Enantioselective synthesis of an advanced intermediate for the synthesis of brefeldin A and analogues

Article abstract of DOI:10.1055/s-2008-1032041

A synthesis of methyl (1R,2R,4S)-2-[(E)-2-iodovinyl]-4-(methoxymethoxy) cyclopentanecarboxylate is described in nine steps from a prochiral anhydride. A desymmetrization reaction followed by an epimerization and a Takai reaction are the key steps of the t

Full text of DOI:10.1055/s-2008-1032041

LETTER
389
Enantioselective Synthesis of an Advanced Intermediate for the Synthesis of
Brefeldin A and Analogues
Synthesis of
a
r
nAdvanc
é
edInterm
e
d
diate for the
é
Synthesis
of
Brefel
i
din
A
c Legrand,a Sylvie Archambaud,a Sylvain Collet,a Karine Aphecetche-Julienne,a André Guingant,*a
Michel Evainb
a
Faculté des Sciences et des Techniques, Laboratoire de Synthèse Organique (LSO), Université de Nantes, Nantes Atlantique Universités,
CNRS, UMR CNRS 6513, 2 Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 03, France
Fax +33(2)51125402; E-mail: Andre.Guingant@univ-nantes.fr
b
Institut des Matériaux Jean Rouxel, 2 Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 03, France
Received 8 October 2007
with a tyrosine residue (Tyr 190) of the Sec7 domain.5 In
Abstract: A synthesis of methyl (1R,2R,4S)-2-[(E)-2-iodovinyl]-4-
order to best delineate the mode of action of 1, it is thus of
importance to synthesize several analogues of this mole-
cule displaying structural modifications on the thirteen-
(methoxymethoxy)cyclopentanecarboxylate is described in nine
steps from a prochiral anhydride. A desymmetrization reaction fol-
lowed by an epimerization and a Takai reaction are the key steps of
the transformation. Based on previous work, this vinylic iodide membered lactone ring while retaining the OH at C7. We
product should be a useful precursor for the synthesis of brefeldin
A and analogues.
thus thought that a cyclopentane derivative such as 4, sub-
stituted at its C4 position by a MOM-protected hydroxyl
Key words: brefeldin A, desymmetrization reaction, Takai reac-
tion
group, would be an efficient scaffold to prepare analogues
of 1. In this paper, we detail the extension of our initial
protocol to the successful enantioselective synthesis of 4
from the prochiral anhydride 6.
Guanine-nucleotide exchange factors (GEF) are proteins
that activate small GTP-binding proteins (G-proteins) by
allowing the dissociation of the tightly bound GDP nucle-
otide and its replacement by a GTP. In their activated
form the small G proteins interact with protein effectors to
which they transmit signals of action. Signal transduction,
cellular traffic, and organization of the cytoskeleton are
all regulated by small G-proteins so that these proteins,
and their associated GEF, appear as potential targets for
therapeutic intervention.1 However, because a GEF is not
specific for a given G-protein, competitive inhibitors of
G-protein–GEF interactions may well block several trans-
duction pathways causing deleterious cellular effects.
Brefeldin A (1), a macrolide lactone first isolated2 from
Penicillium decumbens, presents the rare and distinct ad-
vantage of being an in vivo noncompetitive inhibitor of
the activation of the small G-protein Arf1, an essential
regulator of membrane traffic at the Golgi, by its GEF. In
fact, 1 was shown to bind in a cavity at the interface be-
tween Arf-GDP and the catalytic domain of the GEF
(called the Sec7 domain) thus stabilizing a transient reac-
tion intermediate (interfacial inhibition).3 Recently, we
reported4 an enantioselective synthesis of brefeldin C (2),
a biological precursor of 1 lacking the hydroxyl group at
C7, from a chiral substituted cyclopentane precursor 3, it-
self prepared from the prochiral anhydride 5 (Scheme 1).
