Remote asymmetric induction with vinylketene silyl N,O-acetal

Article abstract of DOI:10.1021/ja0465855

A highly regio- and diastereoselective TiCl₄-mediated vinylogous Mukaiyama aldol reaction using the chiral vinylketene silyl N,O-acetal has been developed. The present vinylogous Mukaiyama aldol reaction provides a unique and effective means of

Full text of DOI:10.1021/ja0465855

Published on Web 09/30/2004
Remote Asymmetric Induction with Vinylketene Silyl N,O-Acetal
Shin-ichi Shirokawa, Masato Kamiyama, Tomoaki Nakamura, Masakazu Okada, Atsuo Nakazaki,
Seijiro Hosokawa, and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo UniVersity of Science (RIKADAI), 2641 Yamazaki, Nodashi,
Chiba 278-8510, Japan
Received June 10, 2004; E-mail: kobayash@rs.noda.tus.ac.jp
Scheme 1. Stereoselective Formation of Vinylketene Silyl
N,O-Acetal 4
In contrast to the well-established methods of controlling acyclic
stereochemistry at sites in close proximity to one another (i.e., 1,2-
or 1,3-relationships),1 there are only a limited number of effective
methodologies to control stereoselectivity at more remote sites.2,3
Furthermore, these asymmetric induction procedures often utilize
intramolecular chelation with metal species, and development of
an effective and general methodology of remote asymmetric
induction is a challenging reaction in organic synthesis.4 In this
communication, we describe the highly stereoselective vinylogous
Mukaiyama aldol reaction5,6 using the vinylketene silyl N,O-acetals,
which provides a efficient and hitherto unprecedented high degree
of remote (1,7- and 1,6,7-) asymmetric induction.
Table 1. Vinylogous Mukaiyama Aldol Reaction with Vinylketene
Silyl N,O-Acetal 4
During the course of our total synthesis of madindoline A,7 we
developed a efficient method for the stereoselective construction
of a chiral quaternary carbon by regio- and stereoselective alkylation
of an R,â-unsaturated chiral imide 18 (Scheme 1). A relatively high
degree of stereocontrol (∼10:1) can be achieved by both the initial
stereoselective formation of E-O-enolate 2 and the diastereoselective
alkylation of 2. The stereochemistry of an intermediary dienolate
anion 2 was established by treatment with TBSCl to obtain 4 in
90% yield. The fact that 4 was isolated as a single isomer prompted
us to examine vinylogous Mukaiyama aldol reaction using 4 with
remote asymmetric induction in mind. Furthermore, the vinylketene
silyl N,O-acetal was unknown, and the reactivity and stereochemical
behavior of 4 was of interest.
entry
R
product
yield (%)
d.s.c
1
2
3
4
5
6
CH3(CH2)4
CH3(CH2)10
(CH3)2CH
5a
5b
5c
5d
5e
5f
97
42:1
94:1
40:1
20:1
86:1
30:1
92
95
(E)-CH3CHdCH
(E)-CH3CH2CHdC(CH3)
Ph
54 (87b)
55 (65b)
94
a 1.0 equiv of TiCl4, 2.0 equiv of aldehyde, 1.0 equiv of 4, 0.1 M in
CH2Cl2, -78 °C. b Conversion yield. c Determined by HPLC analysis.
Scheme 2. Vinylogous Mukaiyama Aldol Reaction with
Vinylketene Silyl N,O-Acetal 7a
First, we examined the reaction of 4 and hexanal, as a model
aldehyde, in the presence of a Lewis acid. We found TiCl4 to be
most effective in terms of both yield and stereoselectivity.9 The
reaction took place only at the γ-position, affording δ-hydroxy-R-
methyl-R,â-unsaturated imide 5a in 97% yield with 42:1 diaste-
reoselectivity. The stereochemistry at the newly formed chiral center
was determined by comparison to the known compound.10
There are a few precedents for C-C bond formation with such
a high degree of remote 1,7-asymmetric induction in an acyclic
system.2 Table 1 summarizes the results with other typical alde-
hydes. Excellent diastereoselectivity was achieved using aliphatic
aldehydes (entries 1-3), whereas the reaction with conjugated
aldehydes, such as crotonaldehyde and 2-methyl-2-pentenal, gave
moderate yield and high selectivity (entries 4 and 5). Stereochem-
istry of major isomers was determined by the modified Mosher’s
method11 except for the case of benzaldehyde.12
The R,â-unsaturated imide 6, derived from crotonic acid, was
transformed into the vinylketene silyl N,O-acetal 7 using a method
similar to that for 1. (Scheme 2) The stereochemistry of 7 was
established as Z-O-enolate by NOE experiments (Figure 1). The
TiCl4-mediated vinylogous Mukaiyama aldol reaction of silyl acetal
7 and hexanal was then carried out to obtain the aldol adduct 8 in
38% yield with 4:1 diastereoselectivity. The low yield was probably
due to the relative instability of 7 under acidic conditions. The
stereochemistry of 8, determined by the modified Mosher’s method,
a Reagents: (i) NaHMDS, TBSCl, THF, -78 °C (63%). (ii) Hexanal,
b
1
TiCl4, CH2Cl2, -78 °C (38%). Determined by H NMR spectroscopy.
Figure 1. NOE experiments of vinylketene silyl N,O-acetal 4 and 7.
was found to be 5S. Interestingly, this stereochemistry is the
opposite of that of 5a.
The methyl group at the R-position is important in achieving a
high level of stereoselectivity in the present vinylogous Mukaiyama
aldol reaction. We propose the transition states depicted in Figure
2. It is assumed that the oxazolidin-2-one ring is almost perpen-
dicular to the dienol ether plane and that the isopropyl group
overhangs the upper face of the dienol ether.13 The aldehyde
presumably approaches from the less hindered side to give the
