Synthesis of (E)-α,β-unsaturated esters with total or high diastereoselectivity from α,β-epoxyesters

Article abstract of DOI:10.1021/ol016894p

Chemical equation presented High stereoselective β-elimination in 2,3-epoxyesters 1 was achieved using samarium diiodide, yielding α,β-unsaturated esters 2, in which the C=C bond is di-, tri- or tetrasubstituted. The starting compounds 1 are easily prepared by reaction of the corresponding lithium enolates of a-chloroesters with aldehydes or ketones at -78 °C. The influence of the reaction conditions and the structure of the starting compounds in the stereoselectivity of the β-elimination reaction is also discussed.

Full text of DOI:10.1021/ol016894p

ORGANIC
LETTERS
2002
Vol. 4, No. 2
189-191
Synthesis of (E)-r,â-Unsaturated Esters
with Total or High Diastereoselectivity
from r,â-Epoxyesters
Jose´ M. Concello´n* and Eva Bardales
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica UniVersidad
de OViedo, Julia´n ClaVer´ıa, 8, 33071 OViedo, Spain
jmcg@sauron.quimica.unioVi.es
Received October 11, 2001
ABSTRACT
High stereoselective â-elimination in 2,3-epoxyesters 1 was achieved using samarium diiodide, yielding r,â-unsaturated esters 2, in which the
CdC bond is di-, tri- or tetrasubstituted. The starting compounds 1 are easily prepared by reaction of the corresponding lithium enolates of
r-chloroesters with aldehydes or ketones at −78 °C. The influence of the reaction conditions and the structure of the starting compounds in
the stereoselectivity of the â-elimination reaction is also discussed.
Although deoxygenation reactions of epoxides promoted by
SmI2 to afford alkenes with very poor diastereoselection are
well-known, no application of this methodology to R,â-
epoxyesters has been published. Moreover, to the best of
our knowledge, no selective, general methodology has been
developed to deoxygenate noncyclic R,â-epoxyesters to
obtain R,â-unsaturated esters with high diastereoselectivity.1
Several papers have described the transformation of cyclic
R,â-epoxyesters into cyclic R,â-unsaturated esters,2 in which
no mixture of Z/E diastereoisomers can be obtained. How-
ever, the scarce examples reported starting from noncyclic
R,â-epoxyesters afford noncyclic R,â-unsaturated esters in
low yield3 or lead to a mixture of diastereoisomers4 or
compounds,5 while in other papers no information of the
diastereoselection is available.6 Moreover, taking into account
that R,â-unsaturated esters can be easily transformed into
R,â-epoxyesters,7 the sequence R,â-unsaturated ester f R,â-
epoxyester f R,â-unsaturated ester can be used as a
protection-deprotection methodology of the CdC double
bond of R,â-unsaturated esters. For this reason a new general
and easy transformation of R,â-epoxyesters into R,â-unsatur-
ated esters with high diastereoselection would be desirable.
Recently we developed a new, easy, and simple highly
diatereoselective â-elimination reaction promoted by sa-
marium diiodide and starting from different functionalized
(1) In the best of our knowledge, the scarce papers published contain
only one example of this transformation, and only the synthesis of (E)-
ethyl cinnamate from the corresponding R,â-epoxyester has been described
in high yield and with total diastereoselection: Fu¨rstner, A.; Hupperts, A.
J. Am. Chem. Soc. 1995, 117, 4468-4475.
(2) By using Zn/AcOH: (a) Trost, B. M.; Krische, M. J. J. Am. Chem.
Soc. 1999, 121, 6131-6141. By using WCl6 + BuLi: (b) Krische, M. J.;
Trost, B. M. Tetrahedron 1998, 54, 7109-7120. By using CrCl2: (c)
Emmer, G.; Graf, W. HelV. Chim. Acta 1981, 64, 1398-1406. (d) Kehrli,
A. R. H.; Taylor, D. A. H. J. Chem. Soc., Perkin Trans. 1 1990, 2067-
2070. (e) Ekong, D. E. U.; Olagbemi, E. O. J. Chem. Soc. C 1966, 944-
946. (f) Nozaki, H.; Hiroi, M.; Takaoka, D.; Nakayama, M. J. Chem. Soc.,
Chem. Commun. 1983, 1107-1108. (g) Banerji, J.; Chatterjee, A.; Ghoshal,
N.; Das, A.; Sarkar, S. J. Indian Chem. Soc. 1982, 59, 145-149. (h) Bennett,
R. D.; Hasegawa, S. Phytochemistry 1982, 21, 2349-2354.
(3) (a) Ameer, F.; Drewes, S. E.; Hoole, R.; Kaye, P. T.; Pitchford, A.
T. J. Chem. Soc., Perkin Trans. 1 1985, 2713-2717. (b) Kobayashi, T.;
Nitta, M. Chem. Lett. 1982, 325-328. (c) Vedejs, E.; Fuchs, P. L. J. Am.
Chem. Soc. 1973, 95, 822-825.
(4) (a) Rosenblum, M.; Saidi, M. R.; Madhavarao, M. Tetrahedron Lett.
1975, 16, 4009-4011. (b) Bissing, D. E.; Speziale, A. J. J. Am. Chem.
Soc. 1965, 87, 2683-2690.
(5) Mawson, S. D.; Weavers, R. T. Tetrahedron 1995, 51, 11257-11270.
(6) (a) Frazier, J. W.; Staszak, M. A.; Weigel, L. O. Tetrahedron Lett.
1992, 33, 857-860. (b) Alper, H.; Des Roches, D. Tetrahedron Lett. 1977,
18, 4155-4158.
(7) (a) Meth-Cohn, O.; Moore, C.; Taljaard, H. T. J. Chem. Soc., Perkin
Trans. 1 1988, 2663-2674. (b) Kehrli, A. R. H.; Taylor, D. A. H. J. Chem.
Soc., Perkin Trans. 1 1990, 2067-2070.
10.1021/ol016894p CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/20/2001

