%; b) NBS (1.0 equiv.), DMF, room temp., 16 h;
O
O
O
92%; c) 30 (3.0 equiv), Pd2dba3·CHCl3 (2.0 mol-%), P(tBu)3 (8.0 mol-%),
Cy2NMe (3.0 equiv.), toluene, reflux, 2d; 60% (of a 87:13 mixture of 15d with
the trans-configured α,β-unsaturated isomer); d) K2OsO2(OH)4 (0.4 mol-%),
epi-3 [( )-5-epi-arizonin B1] epi-4 [( )-5-epi-arizonin C1]
39 (ds = 100:0)
i)
j)
(DHQ)2PHAL (1.0 mol-%), K3Fe(CN)6 (3.0 equiv.), K2CO3 (3.0 equiv.),
NaHCO3 (3.0 equiv.), MeSO2NH2 (1.0 equiv.), tBuOH/H2O (3:1), room temp.,
2 d; 46% of
a 55:45 mixture of rotamers (97% ee); e) acetaldehyde
Scheme 7. Total syntheses of (+)-5-epi-arizonin B1 (epi-3) und (+)-5-epi-
arizonin C1 (epi-4). Reagents and conditions: a) Me2SO4 (10 equiv.) KOH (8
equiv.), Bu4NBr (20 mol-%), THF/H2O (2:1), 0°C → room temp., 19 h; 70%;
b) H2, Pd (10 w-% on C, 1.5 mol-%), EtOAc, room temp., 15 h; 99%; c)
CH2BrCl (1.2 equiv.), K2CO3 (1.2 equiv.), CsF (1.2 equiv.), DMF, 100°C,
16 h; 85%; d) NBS (1.0 equiv.), DMF, room temp., 16 h; 92%; e) 30
(3.0 equiv), Pd2dba3·CHCl3 (1.0 mol-%), P(tBu)3 (4.0 mol-%), Cy2NMe
(3.0 equiv.), toluene, reflux, 2 d; 66% of a 93:7 mixture of 15h with the trans-
(7.5 equiv.), BF3·OEt2 (10 equiv.), CH2Cl2, 0°C → room temp., 30 min; 58%
(ds = 100:0); f) CAN (2.0 equiv.) MeCN/H2O (1:1), room temp., 30 min;
treatment of the crude product either with KOH (2.0 equiv.), MeOH, room
temp., 30 min or: with conc. HCl/MeOH (1:1), room temp., 16 h.
Scheme 6 shows what would have been a highly stereoselec-
tive total synthesis of (–)-arizonin B1 [(–)-3] – had we only been
able to oxidize the oxa-Pictet-Spengler product 36 to the naph-
thoquinonopyrano-γ-lactone 37 and the latter, through
depivaloylation, into (–)-arizonin B1. The route of Scheme 6
starts with a pivaloylation of the previously mentioned (Scheme
5) naphthol 16b. It gave a 97% yield of the pivaloate 16d. It
was brominated with NBS in DMF in 92% yield to give the bro-
monaphthalene 14d without any regioisomer iso-14d.[48] The
bromonaphthalene 14d was Heck-coupled with the β,γ-unsat-
urated ester 30. The resulting 87:13 mixture of trans-configured
β,γ-unsaturated ester 15d and α,β-unsaturated isomer (not de-
picted) was Sharpless-dihydroxylated asymmetrically under
“buffered conditions[42]”. This gave the hydroxylactone 35[49] in
46% yield with 97% ee. Subjecting this compound and acet-
aldehyde to an oxa-Pictet-Spengler cyclization[44] in the pres-
ence of BF3-etherate, we obtained the 3a,5trans-configured[50]
dihydropyran diastereomer 36 exclusively (58% yield).[51] As in-
configured
α,β-unsaturated isomer; f) K2OsO2(OH)4 (0.4 mol-%),
(DHQ)2PHAL (1.0 mol-%), K3Fe(CN)6 (3.0 equiv.), K2CO3 (3.0 equiv.),
NaHCO3 (3.0 equiv.), MeSO2NH2 (1.0 equiv.), tBuOH/H2O (1:1), room temp.,
2 d; 52% (> 99% ee); g) acetaldehyde (7.5 equiv.), BF3·OEt2 (10 equiv.),
CH2Cl2, 0°C → room temp., 30 min; 78% (ds = 100:0); h) acetaldehyde di-
methyl acetal (7.5 equiv.), BF3·OEt2 (10 equiv.), CH2Cl2, 0°C → room temp.,
30 min; 78% (ds = 100:0); i) (NH4)2Ce(NO3)6 (2.0 equiv.), MeCN/H2O (1:1),
room temp., 30 min; 79% (dr = 100:0); j) MeI (20 equiv.), Ag2O (14 equiv.),
CH2Cl2, room temp., 18 h; 34%.
Counting from isovanillin (19) our (–)-arizonin B1 [(–)-3] syn-
thesis of Scheme 6 lasted 16 steps. This was partly due to
three protective group changes: Å SiiPr3 → Me (28 → 16a); Ç
Bn → Boc (16a → 16c); 3 H → Boc [32 (wherein the Boc
group had been lost) → 33]. In order to obviate such unproduc-
tive steps we varied our protective group strategy once more
(Scheme 7). We started by O-methylating the ring-opening
product 28 of the Diels-Alder adduct 27 of Scheme 4. The re-
sulting ether 16f was debenzylated by hydrogenolysis (→16g).
The silyl group was removed at 100°C by treatment with CsF in
DMF in the presence of K2CO3 and CH2BrCl. The latter two re-
48
The bromonaphthalene 14d was told apart from iso-14d analogously as
decibed in footnote [41] for the diffentiation of the bromonaphthalene struc-
tures 14c vs. iso-14c.
49 Compound 35 was depicted as a 55:45 mixture of two rotamers in the 1H-
NMR spectrum (400 MHz, CDCl3). However, chiral HPLC showed it to be
one 98:5:1.5 mixture of two enantiomers.
52
We tried to “save” our approach of Scheme 6 starting from the trichloro-
50
This configuration was proved analogously as detailed for the oxa-Pictet-
acetate analog 16i of pivaloate 16d. While it was brominated allright the re-
sulting bromide 14i did not Heck-couple with methyl 2-vinylacetate (30); in-
stead, it was was reduced to the corresponding dichloroacetate 16j (details:
Supporting Information).
Spengler product 3a,5trans-32 in footnote [47].
51 The dihydropyran 36 was a 85:15 mixture of rotamers in a room tempera-
ture 1H-NMR spectrum (500.4 MHz, CDCl3) but a single species at +60°C.
8
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
agents incorporated the available OH groups in the methylene
acetal 16h in 85% yield.[53] The four ensuing transformations of
Scheme 7 equalled those in the syntheses of Scheme 5 and
Scheme 6: 1) bromination with NBS/DMF (→ bromonaphtha-
lene 14h without any regioisomer iso-14h); 2) Heck coupling
with ester 30 [method: ref.[26]; → β,γ-unsaturated ester 15h con-
taminated by the α,β-unsaturated isomer (not depicted)]; 3)
asymmetric Sharpless dihydroxylation in the presence of
[42]
NaHCO3
(→ hydroxylactone 38; >99% ee); 4) oxa-Pictet-
Spengler reaction[44] of the latter compound with acetaldehyde
– or, giving the same result, with acetaldehyde dimethyl acetal
– and BF3 etherate. This step, however, proceeded with the op-
posite diastereoselectivity than the hydroxylactones 31 of
Scheme 5 and 35 of Scheme 6. In fact, the hydroxylactone 38
of Scheme 7 was the only substrate favoring the 3a,5cis-
diastereomer: the respective dihydropyran 39 formed even with
ds = 100:0[54] (78% yield)! An (NH4)2Ce(NO3)6 oxidation of the
oxa-Pictet-Spengler
product
3a,5cis-39
generated
the
naphthoquinone moiety. The concomitant loss of the methylene
acetal moiety liberates the OH group of what was synthetic (+)-
5-epi-arizonin B1 [(+)-5-epi-3]. O-methylation allowed to gain
synthetic (+)-5-epi-arizonin C1 [(+)-5-epi-4], too. Previously,
these two compounds were synthesized only as racemic mix-
tures.[15]
Protective Group Effects on the Induced Dia-
stereoselectivity of Acetaldehyde-Incorpora-
ting oxa-Pictet-Spengler Cyclizations
The oxa-Pictet-Spengler cyclizations 35→36 (Scheme 6) and
38→39 (Scheme 7) disclosed in the preceding Section are
unique in one regard: They proceed with perfect and comple-
mentary diastereoselectivities. Substrate 35 establishes
a
3a,5trans-substituted dihydropyran ring exclusively. Substrate 38
delivers a 3a,5cis-substituted dihydropyran moiety selectively.
Nonetheless, the oxygenation pattern of these oxa-Pictet-
Spengler substrates is the same. It is just the differential O-
protection, which makes these oxa-Pictet-Spengler reactions
take opposite steric courses. We are unaware of literature pre-
cedents, where exactly that has been observed: the tunability –
invertibility! – of the induced diastereoselectvity of such oxa-
Pictet-Spengler reactions by protective group variations in the
electron-rich aromatic nucleophile. These are remarkably re-
mote substituent effects.
53
F. Dallacker, J. Jacobs, W. Coerver, Z. Naturforsch. B 1983, 38, 1000-
1007 treated naphthalene-1,4,5,8-tetraol likewise, i. e., with K2CO3 and
CH2BrCl in DMF at 100°C. This introduced two methylene acetal moieties.
54
The cis-orientation of 5-CH3 and 3a-C in the dihydropyran moiety of tetra-
cycle 3a,5cis-39 implies a cis-orientation of 5-H and 3a-H [if numbered, for
consistency, not according to IUPAC but as shown in Scheme 7; this num-
bering adheres to the numbering principle in the congeners 32 (Scheme 5)
and 36 (Scheme 6)]. The latter followed from the occurrence of a respective
cross-peak in the NOESY spectrum.
9
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10.1002/ejoc.201700013
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FULL PAPER
Table 2: Acetaldehyde-incorporating oxa-Pictet-Spengler cyclizations in naphthoquinonopyrano-γ-lactone synthesis. Juxtaposition of substitution pat-
terns in the naphthalene moiety and the 3a,5-trans- or 3a,5-cis-selectivities, which they induce. For easier understanding, all lactones are depicted with the
identical absolute configuration. However, at times, the respective formula represents the mirror image of the enantiomer actually employed/obtained. It
should be noted that the span of reaction conditions is very wide. This concerns the reagent (acetaldehyde vs. acetaldehyde dimethyl acetal), the pro-
motor (usually BF3 etherate, once Me3SiOTf), the solvent (usually CH2Cl2, else Et2O/THF or CF3CO2H/THF), the temperature (between 0 and +70°C),
and the allotted time (between 55 s and 1 d).− Gray backgrounds indicate a suspected remote substituent effect, which is conformationally relayed.
10
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10.1002/ejoc.201700013
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.
Table 2 represents the just-mentioned substituent/diastereose-
lectivity effects amidst a pertinent collection of literature data.
They all are about acetaldehyde-incorporating oxa-Pictet-
Spengler cyclizations for naphthoquinonopyrano-γ-lactone syn-
thesis. Table 2 shows 8 differently γ-naphthylated β-hydroxy-γ-
lactone substrates. It details, how they were carried on – with
acetaldehyde or its dimethyl acetal – 8 different dihydropyrans
and what the respective 3a,5trans:3a,5cis-selectivities were. Half
of the substrate/product pairs stem from the current study
(31/32, 35/36, and 38/39) or (48/49) from our total synthesis of
γ-actinorhodin.[20] Three additional substrate/product pairs were
studied by others and ourselves (42/43,[10c] 44/45,[18a] and
46/47[20]). The substrate/product pair 40/41 was investigated by
others[26a,55] only. The substrates of Table 2 are ordered by the
number of substituents – mostly methoxy group – in the naph-
thalene moiety. The entries into Table 2 begin with 2 substitu-
ents besides the omnipresent hydroxylactone group (in naph-
thyllactone 40). The table continues with naphthyllactone 42,
which contains 3 extra-substituents. The five ensuing naphthyl-
lactones contain 4 extra-substituents. They define two substitu-
tion patterns (44, 31, 35, and 38 vs. 46). The last substrate of
Table 2 (48) contains 5 substituents beyond the hydroxylactone
group.
tet-Spengler cyclizes with an opposite 90:10 3a,5trans-pref-
erence (entry 16).[56]
•
Suppressing diastereocontrol of oxa-Pictet-Spengler cycli-
zations as shown in Table 2 exertable by a substituent at
C-6: The oxa-Pictet-Spengler cyclizations of lactones 44,
31, and 35 gave trans-dihydropyrans preferentially or ex-
clusively (entries 5-7 and 9-10) – “due” (cf. above) to their
6’-bound MeO group. Although lactone 38 contains a 6’-
bound MeO group, too, it cyclized to give
a cis-
dihydropyran with ds = 100:0 (entries 11-12). Lactone 38
differs from lactones 44, 31, and 35 by the installment of a
bridging protective group between 5’-O and 4’-O.[57]
Controlling the diastereoselectivity of naphthoquinonopyra-
nolactone-targeting oxa-Pictet-Spengler cyclizations by “remote
substituent effects” as brought to light in Table 2 is a new syn-
thetic handle. It complements the previous handle, i. e., promo-
tor-control of diastereoselectivity.[58] The scope of either handle
is still underexplored.
Experimental Section
General Working Technique and Analytic Techniques
Table 2 displays oxa-Pictet-Spengler cyclizations, which are
perfectly 3a,5trans-selective (entries 1, 7, and 10), and others,
which are as 3a,5cis-selective (entries 3-4, 11-12, and 14-15).
Moreover, Table 2 reveals that the substitution pattern of the
naphthalene moiety influences the diastereoselectivity of the
oxa-Pictet-Spengler cyclization, to which it is subjected. E. g., 2
methoxy groups let the naphthyllactone 40 cyclize 3a,5trans-se-
lectively (entries 1-2). In contrast, 3 methoxy groups make the
naphthyllactone 42 cyclize 3a,5cis-selectively entries 3-4). 4
methoxy groups may be distributed such that the correspond-
ing cyclization is 3a,5trans-selective (entries 5-7) or 3a,5cis-
selective (entries 13-15). We have no straightforward rationali-
zation for these substituent effects. This is due to the widely
varying reaction conditions (details: Table 2) and the incertitude
whether the respective cyclization proceeds under kinetic or
thermodynamic control.
Working technique: If not indicated differently, all reactions were car-
ried out under a nitrogen atmosphere. Reaction flasks were dried in
vacuo with a heat gun prior to use. Small amounts of liquids were add-
ed with a syringe through a rubber septum. If solids were suspended,
the flask was evacuated again and flushed with nitrogen prior to addi-
tion 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 at-
mosphere prior to use. Diethyl ether (Et2O) was distilled over a
sodium/potassium alloy under a nitrogen atmosphere. Dichloromethane
(CH2Cl2), acetonitrile (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.[59] Solvents for extraction and flash
chromatography
[i.e.
methyl
tert-butyl
ether
(tBuOMe),
Last but not least, Table 2 highlights a potential steering tool –
and a way to “mute” it – for imposing the desired diastereose-
lectivity on an oxa-Pictet-Spengler cyclization: introducing a
substituent at C-6’ of the naphthalene core – or suppressing its
effect by a suitable protective group:
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:[46] Macherey-Nagel silica gel 60® (230-400 mesh)
was used for flash chromatography. All eluents were distilled prior to
•
Diastereocontrol by a substituent at C-6’ of oxa-Pictet-
Spengler cyclizations as shown in Table 2: (a) The naph-
thalene moiety of lactone 42 contains 3 MeO groups. This
compound oxa-Pictet-Spengler cyclizes 3a,5cis-selectively
(entries 3-4). With another MeO substituent at C-6’, lactone
42 becomes lactone 44. The latter oxa-Pictet-Spengler cy-
clizes oppositely, namely 3a,5trans-selectively (entries 5-8).
(b) The trans-inducing effect of the mentioned 6’-MeO
group persists when the 5’-substituent MeO (in lactone 44)
is replaced by OBoc (in lactone 31, entry 9) or OPiv (in lac-
tone 35, entry 10). (c) The naphthalene moiety of lactone
46 contains 4 MeO groups. This compound oxa-Pictet-
Spengler cyclizes with a 3a,5cis-preference (entry 13) or
3a,5cis-selectively (entries 14-15). With another MeO sub-
stituent at C-6’, lactone 46 becomes lactone 48. It oxa-Pic-
56
a) One may speculate whether the 6’-substituent exerts its remote effect
somehow (!) as a consequence of relaying steric hindrance from its own site
(≡ C-‘6) towards the site of attack (≡ C-3’) of the oxa-Pictet-Spengler electro-
phile. This relay would be tantamount to the 6’-substituent shoving the oxy-
gen-bound substituents “in between” − i. e., first OMe, OBoc or OPiv at C-5’
and then OMe at C-4’ towards C-3’. In order for this to be the case, these
substituents at C-4’ and C-3’ would need to be conformationally mobile; b)
for a similar line of reasoning see ref.[20].
57 Such a bridging protective group would be unable to relay the steric effect,
which we contemplate in footnote [56] for rationalizing the remote effect of 6‘-
OMe and 6‘-Br moieties.
58
a) BF3 etherate let lactone 44 (formula: Table 2) and acetaldehyde dime-
thyl acetal cyclize with a 73:27 cis-preference (Table 2, entry 6) or cis-selec-
tively (Table 2, entry 7), while a 65:35 trans-preference results using TMS tri-
flate (Table 2, entry 8); b) ref.[14e] varied the Lewis acid in aldehyde-incorpor-
ating oxa-Pictet-Spengler cyclizations of the mirror image of structure 42 (for-
mula: Table 2). Cu(OTf)2 in CH2Cl2 incorporated 11 aldehydes – among them
1 α-sustituted aldehyde and 2 aromatic aldehydes – in 3a,5cis-configured
dihydropyrans with ds ≥88:12 (only benzaldehyde gave a 3a,5trans-configured
dihydropyran under these conditions, ds = 75:25). FeCl3 in THF incorporated
butanal in a 3a,5trans-configured dihydropyran with ds = 66:34.
55 S. Korwar, T. Nguyen, K. C. Ellis, Bioorg. Med. Chem. Lett. 2014, 14, 271-
274.
59 J. Suffert, J. Org. Chem. 1989, 54, 509-510.
11
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
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, 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
CH3,5 = 6.9 Hz, 5-CH3), AB signal (δA = 2.69, δB = 2.96, JAB = 18.0 Hz, A
signal shows no further splitting, B signal further splitted by JB,3a
5.2 Hz, 3-HA and 3-HB), 4.00 (s, 3H, 8-OMe), 4.68 (dd, 1H, J3a,B
=
=
5.2 Hz, J3a,11b = 3.0 Hz, 3a-H), 5.07 (q, 1H, J5,5-CH3 = 6.9 Hz, 5-H), 5.25
(d, 1H, J11b,3a = 2.9 Hz, 11b-H), 7.12 (d, 1H, J9,10 = 8.2 Hz, 9-H), 7.74 (d,
1H, J10,9 = 8.4 Hz, 10-H), 12.27 (s, 1H, 7-OH). A NOESY spectrum
1
(500.32 MHz, CDCl3) allowed additional assignments of H resonances
by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.56 (5-CH3) ↔ δ
= 4.68 (3a-H, this cross-peak proves that 5-CH3 and 3a-H are oriented
cis relative to one another), δB = 2.96 (3-HB) ↔ δ = 5.25 (11b-H, this
cross-peak proves that 3-HB and 11b-H are oriented cis relative to one
another), δ = 4.00 (8-OMe) ↔ δ = 7.12 (9-H). 13C NMR (125.81 MHz,
CDCl3): δ = 18.60 (5-CH3), 37.00 (C-3), 56.57 (8-OCH3), 66.32 (C-5),
66.54 (C-3a), 68.86 (C-11b), 114.88 (C-6a), 115.83 (C-9), 121.54 (C-
10), 123.41 (C-10a), 135.86 (C-11a), 149.51 (C-5a), 152.54 (C-7),
154.46 (C-8), 174.13 (C-2), 180.48 (C-11), 188.56 (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
3
3
1
cross-peaks with the independently assigned H resonances [δ(13C) ↔
data are reported as follows: chemical shift (δ in ppm), multiplicity (s for
δ(1H)]: δ = 18.60 (5-CH3) ↔ δ = 1.56 (5-CH3), δ = 37.00 (C-3) ↔ [δA
=
singlet; d for doublet; 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.
2.69 (3-HA) and δB = 2.96 (3-HB)], δ = 56.57 (8-OCH3) ↔ δ = 4.00 (8-
OMe), δ = 66.32 (C-5) ↔ δ = 5.07 (5-H), δ = 66.54 (C-3a) ↔ δ = 4.68
(3a-H), δ = 68.86 (C-11b) ↔ δ = 5.25 (11b-H), δ = 115.83 (C-9) ↔ δ =
7.12 (9-H), δ = 121.54 (C-10) ↔ δ = 7.74 (10-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 = 114.88 (C-6a) ↔ δ =
7.74 (10-H), δ = 123.41 (C-10a) ↔ δ = 7.12 (9-H), δ = 135.86 (C-11a)
↔ δ = 5.07 (5-H), δ = 135.86 (C-11a) ↔ δ = 5.25 (11b-H), δ = 149.51
(C-5a) ↔ δ = 1.56 (5-CH3), δ = 149.51 (C-5a) ↔ δ = 5.07 (5-H), δ =
149.51 (C-5a) ↔ δ = 5.25 (11b-H), δ = 152.54 (C-7) ↔ δ = 7.12 (9-H), δ
= 152.54 (C-7) ↔ δ = 12.27 (7-OH), δ = 154.46 (C-8) ↔ δ = 4.00 (8-
OMe), δ = 154.46 (C-8) ↔ δ = 7.12 (9-H), δ = 154.46 (C-8) ↔ δ = 7.74
(10-H), δ = 154.46 (C-8) ↔ δ = 12.27 (7-OH), δ = 174.13 (C-2) ↔ [δA =
2.69 (3-HA) and δB = 2.96 (3-HB)], δ = 174.13 (C-2) ↔ 4.68(3a-H), δ =
180.48 (C-11) ↔ 5.25 (11b-H), δ = 180.48 (C-11) ↔ 7.74 (10-H), δ =
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-lamp). [α]λ20 values were calculated by the following equation: [α]λ
20
= (αexp · 100)/(c · d), where λ is the wavelength, αexp is the experimental
result (given as arithmetic mean of 10 measurements), c is the
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.[60] 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 Elmer Paragon 1000 spectrometer for a
film of the substance on a NaCl crystal plate.
188.56 (C-6) ↔ 5.07 (5-H), δ = 188.56 (C-6) ↔ 7.74 (10-H). Melting
20
point: 206°C (decomp.). Optical rotation: [
α
]
= –169.7 (c = 0.094,
D
MeOH). HRMS (pos. ESI, file: nebrc06s_hr1): calcd. for C17H14O7Na
[M+Na]+
353.06317; found 353.06351 (+0.94 ppm). IR (film):
=
ν = 3060, 2935, 2850, 1790, 1775, 1650, 1620, 1590, 1460, 1440,
1410, 1365, 1340, 1270, 1240, 1200, 1155, 1100, 1085, 1070, 1035,
995, 955, 920, 905, 785, 765, 755, 735, 700, 680 cm-1.
(3aS,5S,11bS)-7,8-Dimethoxy-5-methyl-3,3a-dihydro-2H-
benzo[g]furo[3,2-c]isochromene[5H,11bH]-trione
[(−)-4]
= Arizonin C1,
(3aS,5S,11bS)-7-Hydroxy-8-methoxy-5-methyl-3,3a-dihydro-2H-
benzo[g]furo[3,2-c]isochromene[5H,11bH]-trione
[(−)-3]
= Arizonin B1
Under a nitrogen atmosphere arizonin B1 (3, 8.0 mg, 22.2 µmol) was
dissolved in a freshly prepared solution of MeI (27.7 µL, 63.0 mg,
444 µmol, 20.0 equiv.) in CH2Cl2 (1 mL). Ag2O (72.0 mg, 311 µmol,
14.0 equiv.) was added in one portion to initiate the reaction. The
mixture was stirred at room temperature for 18 h. The reaction mixture
was filtered over a small pipet (silica gel pad: h = 2 cm) and thoroughly
rinsed with CH2Cl2 (10 mL). Afterwards the solvent was removed in
vacuo. Flash chromatography [d = 1.5 cm, h = 8 cm, F = 8 mL; CH/EE
3:2 (F1-11), CH/EE 1:2 (F12-23)] afforded the title compound (F12-20,
3.2 mg, 41%, dr = 100:0)]. 1H NMR (500.32 MHz, CDCl3): δ = 1.54 (d,
tert-Butyl
(3aS,5S,11bS)-8-methoxy-5-methyl-2,6,11-trioxo-
3,3a,5,6,11,11b-hexahydro-2H-benzo[g]furo[3,2-c]isochromen-7-yl
carbonate (34, 12.2 mg, 28.3 µmol) was dissolved in CH2Cl2 (0.5 mL).
At room temperature trifluoroacetic acid (0.5 mL) was added dropwise
and the mixture was stirred for 30 min. The solvent was removed in
vacuo. The title compound (9.8 mg, quant.) was obtained without
further purification.– 1H NMR (500.32 MHz, CDCl3): δ = 1.56 (d, 3H, J5-
60
The melting points are neither corrected nor uncorrected, as these terms
3H, J5-CH = 6.9 Hz, 5-CH3), AB signal (δA = 2.68, δB = 2.95, JAB
=
,5
refer to total immersion thermometers. In our laboratory, like in most modern
laboratories, only partial immersion thermometers are used, which per
definition need no correction for immersion depth, as they are intended to be
only partially immersed: G. V. D. Tiers, J. Chem. Educ. 1990, 67, 258-259.
