Rapid Generation of Complex Molecular Architectures by a Catalytic Enantioselective Dearomatization Strategy

Article abstract of DOI:10.1055/s-0035-1560514

A catalytic enantioselective dearomatization strategy can be used to convert readily assembled phenols into complex polycyclic architectures. By combining oxidative dearomatization of phenols bearing a pendent nucleophile with enantioselective secondary a

Full text of DOI:10.1055/s-0035-1560514

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 116–120
letter
116
A. E. Williamson et al.
Letter
Synlett
Rapid Generation of Complex Molecular Architectures by a Cata-
lytic Enantioselective Dearomatization Strategy
RO
RO
RO
Alice E. Williamson
Tifelle Ngouansavanh
Robert D. M. Pace
Anna E. Allen
OR
OR
OR
Ar
Ar
N
O
O
OH
H
H
oxidant
OTMS
O
James D. Cuthbertson
Matthew J. Gaunt*
N
N
N
O
O
O
H
H
O
O
H
H
Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
mjg32@cam.ac.uk
6 examples
35–67% yield
>90% ee
simple planar
precursor
Received: 22.09.2015
Accepted after revision: 05.10.2015
Published online: 09.11.2015
(CED) protocol, we felt that this could be a powerful strate-
gy for the synthesis of a broad range of complex molecular
scaffolds. This report summarizes results that we obtained
while attempting to develop a broadly applicable strategy
for accessing natural product frameworks and other natural
product-like architectures.
DOI: 10.1055/s-0035-1560514; Art ID: st-2015-d0759-l
Abstract A catalytic enantioselective dearomatization strategy can be
used to convert readily assembled phenols into complex polycyclic ar-
chitectures. By combining oxidative dearomatization of phenols bear-
ing a pendent nucleophile with enantioselective secondary amine catal-
ysis, high enantiomeric excesses were obtained for the natural product-
like products.
catalytic enantioselective dearomatization (CED) towards
chiral decalin frameworks (eq. 1)
O
OH
O
Ph
Ph
O
N
PhI(OAc)2
MeOH
Key words asymmetric catalysis, biomimetic synthesis, phenols, ste-
reoselectivity, tandem reactions
O
O
H
H
OTMS
H
H
H
MeO
oxidative
MeO
dearomatization
organocatalytic
conjugate addition
The development of strategies that enable the expedient
buildup of molecular complexity from simple and readily
available starting materials remains an ongoing challenge
at the forefront of chemical synthesis.1 In this respect, oxi-
dative dearomatization has emerged as a highly effective
way to increase the molecular complexity of simple planar
architectures.2,3 Such processes generate reactive interme-
diates that readily participate in carbon–carbon or carbon–
heteroatom bond-forming reactions. From a synthetic
standpoint, the dearomatization of phenols is of particular
appeal as this produces a reactive cyclohexadienone inter-
mediate, a motif that is amenable to further elaboration
through a myriad of enantioselective protocols, as demon-
strated by the seminal works of Feringa, Hayashi, Rovis,
You, and Buchwald, in addition to our group.4
In 2008, we reported a merger of hypervalent iodine-
mediated dearomatization of phenols with a secondary
amine-catalyzed enantioselective desymmetrization of cy-
clohexadienones (Figure 1, eq. 1).4d This one-pot protocol
expediently converts planar phenol moieties into chiral
decalin frameworks bearing three contiguous stereocen-
ters. Whilst our initial report successfully demonstrated the
utility of this catalytic enantioselective dearomatization
this work: application of the CED strategy to the synthesis of
natural product scaffolds (eq. 2)
RO
OR
RO
RO
OR
OR
Ar
Ar
OH
N
H
O
H
H
O
OTMS
N
O
O
N
N
O
O
O
H
H
O
simple planar
precursor
rapid access to Erythrina
alkaloid scaffolds
H
O
O
MeO
OMe
OMe
OMe
OMe
O
N
N
N
erythramine
3-demethoxyerythratidinone
coccuvinine
Figure 1 Catalytic enantioselective dearomatization strategies for nat-
ural product synthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 116–120

