Diastereoselective conjugate addition of organocuprates to chiral N-enoyl oxazolidinethiones

Article abstract of DOI:10.1021/ol101687e

Figure Presented. Addition of organocuprates, generated in situ using an excess of a 1:2 mixture of CuIDMS and Grignard reagent, to N-enoyl oxazolidinethiones in the presence of excess TMSI gave preferentially the anti diastereomer where the addition took place when the conformation of the substrate was syn-s-cis. The reaction was investigated with indene-based and three different phenyl glycine derived oxazolidinethiones.

Full text of DOI:10.1021/ol101687e

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4268-4270
Diastereoselective Conjugate Addition of
Organocuprates to Chiral N-Enoyl
Oxazolidinethiones
Roc´ıo Sabala,† Luis Herna´ndez-Garc´ıa,‡ Aurelio Ortiz,† Moise´s Romero,‡ and
Horacio F. Olivo*,‡
Facultad de Ciencias Qu´ımicas, Beneme´rita UniVersidad Auto´noma de Puebla,
Pue. 72570, Mexico, and DiVision of Medicinal and Natural Products Chemistry,
The UniVersity of Iowa, Iowa City, Iowa 52242
horacio-oliVo@uiowa.edu
Received July 20, 2010
ABSTRACT
Addition of organocuprates, generated in situ using an excess of a 1:2 mixture of CuI·DMS and Grignard reagent, to N-enoyl oxazolidinethiones
in the presence of excess TMSI gave preferentially the anti diastereomer where the addition took place when the conformation of the substrate
was syn-s-cis. The reaction was investigated with indene-based and three different phenyl glycine derived oxazolidinethiones.
Conjugate addition of active methylene compounds, the
Michaelreaction,isoneofthemostfundamentalcarbon-carbon
bond forming reactions in organic chemistry.1 Organocuprate
additions to R,ꢀ-unsaturated carboxylic acids attached to
chiral oxazolidinones have been well studied. The asym-
metric 1,4-addition of organocuprates to chiral R,ꢀ-unsatur-
ated N-acyl-4-phenyl-2-oxazolidinones was initially reported
by Hruby in 1993.2 Appropriate reagents and conditions have
been found to achieve diastereoselective additions of orga-
nocuprates to N-enoyl oxazolidinones.3 When the conforma-
tion of the N-enoyl oxazolidinone is anti-s-cis, the syn
addition product is obtained, and when the conformation is
syn-s-cis, the anti addition product is then obtained (Figure
1). The conjugate addition of organocuprates to chiral
Figure 1. anti-s-cis and syn-s-cis conformations of N-enoyl
oxazolidinones.
† Beneme´rita Universidad Auto´noma de Puebla.
‡ The University of Iowa.
(1) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959,
10, 182–542. (b) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92,
771–806. (c) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992. (d) Alexakis, A.; Backvall, J. E.;
Krause, N.; Pamies, O.; Dieguez, M. Chem. ReV. 2008, 108, 2796–2823.
(2) Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
766–770.
N-enoyl oxazolidinones has been employed in the syntheses
of several natural products.4
Thiazolidinethione and oxazolidinethione chiral auxiliaries
are becoming more popular because of their highly diaste-
10.1021/ol101687e  2010 American Chemical Society
Published on Web 08/31/2010

reoselective aldol reactions and particularly in the more
troublesome acetate aldol reaction.5 In addition, these
auxiliaries have shown to be directly displaced by different
nucleophiles. N-Acyl derivatives can be easily prepared from
coupling of the auxiliary with a carboxylic acid or with an
acyl chloride.6
Table 1. Conjugate Addition to N-Crotonoyl Oxazolidinethione 1
Palomo et al. have shown that N-enoyl oxazolidinethiones
undergo a Lewis acid-promoted intramolecular Michael
addition with high diastereoselectivity to yield ꢀ-sulfanyl
imides.7,8 Kataoka et al. have shown that N-cinnamoyl
oxazolidinethiones can react with benzaldehydes in the
presence of BF3·OEt2 in a tandem Michael-aldol reaction.9,10
Other rearranged products can also be obtained during the
preparation of N-enoyl oxazolidinethiones when employing
sodium hydride and the corresponding acid chloride.11
Despite the interest in asymmetric transformations with chiral
oxazolidinethione auxiliaries, no report has yet appeared of
conjugate addition of organocuprate nucleophiles.12 Herein,
we describe reaction conditions to carry out this reaction.