3
17.7 Hz, A signal shows no further splitting, B signal further split by JB,3a
= 5.2 Hz, 3-HA and 3-HB), 3.92 (s, 3H, 7-OMe), 3.98 (s, 3H, 8-OMe),
4.66 (dd, 1H, J3a,B = 5.2 Hz, J3a,11b = 3.0 Hz, 3a-H), 5.06 (q, 1H, J5,5-CH
3
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
= 6.9 Hz, 5-H), 5.25 (d, 1H, J11b,3a = 3.0 Hz, 11b-H), 7.23 (d, 1H, J9,10
=
3H, 8-OMe), 4.33 (dd, 1H, J3a,B = 4.5 Hz, J3a,11b = 2.5 Hz, 3a-H), 4.78
5
8.7 Hz, 9-H), 7.98 (d, 1H, J10,9
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 that
allowed additional assignments of H resonances by the occurrence of
=
8.7 Hz, 10-H). 8-OMe was
(q, 1H, J5,5-CH = 6.6 Hz, J5,11b = 1.7 Hz, 5-H), 5.26 (d, 1H, J11b,3a
=
3
5
2.4 Hz, J11b,5 = 1.8 Hz, 11b-H), 7.14 (d*, 1H, J9,10 = 8.4 Hz, 9-H), 7.73
5
(d, 1H, J10,9 = 8.4 Hz, 10-H), 12.19 (dFehler! Textmarke nicht definiert., 1H, J7-
1
= 0.7 Hz**, 7-OH). * δ = 7.14 (9-H) is represented by a broad
OH,9
cross-peaks (500.32 MHz, CDCl3) [δ(1H) ↔ δ(1H)]: δ = 1.54 (5-CH3) ↔
δ = 4.66 (3a-H, this cross-peak proves that 5-CH3 and 3a-H are
oriented cis relative to one another), δB = 2.95 (3-HB) ↔ δ = 5.25 (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 = 7.23 (9-H). δ = 3.92 (7-OMe)
exhibited no cross-peak. 13C NMR (125.81 MHz, CDCl3): δ = 18.66 (5-
CH3), 37.06 (C-3), 56.45 (8-OCH3), 61.27 (7-OCH3), 66.47 (C-3a),
66.82 (C-5), 69.04 (C-11b), 116.27 (C-9), 124.97 (C-10), 124.97 (C-6a),
125.26 (C-10a), 133.20 (C-11a), 149.66 (C-7), 150.61 (C-5a), 159.29
(C-8), 174.23 (C-2), 181.46 (C-11), 182.47 (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
doublet that could also be interpreted as a dd. **A 5J7-OH,9-coupling was
not found in the DQF-COSY spectrum (500.32 MHz, CDCl3). A NOESY
spectrum allowed additional assignments of 1H resonances by the
occurrence of crosspeaks (500.32 MHz, CDCl3) [δ(1H) ↔ δ(1H)]: δB
=
2.88 (3-HB) ↔ δ = 5.26 (11b-H, this cross-peak proves that 3-HB and
11b-H are oriented cis relative to one another), δ = 4.01 (8-OMe) ↔ δ =
7.14 (9-H), δ = 4.78 (5-H) ↔ δ = 4.33 (3a-H, this cross-peak proves that
5-H and 3a-H are oriented cis relative to one another). 13C NMR
(125.81 MHz, CDCl3): δ = 20.72 (5-CH3), 37.40 (C-3), 56.59 (8-OCH3),
68.68 (C-5), 69.94 (C-11b), 71.16 (C-3a), 115.84 (C-9), 121.40 (C-10),
115.25 (C-6a), 123.40 (C-10a), 136.44 (C-11a), 149.95 (C-5a), 152.41
(C-7), 154.53 (C-8), 174.33 (C-2), 180.59 (C-11), 189.28 (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 = 20.72 (5-CH3) ↔ δ = 1.64 (5-CH3), δ = 37.40 (C-3)
↔ [δA = 2.74 (3-HA) and δB = 2.88 (3-HB)], δ = 56.59 (8-OCH3) ↔ δ =
4.03 (8-OMe), δ = 68.68 (C-5) ↔ δ = 4.78 (5-H), δ = 69.94 (C-11b) ↔ δ
= 5.26 (11b-H), δ = 71.16 (C-3a) ↔ δ = 4.33 (3a-H), δ = 115.84 (C-9) ↔
δ = 7.14 (9-H), δ = 121.40 (C-10) ↔ δ = 7.73 (10-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 = 115.25 (C-
6a) ↔ δ = 7.73 (10-H), δ = 123.40 (C-10a) ↔ δ = 7.14 (9-H), δ = 136.44
(C-11a) ↔ δ = 4.78 (5-H), δ = 136.44 (C-11a) ↔ δ = 5.26 (11b-H), δ =
149.95 (C-5a) ↔ δ = 1.64 (5-CH3), δ = 149.95 (C-5a) ↔ δ = 4.78 (5-H),
δ = 149.95 (C-5a) ↔ δ = 5.26 (11b-H), δ = 152.41 (C-7) ↔ δ = 7.14 (9-
H), δ = 154.53 (C-8) ↔ δ = 4.01 (8-OMe), δ = 154.53 (C-8) ↔ δ = 7.14
1
cross-peaks with the independently assigned H resonances [δ(13C) ↔
δ(1H)]: δ = 18.66 (5-CH3) ↔ δ = 1.54 (5-CH3), δ = 37.06 (C-3) ↔ [δA
=
2.68 (3-HA) and δB = 2.95 (3-HB)], δ = 56.45 (8-OCH3) ↔ δ = 3.98 (8-
OMe), δ = 61.27 (7-OCH3) ↔ δ = 3.92 (7-OMe), δ = 66.47 (C-3a) ↔ δ =
4.66 (3a-H), δ = 66.82 (C-5) ↔ δ = 5.07 (5-H), δ = 69.04 (C-11b) ↔ δ =
5.25 (11b-H), δ = 116.27 (C-9) ↔ δ = 7.23 (9-H), δ = 124.97 (C-10) ↔ δ
=
7.98 (10-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 = 124.97 (C-6a) ↔ δ = 7.98 (10-H), δ = 125.26 (C-
10a) ↔ δ = 7.23 (9-H), δ = 133.20 (C-11a) ↔ δ = 5.06 (5-H), δ = 133.20
(C-11a) ↔ δ = 5.25 (11b-H), δ = 149.66 (C-7) ↔ δ = 3.92 (7-OMe), δ =
149.66 (C-7) ↔ δ = 7.23 (9-H), δ = 150.61 (C-5a) ↔ δ = 1.54 (5-CH3), δ
= 150.61 (C-5a) ↔ δ = 5.06 (5-H), δ = 150.61 (C-5a) ↔ δ = 5.25 (11b-
H), δ = 159.29 (C-8) ↔ δ = 3.98 (8-OMe), δ = 159.29 (C-8) ↔ δ = 7.23
(9-H), δ = 159.29 (C-8) ↔ δ = 7.98 (10-H), δ = 174.23 (C-2) ↔ [δA
=
2.68 (3-HA) and δB = 2.95 (3-HB)], δ = 174.23 (C-2) ↔ 4.66(3a-H), δ =
181.46 (C-11) ↔ 5.25 (11b-H), δ = 181.46 (C-11) ↔ 7.98 (10-H), δ =
(9-H), δ = 154.53 (C-8) ↔ δ = 7.73 (10-H), δ = 174.33 (C-2) ↔ [δA =
2.74 (3-HA) and δB = 2.88 (3-HB)], δ = 174.33 (C-2) ↔ 4.33(3a-H), δ =
182.47 (C-6) ↔ 5.06 (5-H), δ = 182.47 (C-6) ↔ 7.98 (10-H). Melting
180.59 (C-11) ↔ 5.26 (11b-H). δ = 189.28 (C-6) exhibited no cross-
[6a]
D
point: 126°C (decomp.); ref
:
110-135°C (decomp.). Optical
peak. Melting point: 206-210°C (decomp). Optical rotation: [
α
]
=
20
20
rotation: [
α
]
= –159.2 (c = 0.34, MeOH). HRMS (pos. ESI): Calcd.
+131.2 (c = 0.34, MeOH). HRMS (pos. APCI): Calcd. for C17H14O7
[M+NH4]+ = 348.10778; found 348.10791 (+0.38 ppm). IR (film): ν =
2930, 2855, 1785, 1645, 1615, 1455, 1440, 1410, 1365, 1320, 1270,
1205, 1150, 1115, 1080, 1035, 995, 960, 930, 910, 880, 845, 795, 740,
700, 670 cm-1.
D
for C18H16O7Na [M+Na]+ = 367.07882; found 367.07898 (+0.42 ppm).
IR (film): ν = 3295, 2940, 2850, 1790, 1725, 1665, 1620, 1575, 1485,
1455, 1405, 1365, 1335, 1275, 1235, 1200, 1155, 1070, 1035, 995,
955, 905, 880, 845, 820, 785, 735, 700 cm-1.
(3aS,5R,11bS)-7,8-Dimethoxy-5-methyl-3,3a-dihydro-2H-
(3aS,5R,11bS)-7-Hydroxy-8-methoxy-5-methyl-3,3a-dihydro-2H-
benzo[g]furo[3,2-c]isochromene[5H,11bH]-trione
arizonin C1 [(+)-5-epi-4]
=
(+)-5-epi-
benzo[g]furo[3,2-c]isochromene[5H,11bH]-trione
arizonin B1 [(+)-5-epi-3]
=
(+)-5-epi-
(7bS,10aS,12R)-4,7-Dimethoxy-12-methyl-7b,10,10a,12-tetrahydro-9H-
furo[2’’,3’’:5’,6’]-pyrano[3’,4’:2,3]naphtho[1,8-de][1,3]dioxin-9-one (39,
Under
a nitrogen atmosphere 5-epi-arizonin B1 (5-epi-3, 9.5 mg,
25.3 µmol) was dissolved in freshly prepared solution of MeI (31.6 µL,
72.0 mg, 507µmol, 20.0 equiv.) in CH2Cl2 (1 mL). Ag2O (82.1 mg,
354 µmol, 14.0 equiv.) was added in one portion to initiate the reaction.
The mixture was stirred at room temperature for 18 h. The reaction
mixture was filtered over a small pipet (silica gel pad: h = 2 cm) and
thoroughly rinsed with CH2Cl2 (10 mL). Afterwards the solvent was
removed in vacuo. Flash chromatography [d = 1.5 cm, h = 8 cm,
F = 8 mL; CH/EE 3:2 (F1-10), CH/EE 1:2 (F11-20)] afforded the title
compound (F11-17, 3.2 mg, 34%, dr = 100:0)].– H NMR (500.32 MHz,
CDCl3): δ = 1.56 (d, 3H, J5-CH ,5 = 6.7 Hz, 5-CH3), AB signal (δA = 2.73,
δB = 2.88, JAB = 17.5 Hz, A signal shows no further splitting, B signal
further split by JB,3a = 4.8 Hz, 3-HA and 3-HB), 3.93 (s, 3H, 7-OMe), 3.99
(s, 3H, 8-OMe), 4.32 (dd, 1H, J3a,B = 4.7 Hz, J3a,11b = 2.6 Hz, 3a-H), 4.78
15.5 mg, 43.3 µmol) was dissolved in acetonitrile (2 mL). A solution of
CAN (47.4 mg, 86.5 µmol, 2.0 equiv.) in H2O (1 mL) was added
dropwise at room temperature. The reaction mixture was stirred for
30 min and afterwards diluted with EtOAc (5 mL). The organic phase
was separated and the organic phase was extracted with EtOAc
(2×5 mL). The combined organic extracts were dried over Na2SO4 and
the solvent was removed in vacuo. Flash chromatography (d = 1.5 cm,
h = 6 cm, F = 8 mL; CH/EE/HCO2H 49:49:2) afforded the title
compound [F7-13, Rf (49:49:2) = 0.2, 11.3 mg, 79%, dr = 100:0] as an
1
1
3
orange solid.– H NMR (500.32 MHz, CDCl3, spectrum contains 8 w-%
MeOH with a singulet at δ = 3.49 ppm and 8 w-% water with a broad
singulet at δ = 1.54 ppm): δ = 1.64 (d, 3H, J5-CH ,5 = 6.7 Hz, 5-CH3), AB
3
signal (δA = 2.74, δB = 2.88, JAB = 17.4 Hz, A signal shows no further
splitting, B signal further split by JB,3a = 4.6 Hz, 3-HA and 3-HB), 4.01 (s,
5
(q, 1H, J5,5-CH = 6.7 Hz, J5,11b = 1.7 Hz, 5-H), 5.28 (d, 1H, J11b,3a
=
3
13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
5
2.5 Hz, J11b,5 = 1.7 Hz, 11b-H), 7.21 (d, 1H, J9,10 = 8.7 Hz, 9-H), 7.95
(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 cross-
peaks [δ(1H) ↔ δ(1H)]: δB = 2.88 (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 = 7.21 (9-H), δ = 4.78 (5-H) ↔ δ = 4.32
(3a-H, this cross-peak proves that 5-H and 3a-H are oriented cis
(C-2), 151.74 (C-8), 151.90 (carbonate-C). 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 =
27.89 [C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 56.60 (8-OCH3) ↔ δ = 3.90
(8-OMe), δ = 57.03 (2-OCH3) ↔ δ = 3.95 (2-OMe), δ = 61.47 (5-OCH3)
↔ δ = 3.91 (5-OMe), δ = 110.60 (C-7) ↔ δ = 6.86 (7-H), δ = 115.28 (C-
3) ↔ δ = 7.35 (3-H), δ = 121.22 (C-4) ↔ δ = 7.96 (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 = 82.86
[C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 109.60 (C-6) ↔ δ = 6.86 (7-H), δ =
120.87 (C-8a) ↔ δ = 6.86 (7-H), δ = 120.87 (C-8a) ↔ δ = 7.96 (4-H), δ
= 125.61 (C-4a) ↔ δ = 7.35 (3-H), δ = 134.65 (C-1) ↔ δ = 6.86 (7-H), δ
= 134.65 (C-1) ↔ δ = 7.35 (3-H), δ = 134.65 (C-1) ↔ δ = 7.96 (4-H), δ =
147.03 (C-5) ↔ δ = 3.91 (5-OMe), δ = 147.03 (C-5) ↔ δ = 6.86 (7-H), δ
= 147.03 (C-5) ↔ δ = 7.96 (4-H), δ = 149.73 (C-2) ↔ δ = 3.96 (2-OMe),
δ = 149.73 (C-2) ↔ δ = 7.35 (3-H), δ = 149.73 (C-2) ↔ δ = 7.96 (4-H), δ
= 151.74 (C-8) ↔ δ = 3.90 (8-OMe), δ = 151.74 (C-8) ↔ δ = 6.86 (7-H).
δ = 151.90 (carbonate-C) exhibited no cross-peak. Melting point:
90°C. Elemental analysis: Calculated: C: 52.31%, H: 5.12%; found: C:
51.94%, H: 5.00%; deviation: C:0.37%, H: 0.12%. HRMS (pos. ESI):
calcd. for C18H2179BrO6: [M+Na]+ = 435.04137; found: 435.04153 (0.37
ppm). IR (film): ν = 3005, 2980, 2935, 2845, 1760, 1625, 1585, 1510,
1465, 1440, 1380, 1370, 1320, 1285, 1255, 1160, 1145, 1075, 1050,
1030, 1005, 980, 930, 865, 820, 805, 790, 775, 735, 700 cm-1.
relative to one another). δ = 3.92 (7-OMe) exhibited no cross-peak. 13
C
NMR (125.81 MHz, CDCl3): δ = 19.91 (5-CH3), 37.34 (C-3), 56.45 (8-
OCH3), 61.27 (7-OCH3), 69.01 (C-5), 69.79 (C-11b), 71.36 (C-3a),
116.08 (C-9), 124.75 (C-10), 125.31 (C-10a), 126.05 (C-6a), 133.19 (C-
11a), 149.12 (C-7), 152.16 (C-5a), 159.09 (C-8), 174.45 (C-2), 181.39
(C-11), 184.10 (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
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 19.91 (5-
CH3) ↔ δ = 1.56 (5-CH3), δ = 37.34 (C-3) ↔ [δA = 2.73 (3-HA) and δB
=
2.88 (3-HB)], δ = 56.45 (8-OCH3) ↔ δ = 3.99 (8-OMe), δ = 61.27 (7-
OCH3) ↔ δ = 3.92 (7-OMe), δ = 69.01 (C-5) ↔ δ = 4.78 (5-H), δ =
69.79 (C-11b) ↔ δ = 5.28 (11b-H), δ = 71.36 (C-3a) ↔ δ = 4.32 (3a-H),
δ = 116.08 (C-9) ↔ δ = 7.21 (9-H), δ = 124.75 (C-10) ↔ δ = 7.95 (10-
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 = 125.31 (C-10a) ↔ δ = 7.21 (9-H), δ = 126.05 (C-6a) ↔ δ = 7.95
(10-H), δ = 133.19 (C-11a) ↔ δ = 4.78 (5-H), δ = 133.20 (C-11a) ↔ δ =
5.28 (11b-H), δ = 149.12 (C-7) ↔ δ = 3.93 (7-OMe), δ = 149.12 (C-7) ↔
δ = 7.21 (9-H), δ = 152.16 (C-5a) ↔ δ = 1.56 (5-CH3), δ = 152.16 (C-
5a) ↔ δ = 4.78 (5-H), δ = 152.16 (C-5a) ↔ δ = 5.28 (11b-H), δ = 159.09
(C-8) ↔ δ = 3.99 (8-OMe), δ = 159.09 (C-8) ↔ δ = 7.21 (9-H), δ =
159.09 (C-8) ↔ δ = 7.95 (10-H), δ = 174.45 (C-2) ↔ [δA = 2.73 (3-HA)
and δB = 2.88 (3-HB)], δ = 174.45 (C-2) ↔ 4.32(3a-H), δ = 181.39 (C-
6-Bromo-2,5,8-trimethoxynaphthalen-1-yl Pivalate (14d)
11) ↔ 7.95 (10-H), δ = 184.10 (C-6) exhibited no cross-peak. Optical
20
rotation: [
α
]
= +143.1 (c = 0.32, MeOH). HRMS (pos. ESI): Calcd.
D
Under a nitrogen atmosphere 2,5,8-trimethoxynaphthalen-1-yl pivalate
(16d, 768 mg, 2.13 mmol) was dissolved in dry DMF (20 mL). Solid N-
Bromosuccinimide (417 mg, 2.34 mmol, 1.1 equiv.) was added 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 = 4, h = 12 cm,
F = 50 ml; CH/EE 5:1) afforded the title compound (F5-11, Rf
(5:1) = 0.3, 780 mg, 92%) as a yellow solid.– 1H NMR (400.13 MHz,
CDCl3): δ = 1.44 [s, 9H, C(CH3)3], 3.84 (s, 3H, 8-OMe), 3.90 (s, 3H, 2-
OMe), 3.91 (s, 3H, 5-OMe), 6.82 (s, 1H, 7-H), 7.33 (d, 1H, J3,4 = 9.2 Hz,
3-H), 7.96 (d, 1H, J4,3 = 9.2 Hz, 4-H). A NOESY spectrum (400.13 MHz,
CDCl3) allowed additional assignments of 1H resonances by the
occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 3.84 (8-OMe) ↔ δ = 6.82
(7-H), δ = 3.90 (2-OMe) ↔ δ = 7.33 (3-H). 13C NMR (100.61 MHz,
CDCl3): δ = 27.41 [C(CH3)3], 39.24 [C(CH3)3], 55.90 (8-OCH3), 56.88 (2-
OCH3), 61.40 (5-OCH3), 109.42 (C-6), 110.03 (C-7), 114.96 (C-3),
120.87 (C-4), 120.96 (C-8a), 125.64 (C-4a), 135.01 (C-1), 146.83 (C-5),
149.12 (C-2), 151.94 (C-8), 176.75 (1-O2C-C(CH3)3]. An edHSQC
spectrum (“short-range C,H COSY”; 100.61/400.13 MHz, CDCl3)
allowed the assignment of all nonquaternary 13C atoms through their
for C18H17O7 [M+H]+ = 345.09688; found 345.09695 (+0.22 ppm). IR
(film): ν = 3410, 3060, 2940, 2850, 1790, 1740, 1665, 1575, 1485,
1455, 1420, 1335, 1275, 1205, 1155, 1115, 1075, 1040, 995, 960, 905,
880, 845, 825, 785, 735, 700 cm-1.
6-Bromo-2,5,8-trimethoxynaphthalen-1-yl tert-Butyl Carbonate
(14c)
Under a nitrogen atmosphere 2,5,8-trimethoxynaphthalen-1-yl tert-butyl
carbonate (16c, 2.79 g, 8.34 mmol) was dissolved in dry DMF (42 mL).
Solid N-Bromosuccinimide (1.48 g, 8.34 mmol, 1.0 equiv.) was added
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 = 12,
h = 12 cm, F = 100 ml; CH/EE 5:1) afforded the title compound (F9-14,
1
cross-peaks with the independently assigned H resonances [δ(13C) ↔
δ(1H)]: δ = 27.41 [C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ = 55.90 (8-OCH3) ↔
δ = 3.84 (8-OMe), δ = 56.88 (2-OCH3) ↔ δ = 3.90 (2-OMe), δ = 61.40
(5-OCH3) ↔ δ = 3.91 (5-OMe), δ = 110.03 (C-7) ↔ δ = 6.82 (7-H), δ =
114.96 (C-3) ↔ δ = 7.33 (3-H), δ = 120.87 (C-4) ↔ δ = 7.96 (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 = 39.24
[C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ = 109.42 (C-6) ↔ δ = 6.82 (7-H), δ =
120.96 (C-8a) ↔ δ = 6.82 (7-H), δ = 120.96 (C-8a) ↔ δ = 7.96 (4-H), δ
= 125.64 (C-4a) ↔ δ = 7.33 (3-H), δ = 135.01 (C-1) ↔ δ = 6.82 (7-H), δ
= 135.01 (C-1) ↔ δ = 7.33 (3-H), δ = 135.01 (C-1) ↔ δ = 7.96 (4-H), δ =
1
Rf (5:1) = 0.25, 3.23 g, 94%) as a yellow solid.– H NMR (400.13 MHz,
CDCl3): δ = 1.58 [s, 9H, C(CH3)3], 3.90 (s, 3H, 8-OMe), 3.91 (s, 3H, 5-
OMe), 3.95 (s, 3H, 2-OMe), 6.86 (s, 1H, 7-H), 7.35 (d, 1H, J3,4 = 9.3 Hz,
3-H), 7.96 (d, 1H, J4,3 = 9.3 Hz, 4-H). 2-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
(400.13 MHz, CDCl3) [δ(1H) ↔ δ(1H)]: δ = 3.90 (8-OMe) ↔ δ = 6.86 (7-
H), δ = 3.95 (2-OMe) ↔ δ = 7.35 (3-H). 13C NMR (100.61 MHz, CDCl3):
δ = 27.89 [C(CH3)3], 56.60 (8-OCH3), 57.03 (2-OCH3), 61.47 (5-OCH3),
110.60 (C-7), 115.28 (C-3), 121.22 (C-4), 82.86 [C(CH3)3], 109.60 (C-
6), 120.87 (C-8a), 125.61 (C-4a), 134.65 (C-1), 147.03 (C-5), 149.73
14
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
146.83 (C-5) ↔ δ = 3.91 (5-OMe), δ = 146.83 (C-5) ↔ δ = 6.82 (7-H), δ
= 146.83 (C-5) ↔ δ = 7.96 (4-H), δ = 149.12 (C-2) ↔ δ = 3.90 (2-OMe),
δ = 149.12 (C-2) ↔ δ = 7.33 (3-H), δ = 149.12 (C-2) ↔ δ = 7.96 (4-H), δ
= 151.94 (C-8) ↔ δ = 3.84 (8-OMe), δ = 151.94 (C-8) ↔ δ = 6.82 (7-H),
δ = 176.75 (1-O2C-C(CH3)3] ↔ δ = 1.44 [C(CH3)3]. Melting point: 142-
(E)-Methyl
4-(5-(tert-butoxycarbonyloxy)-1,4,6-
trimethoxynaphthalen-2-yl)but-3-enoate (15c) and (E)-Methyl 4-(5-
(tert-butoxycarbonyloxy)-1,4,6-trimethoxynaphthalen-2-yl)but-2-
enoate (iso-15c)[61]
143°C. HRMS (pos. APCI): calcd. for C18H2279BrO5: [M+H]+
397.06506; found: 397.06530 (+0.6 ppm), C18H2281BrO5: [M+H]+
=
=
399.06301; found: 399.06320 (+0.5 ppm). IR (film): ν = 2970, 1745,
1590, 1575, 1470, 1455, 1380, 1365, 1320, 1280, 1250, 1135, 1120,
1070, 1025, 1020, 815, 790 cm-1.
