Asymmetric syntheses of α-mercapto carboxylic acid derivatives by dynamic resolution of N-methyl pseudoephedrine α-bromo esters

Article abstract of DOI:10.1016/S0040-4039(02)02020-8

Dynamic resolution of N-methyl pseudoephedrine α-bromo esters in nucleophilic substitution reaction with trityl thiol has been successfully used for the asymmetric preparation of α-mercapto carboxylic acid derivatives up to 97:3 dr. The best results are obtained when α-bromo esters are allowed to equilibrate to the thermodynamic ratios before the addition of sulfur nucleophile. We have shown that the chiral auxiliary can be removed by both reductive cleavage and acidic alcoholysis to provide β-tritylthio alcohol 15 and α-tritylthiolated ester 16, respectively, without detectable racemization.

Full text of DOI:10.1016/S0040-4039(02)02020-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8253–8255
Asymmetric syntheses of a-mercapto carboxylic acid derivatives
by dynamic resolution of N-methyl pseudoephedrine
a-bromo esters
Jiyoun Nam, Sang-kuk Lee, Kee Yong Kim and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, South Korea
Received 29 August 2002; revised 13 September 2002; accepted 17 September 2002
Abstract—Dynamic resolution of N-methyl pseudoephedrine a-bromo esters in nucleophilic substitution reaction with trityl thiol
has been successfully used for the asymmetric preparation of a-mercapto carboxylic acid derivatives up to 97:3 dr. The best results
are obtained when a-bromo esters are allowed to equilibrate to the thermodynamic ratios before the addition of sulfur
nucleophile. We have shown that the chiral auxiliary can be removed by both reductive cleavage and acidic alcoholysis to provide
b-tritylthio alcohol 15 and a-tritylthiolated ester 16, respectively, without detectable racemization. © 2002 Elsevier Science Ltd.
All rights reserved.
Optically active a-mercapto carboxylic acids are ubiqui-
tous structural subunits in numerous biologically active
natural and unnatural peptides.1 Accordingly, there is
growing interest in the preparation of enantioenriched
a-mercapto carboxylic acids and several efficient meth-
ods have been developed.2 Most of straightforward
methods are based on the stereospecific substitution
reaction of enantioenriched a-halo or a-hydroxy car-
boxylic acid derivatives with sulfur nucleophiles. How-
ever, very few methods for high asymmetric
nucleophilic substitution of readily accessible racemic
precursors were reported so far. Here we wish to report
an efficient method for asymmetric syntheses of a-mer-
capto carboxylic acid derivatives via nucleophilic sub-
stitution reactions of racemic a-bromo esters with
sulfur nucleophile.
h (>99% conversion) and produced a-benzylthio substi-
tuted ester 2a in 70% yield with 76:24 diastereomeric
ratio (dr), as shown in Table 1 (entry 1). For an
efficient dynamic resolution, there must be a fast
epimerization of the diastereomers with respect to their
Table 1.
Entry
Epimerizationa Nucleophile
(time, dr of 1)
Yield of 2
dr of 2c
(aR:aS)
The methodology reported here makes use of the
dynamic resolution of (S,S)-N-methyl pseudoephedrine
a-bromo esters.3 Initial studies on the dynamic resolu-
tion of a-alkyl-a-bromo esters were carried out with
a-ethyl-a-bromo ester 1 and benzyl thiol as a nucle-
ophile. The reaction of N-methyl pseudoephedrine a-
ethyl-a-bromo ester (aRS)-1 (58:42 dr) with benzyl
thiol (BnSH, 1.2 equiv.) and Et3N (1.0 equiv.) in
CH3CN at room temperature was completed within 0.5
(%)b
1
2
3
4
5
0 h, 58:42 dr
0 h, 58:42 dr
0 h, 58:42 dr
BnSH
70 (2a)
52 (2b)
80 (2c)
50 (2a)
65 (2b)
76:24
91:9
65:35
92:8
TrSH
AcS−K+
24 h, 89:11 dr BnSH
24 h, 89:11 dr TrSH
96:4
a Time for epimerization with Et3N and dr (aS:aR) before the
addition of nucleophile are shown.
b All reactions were carried out at rt in CH3CN and yields are not
optimized.
Keywords: asymmetric synthesis; a-mercapto carboxylic acids; chiral
auxiliaries; dynamic resolution.
* Corresponding author. Fax: +822-3436-5382; e-mail: parkyong@
kkucc.konkuk.ac.kr
c Drs of 2a, 2b and 2c were determined by 1H NMR of reaction
mixture and drs of 2b were confirmed by CSP-HPLC analyses of the
corresponding b-tritylthio alcohol 15.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02020-8

