Asymmetric synthesis of β-hydroxyesters by aldol type condensation of enantiomerically pure t-butyl p-tolyl sulfinyl acetate: Unexpected substituent effect on the absolute configuration of the product

Article abstract of DOI:10.1016/S0040-4039(01)00318-5

Aldol type condensation of enantiomerically pure t-butyl p-tolyl sulfinyl acetate was shown to give the opposite configuration at the hydroxylic center in the case of an α,β-unsaturated aldehyde, a result which is in sharp contrast with literature results. The absolute configurations of the aldol products were determined by X-ray crystallography.

Full text of DOI:10.1016/S0040-4039(01)00318-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2923–2925
Asymmetric synthesis of b-hydroxyesters by aldol type
condensation of enantiomerically pure t-butyl p-tolyl sulfinyl
acetate: unexpected substituent effect on the absolute
configuration of the product
Guy Solladie´,* Claude Bauder, Eva Arce-Dubois and Yacine Pasturel-Jacope´
Laboratoire de Ste´re´ochimie associe´ au CNRS, Universite´ Louis Pasteur, ECPM, 25 Rue Becquerel,
67087 Strasbourg Cedex 2, France
Received 21 November 2000; revised 2 February 2001; accepted 21 February 2001
Abstract—Aldol type condensation of enantiomerically pure t-butyl p-tolyl sulfinyl acetate was shown to give the opposite
configuration at the hydroxylic center in the case of an a,b-unsaturated aldehyde, a result which is in sharp contrast with literature
results. The absolute configurations of the aldol products were determined by X-ray crystallography. © 2001 Elsevier Science Ltd.
All rights reserved.
Several years ago, we reported a very efficient asymmet-
ric synthesis of b-hydroxyacids based on the aldol type
condensation of R-(+)-t-butyl p-tolyl sulfinyl acetate on
carbonyl compounds (Scheme 1).1–5
pyrolytic sulfoxide cis elimination of the corresponding
acetate derivative of 2 (R=Ph). An empirical model,
based on the stereochemical results shown in Scheme 1,
was proposed in order to predict the configuration at
the hydroxylic center.3 In many applications the abso-
lute configuration of the second created chiral center
(C2) was not determined and was assumed to be the
same as in the case of the condensation of benzalde-
hyde. However, a recent report12 showed a different
mechanism for the pyrolytic sulfoxide elimination in
type 2 substrates: intermediate formation of a vinylic
sulfoxide. This result prompted us to control the
configurations of the type 2 adducts.
The sulfinyl acetate enolate has to be made with a
Grignard as a base, t-BuMgBr, the magnesium chelat-
ing effect being important to quench the adduct with
carbonyl compounds. It was shown by many examples
that the diastereoselection was very high, giving mainly
one diastereomer of 2. After desulfurization, the result-
ing b-hydroxyester had always the configuration shown
in Scheme 1, in 85–95% ee, determined by chemical
correlation. Many applications to natural-product syn-
thesis confirmed this assignment.4–8 The absolute
configuration of C2 in the first adduct 2 was determined
only in the case of benzaldehyde and shown to be
(R,R,R) from the (R)-a-sulfinyl acetate 1.3 The C2ꢀC3
relative configuration assignment was carried out via a
We report in this paper that the configuration of the
hydroxylic center, which depends in many cases only on
the absolute configuration at sulfur, can also depend, in
a few cases, on the aldehyde substituent R. We describe
here the cases of a,b-unsaturated aldehydes.
Scheme 1.
* Corresponding author. Fax: 33388136949; e-mail: solladie@chimie.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00318-5