8-Bromo-4,7-dimethoxynaphtho[1,8-de][1,3]dioxine (14h)
6-Bromo-2,5,8-trimethoxynaphthalen-1-yl tert-butyl carbonate (14c,
1.38 g, 3.34 mmol) and Pd2dba3·CHCl3 (69.0 mg, 66.8 µmol, 2.0 mol-%)
were dissolved in freshly distilled toluene (34 mL). P(t-Bu)3 (54.2 mg,
267 µmol, 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
(2.15 mL, 1.96 g, 10.0 mmol, 3.0 equiv.) and methyl vinylacetate
(1.07 mL, 1.00 g, 10.0 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 EtOAc (40 mL) was
Under a nitrogen atmosphere 4,7-dimethoxynaphtho[1,8-de][1,3]dioxine
(16h, 60.2 mg, 0.26 mmol) was dissolved in dry DMF (2 ml). Solid N-
bromosuccinimide (46.3 mg, 0.26 mmol, 1.0 equiv.) was added 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 = 1.5 cm, h = 12 cm,
F = 8 ml; CH/EE 9:1 (F1-12), CH/EE 5:1 (F13-25)] afforded the title
compound (F10-15, Rf (9:1) = 0.2, Rf (5:1) = 0.4, 74.4 mg, 92%) as a
pale-yellow solid. Note: An upscaling of this reaction was easily
achieved: Bromination of 39 (2.06 g, 8.87 mmol) with N-
bromosuccinimide (1.58 g, 8.87 mmol, 1.0 equiv.) in DMF (44 ml)
furnished the title compound (2.48 g, 90%) in a slightly lower yield
(Flash chromatography data: d = 12 cm, h = 12 cm, F = 100 ml; CH/EE
5:1, product: F9-13).– 1H NMR (400.13 MHz, CDCl3): 3.94 (s, 3H, 7-
OMe), 4.00 (s, 3H, 4-OMe), 5.53 (s, 2H, 2-H2), 7.00 (s, 1H, 9-H), 7.30
(d, 1H, J5,6 = 9.0 Hz, 5-H), 7.67 (d, 1H, J6,5 = 9.0 Hz, 6-H). A NOESY
spectrum allowed additional assignments of 1H resonances by the
occurrence of crosspeaks (400.13 MHz, CDCl3) [δ(1H) ↔ δ(1H)]: δ =
added. The organic phase was washed with aq. HCl (1
M, 2×40 mL)
and brine (40 ml) and dried over Na2SO4. The solvent was removed in
vacuo and the oily residue was purified by flash chromatography
[d = 4 cm, h = 12 cm, F = 50 mL; CH/EE 5:1 (F1-14), CH/EE 3:1 (F15-
33)] to obtain the product [F15-23, Rf (5:1) = 0.1, Rf (3:1) = 0.25, 1.19 g,
82%] as a yellow-brownish oil and as a 87:13 mixture of 15c and its
α,β-unsaturated carboxylic ester isomer iso-15c.– NMR analysis of 15c:
1H NMR (400.13 MHz, CDCl3): δ = 1.58 [s, 9H, C(CH3)3], 3.34 (dd, 2H,
J2,3 = 7.1 Hz, 4J2,4 = 1.5 Hz, 2-H2), 3.74 (s, 3H, 1-OMe), 3.83 (s, 3H, 1’-
OMe), 3.93 (s, 3H, 4’-OMe), 3.95 (s, 3H, 6’-OMe), 6.32 (dt, 1H, J3,4
=
=
16.0 Hz, J3,2 = 7.2 Hz, 3-H), 6.88 (s, 1H, 3’-H), 6.92 (dt, 1H, J4,3
4
16.1 Hz, J4,2 = 1.5 Hz, 4-H), 7.30 (d, 1H, J7’,8’ = 9.3 Hz, 7’-H), 7.95 (d,
1H, J8’,7’ = 9.3 Hz, 8‘-H). A NOESY spectrum (400.13 MHz, CDCl3)
1
allowed additional assignments of H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.58 [C(CH3)3] ↔ δ = 3.93 (4’-OMe), δ
= 3.83 (1’-OMe) ↔ δ = 6.92 (4-H), δ = 3.83 (1’-OMe) ↔ δ = 7.95 (8’-H),
δ = 3.93 (4’-OMe) ↔ δ = 6.88 (3’-H), δ = 3.95 (6’-OMe) ↔ δ = 7.30 (7’-
H). 13C NMR (100.61 MHz, CDCl3): δ = 27.91 [C(CH3)3], 38.68 (C-2),
52.00 (1-OCH3), 56.46 (4’-OCH3), 57.03 (6’-OCH3), 62.55 (1’-OCH3),
82.66 [C(CH3)3], 103.77 (C-3’), 114.72 (C-7’), 121.37 (C-4’a), 121.45
(C-8’), 122.14 (C-3), 122.96 (C-2’), 125.54 (C-8’a), 127.74 (C-4), 134.66
(C-5’), 147.29 (C-1’), 149.61 (C-6’), 151.48 (C-4’), 151.96 (5’-OCO2tBu),
172.17 (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 = 27.91
[C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 38.68 (C-2) ↔ δ = 3.34 (2-H2), δ =
52.00 (1-OCH3) ↔ δ = 3.74 (1-OMe), δ = 56.46 (4’-OCH3) ↔ δ = 3.93
(4’-OMe), δ = 57.03 (6’-OCH3) ↔ δ = 3.95 (6’-OMe), δ = 62.55 (1’-
OCH3) ↔ δ = 3.83 (1’-OMe), δ = 103.77 (C-3’) ↔ δ = 6.88 (3’-H), δ =
114.72 (C-7’) ↔ δ = 7.30 (7’-H), δ = 121.45 (C-8’) ↔ δ = 7.95 (8’-H), δ
= 122.14 (C-3) ↔ δ = 6.32 (3-H), δ = 127.74 (C-4) ↔ δ = 6.92 (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 = 82.66
[C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 121.37 (C-4’a) ↔ δ = 6.88 (3’-H), δ
= 121.37 (C-4’a) ↔ δ = 7.95 (8’-H), δ = 122.96 (C-2’) ↔ δ = 6.32 (3-H),
δ = 122.96 (C-2’) ↔ δ = 6.88 (3’-H), δ = 125.54 (C-8’a) ↔ δ = 7.30 (7’-
H), δ = 134.66 (C-5’) ↔ δ = 7.30 (7’-H), δ = 134.66 (C-5’) ↔ δ = 7.95
(8’-H), δ = 147.29 (C-1’) ↔ δ = 3.83 (1’-OMe), δ = 147.29 (C-1’) ↔ δ =
6.88 (3’-H), δ = 147.29 (C-1’) ↔ δ = 7.95 (8’-H), δ = 149.61 (C-6’) ↔ δ
3.94 (7-OMe) ↔ δ = 7.67 (6-H), δ = 4.00 (4-OMe) ↔ δ = 7.30 (5-H). 13
C
NMR (100.61 MHz, CDCl3): δ = 57.32 (4-OCH3), 61.57 (7-OCH3), 91.35
(C-2), 112.72 (C-9), 110.47 (C-8), 116.11 (C-9b), 116.39 (C-6), 116.56
(C-5), 121.48 (C-6a), 137.62 (C-3a), 141.99 (C-4), 145.56 (C-9a),
147.90 (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
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 57.32 (4-
OCH3) ↔ δ = 4.00 (4-OMe), δ = 61.57 (7-OCH3) ↔ δ = 3.94 (7-OMe), δ
= 91.35 (C-2) ↔ δ = 5.53 (2-H2), δ = 112.72 (C-9) ↔ δ = 7.00 (9-H), δ =
116.39 (C-6) ↔ δ = 7.67 (6-H), δ = 116.56 (C-5) ↔ δ = 7.30 (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 = 110.47 (C-8)
↔ δ = 7.00 (9-H), δ = 116.11 (C-9b) ↔ δ = 7.00 (9-H), δ = 116.11 (C-
9b) ↔ δ = 7.67 (6-H), δ = 121.48 (C-6a) ↔ δ = 7.30 (5-H), δ = 137.62
(C-3a) ↔ δ = 5.53 (2-H2), δ = 137.62 (C-3a) ↔ δ = 7.30 (5-H), δ =
141.99 (C-4) ↔ δ = 4.00 (4-OMe), δ = 141.99 (C-4) ↔ δ = 7.30 (5-H), δ
= 141.99 (C-4) ↔ δ = 7.67 (6-H), δ = 145.56 (C-9a) ↔ δ = 5.53 (2-H2),
δ = 145.56 (C-9a) ↔ δ = 7.00 (9-H), δ = 147.90 (C-7) ↔ δ = 3.94 (7-
OMe), δ = 147.90 (C-7) ↔ δ = 7.00 (9-H), δ = 147.90 (C-7) ↔ δ = 7.67
(6-H). Melting point: 98°C. Elemental analysis: Calculated: C:
65.45%, H: 5.49%; found: C: 65.32%, H: 5.83%; deviation: C: 0.13%, H:
0.34%. HRMS (pos. ESI): calcd. for C13H1181BrO4 [M]+ = 311.98148;
found 311.98154 (+0.19 ppm). IR (film): ν = 3000, 2945, 2905, 2840,
1735, 1620, 1610, 1575, 1505, 1480, 1445, 1410, 1380, 1340, 1275,
1210, 1165, 1105, 1070, 1040, 1030, 1015, 995, 975, 935, 895, 855,
810, 785, 730, 710, 690 cm-1.
61
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(t-Bu)3 has
to be weighed out in a glove box.
15
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10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
= 3.95 (6’-OMe), δ = 149.61 (C-6’) ↔ δ = 7.30 (7’-H), δ = 149.61 (C-6’)
↔ δ = 7.95 (8’-H), δ = 151.48 (C-4’) ↔ δ = 3.93 (4’-OMe), δ = 151.48
(C-4’) ↔ δ = 6.88 (3’-H), δ = 172.17 (C-1) ↔ δ = 3.34 (2-H2), δ = 172.17
(C-1) ↔ δ = 3.74 (1-OMe). δ = 151.96 (5’-OCO2tBu) exhibited no
crosspeak. NMR analysis of iso-15c: Only an assignment of the 1H
NMR (400.13 MHz, CDCl3) resonances was possible: δ = 1.58 [s, 9H,
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 = 39.30
[C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ = 121.48 (C-4’a) ↔ δ = 6.83 (3’-H), δ
= 121.48 (C-4’a) ↔ δ = 7.95 (8’-H), δ = 122.76 (C-2’) ↔ δ = 6.31 (3-H),
δ = 122.76 (C-2’) ↔ δ = 6.83 (3’-H), δ = 125.59 (C-8’a) ↔ δ = 6.83 (3’-
H), δ = 125.59 (C-8’a) ↔ δ = 7.29 (7’-H), δ = 134.99 (C-5’) ↔ δ = 6.83
(3’-H), δ = 134.99 (C-5’) ↔ δ = 7.29 (7’-H), δ = 134.99 (C-5’) ↔ δ =
7.95 (8’-H), δ = 147.13 (C-1’) ↔ δ = 3.83 (1’-OMe), δ = 147.13 (C-1’) ↔
δ = 6.83 (3’-H), δ = 147.13 (C-1’) ↔ δ = 6.92 (4-H), δ = 149.06 (C-6’) ↔
δ = 3.95 (6’-OMe), δ = 149.06 (C-6’) ↔ δ = 7.29 (7’-H), δ = 149.06 (C-
6’) ↔ δ = 7.95 (8’-H), δ = 151.72 (C-4’) ↔ δ = 3.88 (4’-OMe), δ =
151.72 (C-4’) ↔ δ = 6.83 (3’-H), δ = 172.26 (C-1) ↔ δ = 3.35 (2-H2), δ =
172.26 (C-1) ↔ δ = 3.74 (1-OMe), δ = 172.26 (C-1) ↔ δ = 6.31 (3-H), δ
= 176.86 (5’-O2CtBu) ↔ δ = 1.44 [C(CH3)3]. NMR analysis of iso-15d:
Due to the small amount of the minor product structural assignments in
4
C(CH3)3], 3.65 (dd, 2H, J4,3 = 6.5 Hz, J4,3 = 1.8 Hz, 4-H2), 3.71, 3.81,
3.88, and 3.95 (4×s, 4×3H, 1-OMe, 1’-OMe, 4’-OMe, and 6’-OMe), 5.86
4
(dt, 1H, J2,3 = 15.7 Hz, J2,4 = 1.8 Hz, 2-H), 6.52 (s, 1H, 3’-H), 7.15 (dt,
1H, J3,2 = 15.6 Hz, J3,4 = 6.5 Hz, 3-H), 7.33 (d, 1H, J7’,8’ = 9.3 Hz, 7’-H),
7.92 (d, 1H, J8’,7’ = 9.3 Hz, 8‘-H). Melting point: Oil. HRMS (pos. ESI):
Calcd. for C23H28O8Na [M+Na]+ = 455.16764; found 455.16757 (–
0.15 ppm). IR (film): ν = 3450, 3055, 2980, 2945, 2845, 1745, 1660,
1605, 1510, 1480, 1460, 1440, 1375, 1340, 1280, 1255, 1200, 1155,
1140, 1070, 1010, 980, 895, 850, 820, 800, 775, 735, 705 cm-1.
the NOESY and HMBC spectra were impossible. 1H NMR (500.42 MHz,
(E)-Methyl 4-[1,4,6-trimethoxy-5-(pivaloyloxy)-naphthalen-2-yl]but-
4
CDCl3): δ = 1.44 [s, 9H, C(CH3)3], 3.65 (ddd, 2H, J4,3 = 7.2 Hz, J4,2
=
3-enoate
(15d)
and
(E)-Methyl
4-(1,4,6-trimethoxy-5-
4
pivaloyloxynaphthalen-2-yl)but-2-enoate (iso-15d)[61]
1.5 Hz, J4,3’ = 1.5 Hz, 4-H2,), 3.71, 3.82, 3.83, and 3.90 (4×s, 4×3H, 1-
OMe, 1’-OMe, 4’-OMe, and 6’-OMe), 5.82 (dt, 1H, J2,3 = 15.5 Hz, 4J2,4
=
1.7 Hz, 2-H), 6.48 (br. s, 1H, 4J3’,4 not observed 3’-H,), 7.15 (dt, 1H, J3,2
= 15.5 Hz, J3,4 = 6.4 Hz, 3-H), 7.33 (d, 1H, J7’,8’ = 9.1 Hz, 7’-H), 7.92 (d,
1H, J8’,7’ = 9.1 Hz, 8‘-H). 13C NMR (125.83 MHz, CDCl3):δ = 27.50
[C(CH3)3], 32.58 (C-4), 39.30 [C(CH3)3], 51.53, 55.77, 57.02, and 62.41
(1-OCH3, 1’-OCH3, 4’-OCH3, and 6’-OCH3,) could not be assigned
unambiguously, 107.70 (C-3’), 114.59 (C-7’), 120.83, 123.27, and
125.53 (C-2’, C-4’a, and C-8’a) could not be assigned unambiguously,
120.98 (C-8’), 122.06 (C-2), 134.99 (C-5’), 147.33 (C-3), 147.61,
148.71, and 151.76 (C1’, C-4’, and C-6’) could not be assigned
unambiguously, 166.99 (C-1), 176.92 (5’-O2CtBu). An edHSQC
spectrum (“short-range C,H COSY”; 125.83/500.42 MHz, CDCl3)
allowed the assignment of all nonquaternary 13C atoms through their
6-Bromo-2,5,8-trimethoxynaphthalen-1-yl pivalate (14d, 280 mg,
0.70 mmol) and Pd2dba3·CHCl3 (14.5 mg, 14.0 µmol, 2.0 mol-%) were
dissolved in freshly distilled toluene (7 mL). P(t-Bu)3 (11.3 mg, 56 µmol,
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 (0.45 mL, 0.41 g,
2.1 mmol, 3.0 equiv.) and methyl vinylacetate (0.22 mL, 0.21 g,
2.1 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 (25 mL) was added. The organic phase was
1
cross-peaks with the independently assigned H resonances [δ(13C) ↔
δ(1H)]: δ = 27.50 [C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ = 32.58 (C-4) ↔ δ =
3.65 (4-H2), δ = 51.53, 55.77, 57.02, and 62.41 (1-OCH3, 1’-OCH3, 4’-
OCH3, and 6’-OCH3,) could not be assigned unambiguously, δ = 107.70
(C-3’) ↔ δ = 6.48 (3’-H), δ = 114.59 (C-7’) ↔ δ = 7.32 (7’-H), δ =
120.98 (C-8’) ↔ δ = 7.92 (8’-H), δ = 122.06 (C-2) ↔ δ = 5.82 (2-H), δ =
147.33 (C-3) ↔ δ = 7.15 (3-H). Melting point: Oil. HRMS (pos. APCI):
calcd. for C23H29O7 [M+H]+ = 417.19133; found 417.19090 (–1.0 ppm).
IR (film): ν = 3325, 2975, 2875, 1750, 1665, 1605, 1590, 1480, 1460,
1440, 1395, 1365, 1335, 1280, 1200, 1105, 1075, 1030, 890, 825, 780,
750 cm-1.
washed with aq. HCl (1M, 2×25 mL) and brine (25 ml) and dried over
Na2SO4. The solvent was removed in vacuo and the oily residue was
purified by flash chromatography [d = 3 cm, h = 12 cm, F = 25 mL;
CH/EE 5:1] to obtain the product [F19-22, Rf (5:1) = 0.15, 175 mg, 60%]
as a yellow-brownish oil and as a 87:13 mixture of 15d and its α,β-
unsaturated carboxylic ester isomer iso-15d.– NMR analysis of 15d: 1H
NMR (500.42 MHz, CDCl3): δ = 1.44 [s, 9H, C(CH3)3], 3.35 (dd, 2H, J2,3
(E)-Methyl 4-(6,9-dimethoxynaphtho[1,8-de][1,3 dioxine-5-yl]but-3-
enoate (15h) and (E)-Methyl 4-(6,9-dimethoxynaphtho[1,8-de][1,3
dioxine-5-yl]but-2-enoate (iso-15h)[61]
4
= 7.2 Hz, J2,4 = 1.5 Hz, 2-H2), 3.74 (s, 3H, 1-OMe), 3.83 (s, 3H, 1’-
OMe), 3.88 (s, 3H, 4’-OMe), 3.89 (s, 3H, 6’-OMe), 6.31 (dt, 1H, J3,4
=
=
16.0 Hz, J3,2 = 7.2 Hz, 3-H), 6.83 (s, 1H, 3’-H), 6.92 (dt, 1H, J4,3
4
16.0 Hz, J4,2 = 1.5 Hz, 4-H), 7.29 (d, 1H, J7’,8’ = 9.2 Hz, 7’-H), 7.95 (d,
1H, J8’,7’ = 9.2 Hz, 8‘-H). A NOESY spectrum (500.42 MHz, CDCl3)
2'
2'
1' O
O 3'
1' O
O 3'
1
9'a
3'a
9'a
3'a
allowed additional assignments of H resonances by the occurrence of
MeO
MeO
4'
5'
4'
5'
O
9
8
9
8
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 3.83 (1’-OMe) ↔ δ = 6.92 (4-H), δ =
3.88 (4’-OMe) ↔ δ = 6.83 (3’-H), δ = 3.89 (6’-OMe) ↔ δ = 7.29 (7’-H), δ
= 6.83 (3’-H) ↔ δ = 6.31 (3-H). 13C NMR (125.83 MHz, CDCl3): δ =
27.50 [C(CH3)3], 38.69 (C-2), 39.30 [C(CH3)3], 52.03 (1-OCH3), 55.73
(4’-OCH3), 56.94 (6’-OCH3), 62.58 (1’-OCH3), 102.97 (C-3’), 114.43 (C-
7’), 121.18 (C-8’), 121.95 (C-3), 121.48 (C-4’a), 122.76 (C-2’), 125.59
(C-8’a), 127.80 (C-4), 134.99 (C-5’), 147.13 (C-1’), 149.06 (C-6’),
151.72 (C-4’), 172.26 (C-1), 176.86 (5’-O2CtBu). An edHSQC spectrum
(“short-range C,H COSY”; 125.83/500.42 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 =
27.50 [C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ = 38.69 (C-2) ↔ δ = 3.35 (2-
H2), δ = 52.03 (1-OCH3) ↔ δ = 3.74 (1-OMe), δ = 55.73 (4’-OCH3) ↔ δ
= 3.88 (4’-OMe), δ = 56.94 (6’-OCH3) ↔ δ = 3.89 (6’-OMe), δ = 62.58
(1’-OCH3) ↔ δ = 3.83 (1’-OMe), δ = 102.97 (C-3’) ↔ δ = 6.83 (3’-H), δ =
114.43 (C-7’) ↔ δ = 7.29 (7’-H), δ = 121.18 (C-8’) ↔ δ = 7.95 (8’-H), δ
= 121.95 (C-3) ↔ δ = 6.31 (3-H), δ = 127.80 (C-4) ↔ δ = 6.92 (4-H). An
HMBC spectrum (“long-range C,H COSY”; 125.83/500.42 MHz, CDCl3)
9'b
6'a
9'b
6'a
and
3
3
2
1
OMe
6'
6'
7
4
7
4
2
1
OMe
OMe
MeO
O
as an inseparable 93:7 mixture
8-Bromo-4,7-dimethoxynaphtho[1,8-de][1,3]dioxine
(14h,
1.56 g,
5.01 mmol) and Pd2dba3·CHCl3 (51.8 mg, 0.05 mmol, 1.0 mol-%) were
dissolved in freshly distilled toluene (50mL). P(t-Bu)3 (40.6 mg,
0.20 mmol, 4.0 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
(3.23 mL, 2.94 g, 15.0 mmol, 3.0 equiv.) and methyl vinylacetate
(1.60 mL, 1.50 g, 15.0 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 EtOAc (100 mL) was
added. The organic phase was washed with aq. HCl (1
M, 2×50 mL) and
brine (50 ml) and dried over Na2SO4. The solvent was removed in
16
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
vacuo and the oily residue was purified by flash chromatography
(d = 5 cm, h = 12 cm, F = 50 mL; CH/EE 5:1) to obtain the product
[F16-20, Rf (5:1) = 0.2, 571.7 mg] as pale-yellow oil and a second
fraction (F11-15, 620.7 mg) containing unidentified impurities This
second fraction was purified again by a second flash chromatography
(d = 4 cm, h = 12 cm, F = 50 mL; CH/EE 7:1) to obtain the product
(F16-22, 527.0 mg). Combined yield: 1.099 g, 66%, obtained as a 93:7
mixture of the title compound with its α,β-unsaturated ester isomer iso-
15h.– NMR-analysis of 15h: 1H NMR (400.13 MHz, CDCl3): δ = 3.33
(dd, 2H, J2,3 = 7.2 Hz, 4J2,4 = 1.6 Hz, 2-H2), 3.73 (s, 3H, 1-OMe), 3.87 (s,
3H, 6’-OMe), 4.00 (s, 3H, 9’-OMe), 5.55 (s, 2H, 2’-H2), 6.32 (dt, 1H, J3,4
= 16.0 Hz, J3,2 = 7.2 Hz, 3-H), 6.93 (dt, 1H, J4,3 = 16.0 Hz, 4J4,2 = 1.6 Hz,
4-H), 7.02 (s, 1H, 4’-H), 7.28 (d, 1H, J8’,7’ = 9.2 Hz, 8’-H), 7.67 (d, 1H,
J7’,8’ = 9.2 Hz, 7‘-H). A NOESY spectrum (400.13 MHz, CDCl3) allowed
additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 4.00 (9’-OMe) ↔ δ = 7.28 (8’-H), δ =
7.02 (4’-H) ↔ δ = 6.32 (3-H). 13C NMR (100.61 MHz, CDCl3): δ = 38.68
(C-2), 52.00 (1-OCH3), 57.31 (9’-OCH3), 62.62 (6’-OCH3), 91.37 (C-2’),
105.65 (C-4’), 115.89 (C-8’), 116.45 (C-9’b), 116.59 (C-7’), 122.78 (C-
3), 124.08 (C-6’a), 124.38 (C-5’), 127.54 (C-4), 137.69 (C-9’a), 141.91
(C-9’), 145.36 (C-3’a), 147.96 (C-6’), 172.03 (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
5.0 mol-%) were suspended in freshly distilled THF (12 ml) under a N2
atmosphere. At 0°C a solution of KOH [85%, technical grade, 3.37g
(≙2.86 g), 51.0 mmol, 8.0 equiv.] in degassed H2O (6 ml) was added
dropwise. The methylation reaction was started by the dropwise
addition of Me2SO4 (6.05 ml, 8.05 g, 63.8 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 (10 ml) and stirred for 1 h at room temperature.