Subsequently, comparative studies of the inhibition of the
nucleotide exchange reaction using both 1 and 2 showed
that the hydroxyl group at C7 in 1 plays a crucial role in
this process due to the establishment of a hydrogen bond
O
OH
H
H
O
OMe
I
R
R
O
Me
H
H
brefeldin A (1) R = OH
brefeldin C (2) R = H
3 R = H
4 R = OMOM
O
H
R
O
H
O
5 R = H
6 R = O(=)
Scheme 1
The synthesis of 6 commences with the 3a,4,7,7a-tetrahy-
dro-2-benzofuran-1,3-dione (7, tetrahydrophthalic anhy-
dride) which was transformed into keto diester 8
following a reported three-step procedure6 with slight
modifications. Although formation of keto diacid 9 could
be effected by saponification of 8, it was found most ap-
propriate, both in terms of efficiency and practicability, to
prepare 9 by acidic hydrolysis7 of 8. Cyclization of 9 to
form anhydride 6 was best accomplished in acetyl chlo-
ride at reflux.8 In contrast to its nor-carbonyl analogue,4
keto diacid 9 failed to give 6 in practical yields when treat-
ed with acetic anhydride or under several other condi-
tions.9 Thus, following the reaction sequence shown in
SYNLETT 2008, No. 3, pp 0389–0393
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.01.2008
DOI: 10.1055/s-2008-1032041; Art ID: D32007ST
© Georg Thieme Verlag Stuttgart · New York

390
F. Legrand et al.
LETTER
O
with methanol and a catalytic amount of hydroquinidine
(anthraquinone-1,4-diyl)diether [(DHQD)2AQN]. Trying
to reproduce the conditions prescribed we discovered that
the anhydride concentration (not mentioned in the patent)
was a crucial parameter to achieve an optimal enantiomer-
ic excess. In the best conditions found {MeOH (10 equiv),
(DHQD)2AQN (0.10 equiv), MeOt-Bu, –30 °C for 90 h;
[6] = 0.02 M} an enantiomeric excess within the range of
80–88% could be attained for 10. A direct measurement of
the enantiomeric excess of 10 could not be achieved but
this was easily made after transformation of 10 into its
benzyl ester 11.12 In addition to providing an excellent UV
detectability and accuracy in the determination of enan-
tiomeric excess, the benzyl protection also facilitated, in a
practical point of view, the realization of the subsequent
steps (Scheme 3). Reduction of keto diester 11 could next
be accomplished by exposure to L-Selectride in THF at
–78 °C to give alcohol (1R,2S,4R)-12 in 87% yield13 and
with an almost total control of the stereoselectivity at C4.
The R-configuration at the newly generated chiral center
of alcohol 12 could be established after the latter was
transformed into the diastereomeric acetates 13 and 14
and correlation peaks between H1, H2, and H4 were ob-
served in the NOESY spectrum of 13. Installation of a
MOM protecting group to afford 15 was readily accom-
plished by treatment of 12 with dimethoxymethane in the
presence of P2O5. Reductive deprotection of the benzyl es-
ter group of 15 afforded the key 2-(methoxycarbonyl)-4-
(methoxymethoxy)cyclopentanecarboxylic acid interme-
diate 16 (Scheme 3).
H
i–iii
CO2Me
CO2Me
iv
O
O
H
O
7
8
O
O
O
H
H
CO2H
v
O
O
CO2H
H
H
6
9
Scheme 2 Reagents and conditions: (i) concd H2SO4 (10 equiv),
MeOH, reflux, 18 h, 96%; (ii) preceding crude product, aq KMnO4,
20 °C, 5 h, then Na2SO4, then pH lowered to 1–2 with 12 N aq HCl,
96%; (iii) preceding crude product, NaOAc, Ac2O, reflux, 6 h, then
purification by chromatography (EtOAc–PE, 1:1) followed by cry-
stallization (hot Et2O), 82%; (iv) 10% aq HCl, reflux, 6 h, 99%; (v)
AcCl, reflux, 3 h then filtration (→ 6, 55%); filtrate concentrated in
vacuo, residue heated at 100 °C for 2 h under a pressure of 1–2 mm
Hg, then cooled to 20 °C and taken up in CH2Cl2, filtration (→ 6,
30%; 85% total yield).
Scheme 2 (steps 1–5), anhydride 6 could be routinely pre-
pared on a multigram scale in 66% overall yield.