117
A. E. Williamson et al.
Letter
Synlett
Our initial investigations focused on the core of the
Erythrina alkaloids, an important family of bioactive natu-
ral products known for their curare-like properties and
their use in indigenous medicine.5,6 We reasoned that the
requisite tetracyclic scaffold might be obtained from a sim-
ple linear precursor by using a CED process involving an
anisidine derivative bearing a tethered aromatic nucleop-
hile (Figure 1, eq. 2). The dearomatization of the phenol
moiety should proceed with concomitant addition of the
pendent arene through a Freidel–Crafts mechanism to gen-
erate the required spiro center. The resulting cyclohexadie-
none intermediate would be subsequently desymmetrized
by an organocatalytic conjugate addition,4b rapidly generat-
ing the tetracyclic core present in many of the Erythrina al-
kaloids.
The required precursor 1a was readily prepared in four
steps from commercially available starting materials by us-
ing Ullman and peptide-coupling reactions (see the Sup-
porting Information for details). Optimal conditions for the
dearomatization of phenol 1a were quickly established;
upon treatment with bis[(trifluoroacetoxy)iodo]benzene in
2,2,2-trifluoroethanol at –40 °C, complete conversion to the
intermediate cyclohexadienone 2a, containing the desired
benzylic spiro center, was observed (Scheme 1).
Table 1 Optimization of the Desymmetrizing Michael Addition
MeO
MeO
OMe
H
OMe
H
PhI(OTFA)2 (1.1 equiv)
MeO
OMe
TFE (0.03 M)
–40 °C, 30 min
then
O
O
OH
O
N
O
N
O
Ph
Ph
OTMS
O
N
H
N
O
H
H
H
H
O
5a (10 mol%)
1a
3
4a
H
solvent, temp
Entry
Solvent
Concn
(mmol)
Time
(h)a
Temp
(°C)
Yield (%) eeb (%)
of 4a
of 4a
1
2
3
4
5
6
7
8
CH2Cl2
MeCN
THF
0.26
0.26
0.26
0.26
0.26
0.26
0.26
0.058
4
16
16
16
60
60
60
60
23
23
43
69
98
89
0
0
11
17
18
–
23
toluene
THF
23
–40
–40
–40
–40
toluene
MeCN
MeCN
0
–
61
60
37
>99
a Reactions were run until 100% consumption of the starting material was
observed.
b Treatment of the crude product with Et3N in CH2Cl2 gave 4a as a single
MeO
MeO
diastereomer.
OMe
OMe
PhI(OTFA)2 (1.1 equiv)
TFE, –40 °C, 30 min
Having established the optimal conditions for accessing
the framework of many Erythrina alkaloids, we sought to
explore the utility of our method in generating other natu-
ral and nonnatural alkaloid scaffolds by altering the nature
of the tethered aromatic nucleophile (Table 2). We initially
considered a meta-anisole fragment to form the nonnatural
alkaloid analogue 4b.12 Surprisingly, substrate 1b, bearing a
single methoxy substituent, was found to be considerably
less tolerant of the dearomatization conditions than was
the catechol-derived substrate 1a, and it gave numerous
unidentified byproducts. Pleasingly, however, we found
that switching the oxidant to (diacetoxyiodo)benzene and
raising the temperature to 0 °C resulted in clean conversion
to the intermediate cyclohexadienone after just 30 minutes.
Subjecting the crude cyclohexadienone to the optimized
organocatalytic cyclization conditions resulted in poor lev-
els of enantioselectivity (28% ee); however, we found that
by using catalyst 5b bearing larger 2-naphthyl substituents
and by adding benzoic acid as a cocatalyst, we obtained the
desired tetracyclic scaffold 4b as a single diastereoisomer in
35% yield and 84% ee. These conditions also proved to be ef-
fective for a 1,3-benzodioxole nucleophile, enabling the
generation of the pentacyclic scaffold 4c in 58% yield and
92% ee; this scaffold is present in several Erythrina alka-
loids.
