Highly enantioselective synthesis of 1,3-mercaptoalcohols from α,β- unsaturated ketones: Asymmetric bifunctional group exchange reaction

Article abstract of DOI:10.1016/S0040-4039(00)00395-6

Optically active 1,3-mercapto alcohols were synthesized from α,β- unsaturated ketones using a chiral reagent B and dimethylaluminum chloride in two steps. The transformation involved a tandem Michael addition-MPV reduction and a base-catalyzed elimination. The two newly created chiral carbons in trans-chalcone derivatives were enantioselectively controlled to a high degree. Using the above transformation, an asymmetric bifunctional group exchange reaction between the substrate and chiral reagent was developed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00395-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3437–3441
Highly enantioselective synthesis of 1,3-mercapto alcohols from
α,β-unsaturated ketones: asymmetric bifunctional group
exchange reaction
Hiroaki Shiraki, Kiyoharu Nishide and Manabu Node ∗
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 14 February 2000; accepted 03 March 2000
Abstract
Optically active 1,3-mercapto alcohols were synthesized from α,β-unsaturated ketones using a chiral reagent
B and dimethylaluminum chloride in two steps. The transformation involved a tandem Michael addition–MPV
reduction and a base-catalyzed elimination. The two newly created chiral carbons in trans-chalcone derivatives
were enantioselectively controlled to a high degree. Using the above transformation, an asymmetric bifunctional
group exchange reaction between the substrate and chiral reagent was developed. © 2000 Elsevier Science Ltd. All
rights reserved.
The Meerwein–Ponndorf–Verley (MPV) reduction is a useful method for the chemoselective reduction
of a ketone moiety among several types of carbonyl compounds.1 Although many researchers2 have
tried to develop an asymmetric MPV reduction, high enantiomeric excess has been observed only in the
intramolecular MPV reaction,3 with the exception of the catalytic reaction by Evans and co-workers.4 We
have recently developed a tandem Michael addition–MPV reduction of α,β-unsaturated ketones using
chiral mercapto alcohol A and Lewis acid. The resulting product 2A was utilized in the asymmetric
synthesis of secondary alcohols and allylic alcohols, as shown in equation (1) in Scheme 1.5 The
stereochemistry of the two newly created chiral carbons in the sulfide 2A is completely controlled by
dynamic kinetic resolution via a reversible Michael addition. In order to utilize the two chiral carbons
effectively, we designed a new method for asymmetric synthesis of 1,3-mercapto alcohols 3 from α,β-
unsaturated ketones 1 using a new chiral reagent B, as shown equation (2) in Scheme 1.
Chiral reagent A is not adequate for the strategy of the above asymmetric synthesis, because the
transformation from the sulfide 2A into the thiol 3 is not easy to carry out. Therefore, we designed a
new type of chiral reagent which has a hydrogen atom on the carbon atom between the two carbon atoms
bearing the thiol and hydroxyl groups, as shown in the structure B. The sulfides 2B utilizing a chiral
reagent B should be easily converted with the aid of an amine base into the 1,3-mercapto alcohols 3 and
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00395-6
tetl 16675

3438
Scheme 1.
the α,β-unsaturated ketone 4, which is the starting material used in the preparation of the reagent B. The
product 3 should have a high de and ee if the sulfide 2B is produced under dynamic kinetic resolution
conditions.5 The above transformation corresponds to a novel exchange reaction of bifunctional groups
between the substrate and the reagent.
6
The exchange reaction using methyl vinyl ketone and a known chiral reagent B1 prepared from (−)-
pulegone was carried out first (Scheme 2). The sulfide 2B1 obtained by the tandem reaction was subjected
to the elimination reaction using DBU in refluxing toluene for 24 h to give the desired 1,3-mercapto
alcohol 3a (90% ee) and (−)-pulegone (4B1) in 70 and 79% yields, respectively. Because of the low
chemical yield (38%) of 2B1, we further investigated the exchange reaction using a new chiral reagent
7
B2 (98% ee), which was prepared from (+)-camphor. The tandem reactions of mesityl oxide 1b and
trans-chalcone 1c with the reagent B2 afforded the sulfides 2b and 2c in 94 and 60% yields, respectively.
These sulfides were next converted by base-catalyzed elimination to the 1,3-mercapto alcohols 3b (74%
yield, 82% ee) and 3c (72% yield, 96% ee) together with the α,β-unsaturated ketone 4B2 (≤76% yield).
The mercapto alcohol 3c, having two chiral carbons, showed an especially high optical purity and high
syn–anti selectivity.8 Reagent B2 was more effective compared to reagent B1, although the chemical yield
was lower than that in the reaction using A, even given the fact that 2 equivalents of the substrate were
used compared to 1 equivalent of the chiral reagent.
Scheme 2.