CH2Cl2 (30 ml) was added, the organic phase was separated and the
aq. phase was extracted with CH2Cl2 (3×30 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 = 12 cm, F = 50 mL; CH/EE 5:1) afforded the title compound [F5-8, Rf
(5:1) = 0.5, 1.55 g, 75%] as a white solid.– 1H NMR (500.32 MHz,
CDCl3): δ = 3.84 (s, 3H, 8-OMe), 3.95 (s, 3H, 5-OMe), 3.96 (s, 3H, 2-
OMe), 5.03 (s, 2H, 1-OCH2), AB signal (δA = 6.59, δB = 6.76, JAB
=
8.4 Hz, A and B signal show no further splitting, 6-H and 7-H), 7.30 (d,
1H, J3,4 = 9.3 Hz, 3-H), 7.32-7.35 (m, 1H, 4’-H), 7.39-7.43 (m, 2H, 3’-H
and 5’-H), 7.59-7.62 (m, 2H, 2’-H, and 6’-H), 8.06 (d, 1H, J4,3 = 9.2 Hz,
4-H). A NOESY spectrum (500.32 MHz, CDCl3) allowed additional
1
assignments of H resonances by the occurrence of crosspeaks [δ(1H)
↔ δ(1H)]: δ = 3.84 (8-OMe) ↔ δB = 6.76 (7-H), δ = 3.95 (5-OMe) ↔ δA
= 6.59 (6-H), δ = 3.96 (2-OMe) ↔ δ = 7.30 (3-H), δ = 5.03 (1-OCH2) ↔
δ = 7.59-7.62 (m, 2H, 2’-H, and 6’-H). 13C NMR (125.81 MHz, CDCl3): δ
= 55.78 (5-OCH3), 57.22 (2-OCH3), 57.30 (8-OCH3), 76.12 (5-OCH2),
101.55 (C-6), 107.33 (C-7), 114.67 (C-3), 119.03 (C-4), 122.94 (C-8a),
123.62 (C-4a), 127.63 (C-4’), 128.28 (C-3’ and C-5’), 128.39 (C-2’ and
C-6’), 138.60 (C-1’), 142.86 (C-1), 149.82 (C-8), 149.94 (C-5), 151.24
(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
cross-peaks with the independently assigned H resonances [δ(13C) ↔
1
δ(1H)]: δ = 38.68 (C-2) ↔ δ = 3.33 (2-H2), δ = 52.00 (1-OCH3) ↔ δ =
3.73 (1-OMe), δ = 57.31 (9’-OCH3) ↔ δ = 4.00 (9’-OMe), δ = 62.62 (6’-
OCH3) ↔ δ = 3.87 (6’-OMe), δ = 91.37 (C-2’) ↔ δ = 5.55 (2’-H2), δ =
105.65 (C-4’) ↔ δ = 7.02 (4’-H), δ = 115.89 (C-8’) ↔ δ = 7.28 (8’-H), δ
= 116.59 (C-7’) ↔ δ = 7.67 (7’-H), δ = 122.78 (C-3) ↔ δ = 6.32 (3-H), δ
= 127.54 (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 = 116.45 (C-9’b) ↔ δ = 7.02 (4’-H), δ =
116.45 (C-9’b) ↔ δ = 7.67 (7’-H), δ = 124.08 (C-6’a) ↔ δ = 7.28 (8’-H),
δ = 124.38 (C-5’) ↔ δ = 6.32 (3-H), δ = 137.69 (C-9’a) ↔ δ = 5.55 (2’-
H2), δ = 137.69 (C-9’a) ↔ δ = 7.28 (8’-H), δ = 141.91 (C-9’) ↔ δ = 4.00
(9’-OMe), δ = 141.91 (C-9’) ↔ δ = 7.28 (8’-H), δ = 141.91 (C-9’) ↔ δ =
7.67 (7’-H), δ = 145.36 (C-3’a) ↔ δ = 5.55 (2’-H2), δ = 145.36 (C-3’a) ↔
δ = 7.02 (4’-H), δ = 147.96 (C-6’) ↔ δ = 3.87 (6’-OMe), δ = 147.96 (C-
6’) ↔ δ = 7.02 (4’-H), δ = 147.96 (C-6’) ↔ δ = 7.67 (7’-H), δ = 172.03
(C-1) ↔ δ = 3.33 (2-H2), δ = 172.03 (C-1) ↔ δ = 3.73 (1-OMe), δ =
172.03 (C-1) ↔ δ = 6.32 (3-H). NMR analysis of iso-15h: Only an
assignment of the 1H NMR (400.13 MHz, CDCl3) resonances was
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 55.78 (5-
OCH3) ↔ δ = 3.95 (5-OMe), δ = 57.22 (2-OCH3) ↔ δ = 3.96 (2-OMe), δ
= 57.30 (8-OCH3) ↔ δ = 3.84 (8-OMe), δ = 76.12 (5-OCH2) ↔ δ = 5.03
(5-OCH2), δ = 101.55 (C-6) ↔ δA = 6.59 (6-H), δ = 107.33 (C-7) ↔ δB =
6.76 (7-H), δ = 114.67 (C-3) ↔ δ = 7.30 (3-H), δ = 119.03 (C-4) ↔ δ =
8.06 (4-H), δ = 127.63 (C-4’) ↔ δ = 7.32-7.35 (m, 1H, 4’-H), δ = 128.28
(C-3’ and C-5’) ↔ δ = 7.39-7.43 (m, 2H, 3’-H and 5’-H), δ = 128.39 (C-
2’ and C-6’) ↔ δ = 7.59-7.62 (m, 2H, 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 = 122.94 (C-
8a) ↔ δB = 6.76 (7-H), δ = 122.94 (C-8a) ↔ δ = 8.06 (4-H), δ = 123.62
(C-4a) ↔ δA = 6.59 (6-H), δ = 123.62 (C-4a) ↔ δ = 7.30 (3-H), δ =
138.60 (C-1’) ↔ δ = 5.03 (1-OCH2), δ = 138.60 (C-1’) ↔ δ = 7.39-7.43
(m, 2H, 3’-H and 5’-H), δ = 142.86 (C-1) ↔ δ = 5.03 (1-OCH2), δ =
142.86 (C-1) ↔ δ = 7.30 (3-H), δ = 149.82 (C-8) ↔ δ = 3.84 (8-OMe), δ
= 149.82 (C-8) ↔ δA = 6.59 (6-H), δ = 149.82 (C-8) ↔ δB = 6.76 (7-H),
δ = 149.94 (C-5) ↔ δ = 3.95 (5-OMe), δ = 149.94 (C-5) ↔ δA = 6.51 (6-
H), δ = 149.94 (C-5) ↔ δB = 6.76 (7-H), δ = 149.94 (C-5) ↔ δ = 8.06 (4-
H), δ = 151.24 (C-2) ↔ δ = 3.96 (2-OMe), δ = 151.24 (C-2) ↔ δ = 7.30
(3-H), δ = 151.24 (C-2) ↔ δ = 8.06 (4-H). Melting point: 65-68°C.
Elemental analysis: Calculated: C: 74.06%, H: 6.21%; found: C:
74.17%, H: 6.24%; deviation: C:0.11%, H: 0.03%. HRMS (pos. ESI):
calcd. for C20H21O4: [M+H]+ = 325.14344; found: 325.14340 (‒0.10
ppm). IR (film): ν = 3335, 3065, 3030, 3000, 2940, 2835, 1735, 1660,
1620, 1595, 1520, 1495, 1455, 1440, 1410, 1380, 1350, 1320, 1275,
1260, 1180, 1075, 1050, 995, 910, 875, 805, 785, 735, 700 cm-1.
4
possible: 3.66 (dd, 2H, J4,3 = 6.7 Hz, J4,3 = 1.6 Hz, 4-H2), 3.71, 3.89,
4.01 (3×s, 3×3H, 1-OMe, 6’-OMe, and 9’-OMe), 5.55 (s, 2H, 2’-H2), 5.84
4
(dt, 1H, J2,3 = 15.6 Hz, J2,4 = 1.7 Hz, 2-H), 6.65 (s, 1H, 4’-H), 7.13 (dt,
1H, J3,2 = 15.6 Hz, J3,4 = 6.5 Hz, 3-H), 7.30 (d, 1H, J8’,7’ = 9.2 Hz, 8’-H),
7.64 (d, 1H, J7’,8’ = 9.2 Hz, 7‘-H). Melting point: 105°C. Elemental
analysis: Calculated: C: 65.45%, H: 5.49%; found: C: 65.06%, H:
5.53%; deviation: C: 0.39%, H: 0.04%. HRMS (pos. ESI): calcd. for
C18H18O6 [M+Na]+ = 353.09956; found 353.09988 (+0.92 ppm). IR
(film): ν = 3055, 2985, 2950, 2845, 2305, 1735, 1620, 1575, 1505,
1485, 1440, 1405, 1385, 1340, 1275, 1265, 1205, 1165, 1105, 1070,
1035, 1015, 995, 970, 895, 860, 815, 740, 705 cm-1.
1-(Benzyloxy)-2,5,8-trimethoxynaphthalene (16a)
rel-(S)- 2,5,8-Trimethoxynaphthalen-1-ol (16b)
In a 50 ml round-bottomed flask 5-(benzyloxy)-6-methoxynaphthalene-
1,4-diol (29, 1.89 g, 6.38 mmol) and nBu4NBr (103 mg, 0.32mmol,
17
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
In a 250 mL round-bottomed flask und a nitrogen atmospher 1-
(benzyloxy)-2,5,8-trimethoxynaphthalene (16a, 4.00 g, 12.33 mmol) and
Pd/C (containing 10 w-% of Pd, 0.20 g, 0.19 mmol Pd, 1.5 mol-%) were
dissolved in EE (120 mL) and the mixture was frozen to −196°C with
gentle stirring. At this temperature the flask was evacuated and flushed
saturated NaHCO3 solution (10 mL). After drying over Na2SO4 the
solvent was removed in vacuo. Flash chromatography (d = 1.5 cm,
h = 12 cm, F = 8 ml; CH/EE 5:1) afforded the title compound (F8-15, Rf
(5:1) = 0.25, 133.4 mg, 93%) as a colorless solid. Note: An upscaling of
this reaction was easily achieved: Boc protection of 16b (949 mg,
4.05 mmol) with DMAP (49.5 mg, 0.41 mmol, 10 mol-%), di-t-butyl
dicarbonate (1.74 mL, 1.77 g, 8.11 mmol, 2.0 equiv.), and NEt3
(1.12 mL, 0.82 g, 8.11 mmol, 2.0 equiv.). in CH2Cl2 (40 mL) furnished
the title compound (1.187 g, 88%) in a slightly lower yield (Flash
chromatography data: d = 4 cm, h = 12 cm, F = 50 ml; CH/EE 5:1,
product: F11-21).– 1H NMR (400.13 MHz, CDCl3): δ = 1.58 [s, 9H,
C(CH3)3], 3.88 (s, 3H, 8-OMe), 3.93 (s, 3H, 5-OMe), 3.95 (s, 3H, 2-
OMe), AB signal (δA = 6.56, δB = 6.72, JAB = 8.4 Hz, A and B signal
show no further splitting, 6-H and 7-H), 7.28 (d, 1H, J3,4 = 9.3 Hz, 3-H),
8.12 (d, 1H, J4,3 = 9.3 Hz, 4-H). A NOESY spectrum (400.13 MHz,
CDCl3) allowed additional assignments of 1H resonances by the
with hydrogen (hydrogen balloon) three times (“freeze
& pump
technique”). Afterwards the mixture was allowed to warm to room
temperature and stirred under the hydrogen atmosphere at room
temperature for 16 h. After removing the hydrogen balloon the resulting
suspension was filtered over a pad of silica gel (d = 1.5 cm, h = 4 cm)
and the silica gel pad was washed carefully with CH2Cl2 (100 mL) in
portions. Removal of the solvent under reduced pressure furnished the
title compound (2.89 g, 100%) without further purification. Note: If the
reaction was performed in THF, it yielded the title compound in only
58%.– 1H NMR (400.13 MHz, CDCl3): δ = 3.93 (s, 3H, 5-OMe), 3.99 (s,
3H, 2-OMe), 4.05 (s, 3H, 8-OMe), AB signal (δA = 6.51, δB = 6.64, JAB
8.4 Hz, A and B signal show no further splitting, 6-H and 7-H), 7.25 (d,
=
occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 3.88 (8-OMe) ↔ δB
=
1H, J3,4 = 9.1 Hz, 3-H)*, 7.71 (d, 1H, J4,3 = 9.1 Hz, 4-H), 9.46 (d, 1H, J1-
6.72 (7-H), δ = 3.93 (5-OMe) ↔ δA = 6.56 (6-H), δ = 3.95 (2-OMe) ↔ δ
= 7.28 (3-H). 13C NMR (100.61 MHz, CDCl3): δ = 27.92 [C(CH3)3], 55.84
(5-OCH3), 56.84 (8-OCH3), 56.99 (2-OCH3), 101.78 (C-6), 107.05 (C-7),
113.66 (C-3), 121.12 (C-4), 121.48 (C-8a), 123.00 (C-4a), 133.98 (C-1),
148.99 (C-8), 149.70 and 149.77 (C-2 and C-5), 152.01 (carbonate-C).
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 = 27.92 [C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 55.84
(5-OCH3) ↔ δ = 3.93 (5-OMe), δ = 56.84 (8-OCH3) ↔ δ = 3.88 (8-
OMe), δ = 56.99 (2-OCH3) ↔ δ = 3.95 (2-OMe), δ = 101.78 (C-6) ↔ δA
= 6.56 (6-H), δ = 107.05 (C-7) ↔ δB = 6.72 (7-H), δ = 113.66 (C-3) ↔ δ
= 7.28 (3-H), δ = 121.12 (C-4) ↔ δ = 8.12 (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 = 82.48 [C(CH3)3] ↔ δ
= 1.58 [C(CH3)3], δ = 121.48 (C-8a) ↔ δB = 6.72 (7-H),, δ = 121.48 (C-
8a) ↔ δ = 8.12 (4-H), δ = 123.00 (C-4a) ↔ δA = 6.56 (6-H), δ = 123.00
(C-4a) ↔ δ = 7.28 (3-H), δ = 133.98 (C-1) ↔ δ = 7.28 (3-H), δ = 133.98
(C-1) ↔ δ = 8.12 (4-H), δ = 148.99 (C-8) ↔ δ = 3.88 (8-OMe), [δ =
149.70 and 149.77 (C-2 and C-5)] ↔ [δ = 3.93 and 3.94 (2-OMe and 5-
OMe)]. δ = 152.01 (carbonate-C) exhibited no cross-peak. Melting
point: 86°C. Elemental analysis: Calculated: C: 64.66%, H: 6.63%;
found: C: 64.62%, H: 6.56%, deviation: C: 0.04%, H: 0.07%. HRMS
(pos. ESI): calcd. for C18H22O6: [M+Na]+ = 357.13086; found: 357.13095
(0.26 ppm). IR (film): ν = 2980, 2940, 2840, 1760, 1665, 1630, 1605,
1520, 1460, 1415, 1395, 1370, 1330, 1285, 2160, 1200, 1160, 1145,
1080, 1055, 1015, 980, 920, 895, 855, 805, 775, 730, 705, 685 cm-1.
= 0.5 Hz, 1-OH). *Broad doublet of 3-H does not show J3,1-OH
OH,3
coupling due to insufficient resolution. A NOESY spectrum (400.13
MHz, CDCl3) allowed additional assignments of 1H resonances by the
occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 4.01 (8-OMe) ↔ δB
=
6.64 (7-H), δ = 3.93 (5-OMe) ↔ δA = 6.51 (6-H), δ = 3.99 (2-OMe) ↔ δ
= 7.25 (3-H). 13C NMR (100.61 MHz, CDCl3): δ = 55.75 (5-OCH3), 56.58
(8-OCH3), 57.16 (2-OCH3), 100.75 (C-6), 103.88 (C-7), 113.25 (C-4),
115.04 (C-3), 116.47 (C-8a), 123.11 (C-4a), 142.38 (C-1), 144.14 (C-2),
149.73 (C-8), 150.46 (C-5). 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
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 55.75 (5-
OCH3) ↔ δ = 3.93 (5-OMe), δ = 56.58 (8-OCH3) ↔ δ = 4.01 (8-OMe), δ
= 57.16 (2-OCH3) ↔ δ = 3.99 (2-OMe), δ = 100.75 (C-6) ↔ δA = 6.51
(6-H), δ = 103.88 (C-7) ↔ δB = 6.64 (7-H), δ = 113.25 (C-4) ↔ δ = 7.71
(4-H), δ = 115.04 (C-3) ↔ δ = 7.25 (3-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 = 116.47 (C-8a) ↔ δB = 6.64
(7-H), δ = 116.47 (C-8a) ↔ δ = 7.71 (4-H), δ = 116.47 (C-8a) ↔ δ =
9.46 (1-OH), δ = 123.11 (C-4a) ↔ δA = 6.51 (6-H), δ = 123.11 (C-4a) ↔
δ = 7.25 (3-H), δ = 142.38 (C-1) ↔ δ = 7.25 (3-H), δ = 142.38 (C-1) ↔ δ
= 7.71 (4-H), δ = 142.38 (C-1) ↔ δ = 9.46 (1-OH), δ = 144.14 (C-2) ↔ δ
= 3.99 (2-OMe), δ = 144.14 (C-2) ↔ δ = 7.25 (3-H), δ = 144.14 (C-2) ↔
δ = 7.71 (4-H), δ = 144.14 (C-2) ↔ δ = 9.46 (1-OH), δ = 149.73 (C-8) ↔
δ = 4.01 (8-OMe), δ = 149.73 (C-8) ↔ δA = 6.51 (6-H), δ = 149.73 (C-8)
↔ δB = 6.64 (7-H), δ = 150.46 (C-5) ↔ δ = 3.93 (5-OMe), δ = 150.46
(C-5) ↔ δA = 6.51 (6-H), δ = 150.46 (C-5) ↔ δB = 6.64 (7-H), δ =
150.46 (C-5) ↔ δ = 7.71 (4-H). Melting point: 161°C. Elemental
analysis: Calculated: C: 66.66%, H: 6.02%; found: C: 66.74%, H:
5.99%; deviation: C: 0.08%, H: 0.03%. IR (film): ν = 3315, 2985, 2935,
2835, 1620, 1590, 1520, 1465, 1455, 1440, 1390, 1310, 1275, 1245,
1215, 1180, 1160, 1100, 1075, 1045, 980, 800, 780, 725, 685, 670 cm-
2,5,8-Trimethoxynaphthalen-1-yl Pivalate (16d)
1
.
2,5,8-Trimethoxynaphthalen-1-yl tert-Butyl Carbonate (16c)
2,5,8-Trimethoxynaphthalen-1-ol(16b, 504 mg, 2.19 mmol) and DMAP
(13.4 mg, 0.11 mol, 5 mol-%) were suspended in CH2Cl2 (20 mL). At
0°C pivaloyl chloride (0.32 mL, 0.32 g, 2.63 mmol, 1.2 equiv.) was
added and the reaction was started by slow addition of NEt3 (0.73 mL,
0.53 g, 5.26 mmol, 2.4 equiv.). The ice-bath was removed, the reaction
mixture was allowed to warm to room temperature and stirred for 16 h.
The mixture was quenched with MeOH (5 mL) and stirred for 30 min.
Afterwards the solution was washed with aq. HCl (1M, 20 mL) and dried
over Na2SO4. The solvent was removed in vacuo and the obtained
white solid (678 mg, 97%) was dried in a Schlenk vacuum overnight.–
1H NMR (500.32 MHz, CDCl3): δ = 1.45 [s, 9H, C(CH3)3], 3.83 (s, 3H, 8-
OMe), 3.89 (s, 3H, 2-OMe), 3.93 (s, 3H, 5-OMe), AB signal (δA = 6.55,
δB = 6.67, JAB = 8.4 Hz, A and B signal show no further splitting, 6-H
and 7-H), 7.27 (d, 1H, J3,4 = 9.3 Hz, 3-H), 8.12 (d, 1H, J4,3 = 9.3 Hz, 4-
H). A NOESY spectrum (500.32 MHz, CDCl3) allowed additional
2,5,8-Trimethoxynaphthalen-1-ol(16b, 100 mg, 0.43 mmol) and DMAP
(5.2 mg, 43 µmol, 10 mol-%) were suspended in CH2Cl2 (4 mL). At 0°C
di-t-butyl dicarbonate (0.18 mL, 0.19 g, 0.85 mmol, 2.0 equiv.) was
added and the reaction was started by slow addition of NEt3 (0.12 mL,
86 mg, 0.85 mmol, 2.0 equiv.). The ice-bath was removed, the reaction
mixture was allowed to warm to room temperature and stirred for 16 h.
The mixture was diluted with CH2Cl2 (15 mL) and washed with aq.
1
assignments of H resonances by the occurrence of crosspeaks [δ(1H)
↔ δ(1H)]: δ = 3.83 (8-OMe) ↔ δB = 6.67 (7-H), δ = 3.89 (2-OMe) ↔ δ =
18
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
7.27 (3-H), δ = 3.93 (5-OMe) ↔ δA = 6.55 (6-H). 13C NMR (125.81 MHz,
CDCl3): δ = 27.52 [C(CH3)3], 39.29 [C(CH3)3], 55.80 (5-OCH3), 55.93 (8-
OCH3), 56.91 (2-OCH3), 101.60 (C-6), 106.00 (C-7), 113.42 (C-3),
120.81 (C-4), 121.51 (C-8a), 123.06 (C-4a), 134.32 (C-1), 149.13 (C-2),
149.22 (C-8), 149.77 (C-5), 176.94 [1-O2C-C(CH3)3]. An edHSQC
spectrum (“short-range C,H COSY”; 125.81/500.32 MHz, CDCl3)
allowed the assignment of all nonquaternary 13C atoms through their
150.63 (C-7). 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 = 13.44
(Si[CH(CH3)2]3) ↔ δ = 1.31 (Si[CH(CH3)2]3), δ = 18.18 (Si[CH(CH3)2]3)
↔ δ = 1.05 (Si[CH(CH3)2]3), δ = 55.72 (4-OCH3) ↔ δ = 3.94 (4-OMe), δ
= 56.70 (7-OCH3) ↔ δ = 3.73 (7-OMe), δ = 76.76 (8-OCH2) ↔ δ = 5.05
(8-O CH2), δ = 101.65 (C-3) ↔ δ = 6.51 (3-H), δ = 113.87 (C-2) ↔ δ =
6.75 (2-H), δ = 113.94 (C-6) ↔ δ = 7.16 (6-H), δ = 118.61 (C-5) ↔ δ =
7.99 (5-H), δ = 127.33 and δ = 127.77 (C-3’, C-4’, and C-5’) ↔ δ = 7.22-
7.30 (3’-H, 4’-H, and 5’-H), δ = 128.22 (C-2’ and C-6’) ↔ δ = 7.38-7.42
(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 = 123.62 (C-4a) ↔ δ = 6.51 (3-H), δ = 123.62 (C-4a)
↔ δ = 7.16 (6-H), δ = 124.24 (C-8a) ↔ δ = 6.75 (2-H), δ = 124.24 (C-
8a) ↔ δ = 7.99 (5-H), δ = 138.61 (C-1’) ↔ δ = 5.05 (8-OCH2), δ =
142.87 (C-8) ↔ δ = 5.05 (8-OCH2), δ = 142.87 (C-8) ↔ δ = 7.16 (6-H),
δ = 145.38 (C-1) ↔ δ = 6.51 (3-H), δ = 145.38 (C-1) ↔ δ = 6.75 (2-H), δ
= 149.74 (C-4) ↔ δ = 3.94 (4-OMe), δ = 149.74 (C-4) ↔ δ = 6.51 (3-H),
δ = 149.74 (C-4) ↔ δ = 6.75 (2-H), δ = 149.74 (C-4) ↔ δ = 7.99 (5-H), δ
= 150.63 (C-7) ↔ δ = 3.73 (7-OMe), δ = 150.63 (C-7) ↔ δ = 7.99 (5-H).
Melting point: 85°C. Elemental analysis: Calculated: C: 72.06%, H:
cross-peaks with the independently assigned H resonances [δ(13C) ↔
1
δ(1H)]: δ = 27.52 [C(CH3)3] ↔ δ = 1.45 [C(CH3)3], δ = 55.80 (5-OCH3) ↔
δ = 3.93 (5-OMe), δ = 55.93 (8-OCH3) ↔ δ = 3.83 (8-OMe), δ = 56.91
(2-OCH3) ↔ δ = 3.89 (2-OMe), δ = 101.60 (C-6) ↔ δA = 6.55 (6-H), δ =
106.00 (C-7) ↔ δB = 6.67 (7-H), δ = 113.42 (C-3) ↔ δ = 7.27 (3-H), δ =
120.81 (C-4) ↔ δ = 8.12 (4-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 = 39.29 [C(CH3)3] ↔ δ = 1.45 [C(CH3)3], δ
= 121.51 (C-8a) ↔ δB = 6.67 (7-H), δ = 121.51 (C-8a) ↔ δ = 8.12 (4-H),
δ = 123.06 (C-4a) ↔ δA = 6.55 (6-H), δ = 123.06 (C-4a) ↔ δ = 7.27 (3-
H), δ = 134.32 (C-1) ↔ δ = 7.27 (3-H), δ = 134.32 (C-1) ↔ δ = 8.12 (4-
H), δ = 149.13 (C-2) ↔ δ = 3.89 (2-OMe), δ = 149.22 (C-8) ↔ δ = 3.83
(8-OMe), δ = 149.77 (C-5) ↔ δ = 3.93 (5-OMe), δ = 176.94 [1-O2C-
C(CH3)3] ↔ δ = 1.45 [C(CH3)3]. Melting point: 114°C. HRMS (pos.
APCI): calcd. for C18H26O5N: [M+NH4]+ = 336.18055; found: 336.18054
(‒0.02 ppm). IR (film): ν = 2975, 2940, 2840, 1750, 1630, 1605, 1520,
1465, 1440, 1415, 1365, 1285, 1260, 1235, 1175, 1135, 1115, 1070,
1040, 980, 875, 815, 800, 770, 755 730, 705 cm-1.
8.21%; found: C: 71.94%, H: 8.21%; deviation: C:
IR (film): ν = 698, 810, 831, 883, 1016, 1029, 1055, 1274, 1348, 1383,
1414, 1448, 1462, 1598, 2838, 2865, 2892, 2943 cm-1.
0.12%, H: 0.00%.