O
OH
100% conversion
N
N
O
O
O
O
1a
H
2a
H
Scheme 1 Dearomatization of phenol 1a to form cyclohexadienone in-
termediate 2a
We next turned our attention to the desymmetrizing
organocatalytic conjugate addition. Treatment of the crude
cyclohexadienone 2a with 10 mol% Hayashi–Jørgensen cat-
alyst 5a7 in dichloromethane at room temperature led to
the formation of the desired tetracyclic product in 43% yield
over two steps (Table 1, entry 1). Although mixtures of the
diastereoisomers 3 and 4a were initially formed,8 we quick-
ly established that the crude mixture could be equilibrated
to the configurationally stable anti-diastereoisomer 4a
upon treatment with triethylamine. Evaluation of a variety
of solvents at room temperature led to pleasing levels of
conversion (entries 2–4), but only modest improvements in
the enantioselectivity were observed. Lowering the tem-
perature to –40 °C and diluting the reaction led to dramatic
improvements in the selectivity, permitting the tetracyclic
product 4a to be isolated in 60% yield as a single diastereo-
isomer and with excellent enantioselectivity (>99% ee; en-
try 8).9–11
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 116–120

118
A. E. Williamson et al.
Letter
Synlett
Table 2 Application of CED to Erythrina Alkaloid Scaffolds
quired to form the analogous five-membered ring. Increas-
ing the temperature and catalyst loading allowed the de-
sired tetracycle 4d to be isolated in 47% yield and 91% ee.
Our success in using the CED methodology for the syn-
thesis of the Erythrina alkaloid scaffold motivated us to ex-
plore applications of this strategy in the syntheses of other
complex natural products. In particular, we surmised that
the core structure of morphine might be rapidly accessed
by using this methodology. In contrast to the previous ex-
amples, the core of morphine would require a substrate in
which an aldehyde side-chain is incorporated onto the
arene nucleophile (Scheme 2). Successive cyclizations in-
volving the CED strategy should cause this this linear sub-
strate to fold directly into a complex tetracycle that would
map on to the ABC rings of morphine.
Ar
Ar
1. oxidative dearomatization
OH
O
H
H
2. amine-catalyzed
conjugate addition
N
O
O
N
O
Ar
Ar
5a: Ar = Ph
5b: Ar = 2-naphthyl
O
N
H
1
4
H
H
OTMS
Product
Reaction conditions
Yield
(%)
ee
(%)
MeO
OMe
PhI(O2CCF3)2 (1.1 equiv),
F3CCH2OH (0.03 M), –40 °C,
30 min; then 5a (10 mol%),
MeCN (0.058 M), –40 °C,
2.5 d
60a
>99
O
H
H
HO
O
N
O
O
PhI(OTFA)2 (1.2 equiv)
O
H
O
O
MeO
HFIPA
O
H
0 °C, 10 min
OMe
H
OMe
PhI(OAc)2 (1.1 equiv ),
F3CCH2OH (0.03 M), 0 °C,
30 min; then 5b (10 mol%),
BzOH (10 mol%), MeCN
(0.058 M), –40 °C, 2.5 d
6
7
35b
84
O
H
H
(R)-5b (10 mol%)
CH2Cl2, 0 °C, 2 d
O
N
O
O
C
OH
H
O
Me
H
N
C
O
O
O
O
O
H
B
O
H
H
B
OMe
PhI(OAc)2 (1.1 equiv ),
H
H
A
F3CCH2OH (0.03 M), 0 °C,
30 min; then 5b (10 mol%),
BzOH (10 mol%), MeCN
(0.058 M), –40 °C, 2.5 d
O
58b,c
92
8
A
OH
O
8, 67% yield
95% ee, >20:1 dr
H
H
OMe
morphine
O
N
O
Scheme 2 Generation of the (–)-morphine core by a CED strategy
H
MeO
By using dearomatization conditions similar to those
developed for the Erythrina alkaloid scaffold, the readily ac-
cessible linear precursor 6 was cleanly oxidized with
bis[(trifluoroacetoxy)iodo]benzene in 1,1,1,3,3,3-hexafluo-
ropropan-2-ol to generate cyclohexadienone 7. Direct
treatment of the crude intermediate 7 with the organocata-
lyst (R)-5b in dichloromethane at 0 °C led to stereoselective
formation of the desired tetracycle 8 as a single diastereo-
isomer in 67% yield and 95% ee.13 In addition to the newly
formed C–C bonds, three of the stereocenters required for
the morphine scaffold were correctly established, including
the challenging quaternary center. Current efforts in our
laboratory are focused on transforming tetracycle 8 into
(–)-morphine.14
Thus far our studies on the construction of complex nat-
ural product-like architectures by using the CED protocol
have focused on the addition of arene nucleophiles in the
phenol dearomatization step. As disclosed in our original
report, heteroatom nucleophiles can also be successfully
used in the dearomatization of these phenol substrates, and
we realized that this strategy might be exploited for rapidly
constructing other useful architectures. To demonstrate
OMe
H
PhI(OAc)2 (1.1 equiv),
F3CCH2OH (0.03 M), 0 °C,
30 min; then 5a (20 mol%),
CH2Cl2 (0.20 M), 23 °C, 7 d
47a,d
91
O
O
N
O
H
H
a The product was equilibrated to the anti-diastereomer by treatment of
the crude material with Et3N in CH2Cl2.
