1,3- versus 1,4-Asymmetric induction in Mukaiyama-Michael additions of optically active ketene acetals to 2-methylcyclopent-2-en-1-one: A remarkable inversion of facial selectivity

Article abstract of DOI:10.1016/S0040-4039(00)02166-3

TrSbCl₆-catalyzed addition of selected optically active ketene acetals to 2-methylcyclopent-2-en-1-one for steroid synthesis is described. Inversion of facial selectivity in 1,3- and 1,4-asymmetric induction was observed.

Full text of DOI:10.1016/S0040-4039(00)02166-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1135–1138
1,3- versus 1,4-Asymmetric induction in Mukaiyama–Michael
additions of optically active ketene acetals to
2-methylcyclopent-2-en-1-one: a remarkable inversion of facial
selectivity
Evgueni Gorobets, Zofia Urbanczyk-Lipkowska, Viatcheslav Stepanenko and Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warsaw 48, Poland
Received 22 September 2000; revised 13 November 2000; accepted 22 November 2000
Abstract—TrSbCl6-catalyzed addition of selected optically active ketene acetals to 2-methylcyclopent-2-en-1-one for steroid
synthesis is described. Inversion of facial selectivity in 1,3- and 1,4-asymmetric induction was observed. © 2001 Elsevier Science
Ltd. All rights reserved.
sponding adducts with high diastereoselectivity.1–3
Trityl salt-catalyzed conjugate addition reactions of
Asymmetric variations of the reaction include: (a) the
conjugate addition of prochiral ketene acetals to opti-
prostereogenic silylated ketene acetals to prostereogenic
a,b-unsaturated ketones is known to provide the corre-
Scheme 1. Diastereoselectivity in Mukaiyama–Michael conjugate addition with prostereogenic components and optically active
ketene acetal 8.
Keywords: Mukaiyama–Michael reaction; asymmetric induction; Sharpless dihydroxylation; steroids.
* Corresponding author. E-mail: jwicha@icho.edu.pl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02166-3

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E. Gorobets et al. / Tetrahedron Letters 42 (2001) 1135–1138
Scheme 2. Preparation of cyclic ketene acetal 14 and its reaction with 2-methylcyclopent-2-en-1-one.
Figure 1. X-Ray structure of compound 15.
cally active a,b-unsaturated ketones;4,5 (b) the addition
of optically active ketene acetals bearing a chiral auxil-
iary to prochiral a,b-unsaturated ketones;6 and (c) the
use of chiral catalysts.7–10 The catalytic asymmetric
Mukaiyama–Michael reaction has rarely been applied
to natural product synthesis till now.11
acceptors 2 and 4 occurred with a significant asymmet-
ric induction to provide the desired diastereomer 7 as
the major product16 (7:8 =75:25, 55% yield). The
intermediate 7 was eventually transformed into com-
pound 9 which is a known intermediate in synthesis of
vitamin D3 congeners.17,18
We recently developed12–14 a steroid synthesis based
upon the trityl salt-catalyzed conjugate addition of
ketene acetal 1 to methylcyclopentenone 2 followed by
a second conjugate addition to the a,b-unsaturated
ketone 4 (Scheme 1). The intermediate adduct 3 with
like configuration at the newly formed chiral centers
predominated (dr ca. 9:1). Conjugate addition of 3 and
4 was highly diastereoselective15 affording racemic 5. In
designing an enantioselective approach to 5 and related
intermediates we chose to use optically active deriva-
tives of 1 easily accessible by Sharpless asymmetric
dihydroxylation or by certain microbiological transfor-
mations. Indeed, the tandem conjugate addition reac-
tions of optically active ketene acetal 6 and the Michael
In order to gain insight into the structural factors
determining the asymmetric induction in the conjugated
addition reaction, we examined the behavior of selected
ketene acetals related to 6. Hydroxyketone 10, prepared
by yeast reduction of 2,2-dimethylcyclohexa-1,3-
dione,19 was transformed into lactone 11 by silylation
followed by Baeyer–Villiger oxidation† (Scheme 2).
† Oxidation of hydroxy ketone 10 with M-CPBA
gave the product16 which resisted reaction with
TBSCl under the usual conditions. It was
concluded that the Baeyer–Villiger oxidation
was accompanied by rearrangement to give
a tertiary carbinol 12.

