Enantioselective Synthesis of (R)- and
(S)-r-Alkylcysteines via Phase-Transfer Catalytic
Taek-Soo Kim,†Yeon-Ju Lee,†Byeong-Seon Jeong,‡
Hyeung-geun Park,*,†and Sang-sup Jew*,†
Research Institute of Pharmaceutical Science and College of
Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea,
and College of Pharmacy, Yeungnam UniVersity, Gyeongsan
ReceiVed May 31, 2006
We reported efficient enantioselective synthetic methodolo-
gies for (R)-R-alkylcysteines and (S)-R-alkylcysteines. The
phase-transfer catalytic alkylation of 2-phenyl-2-thiazoline-
4-carboxylic acid tert-butyl ester and 2-o-biphenyl-2-thia-
zoline-4-carboxylic acid tert-butyl ester, in the presence of
chiral catalysts (1 or 2), gave the corresponding alkylated
products, which could be hydrolyzed to provide (R)-R-
alkylcysteines (67->99% ee) and (S)-R-alkylcysteines (66-
88% ee), respectively.
As one of the R,R-dialkyl amino acids, R-alkylcysteines are
valuable building blocks for the biologically active peptidomi-
metics, since they can not only resist enzymatic degradation
but also form the stabilized, preferred conformations of the
peptide backbone.1In addition, they are able to form a further
constrained cyclic peptide structure by disulfide bond formation.
Several natural products involving R-alkylcysteine moieties
exist, such as tantazoles,2mirabazoles,3and thiangazole,4which
exhibit antitumor and anti-HIV-1 activities.
A number of enantioselective synthetic methods for R-alky-
lcysteines have been reported so far. Their main synthetic
strategies can be classified as follows: (1) thiomethylation of
a bislactim ether prepared from valine as a chiral auxiliary,5
(2) nucleophilic ring opening of a chiral aziridine or chiral
?-lactone with thiolates,6(3) self-reproduction of chirality using
oxazolidinone or thiazolidinone derivatives,7and (4) enzymatic
desymmetrization of monomethyl dimethylmalonate.8However,
since most of the reported methods employed chiral starting
materials or chiral auxiliaries, their applications to industrial
processes for the mass production of chiral R-alkylcysteines
might not be straightforward. In this paper, we would like to
report new and efficient synthetic methods for (R)-R-alkylcys-
teines and (S)-R-alkylcysteines via phase-transfer catalytic
R-alkylation of thiazoline-4-carboxylates, which could be ap-
plied to industrial processes.
Quite recently, we reported a new synthetic method for (()-
R-alkylserines by the selective R-alkylation of tert-butyl 2-phen-
yl-2-oxazoline-4-carboxylate in phase-transfer catalytic condi-
tions.9As successive studies, the enantioselective versions using
chiral phase-transfer catalysts were also disclosed (Scheme 1).10
In addition, we reported a chiral auxiliary method via phase-
transfer catalytic alkylation of the oxazoline-4-carboxylate,
possessing camphorsultam as a chiral auxiliary (Scheme 1).11
These studies all showed that the phase-transfer catalytic
conditions are very efficient for the R-alkylation of the oxazo-
line-4-carboxylate system. Based on our previous results, we
attempted to apply the phase-transfer catalytic alkylation condi-
tions to 2-aryl-2-thiazoline-4-carboxylate esters (8) for the
enantioselective synthesis of chiral R-alkylcysteines (Scheme 2).
First, we prepared the thiazoline-4-carboxylate (8a, 8b). The
substrate 8a was easily prepared by the coupling of ethyl
benzimidate and cysteine methyl ester, followed by transesteri-
fication12using AlMe3in 80% yield from 11 (Scheme 3).
The substrate 8b was prepared from 2-biphenylcarboxylic acid
(13) in three steps. The coupling of 13 and 14, followed by
cyclization13in the presence of triphenylphosphine oxide and
trifluoromethanesulfonic anhydride, gave the thiazoline methyl
ester 16, which was converted to the corresponding tert-butyl
ester 8b by transesterification using AlMe3in 81% yield from
14 (Scheme 4).
For the phase-transfer catalytic alkylation, we adapted our
previous reaction conditions.10The phase-transfer catalytic
* To whom correspondence should be addressed. Tel: 82-2-880-7871, Fax:
†Seoul National University.
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10.1021/jo061107t CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006