b The anti-diastereomer was obtained directly from the cyclization
c The dearomatized intermediate was isolated in 72% yield before cycliza-
tion.
d The dearomatized intermediate was isolated in 58% yield before cycliza-
tion.
We next shifted our attention to the B ring of the Eryth-
rina core and explored the formation of a scaffold contain-
ing a six-membered ring in this position. Dearomatization
of the substrate to generate the intermediate cyclohexadie-
none proceeded smoothly with (diacetoxyiodo)benzene at
0 °C; however, the subsequent organocatalytic conjugate
addition proved to be considerably slower than that re-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 116–120

119
A. E. Williamson et al.
Letter
Synlett
this, we prepared the linear precursor 9 bearing a tethered
oxygen nucleophile. Although the dearomatization condi-
tions reported above provided the desired cyclohexadien-
one 10 in moderate yields, an adaptation of the conditions
reported by Ciufolini and Liang was found to be more effec-
tive,15 affording the dearomatized spirocyclic intermediate
10 in 96% isolated yield (Scheme 3). Subsequent enantiose-
lective desymmetrization of the purified intermediate 10
by using 20 mol% of amine catalyst 5b in dichloromethane
at –40 °C provided the structurally complex tricycle 11 in
49% yield, 98% ee, and 7:1 dr.
(2) For recent reviews of oxidative dearomatization, see:
(a) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang,
J.; Chai, D. Synthesis 2007, 3759. (b) Zhuo, C.-X.; Zhang, W.; You,
S.-L. Angew. Chem. Int. Ed. 2012, 51, 12662.
(3) For recent reviews on oxidative dearomatization in natural
product synthesis, see: (a) Pouységu, L.; Deffieux, D.; Quideau,
S. Tetrahedron 2010, 66, 2235. (b) Roche, S. P.; Porco, J. A. Jr.
Angew. Chem. Int. Ed. 2011, 50, 4068.
(4) (a) Imbos, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2002, 124, 184. (b) Hayashi, Y.; Gotoh, H.; Tamura, T.;
Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127,
16028. (c) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
(d) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 404. (e) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L.
J. Am. Chem. Soc. 2010, 132, 4056. (f) Leon, R.; Jawalekar, A.;
Redert, T.; Gaunt, M. J. Chem. Sci. 2011, 2, 1487. (g) Wu, Q.-F.;
Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew.
Chem. Int. Ed. 2011, 50, 4455. (h) Rubush, D. M.; Morges, M. A.;
Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134,
13554. (i) Corbett, M. T.; Johnson, J. S. Chem. Sci. 2013, 4, 2828.
(j) Xu, R.-Q.; Gu, Q.; Wu, W.-T.; Zhao, Z.-A.; You, S.-L. J. Am.
Chem. Soc. 2014, 136, 15469.