E. Gorobets et al. / Tetrahedron Letters 42 (2001) 1135–1138
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Ketene acetal20 13, prepared from 11 in the usual way,
was submitted to the reaction with enone 2 in the
presence of TrSbCl6, followed by hydrolysis to give
three components (69% yield) in a ratio of 79:13:8 (by
1H NMR). All our attempts to separate this mixture by
chromatography failed. Fortunately, the major
diastereomer 15 crystallized and was obtained in a pure
form by recrystallization from pentane (51% yield from
13). Its structure 15 was determined by a single crystal
X-ray analysis (Fig. 1). The formation of 15 must
involve the intermediate silyl enol ether 14 (17R,20S,
AlMe3 afforded thioester 18 (72% yield, 96% ee by
21
HPLC on a Chiralcel OD® column). The latter was
transformed into ketene acetal 19 (E:Z=85:15 by H
NMR) in the usual way.
1
The tandem reaction of 19 with Michael acceptors, 2
and 4 in the presence of the trityl catalyst, afforded an
oily adduct consisting of three diastereomers in a ratio
of 85:11:4 (75% yield). The diastereomers could not be
separated by chromatography but it was found that
annulation followed by the Luche reduction22 afforded
a crystalline material. The main component of the
mixture isolated by crystallization from benzene was 22
according to single crystal X-ray analysis (Fig. 2).
Consequently, the structures of major intermediates
were identified as 20 and 21, respectively.
steroid
numbering)
and,
consequently,
the
Mukaiyama–Michael reaction occurred mainly in the
unlike fashion. The new carbonꢀcarbon bond was
formed on the face of the seven-membered ring that
bears the TBSO group, which suggests that chelation of
the catalyst may involve the oxygen atom of this group.
However, inspection of molecular models indicates that
ketene acetal 13 enters the reaction in a boat conforma-
tion with the bulky tert-butyldimethylsilyl group in the
pseudo equatorial position, as shown in Scheme 2. On
this premise the cyclopentenone approached the elec-
trophile on its re face with the methyl group oriented
outside of the ring and the oxygen atoms of the reac-
tants in a syn orientation.
Reaction of the ketene acetals 6, 13 and 19 with methyl-
cyclopentenone 2 occurs with different stereoselection.
The cyclic reagent 13 gives the major adduct with unlike
relative configuration at the newly formed stereogenic
centers (17R,20S), whereas the linear ketene acetals 6
and 19, both of (S)-configuration, afford products with
like configuration at the newly generated stereogenic
centers, in accord with the rule operating for prostereo-
genic ketene acetals. However, 1,4-asymmetric induc-
tion in 6 provides the major product with absolute
configuration 17R,20R (75% of the diastereomer mix-
ture), whereas 1,3-induction in 19 gives the major
product with 17S,20S configuration (85% of the mix-
ture). To the best of our knowledge, the observed
change in the direction of remote asymmetric induction
has no precedent in the literature.23 Work to determine
further structural requirements for remote asymmetric
induction in the Mukaiyama–Michael reaction is now
in progress.
Initial attempts to conduct in situ conjugate addition of
silyl enol 14 to enone 4 showed that the reaction is slow
and is accompanied by substantial decomposition of
the enone. Since the relative configuration at C17 and
C20 in 14 differs from that occurring in major natural
sterols, attempts to find favorable conditions for its
reaction with 4 were abandoned.
Compound 19 (Scheme 3) was the next objective in our
asymmetric induction studies. Like ketene acetal 6, it
has an asymmetric carbon atom of (S)-configuration,
which is incorporated into a dioxolane ring. However,
in the ketene acetal 19 the asymmetric carbon atom is
closer to the reaction site (1,3). Synthesis of 19 is
presented in Scheme 3. Unsaturated ester 16 underwent
Sharpless asymmetric dihydroxylation using AD-mix-
a® to give hydroxy lactone 17 as the only product (70%
yield after distillation). Treatment of 17 with 2,2-
dimethoxypropane-TsOH and then with tert-BuSH and
Acknowledgements
We thank Professor Philip Kocienski for helpful discus-
sions. Financial support from the State Committee for
Scientific Research, Grant No. 3 T09A 134 18, is
gratefully acknowledged.
Scheme 3. Preparation of ketene acetal 19 and its use in tandem Mukaiyama–Michael reaction.

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E. Gorobets et al. / Tetrahedron Letters 42 (2001) 1135–1138
Figure 2. X-Ray structure of compound 22.
12. Marczak, S.; Michalak, K.; Urbanczyk-Lipkowska, Z.;
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