(8-(Benzyloxy)-4,7-dimethoxynapthalen-1-yloxy)triisopropylsilane
(16f)
2,5-Dimethoxy-8-(triisopropylsilyloxy)napthalene-1-ol (16g)
(8-(Benzyloxy)-4,7-dimethoxynapthalen-1-yloxy)triisopropylsilane (16f,
1.52 g, 3.26 mmol) and Pd/C [10 w-%, 53.0 mg (≙5.3 mg pure Pd),
49.8 µmol, 1.5 mol-%] were suspended in EtOAc (35 ml). The mixture
was flash-frozen with liquid nitrogen, evacuated and flushed with
hydrogen (hydrogen-balloon, freeze & pump technique, 3 times). The
mixture was allowed to warm to room temperature and vigorously
stirred at room temperature for 15 h. Afterwards the mixture was filtered
over silica gel (glass frit, d = 1.5 cm, h = 4 cm) and additional EtOAc
(100 ml) was passed through to remove residual product from the silica
gel phase. The solvent was removed in vacuo and the title compound
(1.26 g, 99%) was obtained without further purification.– 1H NMR
(400.13 MHz, CDCl3): δ = 1.17 (d, 18H, Jsilyl-CH,silyl-CH3 = 7.3 Hz,
Si[CH(CH3)2]3), 1.30-1.50 (m, 3H, Si[CH(CH3)2]3), 3.92 (s, 3H, 5-OMe),
3.99 (s, 3H, 2-OMe), AB signal (δA = 6.42, δB = 6.59, JAB = 8.3 Hz, A
and B signal show no further splitting, 6-H and 7-H), 7.24 (d, 1H,
J3,4 = 9.3 Hz, 3-H), 7.69 (d, 1H, J4,3 = 9.3 Hz, 4-H), 9.93 (s, 1H, 1-OH).
5-(Benzyloxy)-6-methoxy-4-((triisopropylsilyl)oxy)naphthalen-1-ol (28,
7.60 g, 16.8 mmol) and Bu4NBr (1.08 g, 3.35mmol, 20 mol-%) were
suspended in THF (60 ml). The solution was cooled to 0°C and Me2SO4
(15.9 ml, 21.2 g, 168 mmol, 10 equiv.) was added. The reaction was
started by dropwise addition of a solution of KOH [85%, technical
grade, 8.87 g, (≙7.85 g), 134 mmol, 8.0 equiv.] in degassed H2O
(15 ml) at 0°C. Afterwards the ice-bath was removed and the reaction
mixture was stirred at room temperature for 19 h. The reaction was
quenched with conc. ammonium hydroxide solution (30 ml) and stirred
at room temperature for 1 h. The organic phase was separated and the
aq. phase was extracted with CH2Cl2 (2×50 ml). The combined organic
extracts were washed with brine (50 ml) and dried over Na2SO4. The
solvent was removed in vacuo. Flash chromatography (d = 12 cm,
h = 12 cm, F = 100 ml; CH/EE 95:5) afforded the title compound (F5-11,
Rf (9:1) = 0.7, 5.46 g, 70%) as a colorless solid.– 1H NMR (500.32 MHz,
CDCl3): δ = 1.05 (d, 18H, JSilyl-CH,Silyl-CH = 7.5 Hz, Si[CH(CH3)2]3), 1.31
A
NOESY spectrum (400.13 MHz, CDCl3) allowed additional
3
assignments of H resonances by the occurrence of crosspeaks [δ(1H)
↔ δ(1H)]: δ = 3.92 (5-OMe) ↔ δ = 6.42 (6-H), δ = 3.99 (2-OMe) ↔ δ =
7.24 (3-H), δ = 6.59 (7-H) ↔ δ = 1.38-1.50 {Si[CH(CH3)2]3}. 13C NMR
(100.61 MHz, CDCl3): δ = 13.37 {Si[CH(CH3)2]3}, 18.03 {Si[CH(CH3)2]3},
55.67 (5-OCH3), 56.92 (2-OCH3), 100.88 (C-6), 110.24 (C-7), 113.10
(C-4), 114.43 (C-3), 117.50 (C-8a), 123.34 (C-4a), 142.44 (C-1),
143.63 (C-2), 145.32 (C-8), 150.36 (C-5). 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 =
13.37 {Si[CH(CH3)2]3} ↔ δ = 1.38-1.50 {Si[CH(CH3)2]3}, δ = 18.03
{Si[CH(CH3)2]3} ↔ δ = 1.17 {Si[CH(CH3)2]3}, δ = 55.67 (5-OCH3) ↔ δ =
3.92 (5-OMe), δ = 56.92 (2-OCH3) ↔ δ = 3.99 (2-OMe), δ = 100.88 (C-
6) ↔ δA = 6.42 (6-H), δ = 110.24 (C-7) ↔ δB = 6.59 (7-H), δ = 113.10
(C-4) ↔ δ = 7.69 (4-H), δ = 114.43 (C-3) ↔ δ = 7.24 (3-H).An HMBC
spectrum (“long-range C,H COSY”; 100.61/400.13 MHz, CDCl3)
1
(septett, 3H, JSilyl-CH
= 7.5 Hz, Si[CH(CH3)2]3), 3.73 (s, 3H, 7-
,Silyl-CH,
3
OMe), 3.94 (s, 3H, 4-OMe), 5.05 (s, 2H, 8-OCH2), 6.51 (d, 1H, J3,2
=
8.3 Hz, 3-H), 6.75 (d, 1H, J2,3 = 8.3 Hz, 2-H), 7.16 (d, 1H, J6,5 = 9.2 Hz,
6-H), 7.22-7.30 (m, 3H, 3’-H, 4’-H, and 5’-H), 7.38-7.42 (m, 2H, 2’-H
and 6’-H), 7.99 (d, 1H, J5,6 = 9.2 Hz, 5-H). A NOESY spectrum (500.32
MHz, CDCl3) allowed additional assignments of 1H resonances by the
occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.05 (Si[CH(CH3)2]3) ↔ δ
= 5.05 (8-OCH2), δ = 1.05 (Si[CH(CH3)2]3) ↔ δ = 6.75 (2-H), δ = 1.31
(Si[CH(CH3)2]3) ↔ δ = 5.05 (8-OCH2), δ = 1.31 (Si[CH(CH3)2]3) ↔ δ =
6.75 (2-H), δ = 3.94 (4-OMe) ↔ δ = 6.51 (3-H), δ = 3.73 (7-OMe) ↔ δ =
7.16 (6-H), δ = 7.38-7.42 (2’-H and 6’-H), ↔ δ = 5.05 (8-OCH2). 13C
NMR (125.81 MHz, CDCl3):
δ = 13.44 (Si[CH(CH3)2]3), 18.18
(Si[CH(CH3)2]3), 55.72 (4-OCH3), 56.70 (7-OCH3), 76.76 (8-OCH2),
101.65 (C-3), 113.87 (C-2), 113.94 (C-6), 118.61 (C-5), 123.62 (C-4a),
124.24 (C-8a), 127.33 and 127.77 (C-3’, C-4’, and C-5’), 128.22 (C-2’
and C-6’), 138.61 (C-1’), 142.87 (C-8), 145.38 (C-1), 149.74 (C-4),
19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
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 = 117.50 (C-
8a) ↔ δB = 6.59 (7-H), δ = 117.50 (C-8a) ↔ δ = 7.69 (4-H), δ = 117.50
(C-8a) ↔ δ = 9.93 (1-OH), δ = 123.34 (C-4a) ↔ δA = 6.42 (6-H), δ =
123.34 (C-4a) ↔ δ = 7.24 (3-H), δ = 142.44 (C-1) ↔ δ = 7.24 (3-H), δ =
142.44 (C-1) ↔ δ = 9.93 (1-OH), δ = 143.63 (C-2) ↔ δ = 3.99 (2-OMe),
δ = 143.63 (C-2) ↔ δ = 7.69 (4-H), δ = 143.63 (C-2) ↔ δ = 9.93 (1-OH),
δ = 145.32 (C-8) ↔ δA = 6.42 (6-H), δ = 145.32 (C-8) ↔ δB = 6.59 (7-
H), δ = 150.36 (C-5) ↔ δ = 3.92 (5-OMe), δ = 150.36 (C-5) ↔ δA = 6.42
(6-H), δ = 150.36 (C-5) ↔ δB = 6.59 (7-H), δ = 150.36 (C-5) ↔ δ = 7.69
(4-H). Melting point: oil. Elemental analysis: Calculated: C: 66.98%,
H: 8.57%; found: C: 66.56%, H: 8.83%; deviation: C: 0.42%, H: 0.26%.
HRMS (pos. ESI): calcd. for C21H32O4Si [M+Na]+ = 399.19621; found
399.19638 (+0.43 ppm). IR (film): ν = 3345, 2950, 2895, 2870, 1610,
1590, 1520, 1460, 1400, 1365, 1350, 1310, 1275, 1255, 1210, 1190,
1180, 1150, 1100, 1050, 1000, 945, 925, 885, 870, 810, 775, 735, 690,
cm-1.
67.21%, H: 5.18%; deviation: C: 0.02%, H: 0.03%. HRMS (pos. ESI):
calcd. for C13H12O4 [M]+ = 232.07301; found 232.07321 (+0.87 ppm). IR
(film): ν = 3000, 2940, 2905, 2840, 1740, 1620, 1590, 1515, 1450,
1415, 1375, 1335, 1275, 1255, 1210, 1185, 1160, 1130, 1095, 1065,
1045, 1000, 980, 920, 880, 810, 780, 730, 700, 670 cm-1.
2-(Triisopropylsiloxy)furan (18a)
According to a general procedure for the preparation of silyltriflates from
ref.[38] triisopropylsilane (25.9 mL, 20.0 g, 126 mmol) was suspended in
a 50 mL flask and trifluoromethanesulfonic acid (12.3 mL, 20.8 g,
139 mmol, 1.10 equiv.) was added dropwise at 0°C by a dropping
funnel. The solution was stirred for 1 h at 0°C, then was allowed to
warm to room temperature and stirred for 20 h at room temperature.
The resulting product was used as following without further purification.
Furan-2(5H)-one[62] (25, 7.44 ml, 8.85 g, 105 mmol) was suspended in
dry CH2Cl2 (90 mL). The freshly prepared triisopropylsilyl
trifluoromethanesulfonate (see above, 73.6 mmol, 1.2 equiv.) was
transferred via cannula at 0°C. At the same temperature NEt3 (11.1 mL,
8.08 g, 79.8 mmol, 1.30 equiv.) was added dropwise to initiate the
silylation reaction. The mixture was allowed to warm to room
temperature and stirred for 1 h. Afterwards the mixture was quenched
with saturated aq. NaHCO3 solution (50 mL). The organic phase was
separated and the organic phase was extracted with dichloromethane
(3×30 mL). The combined organic extracts were washed with brine
(30 mL) and dried over Na2SO4. The solvent was removed in vacuo and
the residue was purified by distillation (0.1 mbar, 83°C) to furnish the
title compound (5.63 g, 98%, ref.[37]: 94%) as a colorless fluid. .– 1H-
NMR (300.13 MHz, CDCl3, spectrum contains 5 w-% iPr3SiOH): δ =
4,7-Dimethoxynaphtho[1,8-de][1,3]dioxine (16h)
In a Schlenk flask under a nitrogen atmosphere 2,5-dimethoxy-8-
(triisopropylsilyloxy)napthalene-1-ol (16g, 0.98 g, 2.60 mmol), K2CO3
(0.40 g, 3.12 mmol, 1.2 equiv.) and CsF (0.47 g, 3.12 mmol, 1.2 equiv.)
were suspended in dry DMF (5 ml). CH2BrCl (0.21 mL, 0.40 g,
3.12 mmol, 1.2 equiv.) was added and the mixture was stirred at 100°C
(oil-bath temperature) for 16 h. Afterwards the mixture was allowed to
cool to room temperature and silica gel was added. The DMF was
removed in vacuo (60°C, 15 mbar, ~15 min, room temp., 1 mbar,
~15 min). Flash chromatography [d = 3 cm, h = 12 cm, F = 25 ml;
CH/EE 5:1] afforded the title compound (F6-12, Rf (5:1) = 0.4,
513.7 mg, 85%) as a colorless solid.– 1H NMR (400.13 MHz, CDCl3): δ
= 3.95 (s, 3H, 7-OMe), 4.01 (s, 3H, 4-OMe), 5.54 (s, 2H, 2-H2), 6.57 (d,
1H, J8,9 = 8.2 Hz, 8-H), 6.78 (d, 1H, J9,8 = 8.2 Hz, 9-H), 7.24 (d, 1H, J5,6
= 9.2 Hz, 5-H), 7.69 (d, 1H, J6,5 = 9.2 Hz, 6-H). A NOESY spectrum
1.10 (d, 18H, J2-OSi(CH(CH
3 2 3 = 7.5 Hz, 2-OSi(CH(CH3)2)3),
)
)
,2-OSi(CH(CH
) )
3 2 3
1.19-1.32 (m, 3H,2-OSi(CH(CH3)2)3), 5.12 (dd, 1H, J3,4 = 3.2 Hz, 4J3,5
=
1.1 Hz, 3-H), 6.20 (dd, 1H, J4,3 = 3.2 Hz, J4,5 = 2.2 Hz, 4-H), 6.80 (dd,
4
1H, J5,4 = 2.2 Hz, J5,3 = 1.1 Hz, 5-H). The NMR data is in consistent
with the one reported in literature.[37]
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (20)
1
(400.13 MHz, CDCl3) allowed additional assignments of H resonances
by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 3.95 (7-OMe) ↔ δ
= 6.57 (8-H), δ = 4.01 (4-OMe) ↔ δ = 7.26 (5-H). 13C NMR (100.61
MHz, CDCl3): δ = 55.76 (7-OCH3), 57.23 (4-OCH3), 91.40 (C-2), 102.18
(C-8), 107.90 (C-9), 114.75 (C-5), 116.29 (C-6), 116.72 (C-9b), 121.48
(C-6a), 137.08 (C-3a), 142.08 (C-4), 142.67 (C-9a), 150.50 (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 = 55.76 (7-OCH3) ↔ δ = 3.95 (7-OMe), δ = 57.23 (4-
OCH3) ↔ δ = 4.01 (4-OMe), δ = 91.40 (C-2) ↔ δ = 5.54 (2-H2), δ =
102.18 (C-8) ↔ δ = 6.57 (8-H), δ = 107.90 (C-9) ↔ δB = 6.78 (9-H), δ =
114.75 (C-5) ↔ δ = 7.26 (5-H), δ = 116.29 (C-6) ↔ δ = 7.80 (6-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 = 116.72 (C-
9b) ↔ δ = 6.78 (9-H), δ = 116.72 (C-9b) ↔ δ = 7.80 (6-H), δ = 121.48
(C-6a) ↔ δ = 6.57 (8-H), δ = 121.48 (C-6a) ↔ δ = 7.26 (5-H), δ =
137.08 (C-3a) ↔ δ = 5.54 (2-H2), δ = 137.08 (C-3a) ↔ δ = 7.26 (5-H), δ
= 137.08 (C-3a) ↔ δ = 7.80 (6-H), δ = 142.08 (C-4) ↔ δ = 4.01 (4-
OMe), δ = 142.08 (C-4) ↔ δ = 7.26 (5-H), δ = 142.08 (C-4) ↔ δ = 7.80
(6-H), δ = 142.67 (C-9a) ↔ δ = 5.54 (2-H2), δ = 142.67 (C-9a) ↔ δ =
6.57 (8-H), δ = 142.67 (C-9a) ↔ δ = 6.78 (9-H), δ = 150.50 (C-7) ↔ δ =
3.95 (7-OMe), δ = 150. 50 (C-7) ↔ δ = 6.57 (8-H), δ = 150. 50 (C-7) ↔
δ = 6.78 (9-H), δ = 150. 50 (C-7) ↔ δ = 7.80 (6-H). Melting point:
70°C. Elemental analysis: Calculated: C: 67.23%, H: 5.21%; found: C:
Isovanillin (19) (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). It was 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 (20) (55.50 g, 73%; Lit.[33]: 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).
62 Preparation: Experimental details of ref.[37]
20
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
3-Benzyloxy-2-bromo-4-methoxybenzaldehyde (21)
147.36 and 147.53 (C-1, C-3, and 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
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 57.11 (4-
OCH3) ↔ δ = 3.84 (4-OMe), δ = 74.97 (3-OCH2) ↔ δ = 5.08 (3-OCH2),
δ = 110.14 (C-6) ↔ δA = 6.77 (6-H), δ = 113.51 (C-5) ↔ δB = 6.85 (5-
H), [δ = 128.21, 128.42, and 128.56 (C-2’, C-3’, C-4’, C-5’, and C-6’) ↔
δ = 7.31-7.42 (3`-H, 4`-H, and 5`-H) and δ = 7.52-7.56 (2`-H and 6`-H)
could not be assigned unambiguously]. 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 = 107.23 (C-2) ↔ δ = 5.23 (1-
OH), δ = 106.82 (C-2) ↔ δA = 6.77 (6-H), δ = 106.82 (C-2) ↔ δB = 6.85
(5-H), δ = 137.14 (C-1’) ↔ δ = 5.08 (3-OCH2). Note: δ = 145.77,
147.36, and 147.53 (C-1, C-3, and C-4) could not be assigned
unambiguously. Melting point: Oil. Elemental analysis: Calculated: C:
54.39% , H: 4.24%; found: C: 54.14%, H: 4.35%; deviation: C: 0.25%,
To a suspension of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (20)
(20.71 g, 89.63 mmol) and potassium carbonate (37.35 g, 270.3 mmol,
3.02 equiv.) in abs. ethanol (360 mL), benzyl chloride (15.6 mL, 17.2 g,
136 mmol, 1.52 equiv.) was added and the reaction mixture was heated
to reflux for 24 h. After cooling to room temperature, the solvent was
removed in vacuo, the residue was dissolved in EE (200 mL) and H2O
(100 mL) and vigorously stirred for 5 min. The organic phase was
separated and the aq. phase was extracted with EE (3×100 mL). The
combined organic extracts were washed with aq. NaOH (1 M,
2×100 mL), aq. HCl (1 M, 100 mL), brine (100 mL), and dried over
Na2SO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography [d = 10 cm, h = 12 cm, F = 100 mL;
CH/EE 9:1 (F1-15), 5:1 (F16-25), 3:1 (F26-35)], to obtain the product
(F12-30, Rf (5:1) = 0.25, 28.08 g, 98%, ref.[34]: quant.) as a colorless
solid.– 1H-NMR (300.13 MHz, CDCl3): δ = 3.96 (s, 3H, 4-OMe), 5.05 (s,
H: 0.11%. HRMS (pos. ESI): calcd. for C14H1379BrO3Na [M+Na]+
330.99403; found 330.99426 (+0.71 ppm); calcd. for C14H1381BrO3Na
[M+Na]+
332.99198; found 332.99213 (+0.44 ppm). IR (film):
=
=
ν = 3090, 3065, 3030, 3005, 2945, 2880, 2835, 2605, 2555, 1955,
1875, 1815, 1745, 1600, 1585, 1485, 1455, 1440, 1375, 1330, 1305,
1270, 1200, 1170, 1140, 1130, 1080, 1030, 960, 910, 845, 820, 800,
750, 730, 700, 665 cm-1.
3-(Benzyloxy)-2-bromo-4-methoxyphenyl
fonate (23)
4-Methylbenzenesul-
4
2H, 3-OCH2), 6.98 (dd, 1H, J6,5 = 8.7 Hz, J6,1-CHO = 0.9 Hz, 6-H), 7.31-
7.58 (m, 5H, 2`-H, 3`-H, 4`-H, 5`-H, and 6`-H), 7.76 (d, 1H, J5,6 = 8.7 Hz,
5-H), 10.26 (d, 1H, 4J1-CHO,6 = 0.8 Hz, 1-CHO) ppm. The 1H-NMR data is
in a good agreement with that reported in literature.[34]
3-Benzyloxy-2-bromo-4-methoxyphenol (22)
4'
5'
6'
3'
2'
1'
O
3
2
MeO
Br
3-Benzyloxy-2-bromo-4-methoxyphenol (22, 18.78 g, 60.75 mmol) and
TsCl (17.37 g, 91.13 mmol, 1.50 equiv.) were dissolved in CH2Cl2
(120 mL). The solution was cooled to 0°C and NEt3 (12.62 mL, 9.22 g,
91.13 mmol, 1.50 equiv.) was added successively. After stirring for 16 h
at room temperature, the reaction mixture was diluted with CH2Cl2
(200 mL), washed with saturated aq. NaHCO3 (2 × 100 mL), H2O
(100 mL), and dried over Na2SO4. The solvent was removed in vacuo
and the residue was purified by flash chromatography [d = 12 cm,
h = 12 cm, F = 100 mL; CH/EE 5:1 (F1-15), 3:1 (F16-24), 1:1 (F25-35)]
to obtain the pure product (F15-28, Rf (5:1) = 0.2, 27.75 g, 99%) as a
white solid.– 1H-NMR (400.13 MHz, CDCl3): δ = 2.44 (s, 3H, 4’’-CH3),
3.86 (s, 3H, 4-OMe), 4.97 (s, 2H, 3-OCH2), AB signal [δA = 6.84 and
δB = 7.13, JAB = 9.2 Hz, A and B signal show no further splitting, 5-H
and 6-H], 7.28-7.31 (m, 2H, 3’’-H and 5’’-H), 7.31-7.38 (m, 3H, 3’-H, 4’-
H, and 5’-H), 7.46-7.50 (m, 2H, 2’-H and 6’-H), 7.75-7.79 (m, 2H, 2’’-H
and 6’’-H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 21.74 (4’’-CH3),
56.32 (4-OCH3), 74.80 (3-OCH2), 110.89 (C-5), 113.70 (C-2), 118.96
(C-6), 128.21 (C-4’), 128.34 (C-3’ and C-5’), 128.47 (C-2’ and C-6’),
128.79 (C-2’’ and C-6’’), 129.71 (C-3’’ and C-5’’), 132.78 (C-1’’), 136.76
(C-1’), 140.91 (C-1), 145.56 (C-4’’), 146.24 (C-3), 152.50 (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 = 21.74 (4’’-CH3) ↔ δ = 2.44 (4’’- CH3), δ = 56.32 (4-
OCH3) ↔ δ = 3.86 (4-OMe), δ = 74.80 (3-OCH2) ↔ δ = 4.97 (3-OCH2),
δ = 110.89 (C-5) ↔ δA = 6.84 (5-H), δ = 118.96 (C-6) ↔ δB = 7.13 (6-
H), δ = 128.21 (C-4’) ↔ δ = 7.31-7.38 (3’-H, 4’-H, and 5’-H), δ = 128.34
(C-3’ and C-5’) ↔ δ = 7.31-7.38 (3’-H, 4’-H, and 5’-H), δ = 128.47 (C-2’
and C-6’) ↔ δ = 7.46-7.50 (2’-H and 6’-H), δ = 128.79 (C-2’’ and C-6’’)
↔ δ = 7.75-7.79 (2’’-H and 6’’-H), δ = 129.71 (C-3’’ and C-5’’) ↔ δ =
7.28-7.31 (3’’-H and 5’’-H). An HMBC spectrum (“long-range C,H
4
1
5
OH
6
3-Benzyloxy-2-bromo-4-methoxybenzaldehyde
(21,
20.67 g,
64.36 mmol) and mCPBA (77 w-%, 16.66 g, 96.54 mmol, 1.50 equiv.)
were suspended in CH2Cl2 (300 mL) and the mixture was refluxed for
14 h. Saturated aq. Na2SO3 solution (200 mL) was added carefully and
the mixture was stirred for 15 min. The aq. phase was separated and
the organic phase was washed with saturated aq. NaHCO3 solution
(3×100 mL). The combined organic extracts were dried over Na2SO4
and the solvent was removed in vacuo. The oily residue was taken up
in aq. KOH solution (10%, 150 mL, 4.0 equiv., degassed with N2). After
stirring at room temperature for 3 h, the reaction mixture was acidified
with HCl (conc., 25 mL) to pH 1. CH2Cl2 (200 mL) was added and the
mixture was vigorously stirred for 5 min. The organic phase was
separated and the aq. 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 to furnish the
title compound (18.78 g, 94%) as a brown oil that could be used in the
following tosylation step without further purification.– 1H-NMR (400.13
MHz, CDCl3): δ = 3.84 (s, 3H, 4-OMe), 5.08 (s, 2H, 3-OCH2), 5.23 (s,
1H, 1-OH), AB signal (δA = 6.77 and δB = 6.85, JAB = 9.0 Hz, A- and B-
signal show no further splitting, 6-H and 5-H), 7.31-7.42 (m, 3H, 3`-H,
4`-H and 5`-H), 7.52-7.56 (m, 2H, 2`-H and 6`-H) ppm. A NOESY
spectrum (400.13 MHz, CDCl3) allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 3.84
(4-OMe) ↔ δB = 6.84 (5-H), δ = 7.52-7.56 (2`-H and 6`-H) ↔ δ = 5.08
(3-OCH2). 13C-NMR (100.63 MHz, CDCl3): δ = 57.11 (4-OCH3), 74.97
(3-OCH2), 110.14 (C-6), 113.51 (C-5), 128.21, 128.42, and 128.56 (C-
2’, C-3’, C-4’, C-5’, and C-6’), 107.23 (C-2), 137.14 (C-1’), 145.77,
21
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
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 = 113.70 (C-2) ↔ δA = 6.84 (5-H), δ =
113.70 (C-2) ↔ δB = 7.13 (6-H), δ = 132.78 (C-1’’) ↔ δ = 7.28-7.31 (3’’-
H and 5’’-H), δ = 136.76 (C-1’) ↔ δ = 4.97 (3-OCH2), δ = 136.76 (C-1’)
↔ δ = 7.31-7.38 (3’-H, 4’-H, and 5’-H), δ = 140.91 (C-1) ↔ δA = 6.84 (5-
H), δ = 140.91 (C-1) ↔ δB = 7.13 (6-H), δ = 145.56 (C-4’’) ↔ δ = 2.44
(4’’- CH3), δ = 145.56 (C-4’’) ↔ δ = 7.75-7.79 (2’’-H and 6’’-H), δ =
146.24 (C-3) ↔ δ = 4.97 (3-OCH2), δ = 146.24 (C-3) ↔ δA = 6.84 (5-H),
δ = 146.24 (C-3) ↔ δB = 7.13 (6-H), δ = 152.50 (C-4) ↔ δ = 3.86 (4-
δ = 7.38-7.42 (m, 2H, 2`-H and 6`-H), δ = 1.30 (4-OSi[CH(CH3)2]3) ↔
δB = 6.68 (3-H), δ = 5.06 (8-OCH2) ↔ δ = 7.38-7.42 (2`-H and 6`-H),
δ = 7.19 (7-H) ↔ δ = 3.74 (6-OMe). 13C-NMR (125.81 MHz, CDCl3):
δ = 13.44 (4-OSi[CH(CH3)2]3), 18.17 (4-OSi[CH(CH3)2]3), 56.76 (6-
OCH3), 76.77 (5-OCH2), 106.29 (C-2), 114.12 (C-3), 114.13 (C-7),
118.49 (C-8), 122.71 (C-8a), 124.30 (C-4a), 127.37 (C-4’), 127.79 (C-
3`and C-5`), 128.25 (C-2` and C-6`), 138.52 (C-1`), 142.97 (C-5),
145.43 (C-1), 145.76 (C-4), 150.55 (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 = 13.44 (4-OSi[CH(CH3)2]3) ↔ δ = 1.30 (4- Si[CH(CH3)2]3), δ = 18.17
(4-OSi[CH(CH3)2]3) ↔ δ = 1.05 (4-OSi[CH(CH3)2]3), δ = 56.76 (6-OCH3)
OMe), δ = 152.50 (C-4) ↔ δA = 6.84 (5-H), δ = 152.50 (C-4) ↔ δB
=
7.13 (6-H). Melting point: 88-90°C. Elemental analysis: Calculated:
C: 54.44%, H: 4.13%, S: 6.92%; found: C: 54.39%, H: 4.11%, S: 6.86%;
deviation: C: 0.05%, H: 0.02%, S: 0.06%. IR (film): ν = 3090, 3065,
3030, 2940, 2840, 1595, 1495, 1480, 1440, 1425, 1375, 1300, 1270,
1240, 1190, 1175, 1140, 1120, 1095, 1035, 1015, 960, 910, 835, 815,
790, 755, 745, 715, 700, 685, 670, 660 cm-1.