(5) For reviews of the Erythrina alkaloid family, see: (a) Dyke, S. F.;
Quessy, S. N. In The Alkaloids: Chemistry and Physiology; Vol. 18;
Manske, R. F. H.; Rodrigo, R. G. A., Eds.; Academic Press: New
York, 1981, 1. (b) Tsuda, Y.; Sano, T. In The Alkaloids: Chemistry
and Pharmacology; Vol. 48; Cordell, G. A., Ed.; Academic Press:
San Diego, 1996, 249. (c) Parsons, A. F.; Palframan, M. J. In The
Alkaloids: Chemistry and Biology; Vol. 68; Cordell, G. A., Ed.;
Academic Press: San Diego, 2010, 39.
(6) For biological activities of the Erythrina alkaloids, see:
(a) Lehman, A. J. J. Pharmacol. Exp. Ther. 1937, 60, 69. (b) Folkers,
K.; Unna, K. J. Am. Pharm. Assoc. 1938, 27, 693. (c) Folkers, K.;
Unna, K. J. Am. Pharm. Assoc. 1939, 28, 1019. (d) Craig, L. E. In
The Alkaloids: Chemistry and Physiology; Vol. 5; Manske, R. F. H.,
Ed.; Academic Press: New York, 1955, 265.
(7) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. 2005, 44, 4212.
(8) Initially, the syn-diastereomer 3 is formed by the desymmetriz-
ing Michael addition; however, this isomer is configurationally
unstable and epimerizes to the more stable anti-diastereomer
4a upon standing.
OH
O
O
OH
PhI(OTFA)2 (1.2 equiv)
TFA (1.6 equiv)
96% yield
O
O
N
N
O
MeCN (0.008 M)
0 °C, 1 h
O
9
10
H
H
20 mol% 5b
CH2Cl2 (0.056 M)
–40 °C, 2 d
O
O
H
49% yield, 98% ee
7:1 dr
O
N
O
H
H
11
Scheme 3 Application of CED to a complex non-natural scaffold
In summary, we have demonstrated that our CED proto-
col provides a versatile method for rapidly generating mo-
lecular complexity from simple phenol-based precursors.
The generality of this approach has been demonstrated
through the enantioselective assembly of a number of com-
plex natural product scaffolds, including those of the Eryth-
rina alkaloids and (–)-morphine. Further investigations into
the applications of this protocol in natural product synthe-
sis are ongoing in our laboratory.
Acknowledgements
We are grateful to the EPSRC (T.N.) and Pfizer Global Research and De-
velopment (R.D.M.P.) for studentships, and to the Marie Curie Foun-
dation for fellowships (A.E.A and J.D.C). Mass spectrometry data were
acquired at the EPSRC UK National Mass Spectrometry Facility at
Swansea University.
(9) When this is performed as a one-pot procedure in 2,2,2-trifluo-
roethanol, tetracycle 4a is obtained in 50% yield and 82% ee.
(10) Dearomatization of Aromatic Phenols with Intramolecular
Carbon Nucleophiles: General Procedure
The appropriate phenol (1.0 equiv) was dissolved in F3CCH2OH
(0.034 M), and the solution was cooled to 0 °C or –40 °C.
PhI(OAc)2 or PhI(O2CCF3)2 (1.1 equiv) was added, and the
mixture was stirred at 0 °C or at –40 °C for 30 min. The reaction
was quenched by addition of H2O at 0 °C or at –40 °C, and the
mixture was extracted with CH2Cl2 (×2). The combined organic
layers were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo to give a crude product that was either
used in the crude state or purified by flash chromatography to
give the desired cyclohexadienone.
Asymmetric Organocatalytic Conjugate Addition: General
Procedure
The crude cyclohexadienone was dissolved in anhydrous MeCN
(0.056 M), and the mixture was cooled to –40 °C. The appropri-
ate organocatalyst (0.1 equiv) and BzOH (0–0.1 equiv) were
added, and the mixture was stirred at –40 °C for the appropriate
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560514.
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References and Notes
(1) (a) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477.
(b) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
(c) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 116–120

120
A. E. Williamson et al.
Letter
Synlett
time. The mixture was then concentrated in vacuo and the
residue was dissolved in CH2Cl2 (0.1 M). Et3N (0.1 equiv) was
added and the mixture stirred at r.t. for 4 h, then concentrated
in vacuo to give the crude product that was purified by flash
chromatography.