We surveyed different reaction conditions and found that
Grignard reagents added stereoselectively to N-crotonoyl
indene-based oxazolidinethione 1 in THF at low temperature
(Table 1). Poor diastereoselectivity was observed when the
organocuprate reagent was prepared using 6 equiv of
Grignard reagent and 3 equiv of CuBr·DMS (entry 1). The
diastereoselectivity greatly improved when an equimolar
mixture of CuBr·DMS and Grignard reagent was employed
in a 6-fold excess (entry 2). Addition of TMSI as a Lewis
acid improved slightly the yield of the addition without
affecting the diastereoselectivity (entry 3). Increasing the
amount of Grignard reagent and adding the Lewis acid was
also beneficial (entry 4). Better results were obtained when
entry
CuBr
Grignard
TMSI
yielda (%)
2:3b
1
2
3
4
5
6
3
6
3
3
3
6
6
6
3
6
4.5
6
0
0
3
3
3
6
68
58
65
65
70
62
2:1
95:5
95:5
95:5
98:2
95:5
a Isolated total yield of two diastereomers. b As determined by 1H NMR
peak integrations with crude products.
an excess of Grignard reagent was added in the presence of
TMSI (entries 5 and 6). X-ray single-crystal analysis of the
major diastereomer (2) established unambiguously the rela-
tive stereochemistry of the newly formed stereocarbon.13
More reproducible results were obtained when using 3
equiv of CuBr·DMS, 6 equiv of Grignard reagent, and 3
equiv of Lewis acid.14 These conditions were used with other
Grignard reagents (Table 2). We obtained similar results
Table 2. Conjugate Addition to N-Crotonoyl Oxazolidinethionea
(3) (a) Liao, S.; Han, Y.; Qiu, W.; Bruck, M.; Hruby, V. J. Tetrahedron
Lett. 1996, 37, 7917–7920. (b) Williams, D. R.; Kissel, W. S.; Li, J. J.
Tetraheron Lett. 1998, 39, 8593–8596. (c) Schneider, C.; Reese, O. Synthesis
2000, 1689–1694. (d) Pollock, P.; Dambacher, J.; Anness, R.; Bergdahl,
M. Tetrahedron Lett. 2002, 43, 3693–3697. (e) Dambacher, J.; Anness, R.;
Pollock, P.; Bergdahl, M. Tetrahedron 2004, 60, 2097–2110. (f) Perez, L.;
Berne`s, S.; Quintero, L.; Anaya de Parrodi, C. Tetrahedron Lett. 2005, 46,
8649–8652. (g) Sprecher, H.; Pletscher, S.; Mo¨ri, M.; Marti, R.; Gaul, C.;
Patora-Komisarska, K.; Otchertianova, E.; Beck, A. K.; Seebach, D. HelV.
Chim. Acta 2010, 93, 90–110.
entry
N-enoyl
Grignard
yieldb (%)
anti:sync
1
2
3
4
1 R ) Me
1 R ) Me
4 R ) Ph
R′ ) Ph
R′ ) p-Tol
R′ ) Me
76
70
45
30
(2b:3b ) 95:5)
(2a:3a ) 95:5)
(3b:2b ) 1:1)
(3a:2a ) 3:1)
(4) (a) Williams, D. R.; Nold, A. L.; Mullins, R. J. J. Org. Chem. 2004,
69, 5374–5382. (b) Williams, D. R.; Ihle, D. C.; Brugel, T. A.; Patnaik, S.
Heterocycles 2006, 70, 77–82. (c) Esumi, T.; Shimizu, H.; Kashiyama, A.;
Sasaki, C.; Toyota, M. Tetrahedron Lett. 2008, 49, 6846–6849. (d) Morita,
M.; Ishiyama, S.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1675–1678.
(5) (a) Review on thiazolidinethiones: Velazquez, F.; Olivo, H. F. Curr.