↔
δ = 3.74 (6-OMe), δ = 76.77 (5-OCH2) ↔ δ = 5.06 (5-OCH2),
δ = 106.29 (C-2) ↔ δA = 6.52 (2-H), δ = 114.12 (C-3) ↔ δB = 6.68 (3-
H), δ = 114.13 (C-7) ↔ δ = 7.19 (7-H), δ = 118.49 (C-8) ↔ δ = 7.91 (8-
H), [δ = 127.37 (C-4’) and 127.79(C-3`and C-5`)] ↔ δ = 7.22-7.31 (3`-H,
4`-H, and 5`-H), δ = 128.25 (C-2` and C-6`) ↔ δ = 7.38-7.42 (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 = 122.71 (C-8a) ↔ δA = 6.52 (2-H), δ = 122.71 (C-
8a) ↔ δ = 7.19 (7-H), δ = 124.30 (C-4a) ↔ δB = 6.68 (3-H), δ = 124.30
(C-4a) ↔ δ = 7.91 (8-H), δ = 138.52 (C-1`) ↔ δ = 5.06 (5-OCH2),
δ = 138.52 (C-1`) ↔ δ = 7.22-7.31 (3`-H, 4`-H, and 5`-H), δ = 142.97
5-Benzyloxy-6-methoxy-4-(triisopropylsilyloxy)naphthalen-1-ol (28)
and 8-Benzyloxy -7-methoxy-4-(triisopropylsilyloxy)naphthalen-1-
ol (iso-28)
(C-5)
↔ δ = 5.06 (5-OCH2), δ = 142.97 (C-8) ↔ δ = 7.19 (7-H),
δ = 145.43 (C-1) ↔ δB = 6.68 (3-H), δ = 145.43 (C-1) ↔ δ = 7.91 (8-H),
δ = 145.76 (C-4) ↔ δA = 6.52 (2-H), δ = 150.55 (C-6) ↔ δ = 3.74 (6-
OCH3), δ = 150.55 (C-6) ↔ δ = 7.19 (7-H), δ = 150.55 (C-6) ↔ δ = 7.91
(8-H). Melting point: Oil. HRMS (pos. APCI): calcd. for C27H37O4Si
[M+H]+ = 453.24556; found 453.24536 (–0.44 ppm). IR (film): ν = 3428,
3155, 2980, 2940, 2870, 2255, 1795, 1650, 1600, 1570, 1465, 1385,
1350, 1275, 1150, 1110, 1065, 995, 915, 845, 745 cm-1.
Under
a
nitrogen
atmosphere
3-benzyloxy-4-methoxy-[(1-
methylphenylsulfonyl)oxy]benzeneꢀ(23, 9.26 g, 20.0ꢀmmol) and 2-
(triisopropylsiloxy)furan (18a, 7.2 mL, 7.2 g, 30 mmol, 1.5 equiv.) were
dissolved in freshly distilled THF (40 mL) and the solution was cooled to
−78°C. Then BuLi (2.55 M in hexane, 7.84 mL, 20.0 mmol, 1.0 equiv.)
was added dropwise and the solution was stirred at −78°C for 5 min.
Afterwards the reaction mixture was allowed to warm to room
temperature and stirred for 45 min. Aq. HCl (1M, 50 mL) was added
and the mixture was stirred over a period of 5 min. The organic phase
was separated. The aq. phase was extracted with CH2Cl2 (2×50 ml), the
combined organic extracts were washed with brine (50 mL) and dried
over Na2SO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography (d = 12 cm, h = 12 cm, F = 100 mL;
CH/EE 9:1) to obtain iso-28 (F5-8, Rf (9:1) = 0.6, 1.215 g) as a 78:22
mixture with iPr3SiOH and containing an unidentifiable impurity. This
corresponds to 90 w-% of iso-28 (1.094 g, 12%). Another fraction
furnished 28 (F9-18, Rf (9:1) = 0.2, 7.74 g) as a 50:50 mixture with
iPr3SiOH. This corresponds to 72 w-% of 29 (5.57 g, 62%). Side
product iso-28 contained an unidentifiable impurity. The product mixture
was not air-stable and therefore not characterized. If this mixture was
5-(Benzyloxy)-6-methoxynaphthalene-1,4-diol (29)
In a dry round bottomed flask under a nitrogen atmosphere 3-
Benzyloxy-2-bromo-4-methoxy-[(1-methylphenylsulfonyl)oxy]benzene
(23, 9.26 g, 20.0 mmol) and 2-(triisopropylsiloxy)furan (18a, 7.20 g,
30.0 mmol, 1.5 equiv.) were dissolved in freshly distilled THF (40 mL).
At –78°C nBuLi (2.55
M in hexane, 7.84 mL, 20.0 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
treated with Bu4NF (1
naphthohydroquinone 28
M
in THF, 1.5 equiv.) in THF
was obtained. second flash
A
45 min. The solution was cooled to 0°C and TBAF (1
30 mmol, 1.5 equiv.) was added. The ice-bath was removed and the
reaction mixture was stirred at room temperature for 8 min. The
M in THF, 30 mL,
chromatography of the 28 fraction allowed to diminish the content of
triisopropylsilyl alcohol to 9 w-%. The compound was characterized as
follows: 1H-NMR (500.32 MHz, CDCl3, product contains 9 w-%
iPr3SiOH with a s at δ = 1.06 and a m at δ = 1.30 ppm, NMR-file: 2016:
reaction was quenched with aq. HCl (1
M, 50 mL) and stirred for 5 min
at room temperature. CH2Cl2 (50 mL) was added and the organic phase
was separated. The aq. phase was extracted with CH2Cl2 (2×50 mL).
The combined organic extracts were washed with brine (50 mL) and
dried over Na2SO4. The solvent was removed in vacuo. Flash
chromatography [d = 12 cm, h = 12 cm, F = 100 mL; CH/EE 3:1
(contained 1% HCOOH, F1-14), CH/EE 1:1 (contained 1% HCOOH,
F15-26)] afforded the title compound [F9-22, Rf (3:1) = 0.25, 5.02 g,
85%] as a yellow-orange solid. Note: Product is moderately air-stable
as solid but decomposes slowly in solution. Therefore the NMR spectra
contain signals of degradation products.– 1H NMR (400.13 MHz, CDCl3,
NeBrMi25-5050):
δ = 1.05
(d,
18H,
J4-OSi(CH(CH
)
,4-
3 2 3 = 7.5 Hz, 4-OSi(CH(CH3)2)3), 1.30 (sept, 3H, 3)2 3J4-
OSi(CH(CH
)
)
= 7.5 Hz, 4-OSi(CH(CH3)2)3), 3.74 (s, 3H, 6-
) )
OSi(CH(CH
)
)
,4-OSi(CH(CH
OCH3), 352.036 (s, 2H, 352-O3 CH2), AB signal (δA = 6.52, δB = 6.68, JAB
=
8.1 Hz, A and B signal show no further splitting, 2-H and 3-H), 7.19 (d,
1H, J7,8 = 9.2 Hz, 7-H), 7.22-7.31 (m, 3H, 3`-H, 4`-H, and 5`-H), 7.38-
7.42 (m, 2H, 2`-H and 6`-H), 7.91 (d, 1H, J8,7 = 9.2 Hz, 8-H). A NOESY
spectrum (500.32 MHz, CDCl3) allowed additional assignments of 1H
resonances by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.05
(4-OSi[CH(CH3)2]3) ↔ δB = 6.68 (3-H), δ = 1.05 (4-OSi[CH(CH3)2]3) ↔
22
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
spectrum contains degradation products): 4.03 (s, 3H, 6-OMe), 5.09 (br.
s, 1H, 1-OH), 5.25 (s, 2H, 5-OCH2), AB signal (δA = 6.58, δB = 6.65, JAB
= 8.1 Hz, A and B signal show no further splitting, 2-H and 3-H), 7.28
(d, 1H, J7,8 = 9.3 Hz, 7-H), 7.37-7.43 (m, 3H, 3’-H, 4’-H, and 5’-H), 7.51-
7.55 (m, 2H, 2’-H and 6’-H), 7.96 (d, 1H, J8,7 = 9.3 Hz, 8-H), 9.22 (s, 1H,
4-OH). A NOESY spectrum (400.13 MHz, CDCl3) allowed additional
= 2.72, δB = 2.92, JAB = 17.6 Hz, A signal shows no further splitting, B
signal further split by JB,3’ = 5.4 Hz, 4’-HA and 4’-HB), 3.87 (s, 3H, 5-
OMe), 3.92 (s, 3H, 8-OMe), 3.96 (s, 3H, 2-OMe), 4.78 (dd, 1H, J3’,B
=
5.0 Hz, J3’,2’ = 3.8 Hz, 3’-H), 5.82 (d, 1H, J4’,3’ = 3.6 Hz, 2’-H), 6.85 (s,
1H, 7-H), 7.36 (d, 1H, J3,4 = 9.3 Hz, 3-H), 7.89 (d, 1H, J4,3 = 9.3 Hz, 4-
H).
A
NOESY spectrum (500.32 MHz, CDCl3) allowed additional
1
1
assignments of H resonances by the occurrence of crosspeaks [δ(1H)
assignments of H resonances by the occurrence of crosspeaks [δ(1H)
↔ δ(1H)]: δB = 2.92 (4’-HB) ↔ δ = 5.82 (2’-H; this cross-peak proves
that 4’-HB and 2’-H are oriented cis relative to one another), δ = 3.87 (5-
OMe) ↔ δ = 5.82 (2’-H), δ = 3.87 (5-OMe) ↔ δ = 7.89 (4-H), δ = 3.92
(8-OMe) ↔ δ = 1.58 [C(CH3)3], δ = 3.92 (8-OMe) ↔ δ = 6.85 (7-H), δ =
3.96 (2-OMe) ↔ δ = 7.36 (3-H), δ = 6.85 (7-H) ↔ δ = 5.82 (2’-H). 13C
NMR (125.82 MHz, CDCl3): δ = 27.88 [C(CH3)3], 38.36 (C-4’), 56.52 (8-
OCH3), 57.02 (2-OCH3), 62.48 (5-OCH3), 70.00 (C-3’), 81.63 (C-2’),
82.99 [C(CH3)3], 104.65 (C-7), 114.98 (C-3), 119.83 (C-6), 121.04 (C-
4), 121.79 (C-8a), 124.61 (C-4a), 134.56 (C-1), 146.45 (C-5), 149.92
(C-2), 151.86 (C-8), 152.04 (1-OCO2tBu), 175.29 (C-5’). An edHSQC
spectrum (“short-range C,H COSY”; 125.82/500.32 MHz, CDCl3)
allowed the assignment of all nonquaternary 13C atoms through their
↔ δ(1H)]: δ = 4.03 (6-OMe) ↔ δ = 7.28 (7-H), δ = 5.25 (5-OCH2) ↔ δ
=7.51-7.55 (2’-H and 6’-H).13C NMR (100.61 MHz, CDCl3, spectrum
contains degradation products): δ = 57.00 (6-OCH3), 76.93 (5-OCH2),
107.91 (C-2), 109.55 (C-3), 114.37 (C-7), 119.71 (C-8), 128.86, 128.92,
and 129.07 (C-2’, C-3’, C-4’, C-5’, and C-6’), δ = 119.26 (C-4a), δ =
122.01 (C-8a), δ = 135.97 (C-1’), δ = 141.67 (C-5), δ = 144.11 (C-1), δ
= 147.08 (C-4), δ = 148.15 (C-6). 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
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 57.00 (6-
OCH3) ↔ δ = 4.03 (6-OMe), δ = 76.93 (5-OCH2) ↔ δ = 5.25 (5-OCH2),
δ = 107.91 (C-2) ↔ δA = 6.58 (2-H), δ = 109.55 (C-3) ↔ δB = 6.65 (3-
H), δ = 114.37 (C-7) ↔ δ = 7.28 (7-H), δ = 119.71 (C-8) ↔ δ = 7.96 (8-
H), δ = 128.86, 128.92, and 129.07 (C-2’, C-3’, C-4’, C-5’, and C-6’) ↔
7.37-7.43 (3’-H, 4’-H, and 5’-H) and 7.51-7.55 (2’-H, and 6’-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 = 119.26 (C-
4a) ↔ δB = 6.65 (3-H), δ = 119.26 (C-4a) ↔ δ = 7.96 (8-H), δ = 119.26
(C-4a) ↔ δ = 9.22 (4-OH), δ = 122.01 (C-8a) ↔ δA = 6.58 (2-H),, δ =
122.01 (C-8a) ↔ δ = 7.28 (7-H), δ = 135.97 (C-1’) ↔ δ = 5.25 (5-
OCH2), δ = 141.67 (C-5) ↔ δ = 5.25 (5-OCH2), δ = 141.67 (C-5) ↔ δ =
7.28 (7-H), δ = 141.67 (C-5) ↔ δ = 7.96 (8-H), δ = 144.11 (C-1) ↔ δA =
6.58 (2-H), δ = 144.11 (C-1) ↔ δB = 6.65 (3-H), δ = 144.11 (C-1) ↔ δ =
7.96 (8-H), δ = 147.08 (C-4) ↔ δA = 6.58 (2-H), δ = 147.08 (C-4) ↔ δB
= 6.65 (3-H), δ = 147.08 (C-4) ↔ δ = 9.22 (4-OH), δ = 148.15 (C-6) ↔ δ
= 4.03 (6-OMe), δ = 148.15 (C-6) ↔ δ = 7.28 (7-H), δ = 148.15 (C-6) ↔
δ = 7.96 (8-H). Melting point: 130-140°C (decomp.). HRMS (neg.
APCI): calcd. for C18H16O4Cl: [M+Cl]− = 331.07426; found: 331.07437
(+0.34 ppm). IR (film): ν = 3370, 1660, 1610, 1570, 1470, 1455, 1440,
1410, 1365, 1335, 1320, 1270, 1215, 1175, 1035, 970, 750, 700 cm-1.
1
cross-peaks with the independently assigned H resonances [δ(13C) ↔
δ(1H)]: δ = 27.88 [C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 38.36 (C-4’) ↔ [δA
= 2.72 (4’-HA) and δB = 2.92 (4’-HB)], δ = 56.52 (8-OCH3) ↔ δ = 3.92 (8-
OMe), δ = 57.02 (2-OCH3) ↔ δ = 3.96 (2-OMe), δ = 62.48 (5-OCH3) ↔
δ = 3.87 (5-OMe), δ = 70.00 (C-3’) ↔ δ = 4.78 (3’-H), δ = 81.63 (C-2’)
↔ δ = 5.82 (2’-H), δ = 104.65 (C-7) ↔ δ = 6.85 (7-H), δ = 114.98 (C-3)
↔ δ = 7.36 (3-H), δ = 121.04 (C-4) ↔ δ = 7.89 (4-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 = 82.99
[C(CH3)3] ↔ δ = 1.58 [C(CH3)3], δ = 119.83 (C-6) ↔ δ = 5.82 (2’-H), δ =
119.83 (C-6) ↔ δ = 6.85 (7-H), δ = 121.79 (C-8a) ↔ δ = 6.85 (7-H), δ =
121.79 (C-8a) ↔ δ = 7.89 (4-H), δ = 124.61 (C-4a) ↔ δ = 7.36 (3-H), δ
= 134.56 (C-1) ↔ δ = 7.36 (3-H), δ = 134.56 (C-1) ↔ δ = 7.89 (4-H), δ =
146.45 (C-5) ↔ δ = 3.87 (5-OMe), 146.45 (C-5) ↔ δ = 5.82 (2’-H),
146.45 (C-5) ↔ δ = 6.85 (7-H), 146.45 (C-5) ↔ δ = 7.89 (4-H), δ =
149.92 (C-2) ↔ δ = 3.96 (2-OMe), δ = 149.92 (C-2) ↔ δ = 7.36 (3-H), δ
= 149.92 (C-2) ↔ δ = 7.89 (4-H), δ = 151.86 (C-8) ↔ δ = 3.92 (8-OMe),
δ = 151.86 (C-8) ↔ δ = 6.85 (7-H), δ = 175.29 (C-5’) ↔ [δA = 2.72 (4’-
HA) and δB = 2.92 (4’-HB)], δ = 175.29 (C-5’) ↔ 4.72(3’-H). δ = 152.04
(1-OCO2tBu) exhibited no cross-peak. Melting point: 90-95°C
tert-Butyl
6((2S,3S)-3-Hydroxy-5-oxotetrahydrofuran-2-yl)-2,5,8-
20
(decomposition). Optical rotation: [
α
]
= +12.4 (c = 0.755, CHCl3).
D
trimethoxynaphthalen-1-yl Carbonate (31)
HRMS (pos. APCI): Calcd. for C22H26O9 [M+Na]+ = 457.14690; found
457.14682 (–0.18 ppm). IR (film): ν = 3475, 3055, 2980, 2940, 2845,
2305, 1760, 1660, 1630, 1610, 1515, 1480, 1465, 1385, 1370, 1285,
1255, 1155, 1080, 1045, 1030, 1010, 980, 905, 860, 820, 800, 775,
735, 705 cm-1. Enantiomeric excess: 98.6% ee. The ee was
determined by chiral HPLC (OD-3, heptane:EtOH = 75:25, λ = 230 nm,
flow: 0.5 mL/min, tR(31) = 9.40 min, tR(ent-31) = 11.12 min). To develop
a separation method for chiral HPLC a mixture of both enantiomers was
measured (OD-3, heptane:EtOH = 75:25, λ = 230 nm, flow: 0.5 mL/min,
tR(31) = 9.41 min, tR(ent-31) = 11.37 min). The optical antipode ent-31
was synthesized analogously by using the (DHQD)2PHAL-ligand in the
A 87:13 isomeric mixture of (E)-methyl 4-(5-(tert-butoxycarbonyloxy)-
1,4,6-trimethoxynaphthalen-2-yl)but-3-enoate (15c) and its α,β-
unsaturated carboxylic ester isomer (iso-15c) (357.8 mg, 0.826 mmol)
and (DHQ)2PHAL (6.4 mg, 8.3 µmol, 1.0 mol-%) were dissolved in t-
BuOH (26 mL). K3Fe(CN)6 (817 mg, 2.48 mmol, 3.0 equiv.), K2CO3
(343 mg, 2.48 mmol, 3.0 equiv.), NaHCO3 (209 mg, 2.48 mmol,
3.0 equiv.), and Me2SO2NH2 (79.3 mg, 0.826 mmol, 1.0 equiv.) were
dissolved in H2O (13 mL). The aq. solution was added to the vigorously
stirred organic reaction mixture. Solid K2OsO2(OH)4 (1.2 mg, 3.3 µmol,
0.4 mol-%) 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 (0.83 g) and stirred for 30 min. EtOAc
(20 mL) was added and the organic phase was separated. The aq.
phase was extracted with EtOAc (5×10 mL) and the combined organic
extracts were washed with aq. KOH solution (1 M, 2×10 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 (F14-26, Rf
(1:1) = 0.2, 213.9 mg, 60%) as a white solid.– 1H NMR (500.32 MHz,
CDCl3): δ = 1.58 [s, 9H, C(CH3)3], 1.86 (br. s, 1H, 3’-OH), AB signal (δA
Sharpless asymmetric dihydroxylation procedure. Yield: 49%. Optical
20
rotation: [
α
]
= –13.5 (c = 0.755, CHCl3). Enantiomeric excess:
D
97.9% ee. The ee was determined by chiral HPLC (OD-3,
heptane:EtOH = 75:25, λ = 230 nm, flow: 0.5 mL/min, tR(31) = 9.07 min,
tR(ent-31) = 11.35 min).
(3aS,5S,11bS)-7-Hydroxy-6,8,11-trimethoxy-5-methyl-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-2-one (32)
23
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
tert-Butyl
6((2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2-yl)-2,5,8-
tert-Butyl
(3aS,5S,11bS)-6,8,11-trimethoxy-5-methyl-2-trioxo-
trimethoxynaphthalen-1-yl carbonate (31, 201.1 mg, 0.463 mmol) was
suspended in CH2Cl2 (5 mL). At 0°C acetaldehyde (0.19 mL, 0.15 g,
3.47 mmol, 7.5 equiv.) was added and the reaction was started by the
addition of BF3·OEt2 (0.59 mL, 0.66 g, 4.63 mmol, 10 equiv.).
Afterwards the ice-bath was removed. The reaction mixture was
allowed to warm to room temperature and stirred for 20 min. Afterwards
the reaction mixture was quenched by the addition of H2O (5 mL) and
stirred for 5 min. The organic phase was separated and the aq. phase
was extracted with CH2Cl2 (3× 10mL). The combined organic extracts
were dried over Na2SO4 and the solvent was removed in vacuo. Flash
chromatography [d = 3 cm, h = 12 cm, F = 25 mL; CH/EE 2:1 (F1-14),
CH/EE 1:1 (F15-40)] afforded the title compound (F16-23, 84.8 mg,
51%, ds = 100:0) as single diastereomer and two additional fractions
containing diastereomeric mixtures (F24-25, 22.8 mg, 14%, ds = 55:45
and F26-30, 17.0 mg, 10%, ds = 16:84) as colorless solids. Combined
yield: 126.6 mg, 75%, ds = 77:23, Rf (major diastereomer, 1:1) = 0.3, Rf
(minor diastereomer, 1:1) = 0.25.– 1H NMR (400.13 MHz, CDCl3,
substance contains 3 w-% EtOAc with resonances at δ = 1.25, 2.05,
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-7-yl
Carbonate tert-Butyl (3aS,5S,11bS)-6,8,11-trimethoxy-5-methyl-2-
trioxo-3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-7-
yl Carbonate (33)
(3aS,5S,11bS)-6,8,11-Trimethoxy-5-methyl-3,3a,5,11b-tetrahydro-2H-
benzo[g]furo[3,2-c]isochromen-2- one (32, 43.5 mg, 121 µmol) and
DMAP (1.5 mg, 12 µmol, 10 mol-%) were suspended in CH2Cl2 (1 mL).
At 0°C di-t-butyl dicarbonate (51.8 µL, 52.8 mg, 242 µmol, 2.0 equiv.)
was added and the reaction was started by slow addition of NEt3
(33.5 µL, 24.5 mg, 242 µmol, 2.0 equiv.). The ice-bath was removed,
the reaction mixture was allowed to warm to room temperature and
stirred for 16 h. The mixture was diluted with CH2Cl2 (10 mL) and
washed with aq. saturated NaHCO3 solution (5 mL) and brine (5 mL.
