Diastereoselective reduction and carbon-carbon bond formation of α-keto esters/amides with SmI2

Article abstract of DOI:10.1016/S0040-4039(01)00676-1

The stereoselective reduction of α-keto esters/α-keto amides, which have various chiral auxiliaries using SmI₂, is examined. 2(S)-Methoxymethylpyrrolidine, 1,1,2(S)- and 1,1,2(R)-triphenylethanediol were found to be suitable chiral auxiliaries

Full text of DOI:10.1016/S0040-4039(01)00676-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4167–4169
Diastereoselective reduction and carbonꢀcarbon bond formation
of a-keto esters/amides with SmI2
Shin-ichi Fukuzawa,* Manabu Miura and Hiroshi Matsuzawa
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, Kasuga, Bunkyo-ku,
Tokyo 112-8551, Japan
Received 19 March 2001; revised 18 April 2001; accepted 20 April 2001
Abstract—The stereoselective reduction of a-keto esters/a-keto amides, which have various chiral auxiliaries using SmI2, is
examined. 2(S)-Methoxymethylpyrrolidine, 1,1,2(S)- and 1,1,2(R)-triphenylethanediol were found to be suitable chiral auxiliaries
that produced the corresponding a-hydroxy ester and amide in good diastereoselectivity with satisfactory yields. Allylation, the
Reformatsky-type reaction, and the ketyl-alkene coupling reaction with the 1,1,2(R)-triphenylethanediol and 2(S)-methoxymethyl-
pyrrolidine, derivative of the a-keto ester/amide proceeded smoothly with high diastereoselectivity. © 2001 Elsevier Science Ltd.
All rights reserved.
We have succeeded in the SmI2-mediated asymmetric
coupling reaction of carbonyl compounds with chiral
various chiral auxiliaries with SmI2; 1,1,2(S)-, (R)-
triphenylethanediol (1a, 1b), (−)-borneol (1c), (−)-8-
phenylmenthol (1d), 2(S)-methoxymethylpyrrolildine
(1e), 1(S)-phenylethylamine (1f) and (S)-valinol (1g)
were examined with respect to the level of asymmetric
induction during the reduction (Scheme 1).
a,b-unsaturated
esters1
and
with
chiral
a-
bromocarboximides2 with excellent selectivities. Based
on our and other research group studies,3 the use of
SmI2 should produce high stereoselectivity for asym-
metric reactions with chiral molecules by choosing an
appropriate chiral auxiliary due to the chelation con-
trol. Optically active a-hydroxy acids are synthetically
useful intermediates, in addition to being commonly
used building blocks for organic synthesis.4 Their main
synthetic applications are as chiral synthons, stereo
directing groups for the enantioselective synthesis of
natural products, and the synthesis of phosphine lig-
ands for use in transition-metal complex catalysts. The
diastereoselective reduction of chiral a-keto esters/
amides is one of the convenient methods for the synthe-
sis of a-hydroxy acids.5 The reduction of the chiral
a-keto ester by SmI2 may be the simplest and most
promising way to access optically active a-hydroxyl
acids with high stereoselectivity. In this report, we
describe the diastereoselective reduction of chiral a-keto
esters/amides, which have several classes of chiral auxil-
iaries by SmI2. Highly diastereoselective carbonꢀcarbon
bond formation, i.e. allylation and the Reformatsky-
type reaction will also be described.
All the chiral auxiliaries employed here were readily
prepared from inexpensive optically active compounds
such as amino acids. The results are summarized in
Table 1. The reaction was usually carried out at −78°C
for 2 h in tetrahydrofuran (THF), and the a-hydroxyl
esters/amides were isolated by PTLC after the usual
work-up. The diastereomeric excess (% de) was deter-
mined by 1H NMR (400 MHz) and/or GC/MS as esters
of trifluoroacetic acid. The use of water as a proton
source was essential for obtaining a high yield and
selectivity. Methanol, t-butanol and tetrahydrofuryl-
methyl alcohol may be used as a proton source but
gave less selectivity; 40–50% de using 1a as a chiral
auxiliary (entries 2–5).6 The reduction product was only
slightly formed in the absence of a proton source.
Chiral auxiliaries 1a, 1b and 1e, were found to be
efficient to produce the reduction product with good de
values, 63, 60 and 75% de, respectively (entries 1, 6, 9).
It is interesting that this reaction proceeded with a good
selectivity by using a simple chiral auxiliary and non-
sterically demanding SmI2, while good stereoselectivity
could usually be achieved by using a combination of a
steric hindered hydride agent and a more bulky chiral
auxiliary for the reduction of the chiral a-keto ester/
amide.5 The addition of HMPA (1 equiv. to SmI2)
We first investigated the reduction of benzoylformic
acid esters and amides (1), which are derived from
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00676-1