With the prochiral anhydride 6 in hand we were now in a
position to study its desymmetrization reaction to give the
(1R,2S)-2-(methoxycarbonyl)-4-oxocyclopentanecarbox-
ylic acid (10). In our earlier investigations, we used the ef-
ficient Bolm’s conditions10 to desymmetrize anhydride 5.
However, when applying these conditions to 6 {i.e. quini-
dine, toluene, –55 °C, 4 d, [6] = 0.1 M}, the enantiomeric
excess of 10 was only of 60%. Looking for other condi-
tions we found that the patent literature11 reported the de-
symmetrization of 6 to give 10 in 84% ee by treatment
Proceeding on to reach 4, we next addressed the problem
of epimerization at C2 of 16. In our synthesis of 24 this
problem could be solved by treatment of the C4-unsubsti-
tuted analogue of 16 with KOt-Bu (1.5 equiv) in t-BuOH.
Unfortunately, when applied to 16, these conditions
H
H
H
CO2Me
CO2Me
CO2Bn
CO2Me
CO2Bn
i
ii
iii
O
6
O
HO
CO2H
H
H
H
12
10
11
H
H
CO2Me
iv
AcO
AcO
CO2Bn
13
12
H
H
H
CO2Me
CO2H
CO2Me
CO2Bn
vi
vii
H
H
12
MOMO
MOMO
CO2Me
CO2Bn
v
H
15
16
14
Scheme 3 Reagents and conditions: (i) (DHQD)2AQN (0.01 equiv), anhyd t-BuOMe (→ [6] = 0.02 M), anhyd MeOH (0.1 equiv), –30 °C,
90 h, 94%; (ii) BnOH (5 equiv), DCC (1.2 equiv), cat. DMAP, CH2Cl2, 25–30 °C, 10 h, 86%; (iii) L-Selectride (1 M solution in THF; 1.1 equiv),
THF, –78 °C, 2 h then usual workup, 87%; (iv) AcOH (2.4 equiv), DCC (1.5 equiv), cat. DMAP, CH2Cl2, 25–30 °C, 10 h, quant. yield; (v) Ph3P
(1.2 equiv), AcOH (1.2 equiv), DEAD (1.2 equiv), Et2O, 20 °C, 4 h, 81%; (vi) (MeO)2CH2 (70 equiv), P2O5 (20 equiv), CHCl3, 20 °C, 2 h,
89%; (vii) H2, 10% Pd/C, MeOH, 20 °C, 2 h, quant. yield.
Synlett 2008, No. 3, 389–393 © Thieme Stuttgart · New York

LETTER
Synthesis of an Advanced Intermediate for the Synthesis of Brefeldin A
391
H
proved inefficient, affording, next to the desired
(1R,2R,4S)-17, variable amounts of diacid (1R,2R)-18.
Recognizing that diacid 18 originated during the workup
of the reaction,14 we quenched the crude reaction mixture
with AcOH (6 equiv in THF) instead of the usually added
aqueous 1 N HCl. Although these new conditions allowed
us to isolate acid-ester 17 free of diacid 18, the yield was
unsatisfactory. Consequently, we came to favor a differ-
ent route to reach 17 in reproducible conditions and satis-
factory yield. Compound 16 was thus bisdeprotonated by
treatment with LDA in THF at –78 °C then kinetically re-
protonated (2 N HCl in Et2O) to afford a 3:7 mixture of
diastereomers 16 and 17 in quantitative yield (Scheme 4).
CO2Me
i
16 + 17
MOMO
CON(Me)OMe
H
H
H
19
+
CO2Me
MOMO
CON(Me)OMe
20
H
CO2Me
CHO
ii
20
MOMO
H
21
H
CO2Me
i
Scheme 5 Reagents and conditions: (i) NH(OMe)Me·HCl (1.5
equiv), NMM (1.5 equiv), EDC (1.5 equiv), CH2Cl2, 20 °C, 10 h, 20:
65%, 19: 32%; (ii) DIBAL-H in hexane (1.5 equiv), –78 °C, 3 h, 56%.