After drying over Na2SO4 the solvent was removed in vacuo. Flash
chromatography [d = 1.5 cm, h = 12 cm, F = 8 ml; CH/EE 2:1 (F1-20),
CH/EE 1:1 (F21-36)] afforded the title compound [F12-26, Rf
(2:1) = 0.25, 47.5 mg, 85%] as a colorless oil.– 1H NMR (400.13 MHz,
CDCl3): δ = 1.51 (d, 3H, J5-CH3,5 = 6.8 Hz, 5-CH3), 1.55 [s, 9H, C(CH3)3],
AB signal (δA = 2.69, δB = 2.96, JAB = 17.5 Hz, A signal shows no
further splitting, B signal further splitted by JB,3a = 5.0 Hz, 3-HA and 3-
HB), 3.83 (s, 3H, 6-OMe), 3.99 (s, 3H, 8-OMe), 4.06 (s, 3H, 11-OMe),
4.71 (dd, 1H, J3a,B = 4.9 Hz, J3a,11b = 2.8 Hz, 3a-H), 5.33 (q, 1H, J5,5-CH3
and 4.12): δ = 1.56 (d, 3H, J5-CH = 6.7 Hz, 5-CH3), AB signal (δA
=
,5
3
2.71, δB = 2.97, JAB = 17.5 Hz, A signal shows no further splitting, B
signal further splitted by JB,3a = 4.9 Hz, 3-HA and 3-HB), 3.95 (s, 3H, 6-
OMe), 4.03 (s, 3H, 8-OMe), 4.07 (s, 3H, 11-OMe), 4.72 (dd, 1H, J3a,B
=
4.9 Hz, J3a,11b = 2.7 Hz, 3a-H), 5.36 (q, 1H, J5,5-CH3 = 6.8 Hz, 5-H), 5.56
(d, 1H, J11b,3a = 2.7 Hz, 11b-H), 7.32 (d, 1H, J9,10 = 9.2 Hz, 9-H), 7.64 (d,
1H, J10,9 = 9.2 Hz, 10-H), 8.64 (s, 1H, 7-OH). A NOESY spectrum
1
(400.13 MHz, CDCl3) allowed additional assignments of H resonances
by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.56 (5-CH3) ↔ δ
= 4.72 (3a-H; this cross-peak proves that 5-CH3 and 3a-H are oriented
cis relative to one another), δB = 2.97 (3-HB) ↔ δ = 5.56 (11b-H; this
cross-peak proves that 3-HB and 11b-H are oriented cis relative to one
another), δ = 3.95 (6-OMe) ↔ δ = 5.36 (5-H), δ = 3.95 (6-OMe) ↔ δ =
8.64 (7-OH), δ = 4.03 (8-OMe) ↔ δ = 7.32 (9-H), δ = 4.07 (11-OMe) ↔
δ = 5.56 (11b-H), δ = 4.07 (11-OMe) ↔ δ = 7.64 (10-H). 13C NMR
(100.61 MHz, CDCl3): δ = 19.66 (5-CH3), 37.96 (C-3), 57.11 (8-OCH3),
63.31 (6-OCH3), 64.17 (11-OCH3), 66.29 (C-3a), 67.61 (C-5), 72.00 (C-
11b), 114.66 (C-10), 115.13 (C-9), 115.72 (C-11a), 119.45 (C-6a),
124.33 (C-10a), 127.51 (C-5a), 140.92 (C-7), 144.43 (C-8), 146.11 (C-
6), 154.40 (C-11), 175.29 (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
= 6.7 Hz, 5-H), 5.53 (d, 1H, J11b,3a = 2.8 Hz, 11b-H), 7.35 (d, 1H, J9,10
=
9.3 Hz, 9-H), 8.01 (d, 1H, J10,9 = 9.3 Hz, 10-H). A NOESY spectrum
1
(400.13 MHz, CDCl3) allowed additional assignments of H resonances
by the occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.55 (5-CH3) ↔ δ
= 4.71 (3a-H, this cross-peak proves that 5-CH3 and 3a-H are oriented
cis relative to one another), δB = 2.96 (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 = 3.83 (6-OMe) ↔ δ = 5.33 (5-H), δ = 3.99 (8-OMe) ↔ δ =
7.35 (9-H), δ = 4.06 (11-OMe) ↔ δ = 5.53 (11b-H), δ = 4.06 (11-OMe)
↔ δ = 8.01 (10-H). 13C NMR (100.61 MHz, CDCl3): δ = 19.66 (5-CH3),
27.76 [C(CH3)3], 37.93 (C-3), 56.90 (8-OCH3), 62.34 (6-OCH3), 64.34
(11-OCH3), 66.23 (C-3a), 68.00 (C-5), 72.05 (C-11b), 83.13 [C(CH3)3],
114.27 (C-9), 115.97 (C-11a), 122.20 (C-10), 124.24 (C-6a), 124.24 (C-
10a), 130.14 (C-5a), 133.00 (C-7), 145.45 (C-6), 150.43 (C-8), 151.47
(7-OCO2tBu, exclusion principle), 153.82 (C-11), 175.32 (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 = 19.66 (5-CH3) ↔ δ = 1.51 (5-CH3), δ = 27.76
[C(CH3)3] ↔ δ = 1.55 [C(CH3)3], δ = 37.93 (C-3) ↔ [δA = 2.69 (3-HA)
and δB = 2.96 (3-HB)], δ = 56.90 (8-OCH3) ↔ δ = 3.99 (8-OMe), δ =
62.34 (6-OCH3) ↔ δ = 3.83 (6-OMe), δ = 64.34 (11-OCH3) ↔ δ = 4.06
(11-OMe), δ = 66.23 (C-3a) ↔ δ = 4.71 (3a-H), δ = 68.00 (C-5) ↔ δ =
5.33 (5-H), δ = 72.05 (C-11b) ↔ δ = 5.53 (11b-H), δ = 114.27 (C-9) ↔ δ
= 7.35 (9-H), δ = 122.20 (C-10) ↔ δ = 8.01 (10-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 =83.13 [C(CH3)3] ↔ δ =
1.55 [C(CH3)3], δ = 115.97 (C-11a) ↔ δ = 5.33 (5-H), δ = 115.97 (C-
11a) ↔ δ = 5.53 (11b-H),δ = 124.24 (C-6a*) ↔ δ = 8.01 (10-H), δ =
124.24 (C-10a*) ↔ δ = 7.35 (9-H), δ = 130.14 (C-5a) ↔ δ = 1.51 (5-
CH3), δ = 130.14 (C-5a) ↔ δ = 5.33 (5-H), δ = 130.14 (C-5a) ↔ δ =
5.53 (11b-H), δ = 133.00 (C-7) ↔ δ = 7.35 (9-H), δ = 133.00 (C-7) ↔ δ
= 8.01 (10-H), δ = 145.45 (C-6) ↔ δ = 3.83 (6-OMe), δ = 145.45 (C-6)
↔ δ = 5.33 (5-H), δ = 145.45 (C-6) ↔ δ = 8.01 (10-H), δ = 150.43 (C-8)
↔ δ = 3.99 (8-OMe), δ = 150.43 (C-8) ↔ δ = 7.35 (9-H), δ = 150.43 (C-
8) ↔ δ = 8.01 (10-H), δ = 153.82 (C-11) ↔ δ = 4.06 (11-OMe), δ =
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 19.66 (5-
CH3) ↔ δ = 1.51 (5-CH3), δ = 37.96 (C-3) ↔ [δA = 2.71 (3-HA) and δB
=
2.97 (3-HB)], δ = 57.11 (8-OCH3) ↔ δ = 4.03 (8-OMe), δ = 63.31 (6-
OCH3) ↔ δ = 3.95 (6-OMe), δ = 64.17 (11-OCH3) ↔ δ = 4.07 (11-
OMe), δ = 66.29 (C-3a) ↔ δ = 4.72 (3a-H), δ = 67.61 (C-5) ↔ δ = 5.36
(5-H), δ = 72.00 (C-11b) ↔ δ = 5.56 (11b-H), δ = 114.66 (C-10) ↔ δ =
7.64 (10-H), δ = 115.13 (C-9) ↔ δ = 7.32 (9-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 = 115.72 (C-11a) ↔ δ
= 5.36 (5-H), δ = 115.72 (C-11a) ↔ δ = 5.56 (11b-H), δ = 119.45 (C-6a)
↔ δ = 7.64 (10-H), δ = 119.45 (C-6a) ↔ δ = 8.64 (7-OH), δ = 124.33
(C-10a) ↔ δ = 7.32 (9-H), δ = 127.51 (C-5a) ↔ δ = 1.56 (5-CH3), δ =
127.51 (C-5a) ↔ δ = 5.36 (5-H), δ = 125.51 (C-5a) ↔ δ = 5.56 (11b-H),
δ = 140.92 (C-7) ↔ δ = 7.32 (9-H), δ = 140.92 (C-7) ↔ δ = 8.64 (7-OH),
δ = 144.43 (C-8) ↔ δ = 4.03 (8-OMe), δ = 144.43 (C-8) ↔ δ = 7.32 (9-
H), δ = 144.43 (C-8) ↔ δ = 7.64 (10-H), δ = 144.43 (C-8) ↔ δ = 8.64 (7-
OH), δ = 146.11 (C-6) ↔ δ = 3.95 (6-OMe), δ = 146.11 (C-6) ↔ δ =
5.36 (5-H), δ = 154.40 (C-11) ↔ δ = 4.07 (11-OMe), δ = 154.40 (C-11)
↔ δ = 5.56 (11b-H), δ = 154.40 (C-11) ↔ δ = 7.64 (10-H), δ = 175.29
(C-2) ↔ [δA = 2.71 (3-HA) and δB = 2.97 (3-HB)], δ = 175.29 (C-2) ↔
20
4.72(3a-H). Optical rotation: [
α
]
= –218.7 (c = 1.158, CHCl3).
D
HRMS (pos. APCI): Calcd. for C19H21O7 [M+H]+ = 361.12818; found
361.12817 (–0.01 ppm). IR (film): ν = 3365, 2980, 2945, 2845, 1770,
1630, 1455, 1415, 1365, 1345, 1305, 1270, 1200, 1145, 1090, 1065,
1035, 1010, 990, 905, 875, 825, 735, 700 cm-1.
24
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
153.82 (C-11) ↔ δ = 5.53 (11b-H), δ = 153.82 (C-11) ↔ δ = 8.01 (10-
H), δ = 175.32 (C-2) ↔ [δA = 2.69 (3-HA) and δB = 2.96 (3-HB)], δ =
175.32 (C-2) ↔ 4.71(3a-H). δ = 151.47 (7-OCO2tBu) exhibited no
(C-6a) ↔ δ = 8.09 (10-H), δ = 124.94 (C-10a) ↔ δ = 7.30 (9-H), δ =
133.60 (C-11a) ↔ δ = 5.02 (5-H), δ = 133.60 (C-11a) ↔ δ = 5.24 (11b-
H), δ = 138.99 (C-7) ↔ δ = 7.30 (9-H), δ = 138.99 (C-7) ↔ δ = 8.09 (10-
H), δ = 150.25 (C-5a) ↔ δ = 1.51 (5-CH3), δ = 150.25 (C-5a) ↔ δ =
5.02 (5-H), δ = 150.25 (C-5a) ↔ δ = 5.24 (11b-H), δ = 157.51 (C-8) ↔ δ
= 3.97 (8-OMe), δ = 157.51 (C-8) ↔ δ = 7.30 (9-H), δ = 157.51 (C-8) ↔
δ = 8.09 (10-H), δ = 174.09 (C-2) ↔ [δA = 2.67 (3-HA) and δB = 2.94 (3-
HB)], δ = 174.09 (C-2) ↔ 4.66(3a-H), δ = 180.96 (C-11) ↔ 5.24 (11b-
H), δ = 180.96 (C-11) ↔ 8.09 (10-H), δ = 182.12 (C-6) ↔ 5.02 (5-H). δ
cross-peak. *both resonances have the same chemical chift. Melting
point: Oil. Optical rotation: [
D
α
]
= –146.3 (c = 0.7, CHCl3). HRMS
20
(pos. APCI): Calcd. for C24H28O9 [M+H]+ = 461.18061; found 461.18054
(–0.15 ppm). IR (film): ν = 3430, 3060, 2980, 2940, 2850, 1765, 1670,
1625, 1605, 1505, 1495, 1455, 1405, 1395, 1370, 1355, 1340, 1280,
1255, 1200, 1150, 1090, 1065, 1035, 1005, 980, 955, 915, 900, 875,
840, 810, 770, 755, 735, 700, 670 cm-1.
= 150.54 (7-OCO2tBu) exhibited no cross-peak. Melting point: 102-
D
106°C. Optical rotation: [
α
]
20 = –48.1 (c = 0.58, CHCl3). HRMS (pos.
APCI): calcd. for C22H22O9 [M+H]+ = 431.13366; found 431.13409
(+1.01 ppm). IR (film): ν = 2980, 2940, 2850, 1775, 1665, 1590, 1490,
1445, 1400, 1370, 1335, 1290, 1270, 1255, 1220, 1200, 1150, 1100,
1085, 1070, 1035, 995, 950, 905, 875, 845, 825, 740, 700 cm-1. Warum
steht hier nichts über Arizonin B1
tert-Butyl
(3aS,5S,11bS)-8-methoxy-5-methyl-2,6,11-trioxo-
3,3a,5,6,11,11b-hexahydro-2H-benzo[g]furo[3,2-c]isochromen-7-yl
Carbonate (34) and (3aS,5S,11bS)-7-Hydroxy-8-methoxy-5-methyl-
3,3a-dihydro-2H-benzo[g]furo[3,2-c]isochromene[5H,11bH]-trione
(Arizonin B1, 3)
6-[(2S,3S)-3-Hydroxy-5-oxotetrahydrofuran-2-yl]-2,5,8-
trimethoxynaphthalen-1-yl Pivalate (35)
tert-Butyl
(3aS,5S,11bS)-6,8,11-trimethoxy-5-methyl-2-trioxo-
3,3a,5,11b-tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-7-yl carbonate
(33, 48.5 mg, 105 µmol) was dissolved in acetonitrile (2 mL). At room
temperature a freshly prepared solution of CAN (115.5 mg, 210 µmol,
2.0 equiv.) in H2O (2 mL) was added dropwise. The reaction mixture
was stirred for 20 min and afterwards diluted with EE (10 mL). The
organic phase was separated and the aq. phase was extracted with EE
(4×10 mL). The combined organic extracts were dried over Na2SO4 and
the solvent was removed in vacuo. Flash chromatography [d = 1.5 cm,
h = 8 cm, F = 8 mL; CH/EE 2:1 (F1-16), CH/EE 1:1 (F17-30),
CH/EE/HCO2H 49:49:2 (F31-45)] afforded the major product [34, F19-
25, Rf (2:1) = 0.1, 17.7 mg, 39%, dr = 100:0] as an orange solid as well
as the minor product arizonin B1 [3, F33-37, 5.0 mg, 14%, dr = 100:0]
as an orange solid.– Analysis of tert-butyl (3aS,5S,11bS)-8-methoxy-5-
methyl-2,6,11-trioxo-3,3a,5,6,11,11b-hexahydro-2H-benzo[g]furo[3,2-
A
87:13 isomeric mixture of (E)-methyl 4-(5-(pivaloyloxy)-1,4,6-
trimethoxynaphthalen-2-yl)but-3-enoate (15d) and its α,β-unsaturated
carboxylic ester isomer (iso-15d) (96.0 mg, 0.23 mmol) and
(DHQ)2PHAL (1.8 mg, 2.3 µmol, 1.0 mol-%) were dissolved in t-BuOH
(7 mL). K3Fe(CN)6 (227.2 mg, 0.69 mmol, 3.0 equiv.), K2CO3 (95.4 mg,
0.69 mmol, 3.0 equiv.), NaHCO3 (58.0 mg, 0.69 mmol, 3.0 equiv.) and
Me2SO2NH2 (22.1 mg, 0.23 mmol, 1.0 equiv.) were dissolved in H2O
(1.0 mL). The aq. solution was added to the vigorously stirred organic
reaction mixture. An solution of K2OsO2(OH)4 (0.34 mg, 0.9 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 (0.23 g) and stirred for
30 min. EtOAc (8 mL) was added and the organic phase was
separated. The aq. phase was extracted with EtOAc (5×8 mL) and the
combined organic extracts were washed with aq. KOH solution (1 M,
2×8 mL) and brine (8 mL) and dried over Na2SO4. The solvent was
evaporated in vacuo and the residue was purified by flash
chromatography [d = 1.5 cm, h = 12 cm, F = 8 mL; CH/EE 1:1] to obtain
the product (F12-22, Rf (1:1) = 0.2, 44.1 mg, 46%) as a white solid.– 1H
NMR (400.13 MHz, CDCl3): Rotamer 1:* δ = 1.45 [s, 9H, C(CH3)3], 1.71
(br. s, 1H, 3’-OH), AB signal (δA = 2.74, δB = 2.93, JAB = 17.6 Hz, A part
shows no further splitting, B part further split by JB,3’ = 5.3 Hz, 4’-HA and
4’-HB), 3.88 (s, 3H, 5-OMe), 3.89 (s, 3H, 8-OMe), 3.92 (s, 3H, 2-OMe),
4.77 (br. s, 1H, 3’-H), 5.86 (d, 1H, J4’,3’ = 3.5 Hz, 2’-H), 6.82** (s, 1H, 7-
H), 7.36 (d, 1H, J3,4 = 9.2 Hz, 3-H), 7.91 (d, 1H, J4,3 = 9.2 Hz, 4-H).
Rotamer 2:* δ = 1.45 [s, 9H, C(CH3)3], 1.65 (br. s, 1H, 3’-OH), AB
signal (δA = 2.74, δB = 2.93, JAB = 17.6 Hz, A part shows no further
splitting, B part further split by JB,3’ = 5.3 Hz, 4’-HA and 4’-HB), 3.88 (s,
3H, 5-OMe), 3.89 (s, 3H, 8-OMe), 3.92 (s, 3H, 2-OMe), 4.82 (br. s, 1H,
3’-H), 5.82 (d, 1H, J4’,3’ = 3.6 Hz, 2’-H), 6.83** (s, 1H, 7-H), 7.36 (d, 1H,
J3,4 = 9.2 Hz, 3-H), 7.91 (d, 1H, J4,3 = 9.2 Hz, 4-H). * If the rotamer
resonances were not identical they were distinguished from each other
by the assignment of their cross-peaks in a DQF-COSY spectrum
(400.13 MHz, CDCl3). **For δ = 6.82 and 6.83 (7-H) an unambiguous
assignment was impossible, therefore these signals are
interchangeable. In the following spectra (NOESY, 13C NMR, edHSQC
and HMBC) the rotamer resonances could not be distinguished from
each other. Thus, if the resonances were not identical, their δ values
are connected by the word “and”. A NOESY spectrum (400.13 MHz,
CDCl3) allowed additional assignments of 1H resonances by the
occurrence of crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.93 (4’-HB) ↔ δ = 5.85
1
c]isochromen-7-yl carbonate (34): H NMR (400.13 MHz, CDCl3, NMR-
file: 2015: NeBrMi19-4060): δ = 1.51 (d, 3H, J5-CH3,5 = 6.9 Hz, 5-CH3),
1.60 [s, 9H, C(CH3)3], AB signal (δA = 2.67, δB = 2.94, 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), 3.97 (s, 3H, 8-OMe), 4.66 (dd, 1H, J3a,B = 5.2 Hz, J3a,11b
= 3.0 Hz, 3a-H), 5.02 (q, 1H, J5,5-CH3 = 6.9 Hz, 5-H), 5.24 (d, 1H, J11b,3a
3.0 Hz, 11b-H), 7.30 (d, 1H, J9,10 = 8.8 Hz, 9-H), 8.09 (d, 1H, J10,9
=
=
8.8 Hz, 10-H). A NOESY spectrum (400.13 MHz, CDCl3) allowed
additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 1.51 (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 = 3.97 (8-OMe) ↔ δ = 7.30 (9-H). 13C NMR (100.61 MHz,
CDCl3): δ = 18.56 (5-CH3), 27.76 [C(CH3)3], 37.00 (C-3), 56.69 (8-
OCH3), 66.48 (C-3a), 66.71 (C-5), 68.93 (C-11b), 84.60 [C(CH3)3],
116.68 (C-9), 124.52 (C-6a), 124.94 (C-10a), 126.89 (C-10), 133.60 (C-
11a), 138.99 (C-7), 150.25 (C-5a), 150.54 (7-OCO2tBu), 157.51 (C-8),
174.09 (C-2), 180.96 (C-11), 182.12 (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 =
18.56 (5-CH3) ↔ δ = 1.51 (5-CH3), δ = 27.76 [C(CH3)3] ↔ δ = 1.60
[C(CH3)3], δ = 37.00 (C-3) ↔ [δA = 2.67 (3-HA) and δB = 2.94 (3-HB)], δ
= 56.69 (8-OCH3) ↔ δ = 3.97 (8-OMe), δ = 66.48 (C-3a) ↔ δ = 4.66
(3a-H), δ = 66.71 (C-5) ↔ δ = 5.02 (5-H), δ = 68.93 (C-11b) ↔ δ = 5.24
(11b-H), δ = 116.68 (C-9) ↔ δ = 7.30 (9-H), δ = 126.89 (C-10) ↔ δ =
8.09 (10-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 =84.60 [C(CH3)3] ↔ δ = 1.60 [C(CH3)3], δ = 124.52
25
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
and 5.86 (2’-H; this cross-peak proves that 4’-HB and 2’-H are oriented
cis relative to one another), δ = 3.88 (8-OMe) ↔ δ = 1.45 [C(CH3)3], δ =
3.88 (8-OMe) ↔ δ = 6.82 and 6.83 (7-H), δ = 3.89 (5-OMe) ↔ δ = 5.82
(2’-H), δ = 3.89 (5-OMe) ↔ δ = 7.91 (4-H), δ = 3.92 (2-OMe) ↔ δ =
7.36 (3-H), δ = 6.82 and 6.83 (7-H) ↔ δ = 5.85 and 5.86 (2’-H).