4168
S. Fukuzawa et al. / Tetrahedron Letters 42 (2001) 4167–4169
Scheme 1.
a
Table 1. Asymmetric reduction of a-keto esters and amides by SmI2
Entry
AUX in 1
ROH
Yield (%) of 2
de (%)b
Config.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
H2O
70
88
82
59
50
70
48
80
92
57
45
63
45
44
46
51
60
13
12
75
32
8
R
R
R
R
R
S
R
R
S
MeOH
t-BuOH
2-THFCH2OH
AcOH
H2O
H2O
H2O
H2O
H2O
9
10
11
–
S
1g
H2O
a SmI2 (1.5 mmol), ROH (5.5 mmol), 1 (0.5 mmol).
b Determined by GC or HPLC.
with methyl a-bromoacetate afforded the correspond-
ing 1,4-diesters, 6a and 6e, in 80–90% yields with 72
and 60% de, respectively. The de value was improved
to the reaction solution resulted in a decrease of the
diastereoselectivity; a 65% de in the reaction with the
1e derivative of the amide. The absolute configura-
tions of the newly formed alcoholic carbon were
determined after hydrolysis of the esters/amides and
comparison of the sign of the specific rotations of the
a-hydroxyl acid, i.e. mandelic acid. Starting from the
benzoylformate isomers of 1a and 1b, (S)- and (R)-
mandelic acid were produced, respectively. Reduction
of the pyruvate of 3a with SmI2 similarly proceeded
to yield the corresponding a-hydroxyl ester but with
poor selectivity (5% de).7
We next examined the SmI2 induced reductive cou-
pling reaction of benzoylformate and pyruvate of 1a
with the allyl iodide,8 the a-bromo ester2 and the a,b-
unsaturated ester1 (Scheme 2). The allylation of the
1a, and 3a proceeded smoothly at −78°C for 2 h
quantitatively to give the corresponding 2-hydroxy-4-
pentenoic acid esters, 4a and 5a in 57 and 54% de,
respectively. The allylation with 1e proceeded at 0°C
only in THP to give 4e in 70% yield with 35% de. It
is noteworthy that the reaction with allyllithium and
allylmagnesium bromide hardly gave the homoallyl
alcohol.9 The Reformatsky-type reaction of 1a and 1e
Scheme 2. (i) Allyl iodide/SmI2/THP. (ii) Methyl- or t-butyl
a-bromoacetate/SmI2/THF. (iii) Methyl acrylate/t-butanol/
SmI2/THF.

S. Fukuzawa et al. / Tetrahedron Letters 42 (2001) 4167–4169
4169
up to 89% by the use of the t-butyl ester in the reaction
References
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reaction with 1e resulted in a low yield (47%) with 86%
de.
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a
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methylpyrrolidinyl mandelamide (2) as a colorless
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GC/MS analysis after trifluoroacetylation with tri-
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ration of the alcoholic carbon was determined by
hydrolysis leading to the mandelic acid [h]2D0=+117.0
(c=0.46, MeOH).
Acknowledgements
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This work was financially supported by the Institute
of Science and Engineering, Chuo University, Special
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.