MOMO
CO2H
H
17
+
H
H
H
CO2Me
COSEt
CO2Me
COSEt
CO2H
i
H
16 + 17
CO2Me
MOMO
+
MOMO
MOMO
MOMO
CO2H
H
H
H
CO2H
H
22
18
23
16
ii
iii
ii
16
+
17
(16/17 = 3:7)
H
H
CO2Me
CHO
CO2Me
CO2H
Scheme 4 Reagents and conditions: (i) KOt-Bu (1.5 equiv), 20 °C,
1 h, then 1 N aq HCl (1.5 equiv) or AcOH (3 equiv) in THF; (ii) LDA
(3 equiv), –78 °C, THF, 3 h, then 2 M HCl in Et2O, quant. yield.
MOMO
MOMO
H
H
16
21
This mixture of diastereomers could not be separated at
this stage and was thus engaged in the subsequent step
with the final aim of obtaining aldehyde 21. A reduction–
oxidation procedure, which gave us satisfactory results in
earlier investigations,4 was first attempted. However, in
that case, borane reduction of a mixture of diastereomers
16 and 17 led to the corresponding diastereomeric alco-
hols in low yield (30%). Searching for a more practical
Scheme 6 Reagents and conditions: (i) DCC (1.2 equiv), ethanethi-
ol (3 equiv), DMAP (0.1 equiv), CH2Cl2, 20 °C, 3 h, 23: 51%, 22:
21%; (ii) Et3SiH (2.85 equiv), 10% Pd/C, CH2Cl2, 15–20 °C, 20 min,
88%; (iii) Br2 (20 equiv), THF–H2O (5:1), 20 °C, 1 h, quant. yield.
with Br216 and can thus be recycled into the epimerization
reaction.
method for the preparation of aldehyde 21, we trans- We were now in a position to carry out the final stage of
formed the above mixture into the corresponding mixture the synthesis of (1R,2R,4S)-4 by application of the Takai
of Weinreb amides 19 and 20 (Scheme 5), which, fortu- procedure17 to aldehyde 21. The latter was thus exposed to
nately, proved easily separable by column chromatogra- the action of CrCl2 (6 equiv) and iodoform (2 equiv) in a
phy on silica gel. Amide 20, which was isolated in 65% degassed mixture of 1,4-dioxane–THF18 (6:1) at 0 °C for
yield from 16 (two steps), was next reduced to aldehyde 72 h. After usual workup19 and purification through a sil-
21 by exposure to a solution of DIBAL-H in CH2Cl2 (56% ica gel column, the target vinylic iodide 4 could be isolat-
yield).
ed along with variable quantities of alcohol 24 and its
dimer 25 (Scheme 7). The structure of 25, which was fully
ascertained by X-ray crystal structure analysis
(Figure 1),20 provided an a posteriori confirmation of the
absolute configuration attributed to aldehyde 21 and its
precursors. Although 25 could be cleaved to give 24 and
the latter MOM-protected to give 4, it is clear that, in the
course of a total synthesis, a more efficient way to prepare
4 must be found. After some considerable attempts, we fi-
nally discovered that modification of the original workup
of the reaction, i.e. filtration of the crude mixture through
In a different approach to 21, the mixture of diastereomers
16 and 17 was first transformed into a mixture of
thioesters 22 and 23, which could be separated by column
chromatography on silica gel. The thioester 23, isolated in
51% yield from 16, was next reduced by treatment with
Et3SiH and 10% Pd/C15 to give aldehyde 21 in 88% yield
(Scheme 6). A clear advantage of this route is that acid-es-
ter 16 can be regenerated from thioester 22 by treatment
Synlett 2008, No. 3, 389–393 © Thieme Stuttgart · New York

392
F. Legrand et al.
LETTER
H
H
References and Notes
H
CO2Me
CO2Me
i
(1) See, inter alia: (a) Cherfils, J.; Chardin, P. Trends Biochem.
Sci. 1999, 24, 306. (b) Takai, Y.; Sasaki, T.; Matozaki, T.
Physiol. Rev. 2001, 81, 153. (c) Marinissen, M. J.; Gutkind,
J. S. Trends Biochem. Sci. 2005, 30, 423. (d) Zeghouf, M.;
Guibert, B.; Zeeh, J.-C.; Cherfils, J. Biochem. Soc. Trans.
2005, 33, 1265. (e) Hall, A. Biochem. Soc. Trans. 2005, 33,
891.