observed stereochemistry (A). The opposite stereochemical behav-
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J. AM. CHEM. SOC. 2004, 126, 13604-13605
10.1021/ja0465855 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Figure 3. Proposed transition states for the nucleophilic attack of
vinylketene silyl N,O-acetal 10.
a synthetic point of view, our method using 10 can directly afford
the δ-hydroxy-R,γ-dimethyl-R,â-unsaturated carbonyl unit that is
seen in many polyketide natural products.16 Further optimization
and application of the methodology to the synthesis of biologically
interesting natural products are currently under investigation.
Figure 2. Proposed transition states for the nucleophilic attack of
vinylketene silyl N,O-acetal 4 and 7.
Scheme 3. Remote 1,6,7-Asymmetric Induction by Vinylogous
Mukaiyama Aldol Reaction Using 10a
Acknowledgment. This work was supported in part by the
Takeda Science Foundation, Sankyo Co. Ltd., and Grant-in-Aids
for Scientific Research from the Ministry of Education, Culture,
Sports, and, Science and Technology, Japan.
Supporting Information Available: Detailed experimental pro-
cedures, full characterization, and copies of all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
a Reagents: (i) NaHMDS, TBSCl, THF, -78 °C (90%). (ii) Hexanal,
b
1
TiCl4, CH2Cl2, -78 °C (87%). Determined by H NMR spectroscopy.
Table 2. Vinylogous Mukaiyama Aldol Reaction with Vinylketene
Silyl N,O-Acetal 10
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(
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1
2
3
4
CH3(CH2)4
(CH3)2CH
-78
-78
11a 87
11b 99
>50:1
>50:1
(E)-CH3CH2CHdC(CH3) -78 to -40 11c 67 (81b) >50:1
Ph
-78 to -55 11d 90
20:1
a 1.0 equiv of TiCl4, 2.0 equiv of aldehyde, 1.0 equiv of 10, 0.1 M in
CH2Cl2. b Conversion yield. c Determined by 400 MHz 1H NMR spectros-
copy.
ior, as well as the difference in the degree of stereoselectivity in
the cases of 4 and 7, can be rationalized by the Newman projection
models shown in Figure 2 (B for 4 and C for 7). In the case of 7,
approach of hexanal from the upper face is not effectively blocked
by chiral oxazolidin-2-one because the alkyl group of the aldehyde
is located at the opposite site of chiral auxiliary XN. Consequently,
the diastereoselectivity of 7 was lower than that for 4.
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We examined the enol silylation of chiral imide 9, derived from
2-methyl-2-pentenoic acid, with NaHMDS and TBSCl. The vi-
nylketene silyl N,O-acetal 10 was isolated in 90% yield as a single
isomer. The E,E-stereochemistry of 10 was established by NOE
experiments. The TiCl4-mediated vinylogous Mukaiyama aldol
reaction of 10 with hexanal gave the aldol adduct 11a (RdC5H11)
in 87% yield as an almost single isomer. The relative as well as
absolute stereochemistry of 11a was established by correlation to
the known compound.14 Results with other aldehydes are sum-
marized in Table 2. In all cases (entries 2-4), we tentatively
assumed that the major isomer has anti-stereochemistry. This was
confirmed by separate experiments.15 The excellent stereoselectivity
in this strategy with 10 is noteworthy. We assume that the major
anti-isomer was formed from transition state D (Figure 3) by
analogy to the reaction of 4 (transition state B). Transition state E,
which would lead to the syn-isomer, is unfavorable because of
interaction between the R-methyl and the R group, as well as the
δ-methyl and TiCl4.
(9) Other Lewis acids such as BF3‚OEt2, Me2AlCl, TiCl2(OiPr)2, and SnCl4
were not effective in terms of yield and stereoselectivity.
(10) Absolute configuration was determined by chemical correlation to (3R)-
1,3-diacetoxyoctane (i, O3 then Me2S; ii, NaBH4; iii, Ac2O, Et3N). Barchi,
J.; Moore, R. E.; Patterson, M. L. J. Am. Chem. Soc. 1984, 106, 8193.
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’04 version 1.0.1 (PM3) also supported the hypothesis.
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(2R,3R)-3-hydroxy-2-methyloctanoate (i, O3 then Me2S; ii, NaClO2; iii,
TMSCHN2). Watabu, H.; Ohkubo, M.; Matsubara, H.; Sakai, T.; Tsuboi,
S.; Utaka, M. Chem. Lett. 1989, 12, 2183.
(15) Absolute configuration of the hydroxyl group of 11b and 11c was
determined by modified Mosher’s method. (a) 11b was converted to the
known (4S,5R)-4-isopropyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxane.
Harada, T.; Egusa, T.; Igarashi, Y.; Kinugasa, M.; Oku, A. J. Org. Chem.
2002, 67, 7080. (b) Relative stereochemistry of 11c was determined by
correlating to (1S)-1-[(5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-
yl]-ethanone. Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.;
Yoshida, T.; Murase, H.; Nakata, M.; Matsumura, S. J. Org. Chem. 1997,
62, 3271. (c) 11d was converted to the known (2S,3S)-2-methyl-1-
phenylpropane-1,3-diol. Abiko, A.; Liu, J.; Masamune, S. J. Am. Chem.
Soc. 1997, 119, 2586.
In conclusion, we found that the chiral vinylketene silyl N,O-
acetal 4 and 10 underwent a highly regio- and diastereoselective
vinylogous Mukaiyama aldol reaction which provides a unique and
effective means of controlling remote asymmetric induction. From
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