halohydrins. This is the first general stereoselective â-elim-
ination reaction promoted by SmI2. In this respect, we have
described the diastereoselective synthesis of (Z)-vinyl halides
from O-acetylated 1,1-dihaloalkan-2-ols,8 the preparation of
(E)-R,â-unsaturated esters9 or amides10 from 2-halo-3-
hydroxyesters or amides, respectively, and the obtention of
(Z)-vinylsilanes from 1-chloro-1-trialkylsilylalkan-2-ols.11
Here, we describe a new methodology to obtain (E)-R,â-
unsaturated esters with total or high E-selectivity by deoxy-
genation of R,â-epoxyesters using samarium diiodide (Scheme
1).
when the elimination reaction afforded other side products
at room temperature, the reaction was carried out at reflux.
Hence, the reaction of different R,â-epoxyesters 1 with a
solution of SmI2 in THF at room temperature or reflux gave
the corresponding di- or trisubstituted (E)-R,â-unsaturated
esters 2 in high yield and with total or very high stereo-
selectivity (Table 1, entries 1-13).12
The proposed deoxygenation reaction is general for the
preparation of di- or trisubstituted R,â-unsaturated esters.
Thus, R1 can be aliphatic (linear, branched, or cyclic)
unsaturated or aromatic (electron-rich or -deficient), R3 has
been also changed (aliphatic and aromatic), and in addition
the selectivity and yield were unaffected by the presence of
bulky groups R4 on the carbonyl ester (Table 1, entry 4), in
contrast to other elimination reactions.13
Scheme 1. Synthesis of (E)-R,â-Unsaturated Esters
This methodology can be also used to obtain R,â-
unsaturated esters 2, in which the CdC bond is tetrasubsti-
tuted. In this case, all reactions were carried out at reflux,
the R,â-unsaturated esters 2 were isolated in high yield, and
logically, a decrease of the diastereoselectivity was observed
(Table 1, entries 15-17).14
The starting compounds 1 were easily obtained by reaction
of aldehydes or ketones with the potassium enolate of
R-chloroesters (generated by treatment of R-chloroesters with
potassium hexamethyldisilazide at -78 °C) at temperatures
ranging from -78 to 25 °C.
Our first attempts were carried out to establish the reaction
conditions of the â-elimination process to obtain R,â-
unsaturated esters 2. Thus, the R,â-epoxyester 1d was treated
with a solution of SmI2 in THF, at several temperatures (-50
°C, room temperature and reflux of THF). The yield and
diastereoisomeric excess (de) of the elimination reaction of
1d were similar at room temperature and at reflux, whereas
2d was isolated in lower yield at -50 °C (Table 1, entries
Scheme 2. Synthesis of Starting Compounds
Table 1. Synthesis of (E)-R,â-Unsaturated Esters 2
entry
2a
R1
R2
R3
R4
de
yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2a
p-MeOC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
Me
Me
Me
Me
Bu
Me
Me
C6H13 Et
Me
Me
Me
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
>98
>98
93
92
93
>98
>98
>98
>98
>98
>98
>98
>98
79%
81%
68%
80%
77%
62%
84%
72%
83%
90%
82%
85%
59%
70%
85%
75%
66%
2bc MeCH(Ph)
2c
2d c C7H15
2d C7H15
2d d C7H15
2ec
2e
2f
2g
2h
2i
2jc
2k
2l
n-Bu
The de was calculated on the crude reaction products by
1H NMR spectroscopy (300 MHZ) and GC-MS.15
The E stereochemistry in the double bond CdC of the
obtained R,â-unsaturated esters 2, in which the CdC is di-
cyclohexyl
cyclohexyl
Ph
(8) Concello´n, J. M.; Bernad, P. L.; Pe´rez-Andre´s, J. A. Angew. Chem.,
Int. Ed. 1999, 38, 2384-2386.
p-MeOC6H4
p-CNC6H4
MeCH(Ph)
(9) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-Solla, H. Angew.
Chem., Int. Ed. 2000, 39, 2773-2775.
Et
(10) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-Solla, H. Chem.
Eur. J. 2001, 7, 3062-3068.
e
C9H17
Et
Et
Et
Et
Et
-(CH2)5-
Ph
Ph
(11) Concello´n, J. M.; Bernad, P. L.; Bardales, E. Org. Lett. 2001, 3,
937-939.
Me Me
Et Me
Me Me
61
71
70
(12) Representative Experimental Procedure. A solution of SmI2 (1.6
mmol) in THF (19 mL) was added, under nitrogen atmosphere, dropwise
to a stirred solution of the corresponding epoxyester 1 (0.4 mmol) in THF
(4 mL) at room temperature or at reflux. The reaction mixture was stirred
for 90 min (rt) or 2 h (reflux), and then the reaction was quenched with
aqueous HCl (20 mL of a 0.1 M solution). Usual workup afforded crude
R,â-unsaturated ester 2, which was purified by column flash chromatography
over silica gel (10:1 hexane/ethyl acetate).
2m
2n
Bn
a Unless otherwise noted, reactions were carried out at room temperature.
b Isolated yield after column chromatography based on compound 1. c The
reaction was carried out at reflux of THF. d The reaction was carried out at
-50 °C. e C9H17: Me2CdCH(CH2)2CH(Me)CH2.
(13) By example, the diastereoselectivity of the Wittig reaction, to obtain
R,â-unsaturated esters, decreases with bulky alcoholic groups: Maryanoff,
B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
4-6). Taking into account these results, the remaining
reactions were performed at room temperature or at reflux
of THF. In general, the yield and degree of purity of 2 was
higher at reflux than at room temperature; for this reason
(14) To the best of our knowledge, no diastereoselective synthesis of
tetrasubstituted R,â-unsaturated esters from R,â-epoxiesters has been
described.
(15) The 1H NMR determination was in agreement with the de obtained
by GC-MS.
190
Org. Lett., Vol. 4, No. 2, 2002