2924
G. Solladie´ et al. / Tetrahedron Letters 42 (2001) 2923–2925
Scheme 2.
yield) and two other unidentified diastereomers in 21
and 15% yield, respectively.
The absolute configuration of the main isomer (−)-4
was shown to be S(S),2(S),3(R) by X-ray crystallogra-
phy (Scheme 3), an unexpected result with the opposite
configuration at the hydroxylic center with respect to
our previous report with benzaldehyde (and also in
other synthetic applications): the (R) sulfinyl ester lead-
ing to the S(R),2(R),3(R) configuration for the main
isomer (80% de). Therefore, after desulfurization, the
corresponding b-hydroxyester
configuration.
5
had the (S)-
Scheme 3. Computer-generated drawing of (−)-4 derived from
X-ray coordinates.
In addition, we applied this condensation to 3-benzyl-
oxypropanal under exactly the same experimental con-
ditions used for crotonaldehyde, including crystalliza-
tion of the main isomer (−)-6 (90% de by H NMR for
the crude product) (Scheme 4).
1
It had already been shown that a,b-unsaturated alde-
hydes react with chiral sulfinyl acetate to give, after
desulfurization, the corresponding b-hydroxyesters in
high ee. In the final steps of the synthesis of may-
tansine, Corey6 used this aldol type condensation with
phenyl (R) p-tolyl sulfinyl acetate (instead of the t-
butyl ester) and determined the absolute configuration
of the hydroxylic center by comparison with the natural
product. The result was consistent with our empirical
rule,3 predicting the R configuration for the hydroxylic
center from the R sulfoxide.
The absolute configuration of the main isomer obtained
from the (S)-sulfinyl ester was assigned by X-ray analy-
sis (Scheme 5) and shown to be S(S),2(S),3(S), in
agreement with our previous results. In addition, after
desulfurization, (−)-6 afforded the known (+)-(S)-b-
hydroxyester (+)-7.9,10
These results clearly identified the absolute configura-
tions of the two newly created chiral centers in this
aldol type condensation. Finally, starting from the (+)-
(R)-sulfinyl ester 1 and benzyloxypropanal, we obtained
the enantiomer of 6 [60% yield, [h]D=+195 (c 1,
CHCl3, mp 108–110°C)], which gave the enantiomer of
In our program on the total synthesis of natural prod-
ucts we had to prepare the b-hydroxyester 5, but in the
(R) configuration. According to our previous results2–5
this can be done by condensation of the sulfinyl acetate
(−)-(S)-1 on trans crotonaldehyde. For this reaction we
used the usual conditions with only two modifica-
tions:11 t-BuMgCl instead t-BuMgBr in only 4 equiv.
excess, and the main adduct 4 was isolated only by
crystallization, thereby avoiding any chromatographic
purification (Scheme 2). The diastereoselectivity of the
reaction was determined by 1H NMR on the crude
product: 64% yield of the main isomer (59% isolated
7
[86% yield, [h]D=−7.6 (c 1.6, CHCl3)] after
desulfurization.
In conclusion this paper reports the first exception to
the empirical rule proposed to predict the absolute
configuration of the b-hydroxyester obtained by aldol
type condensations with aldehydes. This unexpected
result, established by X-ray analysis, was obtained in
Scheme 4.

G. Solladie´ et al. / Tetrahedron Letters 42 (2001) 2923–2925
2925
6. Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, H.;
Hua, D. H. J. Am. Chem. Soc. 1980, 102, 6613–6615.
7. Masquelin, T.; Hengartner, U.; Streith, J. Helvetica 1997,
80, 43–58.
8. Beecher, J.; Brackenridge, I.; Roberts, M. R.; Tang, J.;
Willets, A. J. J. Chem. Soc., Perkin Trans. 1 1995,
1641–1643.
9. Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994,
116, 1753–1765.
10. Rychnovsky, S. D.; Fryszman, O.; Khire, U. R. Tetra-
hedron Lett. 1999, 40, 41–44.
11. Arce-Dubois, M. E. Ph.D. Dissertation; Universite´ Louis
Pasteur: Strasbourg, France, 1998:
Scheme 5. Computer-generated drawing of (−)-6 derived from
Typical aldolization procedure: To (−)-S(S)-t-butyl p-toly-
lacetate (−)-1 (4.28 g, 17.4 mmol, 1 equiv.) in THF (160
mL) was added at −78°C a solution of t-butylmagnesium
chloride (4 equiv.) in ether. After 40 min the crude
trans-crotonaldehyde (1.65 mL, 19.9 mmol, 1.15 equiv.)
was added dropwise to the slurry and stirring was contin-
ued for 2 h (the temperature rose to −25°C) until no
starting material was detected by TLC. The reaction was
then quenched with satd NH4Cl (50 mL), diluted with
water (50 mL) and acidified to pH 1 with 20% H2SO4.
The aqueous layer was extracted with CH2Cl2 and the
combined organic layers were washed with brine, dried
(MgSO4), and concentrated to obtain a crude oily
product. Crystallization in an ether–hexane mixture gave
a first crop of (−)-4 as white needles (3.2 g, 59%).
Mp=108–110°C, [h]D=−276 (c 0.92, CHCl3).
X-ray coordinates.
the case of an a,b-unsaturated aldehyde. It was also
shown by X-ray analysis that in the absence of the
double bond the configuration was in agreement with
our previous statement. It is important to note that in
the case of the maytansine synthesis, which was also an
a,b-unsaturated aldehyde, the absolute configuration
was in agreement with the empirical rule. The difference
could be due to either the larger steric hindrance of the
aldehyde used in the maytansine synthesis or to the use
of the phenyl instead of the t-butylsulfinyl ester.
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