MOMO
MOMO
I
CHO
H
4
21
iii
(2) Singleton, V. L.; Bohonos, N.; Ullstrup, A. J. Nature
(London) 1958, 181, 1072.
H
H
CO2Me
MeO2C
(3) See, for example: (a) Robineau, S.; Chabre, M.; Antonny, B.
Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 9913. (b) Renault,
L.; Guibert, B.; Cherfils, J. Nature (London) 2003, 426, 525.
(c) Mossessova, E.; Corpina, R. A.; Goldberg, J. Mol. Cell.
2003, 12, 1403. (d) Cherfils, J.; Pacaud, P. Med. Sci. (Paris)
2004, 20, 393. (e) Pommier, Y.; Cherfils, J. Trends
Pharmacol. Sci. 2005, 26, 138.
(4) Archambaud, S.; Aphecetche-Julienne, K.; Guingant, A.
Synlett 2005, 139.
(5) Zeeh, J.-C.; Zeghouf, M.; Grauffel, C.; Guibert, B.; Martin,
E.; Dejaegere, A.; Cherfils, J. J. Biol. Chem. 2006, 281,
11805.
H
H
CO2Me
H
HO
ii
I
I
I
H
O
O
24
25
Scheme 7 Reagents and conditions: (i) anhyd CrCl2 (5.8 equiv),
CHI3 (2 equiv), 1,4-dioxane–THF (6:1), 20 °C, 72 h, 88%, see ref. 19
for more experimental details; (ii) PhSH (5 equiv), BF3·OEt2 (5
equiv), THF, 20 °C, 1 h, 92%; (iii) (MeO)2CH2 (70 equiv), P2O5 (20
equiv), CHCl3, 20 °C, 1 h, 93%.
(6) Gais, H. J.; Bülow, G.; Zatorski, A.; Jentsch, M.; Maidonis,
P.; Hemmerle, H. J. Org. Chem. 1989, 54, 5115.
(7) Yoshihisa, M.; Yoshiyasu, T.; Kazu, A. Chem. Pharm. Bull.
1987, 35, 2266.
(8) Ballini, R.; Bosica, G.; Fiorini, D.; Righi, P. Synthesis 2002,
681.
(9) Heating 9 in Ac2O (or in Ac2O with a catalytic amount of
DMAP) at reflux failed to give anhydride 6. Failure was also
encountered while attempting distillation of 9 in the
presence of a catalytic amount of sulfuric acid. However, 6
could be obtained in low yields when 9 was treated with
ClCO2Me and NMM (1.1 equiv each) in THF at 20 °C for 30
min (35%) or with TFA (4 equiv) in dioxane at 75 °C for 2 h
(38%).
(10) (a) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195.
(b) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org.
Chem. 2000, 65, 6984.
Figure 1 X-ray crystal structure of 25
(11) (a) Deng, L.; Chen, Y.; Tian, S.-K. WO 2001074741, 2001.
(b) See also: Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem.
Soc. 2000, 122, 9542.
(12) Enantiomeric ratio was determined by GPC using a Lipodex
E column; tR (the injector and detector temperatures were
220 °C): 74.9 min (major enantiomer) and 76.6 min (minor
enantiomer).
a pad of Celite and neutral alumina followed by purifica-
tion through a silica gel column [elution first with hexane
to remove iodoform in excess then with a EtOAc–PE mix-
ture (1:9)] afforded 4 (E/Z = 97:3) in up to 88% and in a
reproducible manner.
In conclusion, a synthesis of the methyl (1R,2R,4S)-2-
[(E)-2-iodovinyl]-4-(methoxymethoxy)-cyclopentanecar-
boxylate (4) has been achieved in nine steps from the
prochiral anhydride 6. By comparison with our previous
synthesis of brefeldin C, unanticipated difficulties due to
the presence and (or) the sensitive nature of the OMOM
group were encountered. However, we found conditions
to circumvent all of these difficulties and to reach 4 in
good overall yield (20% from 6). Use of vinylic iodide 4
as a scaffold to prepare several brefeldin A analogues is
under way and the results of these studies will be reported
in due course.