Org. Chem 2002, 6, 303–340. (b) Review on oxazolidinethione: Ortiz, A.;
Sansinenea, E. J. Sulfur Chem 2007, 28, 1–39.
5 R ) p-Tol R′ ) Me
a See Supporting Information for actual structures of products in the
table. b Isolated total yield of two diastereomers. c As determined by 1H
NMR peak integrations with crude products.
(6) Andrade, C. K. Z.; Rocha, R. O.; Vercillo, O. E.; Silva, W. A.; Matos,
R. A. F. Synlett 2003, 2351–2352.
when phenylmagnesium bromide was used instead of the
p-tolyl Grignard reagent (entries 1 and 2). To our surprise,
low yields and poor diastereoselectivities were obtained when
methylmagnesium bromide was used as the Grignard reagent
and added to the N-cinnamoyl and the N-(4-methylcin-
namoyl) oxazolidinethiones (entries 3 and 4). Others have
also observed lower yields and diastereoselectivities when
N-cinnamoyl derivatives are employed.3a
(7) Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A. J. Am.
Chem. Soc. 2001, 123, 5602–5603
.
(8) Ortiz, A.; Quintero, L.; Hernandez, H.; Maldonado, S.; Mendoza,
G.; Bernes, S. Tetrahedron Lett. 2003, 44, 1129–1132
.
(9) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Osamura, T.; Watanabe,
S.-I.; Iwamura, T.; Muraloka, O.; Tanabe, G. Angew. Chem., Int. Ed. 2003,
42, 2889–2891
.
(10) Kinoshita, H.; Takahashi, N.; Iwamura, T.; Watanabe, S.-I.;
Kataoka, T.; Muraoka, O.; Tanabe, G. Tetrahedron Lett. 2005, 46, 7155–
7158
.
(11) Ortiz, A.; Quintero, L.; Mendoza, G.; Bernes, S. Tetrahedron Lett.
2003, 44, 5053–5055.
We decided to explore other chiral oxazolidinethiones with
only a phenyl group on C4 to compare the effect of having
(12) Only one single case of organocuprate addition to an N-enoyl
thiazolidinethione has appeared in the literature: Lu, C.-F.; Zhang, S.-B.;
Li, Y.; Yang, G.-C.; Chen, Z.-X. Tetrahedron: Asymmetry 2009, 20, 2267–
2269.
(13) See Supporting Information for CIF’s.
(14) See Supporting Information for a General Procedure.
Org. Lett., Vol. 12, No. 19, 2010
4269

an aromatic ring locked in the indene-based oxazolidineth-
iones and others with free rotation or different angle of the
phenyl ring. For this purpose, three other oxazolidinethiones
and their N-enoyl derivatives were prepared (Tables 3 and
Table 4. Conjugate Addition to N-Enoyl Phenylglycine-Derived
Oxazolidinethionea
Table 3. Conjugate Addition to N-Enoyl Phenylglycine-Derived
Oxazolidinethionea
entry N-enoyl oxazolidinone Grignard
yieldb (%) anti:sync
1
2
3
4
5
6
7
8
9
12 R ) Me, R′ ) Me
12 R ) Me, R′ ) Me
12 R ) Me, R′ ) Me
13 R ) Me, R′ ) Et
13 R ) Me, R′ ) Et
14 R ) Me, R′ ) Ph
15 R) Me, R′ ) p-Tol R′′ ) Me
14 R ) Me, R′ ) Ph
16 R ) Ph, R′ ) Me
R′′ ) Et
R′′ ) Ph
R′′ ) p-Tol 70 (20c:22c ) 60:40)
R′′ ) Ph
R′′ ) Me
R′′ ) Me
85 (20a:22a ) 98:2)
70 (20b:22b ) 90:10)
72 (20d:22d ) 98:2)
70 (22a:20a )92:8)
80 (22b:20b ) 98:2)
80 (22c:20c ) 98:2)
80 (22d:20d ) 98:2)
75 (21a:23a ) 93:7)
80 (21b:23b ) 98:2)
entry
N-enoyl
Grignard yieldb (%)
anti:sync
1
2
3
4
5
6
6 R ) Me
6 R ) Me
6 R ) Me
7 R ) Ph
8 R ) p-Tol R′ ) Me
9 R ) Et R′ ) Me
R′ ) Ph
R′ ) p-Tol
R′ ) Et
70
93
52
40
36
30
(10a:11a ) 90:10)
(10b:11b ) 80:20)
(10c:11c ) 95:5)
(11a:10a ) 80:20)
(11b:10b ) 2:1)
(11c:10c ) 98:2)
R′′ ) Et
R′′ ) Et
R′′ ) Ph
R′ ) Me
10 16 R ) Ph, R′ ) Me
11 16 R ) Ph, R′ ) Me
12 17 R ) Ph, R′ ) Et
13 17 R ) Ph, R′ ) Et
14 18 R ) Ph, R′ ) Ph
R′′ ) p-Tol 80 (21c:23c ) 98:2)
R′′ ) Ph
R′′ ) Me
R′′ ) Me
75 (21d:23d ) 92:8)
75 (23a:21a ) 96:4)
80 (23b:21b ) 98:2)
85 (23c:21c ) 90:10)
80 (23d:21d ) 98:2)
a See Supporting Information for actual structures of products in the
table. b Isolated total yield of two diastereomers. c As determined by 1H
NMR peak integrations with crude products.