3439
Although a novel asymmetric exchange reaction of bifunctional groups was demonstrated by the above
reactions, nevertheless we attempted to improve the chemical yield in the base-catalyzed elimination.
Since the elimination reaction is an equilibrium reaction, it is expected that the addition of a thiol would
shift the equilibrium to the right. Actually, the thiol exchange reaction of 2c proceeded smoothly using
benzyl mercaptan in refluxing toluene to give the 1,3-mercapto alcohol 3c and the sulfide 5 in 97 and
91% yields, respectively. Generalization of the asymmetric synthesis of 1,3-mercapto alcohols under the
latter elimination conditions was tried. The results of the tandem reaction of α,β-unsaturated ketones
using the chiral reagent B2 and the base-catalyzed elimination of the reaction product are summarized in
Table 1.
Table 1
Asymmetric synthesis of 1,3-mercaptoalcohol from α,β-unsaturated ketone9
Although the tandem reaction of the α,β-unsaturated ketone 1 to give the sulfide 2 proceeded in
moderate yield, the base-catalyzed reaction of 2 with benzyl mercaptan resulted in high yields to give the
1,3-mercapto alcohols 3 with excellent ees,11 except for 3b. The relatively low ee of 3b compared with 3a
might be attributed to the restriction in the transition state of the MPV reduction due to the bulkiness of
the two methyl substituents on the β-carbon. In the reaction of the trans-chalcone derivatives (1c–f), two
chiral carbons were created to give optically active 1,3-mercapto alcohols 3c–f as a single diastereomer.
The controlling factor for this exceedingly high diastereoselectivity8 for anti to syn must be dynamic
kinetic resolution. On the other hand, the tandem reactions of benzalacetone 1g and its derivative 1h
having an alkyl group at R3 afforded a diastereomeric mixture of the sulfides 2, which were converted to
the optically active alcohols 3g and 3h as anti and syn mixtures. This low diastereoselectivity suggests
that the tandem reaction of 1g and 1h proceeded without control by dynamic kinetic resolution. It is
presumed that the above difference between trans-chalcone and benzalacetone is due to the magnitude of
a 1,3-diaxial like interaction of R1 and R2 toward R3 in the transition states of MPV reduction, as shown
in Scheme 3. The MPV reduction of the diastereomer having a large steric interaction between the two
phenyl groups does not take place and the other diastereomer is subject to the MPV reduction because of

3440
a small steric interaction, i.e. that the reaction undergoes control by dynamic kinetic resolution. There are
many papers on asymmetric Michael addition of a thiol to an α,β-unsaturated system;12 however, there
is no precedent for a synthetic method corresponding to the asymmetric Michael addition of hydrogen
sulfide like the one observed in the reaction of the trans-chalcones.
Scheme 3. Plausible transition states for sulfide 2
In conclusion, we have developed the first method for an asymmetric synthesis of the 1,3-mercapto
alcohols 3 from the α,β-unsaturated ketones 1 through the tandem Michael addition–MPV reduction
followed by elimination. An important feature of this method is that the α,β-unsaturated ketone 4 or the
sulfide 5 obtained together with 3 is able to be recycled for the preparation of the chiral reagent B.7 This
is characteristic of an asymmetric bifunctional group exchange reaction.
Acknowledgements
Partial financial support (Grant-in-Aid No. 09470489) for this research by the Ministry of Education,
Science and Culture, Japan, is gratefully acknowledged.
References
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3441
7. Chiral reagent B2 was prepared as follows: (1) The exo methylenation of (+)-camphor with phenyllithium and
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was isolated by silica gel chromatography. A mixture of 2c (28 mg, 0.07 mmol), DBU (0.047 ml, 0.34 mmol), and benzyl
mercaptan (15 µl, 0.13 mmol) in toluene (8 ml) was refluxed for 18 h. The usual work-up and purification by silica gel
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