13C NMR (125.82 MHz, CDCl3): δ = 27.49 [C(CH3)3], 38.30 and 38.40
(C-4’), 39.35 [C(CH3)3], 55.99 (8-OCH3), 57.02 (2-OCH3), 62.35 and
62.59 (5-OCH3), 69.92 (C-3’, rotamer 2), 70.13 (C-3’, rotamer 1), 81.54
(C-2’, rotamer 1), 81.83 (C-2’, rotamer 2), 104.06 and 104.23 (C-7),
114.86 and 114.92 (C-3), 119.58 and 119.66 (C-6),120.71 and 120.83
(C-4), 122.08 (broad resonance, C-8a), 124.80 (C-4a), 135.19 (C-1),
146.16 and 146.58 (C-5), 149.47 (C-2), 152.21 and 152.34 (C-8),
175.46 and 175.60 (C-5’), 176.88 and 177.08. 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 =
27.49 [C(CH3)3] ↔ δ = 1.45 [C(CH3)3], δ = 38.30 and 38.40 (C-4’) ↔ [δA
= 2.74 (4’-HA) and δB = 2.93 (4’-HB)], δ = 55.99 (8-OCH3) ↔ δ = 3.88 (8-
OMe), δ = 57.02 (2-OCH3) ↔ δ = 3.92 (2-OMe), δ = 62.35 and 62.59
(5-OCH3) ↔ δ = 3.89 (5-OMe), δ = 69.92 (C-3’, rotamer 2) ↔ δ = 4.82
(3’-H, rotamer 2), δ = 70.13 (C-3’, rotamer 1) ↔ δ = 4.77 (3’-H, rotamer
1), δ = 81.54 (C-2’, rotamer 1) ↔ δ = 5.86 (2’-H, rotamer 1), δ = 81.83
(C-2’, rotamer 2) ↔ δ = 5.82 (2’-H, rotamer 2), δ = 104.06 and 104.23
(C-7) ↔ δ = 6.82 and 6.83 (7-H), δ = 114.86 and 114.92 (C-3) ↔ δ =
7.36 (3-H), δ = 120.71 and 120.83 (C-4) ↔ δ = 7.91 (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 = 39.35
[C(CH3)3] ↔ δ = 1.45 [C(CH3)3], δ = 119.58 and 119.66 (C-6) ↔ δ =
6.82 and 6.83 (7-H), δ = 122.08 (broad signal, C-8a) ↔ δ = 6.82 and
6.83 (7-H), δ = 122.08 (broad signal, C-8a) ↔ δ = 7.91 (4-H), δ =
124.80 (C-4a) ↔ δ = 7.36 (3-H), δ = 135.19 (C-1) ↔ δ = 7.36 (3-H), δ =
135.19 (C-1) ↔ δ = 7.91 (4-H), δ = 146.16 and 146.58 (C-5) ↔ δ = 3.89
(5-OMe), 146.16 and 146.58 (C-5) ↔ δ = 6.82 and 6.83 (7-H), 146.16
and 146.58 (C-5) ↔ δ = 7.91 (4-H), δ = 149.47 (C-2) ↔ δ = 3.96 (2-
OMe), δ = 149.47 (C-2) ↔ δ = 7.36 (3-H), δ = 149.47 (C-2) ↔ δ = 7.91
(4-H), δ = 152.21 and 152.34 (C-8) ↔ δ = 3.88 (8-OMe), δ = 152.21
and 152.34(C-8) ↔ δ = 6.82 and 6.83 (7-H), δ = 175.46 and 175.60 (C-
5’) ↔ [δA = 2.74 (4’-HA) and δB = 2.93 (4’-HB)], δ = 176.88 and 177.08
6-[(2S,3S)-3-Hydroxy-5-oxotetrahydrofuran-2-yl]-2,5,8-trimethoxynaph-
thalen-1-yl pivalate (35, 11.2 mg, 26.7 µmol) was suspended in CH2Cl2
(0.5 mL). At 0°C acetaldehyde (11.2 µL, 8.9 mg, 0.20 mmol, 7.5 equiv.)
was added and the reaction was started by the addition of BF3·OEt2
(34 µL, 38 mg, 0.27 mmol, 10 equiv.). The ice-bath was removed. The
reaction mixture was allowed to warm to room temperature and stirred
for 30 min. It was quenched by the addition of aq. saturated NaHCO3
(5 mL) and vigorously stirred for 5 min. The organic phase was
separated and the aq. phase was extracted with CH2Cl2 (4× 5mL). The
combined organic extracts were dried over Na2SO4 and the solvent was
removed in vacuo. Flash chromatography [d = 1.5 cm, h = 12 cm,
F = 8 mL; CH/EE 1:1] afforded the title compound [Rf(1:1) = 0.5, F5-10,
6.9 mg, 58%] as a colorless solid. The product came up as a 85:15
rotameric mixture at room temperature (proved by 1H NMR
spectroscopy (500.42 MHz, CDCl3, see below). A 1H-NMR spectrum
(500.32 MHz, CDCl3) recorded at 333 K proved the mixture to be a
single diastereomer.– 1H NMR (500.32 MHz, CDCl3, 333K): δ = 1.46 [s,
9H, C(CH3)3], 1.53 (d, 3H, J5-CH3,5 = 6.7 Hz, 5-CH3), AB signal (δA
=
2.68, δB = 2.93, JAB = 17.5 Hz, A signal shows no further splitting, B
signal further split by JB,3a = 5.0 Hz, 3-HA and 3-HB), 3.78 (br. s, 3H, 6-
OMe), 3.93 (s, 3H, 8-OMe), 4.08 (s, 3H, 11-OMe), 4.70 (dd, 1H, J3a,B
=
4.9 Hz, J3a,11b = 2.8 Hz, 3a-H), 5.31 (q, 1H, J5,5-CH3 = 6.5 Hz, 5-H), 5.52
(d, 1H, J11b,3a = 2.8 Hz, 11b-H), 7.33 (d, 1H, J9,10 = 9.3 Hz, 9-H), 8.02 (d,
1H, J10,9 = 9.2 Hz, 10-H). The NMR analysis (room temperature) only
contains the resonances of the main rotamer. The minor rotamer’s
resonances were too broad to be determined. 1H NMR (500.42 MHz,
CDCl3, room temperature, ): δ = 1.44 [s, 9H, C(CH3)3], 1.51 (d, 3H, J5-
,5 = 6.7 Hz, 5-CH3), AB signal (δA = 2.70, δB = 2.97, JAB = 17.5 Hz, A
CH
3
signal shows no further splitting, B signal further split by JB,3a = 4.9 Hz,
3-HA and 3-HB), 3.78 (br. s, 3H, 6-OMe), 3.93 (s, 3H, 8-OMe), 4.07 (s,
3H, 11-OMe), 4.71 (br. s, 1H, 3a-H), 5.28 (q, 1H, J5,5-CH3 = 6.6 Hz, 5-H),
5.54 (br. s, 1H, 11b-H), 7.34 (d, 1H, J9,10 = 9.3 Hz, 9-H), 8.02 (d, 1H,
J10,9 = 9.3 Hz, 10-H). A NOESY spectrum (500.42 MHz, CDCl3) allowed
additional assignments of 1H resonances by the occurrence of cross-
peaks [δ(1H) ↔ δ(1H)]: δ = 1.51 (5-CH3) ↔ δ = 4.71 (3a-H, this cross-
peak proves that 5-CH3 and 3a-H are oriented cis relative to one
another), δB = 2.97 (3-HB) ↔ δ = 5.54 (11b-H this cross-peak proves
that 3-HB and 11b-H are oriented cis relative to one another), δ = 3.78
(6-OMe) ↔ δ = 1.44 [C(CH3)3], δ = 3.78 (6-OMe) ↔ δ = 5.28 (5-H), δ =
3.93 (8-OMe) ↔ δ = 1.44 [C(CH3)3], δ = 3.93 (8-OMe) ↔ δ = 7.34 (9-H),
δ = 4.07 (11-OMe) ↔ δ = 5.54 (11b-H), δ = 4.07 (11-OMe) ↔ δ = 8.02
(5’-O2CtBu) ↔ δ = 1.45[C(CH3)3]. Optical rotation (35): [
(c = 0.725, CHCl3). HRMS (pos. APCI, 70 eV, file: nebrc62t_hr4):
Calcd. for C22H30O8N [M+NH4]+
436.1966; found 436.1965 (–
α]
20 = +21.4
D
(10-H). 13C NMR (125.81 MHz, CDCl3):
δ = 19.8 (5-CH3), 27.5
=
[C(CH3)3], 38.0 (C-3), 39.4 [C(CH3)3], 56.8 (8-OCH3), 62.6 (6-OCH3),
64.3 (11-OCH3), 66.2 (C-3a), 68.1 (C-5), 72.2 (C-11b), 114.0 (C-9),
115.9 (C-11a), 122.1 (C-10), 124.3, 124.6, and 133.5 (C-6a, C-7, and
C-10a), 129.8 (C-5a), 146.0 (C-6), 149.9 (C-8), 153.7 (C-11), 175.5 (C-
2), 176.7 (7-O2CtBu). An edHSQC spectrum (“short-range C,H COSY”;
125.81/500.42 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 = 19.8 (5-
CH3) ↔ δ = 1.51 (5-CH3), δ = 27.5 [C(CH3)3] ↔ δ = 1.44 [C(CH3)3], δ =
38.0 (C-3) ↔ [δA = 2.70 (3-HA) and δB = 2.97 (3-HB)], δ = 56.8 (8-OCH3)
↔ δ = 3.93 (8-OMe), δ = 62.6 (6-OCH3) ↔ δ = 3.78 (6-OMe), δ = 64.3
(11-OCH3) ↔ δ = 4.07 (11-OMe), δ = 66.2 (C-3a) ↔ δ = 4.71 (3a-H), δ
= 68.1 (C-5) ↔ δ = 5.28 (5-H), δ = 72.2 (C-11b) ↔ δ = 5.54 (11b-H), δ =
114.0 (C-9) ↔ δ = 7.34 (9-H), δ = 122.1 (C-10) ↔ δ = 8.02 (10-H). An
HMBC spectrum (“long-range C,H COSY”; 125.81/500.42 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 =39.4 [C(CH3)3]
↔ δ = 1.44 [C(CH3)3], δ = 115.9 (C-11a) ↔ δA = 2.70 (3-HA), δ = 115.9
(C-11a) ↔ δ = 5.28 (5-H), δ = 115.9 (C-11a) ↔ δ = 5.54 (11b-H), δ =
124.3, 124.6, and 133.5 (C-6a, C-7, and C-10a) ↔ [δ = 7.32 (9-H) and
δ = 8.02 (10-H) could not be assigned unambiguously], δ = 129.8 (C-
5a) ↔ δ = 1.51 (5-CH3), δ = 129.8 (C-5a) ↔ δ = 5.28 (5-H), δ = 129.8
(C-5a) ↔ δ = 5.54 (11b-H), δ = 146.0 (C-6) ↔ δ = 3.78 (6-OMe), δ =
146.0 (C-6) ↔ δ = 5.28 (5-H), δ = 149.9 (C-8) ↔ δ = 3.93 (8-OMe), δ =
149.9 (C-8) ↔ δ = 7.34 (9-H), δ = 149.9 (C-8) ↔ δ = 8.02 (10-H), δ =
153.7 (C-11) ↔ δ = 4.07 (11-OMe), δ = 153.7 (C-11) ↔ δ = 5.54 (11b-
0.28 ppm). IR (film): ν = 3470, 2970, 2935, 2845, 1750, 1665, 1630,
1610, 1515, 1480, 1465, 1385, 1370, 1340, 1280, 1255, 1235, 1200,
1150, 1120, 1075, 1045, 1015, 980, 920, 900, 875, 820, 800, 750 cm-1.
Enantiomeric excess (35): >97% ee. The ee was determined by chiral
HPLC (OD-3, heptane:EtOH = 75:25, λ = 230 nm, flow: 0.5 mL/min,
tR(35) = 8.53 min, tR(ent-35) not detected. To develop a separation
method for chiral HPLC a mixture of both enantiomers was measured
(OD-3, heptane:EtOH = 75:25, λ = 230 nm, flow: 0.5 mL/min, tR(35) =
8.40 min, tR(ent-35)
= 9.47 min). The optical antipode 35 was
synthesized analogously by using the (DHQD)2PHAL-ligand in the
Sharpless’ asymmetric dihydroxylation procedure. Optical rotation
20
(ent-35): [
α
]
= −19.3 (c = 0.87, CHCl3). Enantiomeric excess (ent-
D
35): 97% ee. The ee was determined by chiral HPLC (OD-3,
heptane:EtOH = 75:25, λ = 230 nm, flow: 0.5 mL/min, tR(35) = 8.00 min,
tR(ent-35) = 9.52 min).
(3aS,5S,11bS)-6,8,11-Trimethoxy-5-methyl-2-oxo-3,3a,5,11b-
tetrahydro-2H-benzo[g]furo[3,2-c]isochromen-7-yl Pivalate (36)
26
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
H), δ = 153.7 (C-11) ↔ δ = 8.02 (10-H), δ = 175.5 (C-2) ↔ [δA = 2.70
9’b) ↔ δ = 7.63 (7’-H), δ = 121.05 (C-5’) ↔ δ = 5.84 (5-H), δ = 121.05
(C-5’) ↔ δ = 6.98 (4’-H), δ = 123.15 (C-6’a) ↔ δ = 7.33 (8’-H), δ =
137.64 (C-9’a) ↔ δA = 5.52 (2’-HA) and δB = 5.58 (2’-HB), δ = 137.64 (C-
9’a) ↔ δ = 7.33 (8’-H), δ = 142.05 (C-9’) ↔ δ = 4.01 (9’-OMe), δ =
142.05 (C-9’) ↔ δ = 7.63 (7’-H), δ = 145.76 (C-3’a) ↔ δA = 5.52 (2’-HA)
and δB = 5.58 (2’-HB), δ = 145.76 (C-3’a) ↔ δ = 7.02 (4’-H), δ = 147.38
(C-6’) ↔ δ = 3.95 (6’-OMe), δ = 147.38 (C-6’) ↔ δ = 5.84 (5-H), δ =
147.38 (C-6’) ↔ δ = 6.98 (4’-H), δ = 147.38 (C-6’) ↔ δ = 7.63 (7’-H), δ
(3-HA) and δB = 2.97 (3-HB)], δ = 175.5 (C-2) ↔ 4.71(3a-H), δ = 176. 7
(7-O2CtBu) exhibited no cross-peak. Optical rotation: [
(c = 0.62, CHCl3). HRMS (pos. APCI): Calcd. for C24H32O8N [M+NH4]+ =
462.2122; found 462.2122 (–0.05 ppm). IR (film): ν = 2975, 2935,
2875, 2850, 1785, 1625, 1600, 1505, 1480, 1465, 1405, 1365, 1355,
1340, 1280, 1200, 1130, 1065, 1035, 1010, 980, 955, 915, 900, 820,
795, 760, 735 cm-1.
D
α
]
= –132.9
20
= 175.25 (C-2) ↔ δA = 2.74 (3-HA) and δB = 2.94 (3-HB). Melting point:
20
133°C. Optical rotation (38): [
α
]
= –4.2 (c = 0.793, CHCl3). HRMS
D
(4S,5S)-5-(6,9-dimethoxynaphtho[1,8-de][1,3-dioxin-5-yl]-4-
hydroxydihydrofuran-2(3H)-one (38)
(pos. ESI): Calcd. for C17H16O7 [M+Na]+ = 355.07882; found 355.07901
(+0.52 ppm). IR (film): ν = 3455, 3060, 2945, 2845, 1775, 1625, 1585,
1510, 1485, 1445, 1405, 1385, 1345, 1275, 1205, 1160, 1105, 1070,
1015, 990, 925, 895, 875, 815, 800, 785, 735, 690 cm-1. Enantiomeric
excess (38): >99.9% ee. The ee was determined by chiral HPLC (OD-
3, heptane:EtOH = 50:50, λ = 237 nm, flow: 1.0 mL/min, tR(38) =
4.41 min, tR(ent-38) not detected). To develop a separation method for
chiral HPLC a mixture of both enantiomers was measured (OD-3,
heptane:EtOH = 50:50, λ = 237 nm, flow: 1.0 mL/min, tR(38) = 4.41 min,
tR(ent-38) = 5.36 min). The optical antipode ent-38 was synthesized
A 93:7 isomeric mixture of (E)-methyl 4-(6,9-dimethoxynaphtho[1,8-
de][1,3 dioxine-5-yl]but-3-enoate (15h) and its α,β-unsaturated
carboxylic ester isomer (iso-15h) (197.8 mg, 0.60 mmol) and
(DHQ)2PHAL (4.7 mg, 6.0 µmol, 1.0 mol-%) were dissolved in t-BuOH
(48 mL). K3Fe(CN)6 (0.59 g, 1.79 mmol, 2.99 equiv.), K2CO3 (0.25 g,
1.81 mmol, 3.01 equiv.), NaHCO3 (0.15 g, 1.79 mmol, 2.99 equiv.), and
Me2SO2NH2 (57.6 mg, 0.60 mmol, 1.00 equiv.) were dissolved in H2O
(12 mL). The aq. solution was added to the vigorously stirred organic
reaction mixture. Solid K2OsO2(OH)4 (0.9 mg, 2.4 µmol, 0.4 mol-%) 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 (0.60 g) and stirred for 30 min. EtOAc (50 mL) was added
and the organic phase was separated. The aq. phase was extracted
with EtOAc (4×20 mL) and the combined organic extracts were washed
analogously by using the (DHQD)2PHAL-ligand in the Sharpless
asymmetric dihydroxylation procedure. Optical rotation (ent-38): [α]
D
= +2.9 (c = 0.777, CHCl3). Enantiomeric excess (ent-38): 99.8% ee.
The ee was determined by chiral HPLC (OD-3, heptane:EtOH = 50:50,
λ = 237 nm, flow: 1.0 mL/min, tR(38) = 4.44 min, tR(ent-38) = 5.34 min).
20
(7bS,10aS,12R)-4,7-Dimethoxy-12-methyl-7b,10,10a,12-tetrahydro-
9H-furo[2’’,3’’:5’,6’]pyrano[3’,4’:2,3]naphtho[1,8-de][1,3]dioxin-9-
one (39)
with aq. KOH solution (1 M, 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 cm, h = 12 cm, F = 25 mL;
CH/EE 1:1] to obtain the product (F18-28, Rf (1:1) = 0.2, 102.8 mg,
52%) as a pale-yellow solid.– 1H NMR (500.32 MHz, CDCl3): δ = 1.84
(br. s, 1H, 4-OH), AB signal (δA = 2.74, δB = 2.94, JAB = 17.7 Hz, A
Procedure 1: (4S,5S)-5-(6,9-Dimethoxynaphtho[1,8-de][1,3 dioxin-5-
yl]-4-hydroxydihydrofuran-2(3H)-one (38, 102.8 mg, 0.309 mmol) was
dissolved in CH2Cl2 (3 mL). The suspension was cooled to 0°C and
acetaldehyde (129 µL, 102 mg, 2.32 mmol, 7.5 equiv.) was added. At
this temperature BF·OEt2 (392 µL, 439 mg, 3.09 mmol, 10.0 equiv.) was
added dropwise. Afterwards the ice-bath was removed, the solution
was allowed to warm up to room temperature and stirred for 30 min.
The reaction was quenched by the addition of aq. saturated NaHCO3
solution (5 mL) and the stirred vigorously for 1 min. The organic phase
was separated and the aq. phase was extracted with CH2Cl2 (2×8 mL).
The combined organic extracts were dried over Na2SO4 and the solvent
was removed in vacuo. The oily residue was purified by flash
chromatography [d = 1.5 cm, h = 12 cm, F = 8 mL; CH/EE 2:1 (F1-13),
1:1 (14-36)] to obtain the product [F10-33, Rf (2:1) = 0.2, 86.3 mg, 78%,
signal further splitted by JA,4 = 0.9 Hz, B signal further split by JB,4
=
5.6 Hz, 3-HA and 3-HB), 3.95 (s, 3H, 6’-OMe), 4.01 (s, 3H, 9’-OMe),
4.81 (m, 1H, 4-H), AB signal (δA = 5.52, δB = 5.58, JAB = 5.0 Hz, A and
B signal show no further splitting, 2’-HA and 2’-HB), 5.84 (d, 1H, J5,4
=
3.8 Hz, 5-H), 6.98 (s, 1H, 4’-H), 7.33 (d, 1H, J8’,7’ = 9.2 Hz, 8’-H), 7.63
(d, 1H, J7’,8’ = 9.2 Hz, 7‘-H). A NOESY spectrum (500.32 MHz, CDCl3)
1
allowed additional assignments of H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δB = 2.94 (3-HB) ↔ δ = 5.84 (5-H, this
cross-peak proves that 3-HB and 5-H are oriented cis relative to one
another), δ = 3.95 (6’-OMe) ↔ δ = 5.84 (5-H), δ = 3.95 (6’-OMe) ↔ δ =
7.63 (7’-H), δ = 4.01 (9’-OMe) ↔ δ = 7.33 (8’-H), δ = 6.98 (4-H) ↔ δ =
5.84 (5-H). 13C NMR (125.82 MHz, CDCl3): δ = 38.42 (C-3), 57.34 (9’-
OCH3), 62.55 (6’-OCH3), 69.96 (C-4), 81.65 (C-5), 91.28 (C-2’), 107.33
(C-4’), 116.17 (C-7’), 116.25 (C-8’), 117.14 (C-9’b), 121.05 (C-5’),
123.15 (C-6’a), 137.64 (C-9’a), 142.05 (C-9’), 145.76 (C-3’a), 147.38
(C-6’), 175.25 (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
ds = 100:0] as
a colorless solid.– Procedure 2: (4S,5S)-5-(6,9-
dimethoxynaphtho[1,8-de][1,3 dioxin-5-yl]-4-hydroxydihydrofuran-2(3H)-
one (62, 12.7 mg, 0.038 mmol) was dissolved in CH2Cl2 (1 mL). The
suspension was cooled to 0°C and acetaldehyde dimethyl acetal
(30.4 µL, 25.8 mg, 0.287 mmol, 7.5 equiv.) was added. At this
temperature BF·OEt2 (48.4 µL, 54.2 mg, 0.382 mmol, 10.0 equiv.) was
added dropwise. Afterwards the ice-bath was removed, the solution
was allowed to warm up to room temperature and stirred for 30 min.
The reaction was quenched by the addition of aq. saturated NaHCO3
solution (1 mL) and the stirred vigorously for 1 min. The organic phase
was separated and the aq. phase was extracted with CH2Cl2 (2×5 mL).
The combined organic extracts were dried over Na2SO4 and the solvent
was removed in vacuo. The residue was purified by flash
chromatography (d = 1.5 cm, h = 10 cm, F = 8 mL; CH/EE 2:1) to obtain
the product [F10-20, Rf (2:1) = 0.2, 10.7 mg, 78%, ds = 100:0) as a
colorless solid.– 1H NMR (400.13 MHz, CDCl3): δ = 1.72 (d, 3H, J12-
1
independently assigned H resonances [δ(13C) ↔ δ(1H)]: δ = 38.42 (C-
3) ↔ δA = 2.74 (3-HA) and δB = 2.94 (3-HB), δ = 57.34 (9’-OCH3) ↔ δ =
4.01 (9’-OMe), δ = 62.55 (6’-OCH3) ↔ δ = 3.95 (6’-OMe), δ = 69.96 (C-
4) ↔ δ = 4.81 (4-H), δ = 81.65 (C-5) ↔ δ = 5.84 (5-H), δ = 91.28 (C-2’)
↔ δA = 5.52 (2’-HA) and δB = 5.58 (2’-HB), δ = 107.33 (C-4’) ↔ δ = 6.98
(4’-H), δ = 116.17 (C-7’) ↔ δ = 7.63 (7’-H), δ = 116.25 (C-8’) ↔ δ =
7.33 (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 = 117.14 (C-9’b) ↔ δ = 6.98 (4’-H), δ = 117.14 (C-
,12 = 6.3 Hz, 12-CH3), AB signal (δA = 2.76, δB = 2.90, JAB = 17.1 Hz,
CH
A 3signal shows no further splitting, B signal further splitted by JB,10a
=
27
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700013
European Journal of Organic Chemistry
FULL PAPER
4.5 Hz, 10-HA and 10-HB), 4.03 (s, 3H, 4-OMe), 4.10 (s, 3H, 7-OMe),
4.36 (dd, 1H, J10a,B = 4.2 Hz, J10a,7b = 2.4 Hz, 10a-H), 4.96 (q, 1H, J12,12-
3 = 6.3 Hz, 12-H), 5.56 (d, 1H, J7b,10a = 2.3 Hz, 7b-H), AB signal (δA
CH
=
5.55, δB = 5.58, JAB = 4.9 Hz, A and B signal show no further splitting,
2-HA and 2-HB), 7.33 (d, 1H, J5,6 = 9.2 Hz, 5-H), 7.71 (d, 1H, J6,5
9.2 Hz, 6-H). NOESY spectrum (400.13 MHz, CDCl3) allowed
=
A
additional assignments of 1H resonances by the occurrence of
crosspeaks [δ(1H) ↔ δ(1H)]: δ = 4.03 (4-OMe) ↔ δ = 7.33 (5-H), δ =
4.10 (7-OMe) ↔ δ = 7.71 (6-H), δ = 4.96 (12-H) ↔ δ = 4.36 (10a-H this
cross-peak proves that 12-H and 10a-H are oriented cis relative to one
another). 13C NMR (100.61 MHz, CDCl3): δ = 21.15 (12-CH3), 38.38 (C-
10), 57.30 (4-OCH3), 64.58 (7-OCH3), 69.86 (C-12), 72.01 (C-10a),
73.04 (C-7b), 90.89 (C-2), 115.83 (C-5), 116.66 (C-6), 117.29 and
117.37 (C-7a and C-12c), 119.87 (C-12a), 122.54 (C-6a), 137.27 (C-
3a), 140.76 (C-12b), 142.53 (C-4), 152.73 (C-7), 175.57 (C-9). 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 = 21.15 (12-CH3) ↔ δ = 1.72 (12-CH3), δ = 38.38
(C-10) ↔ δA = 2.76 (10-HA) and δB = 2.90 (10-HB), δ = 57.30 (4-OCH3)
↔ δ = 4.03 (4-OMe), δ = 64.58 (7-OCH3) ↔ δ = 4.10 (7-OMe), δ =
69.86 (C-12) ↔ δ = 4.96 (12-H), δ = 72.01 (C-10a) ↔ δ = 4.36 (10a-H),
δ = 73.04 (C-7b) ↔ δ = 5.56 (7b-H), δ = 90.89 (C-2) ↔ δA = 5.55 (2-HA)
and δB = 5.58 (2-HB), δ = 115.83 (C-5) ↔ δ = 7.33 (5-H), δ = 116.66 (C-
6) ↔ δ = 7.71 (6-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 = 117.29 and δ = 117.37 (C-7a and C-12c)] ↔ [δ =
4.96 (12-H), δ = 5.56 (7b-H) and δ = 7.71 (6-H)], δ = 119.87 (C-12a) ↔
δ = 1.72 (12-CH3), δ = 119.87 (C-12a) ↔ δ = 4.96 (12-H), δ = 119.87
(C-12a) ↔ δ = 5.56 (7b-H), δ = 122.54 (C-6a) ↔ δ = 7.33 (5-H), δ =
137.27 (C-3a) ↔ [δA = 5.55 (2-HA) and δB = 5.58 (2-HB)], δ = 137.27 (C-
3a) ↔ δ = 7.33 (5-H), δ = 137.27 (C-3a) ↔ δ = 7.71 (6-H), δ = 140.76
(C-12b) ↔ δ = 4.96 (12-H), δ = 140.76 (C-12b) ↔ [δA = 5.55 (2-HA) and
δB = 5.58 (2-HB)], δ = 142.53 (C-4) ↔ δ = 4.03 (4-OMe), δ = 142.53 (C-
4) ↔ δ = 7.33 (5-H), δ = 142.53 (C-4) ↔ δ = 7.71 (6-H), δ = 152.73 (C-
7) ↔ δ = 4.10 (7-OMe), δ = 152.73 (C-7) ↔ δ = 5.56 (7b-H), δ = 152.73
(C-7) ↔ δ = 7.71 (6-H), δ = 175.57 (C-9) ↔ [δA = 2.74 (10-HA) and δB =
2.94 (10-HB)], δ = 175.57 (C-9) ↔ δ = 4.36 (10a-H). Melting point:
D
189°C. Optical rotation: [
α
]
20 = –144.3 (c = 1.0, CHCl3). HRMS (pos.
ESI): Calcd. for C19H18O7 [M+Na]+ = 381.09447; found 381.09479
(+0.82 ppm). IR (film): ν = 2965, 2935, 2830, 1775, 1635, 1615, 1505,
1445, 1405, 1390, 1370, 1355, 1310, 1290, 1280, 1210, 1170, 1140,
1115, 1085, 1065, 1035, 980, 965, 910, 895, 780 cm-1.
Acknowledgements
The authors thank Andreas Welle for technical assistance.
Keywords: aryne Diels-Alder reaction • asymmetric Sharpless
dihydroxylation • naphthoquinonopyrano-γ-lactones • natural
product synthesis • oxa-Pictet Spengler cyclizations • protective
groups
28
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