(13) (4aS,12R,12aS)-8-Methoxy-2-oxo-1,5,6,11,12,12a-hexahydro-
2H-naphtho[8a,1,2-de]chromene-12-carbaldehyde (8)
Colorless oil; yield: 134 mg (0.45 mmol, 67%, 95% ee) as a color-
less oil; [α]D25 +123 (c = 1.0, CHCl3). IR (film): 2954, 1721, 1677,
1
1585, 1493, 1443 cm–1. H NMR (400 MHz, CDCl3): δ = 9.59 (d,
(11) 15,16-Dimethoxy-2,10-dioxoerythrinan-7-carbaldehyde (4a)
White solid; yield: 118 mg (0.35 mmol, 60%, >99% ee); mp 169–
J = 0.7 Hz, 1 H), 6.93 (dd, J = 10.2, 2.0 Hz, 1 H), 6.74 (d, J = 8.2 Hz,
1 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.07 (dd, J = 10.2, 0.9 Hz, 1 H), 4.51
(ddd, J = 11.5, 4.4, 2.7 Hz, 1 H), 4.25 (ddd, J = 12.9, 11.6, 2.5 Hz, 1
H), 3.86 (s, 3 H), 2.98 (m, 2 H), 2.91 (ddd, J = 15.8, 8.2, 0.7 Hz, 1
H), 2.67 (dt, J = 7.7, 3.6 Hz, 1 H), 2.60 (m, 1 H), 2.54 (ddd,
J = 17.2, 3.3, 1.0 Hz, 1 H), 2.43 (dt, J = 13.4, 2.5, 1 H), 2.26 (td,
J = 13.1, 4.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 201.6,
197.0, 154.3, 147.8, 143.1, 129.5, 127.0, 124.0, 119.7, 110.9,
63.7, 56.4, 50.7, 40.6, 39.8, 36.8, 36.4, 28.1. HRMS (ES+): m/z [M
+ H]+calcd for C18H19O4: 299.1278; found: 299.1277. HPLC: AD-
H (15% i-PrOH–hexane, 1.0 mL/min, 210 nm): tR (major) = 26.6
min, tR (minor) = 27.9 min (97% ee).
20
170 °C; Rf = 0.52 (CH2Cl2–MeOH, 9:1); [α]D +72 (c = 0.04,
CHCl3). IR (film): 3988 (br), 2924, 1630, 1513, 1450, 1411, 1304,
1254, 1233, 1189, 1120, 1100, 1059, 1037 cm–1 1H NMR (500
.
MHz, CDCl3): δ = 9.73 (d, J = 1.9 Hz, 1 H), 6.93 (s, 1 H), 6.68 (s, 1
H), 6.57 (dd, J = 10.2, 2.1 Hz, 1 H), 6.02 (d, J = 10.2 Hz, 1 H), 4.04
(dd, J = 12.6, 7.8 Hz, 1 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.80 (dd,
J = 12.6, 10.2 Hz, 1 H), 3.74 ( d, J = 20.0 Hz, 1 H), 3.60 (d, J = 20.0
Hz, 1 H), 3.39 (ddd, 10.1, 6.0, 2.1 Hz, 1 H), 3.19 (dd, J = 18.3, 6.0
Hz, 1 H), 3.03 (ddd, 18.1, 10.2, 1.89 Hz, 1 H), 2.90 (br d, J = 18.1
Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 197.8, 194.3, 167.2,
149.9, 148.7, 147.6, 127.3, 127.0, 124.1, 110.9, 106.6, 64.9, 56.3,
56.1, 53.1, 43.0, 42.8, 38.7, 36.8. HRMS (APCI+): m/z [M +
H]+calcd for C19H20NO5: 342.1336; found: 342.1331.
(14) Tissot, M.; Phipps, R. J.; Lucas, C.; Leon, R. M.; Pace, R. D. M.;
Ngouansavanh, T.; Gaunt, M. J. Angew. Chem. Int. Ed. 2014, 53,
13498.
(12) The analogous para-anisole nucleophile failed to react under
the dearomatization conditions, presumably due to its inability
to undergo Friedel–Crafts addition at the ortho- and para-posi-
tions.
(15) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 116–120