or trisubstituted, was established by comparison of their 1H
and 13C spectra with authentic samples, as has been previ-
ously described in the literature.9 The E stereochemistry of
the CdC double bond of the tetrasubstituted R,â-unsaturated
esters 2 was assigned by NOESY experiments (compound
2m).
It is noteworthy that although the starting R,â-epoxyesters
were used as mixtures of cis and trans diastereoisomers, the
corresponding R,â-unsaturated esters were obtained with total
or very high E-selectivity.
membered ring.16 Tentatively we propose a transition state
model A. If R1 > R2, the largest group R1 occupies an
equatorial position and the smallest group R2 an axial position
(to avoid interactions with the samarium coordination
sphere). This transition state could also explain the total or
very high diastereoselectivity observed in the elimination
reaction from a mixture of diastereoisomers of 1. As depicted
in B (another projection of the same transition state), R1 and
R3 show a cis relationship. Consequently, elimination from
A affords (E)-R,â-unsaturated esters.
The mechanism and stereochemistry may be explained
based on the ability of SmI2 to reduce R-heterosubstituted
esters to esters (Scheme 3). Thus, the SmI2-promoted
In conclusion, an easy, general methodology has been
developed to synthesized R,â-unsaturated esters, in which
the double bond CdC is di-, tri-, or tetrasubstituted with
total or high E-diastereoselectity from easily available R,â-
epoxyesters, the reaction being promoted by samarium
diiodide.
Scheme 3. Proposed Mechanism
Acknowledgment. We thank Ministerio de Educacio´n y
Cultura (PB-EX01-11) and Principado de Asturias (BQU2001-
3807) for financial support. J.M.C. thanks Carmen Ferna´ndez
for her time. E.B. thanks the Universidad de Oviedo and
the Principado de Asturias for a predoctoral fellowship. Our
thanks to Robin Walker for his final revision of the
manuscript.
Supporting Information Available: Experimental pro-
cedure of 1, spectroscopic data of 1 and 2, 13C NMR spectra
of 2, and GC of compounds 2l, 2m and 2n. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016894P
(16) Similar six-membered ring transition state models have been
proposed to explain the selectivity in other reactions of SmI2: (a) Urban,
D.; Skrydstrup, T.; Beau, J. M. J. Org. Chem. 1998, 63, 2507-2516. (b)
Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109,
453-463.
reduction of the CR-O bond of 1 affords an intermediate
enolate 3. Chelation of the oxophilic SmIII center of the
enolate 3 with the second oxygen atom produces a six-
Org. Lett., Vol. 4, No. 2, 2002
191