(13) This reaction was also performed under several other
reduction conditions: NaBH(OAc)3 ds (4R) = 90%, 76%;
NaBH4, ds (4R) = 95%, 88%; t-(BuO)3AlLiH, ds
(4R) = 99%, 87%.
(14) Treatment of monoacid 16 and diacid 18 with diazomethane
in Et2O afforded the corresponding cis and trans
diastereomeric methyldiesters that could be easily
differentiated by NMR spectroscopy [cis-isomer, d = 3.67
(CO2Me), 3.01 (H1, H2) ppm; trans-isomer: d = 3.70
(CO2Me), 3.39 (H1 or H2), 3.15 (H1 or H2) ppm].
(15) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990,
112, 7050.
(16) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999,
1, 865.
(17) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
(18) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115,
4497.
(19) Preparation of Methyl (1R,2R,4S)-2-[(E)-2-Iodovinyl]-4-
(methoxymethoxy)cyclopentanecarboxylate (4)
To a suspension of anhyd CrCl2 (1 g, 8.1 mmol) in anhyd and
Synlett 2008, No. 3, 389–393 © Thieme Stuttgart · New York

LETTER
Synthesis of an Advanced Intermediate for the Synthesis of Brefeldin A
393
thoroughly degassed THF (5.1 mL) were added, under a
CDCl3): d = 37.0 (C5), 38.8 (C3), 47.7 (C1), 48.2 (C2), 52.0
(CO2CH3), 55.5 (OCH3), 75.7 (CHI), 77.0 (C4), 95.6
(OCH2O), 148.1 (vinyl CH), 175.1 (CO2Me). FT-IR (KBr):
3054, 2949, 1735, 1437, 1206, 1098, 1041 cm–1. MS (ESI+):
m/z 309 [MH + MeOH]+; 341 [MH]+; 363 [M + Na]+. HRMS
(ESI+): m/z calcd for C11H17IO4Na: 363.0067; found:
363.0069 [M + Na]+.
nitrogen atmosphere, recrystallized CHI3 (1.1 g, 2.8 mmol)
and aldehyde-ester 21 (300 mg, 1.4 mmol) dissolved in
anhyd and thoroughly degassed dioxane (30 mL). After
being stirred at r.t. for 72 h, the resulting brown reaction
mixture was filtered through a pad of mixed Celite and
neutral alumina. The filter cake was rinsed several times
with EtOAc and the filtrate was concentrated under reduced
pressure. The crude product was purified by chromatog-
raphy on a column of silica gel using EtOAc and PE as
eluents (0:10 then 1:9) to afford pure 4 as a colorless oil (414
mg, 1.23 mmol, 88%). The Z/E ratio at the double bond
(3:97) was evaluated by 1H NMR spectroscopic analysis
from the area ratio of the signals of the vinylic protons.
Spectral Data and Specific Rotation
(20) Crystal Data for 25
C19H26I2O6, Mr = 604.2, monoclinic, P21, a = 6.2760(4),
b = 8.3184(5), c = 22.5860(12) Å, b = 96.918(8),
V = 1170.55(12) Å3, Z = 2, rcalcd = 1.714 g cm–3, m = 2.72
mm–1, F(000) = 588, colorless needle, 0.60 × 0.11 × 0.05
mm3, 2qmax = 60°, T = 298 K, 19062 reflections, 5818
unique (98% completeness), Rint = 0.042, 249 parameters,
GOF = 1.57, wR2 = 0.0926, R = 0.0351 for 5107 reflections
with I > 2s(I).
CCDC 660932 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Rf = 0.5 (silica, EtOAc–PE, 1:9); [a]D20 –42.4 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.60 (m, 1 H, 1H3), 2.04
(m, 2 H, H5), 2.26 (m, 1 H, H3), 2.80 (m, 2 H, H1, H2), 3.35
(s, 3 H, OMe), 3.68 (s, 3 H, CO2Me), 4.21 (m, 1 H, H4), 4.61
(s, 2 H, OCH2O), 6.10 (d, 1 H, J = 14.4 Hz, CHI), 6.52 (dd,
1 H, J = 14.4, 7.6 Hz, vinyl CH). 13C NMR (75 MHz,
Synlett 2008, No. 3, 389–393 © Thieme Stuttgart · New York

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