15 19 R ) Ph, R′ ) p-Tol R′′ ) Me
16 18 R ) Ph, R′ ) Ph R′′ ) Et
a See Supporting Information for actual structures of products in the
table. b Isolated total yield of two diastereomers. c As determined by 1H
NMR peak integrations with crude products.
4). Addition of organocuprates to N-crotonoyl derivative 6
was very good when using aromatic Grignard reagents
(entries 1 and 2), but lower yield and higher diastereoselec-
tivity were observed for the ethyl Grignard (entry 3). Lower
yields and diastereoselectivities were obtained with N-
cinnamoyl derivatives 7 and 8 and small size Grignard
reagent (entries 4 and 5). Very good diastereoselectivity but
low yield were observed for the N-pentenoyl derivative and
methyl Grignard (entry 6).
When the phenyl ring on the oxazolidinethiones was
flanked by the gem-dimethyl or a gem-diphenyl substituent,
we observed in general very good diastereoselectivities and
reaction yields (Table 4). Kanemasa and Onimura have
reported the effect of 4-chiral 2,2-dialkyloxazolidines on the
shielding of the diastereotopic acryloyl face.15 Only when
the p-tolylmagnesium bromide was employed in the addition
to N-crotonoyl oxazolidinethione 12, a low diastereoselec-
tivity was always observed (entry 3). X-ray crystallographic
analysis of addition product 20d confirms the relative
stereochemistry on the newly created carbon. The ortep
drawing of 20d shows the C-4 phenyl ring perpendicular to
the oxazolidinethione ring. We conclude this conformation
of the phenyl ring is important to achieve high diastereose-
lectivities.
substituent on C4 on the yield and diastereoselectivity. In
general, better diastereoselectivities were obtained with the
C4-phenyl oxazolidinethione chiral auxiliaries. We found that
by addition of the organocuprate, prepared using a 1:2
mixture of CuI·DMS or CuBr·DMS and Grignard reagent,
in the presence of excess TMSI, the N-enoyl oxazolidineth-
ione adopts a syn-s-cis conformation during the transition
state, and the addition takes place on the less hindered side
of the unsaturation, delivering preferentially the anti-addition
product. This reaction should be valuable in the synthesis
of many natural products.
Acknowledgment. We thank Dr. Dale Swenson (Univer-
sity of Iowa) for obtaining the X-ray analysis of compound
2a and Dr. Sylvain Berne`s (Universidad Auto´noma de Nuevo
Leo´n) for analysis of compound 20d. This project was funded
by an ACS-GCI-PRF grant (HO). We thank CONACyT for
a postdoctoral fellowship (LH) and grant Project 80915 (AO).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds
1
(1-23) and copies of H and 13C NMR spectra. CIF’s for
In summary, we have found reaction conditions for the
diastereoselective addition of organocuprates to N-enoyl
oxazolidinethiones and studied the impact of the phenyl
compounds 2a and 20d. Actual structures for Tables 2-4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8631–8644.
OL101687E
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Org. Lett., Vol. 12, No. 19, 2010