8254
J. Nam et al. / Tetrahedron Letters 43 (2002) 8253–8255
Table 2.
rate of substitution with sulfur nucleophile. The high
reactivity of benzyl thiol nucleophile resulted in a rapid
nucleophilic displacement reaction with respect to the
epimerization process of (aRS)-1 and this may explain
the lack of high stereoselectivity. When the nucleophile
was changed to the more sterically demanding nucle-
ophile, trityl thiol (Ph3CSH),2c,d the sulfur nucleophile
showed sufficient reactivity for the nucleophilic substi-
tution of the secondary bromide (aRS)-1. The reaction
was completed within 5 h (>95% conversion) to provide
the a-tritylthiolated carboxylic acid derivatives (aR)-2b
in 52% yield with a dr of 91:9 (entry 2).4 The size of
trityl thiol nucleophile could decrease the rate of substi-
tution and give the ester (aRS)-1 more time for epimer-
ization before the substitution to increase the
stereoselectivity. In agreement with the reactivity–selec-
tivity relationship shown in entries 1 and 2, the reaction
of (aRS)-1 with a metalated nucleophile, potassium
thioacetate (AcS−K+) was completed within 10 min
(>99% conversion) and produced a-acetylthio substi-
tuted ester 2c in 80% yield with 65:35 dr (entry 3).
Entry
R%
Epimerizationa
Yield (%)b
drc
1
2
3
4
5
6
n-Butyl (3)
PhCH2CH2 (4)
CH3 (5)
iso-Butyl (6)
Ph (7)
24 h, 85:15
7 h, 80:20
2 h, 97:3
24 h, 80:20
0 h, 50:50
0 h, 51:49
60 (9)
95:5
95:5
97:3
91:9
97:3
92:8
71 (10)
80 (11)
61 (12)
57 (13)
12 (14)d
PhCH2 (8)
a Time for epimerization with Et3N and dr before the addition of
nucleophile are shown.
b All reactions were carried out at rt in CH3CN and yields are not
optimized.
c Drs of 9–14 were determined by 1H NMR of reaction mixture and
drs of 11 and 13 were confirmed by CSP-HPLC analyses of the
corresponding methyl a-tritylthio esters.
The treatment of (aRS)-1 with Et3N in CH3CN for 24
h for an epimerization without substitution provided
the equilibrated mixture of 1 with a thermodynamic
ratio of 89:11.3e,5 When the benzylthiol was added to
the equilibrated mixture, a significant and practical
improvement in the stereoselectivity was obtained to
give 2a in 50% yield with 92:8 dr (entry 4). This
stepwise epimerization–substitution protocol also
improved the stereoselectivity of the reaction with trityl
thiol to give (aR)-2b in 65% yield with an increased dr
of 96:4 (entry 5). In the epimerization process induced
by Et3N, the thermodynamically less stable (aR)-1
epimer is converted into more stable (aS)-1 epimer,
which reacts faster with TrSH to give (aR)-2b with
inversion of configuration in the subsequent substitu-
tion. Limited results shown in Table 1 clearly indicate
that the product ratio is dependent on both the size of
nucleophile and the dr of a-bromo ester (aS)-1, which
suggest the asymmetric induction by a dynamic kinetic
and thermodynamic resolution.3e
d Elimination product was obtained in 42% isolated yield.
plished in the reaction of a-aryl-a-bromo ester without
the epimerization–substitution sequences. However, this
methodology is not practical for the preparation of
a-benzyl a-mercapto carboxylic acid or analogues due
to the domination of elimination reaction (entry 6).
We examined the removal of the chiral auxiliary from
a-tritylthio substituted esters, as shown in Scheme 1.
Reductive cleavage of a-ethyl-a-tritylthio ester 2b (96:4
dr) using LiAlH4 (1.5 equiv.) in THF furnished the
enantioenriched b-tritylthio alcohol 15 in 73% yield
with a small amount of trityl group deprotected b-mer-
capto alcohol (11% yield), nicely regenerating the
unchanged chiral auxiliary in 76% yield.6 The enan-
tiomeric ratio (er) of 15 was shown to be 96:4 er
implying no detectable racemization. Also, the N-
methyl pseudoephedrine auxiliary can be removed by
refluxing the esters in methanol with catalytic amounts
of p-toluenesulfonic acid. The acidic methanolysis of
a-methyl-a-tritylthio ester 11 (97:3 dr) furnished methyl
a-tritylthiolated ester 16 in 88% yield with 97:3 er
without any detectable racemization and the unchanged
chiral auxiliary in 80% yield.6
The scope of this epimerization–substitution methodol-
ogy was investigated with six different a-bromo esters
3–8, as shown in Table 2. Treatment of 3 with Et3N in
CH3CN for 24 h for an epimerization provided the
equilibrated mixture 3 with a thermodynamic ratio of
85:15. The substitution with trityl thiol for 18 h pro-
vided 9 in 60% yield with 95:5 dr (entry 1). We were
pleased to observe that the epimerization–substitution
protocol is also efficient for a variety of a-alkyl-a-
bromo esters 4–6, affording a-tritylthio substituted
esters 10–12 in 61–80% isolated yields with high
stereoselectivities, as shown in entries 2–4. On the other
hand, the epimerization–substitution protocol could not
be used for the a-phenyl-a-bromo ester 7 and the
a-benzyl-a-bromo ester 8 due to their instability under
the epimerization condition to give complex reaction
mixture. Upon treatment of 7 (50:50 dr) with trityl thiol
and Et3N for 2 h, the substitution provided 13 in 57%
yield with 97:3 dr (entry 5). It is noteworthy that highly
stereoselective nucleophilic substitution was accom-
Scheme 1.

J. Nam et al. / Tetrahedron Letters 43 (2002) 8253–8255
8255
We have developed a convenient synthetic method for
asymmetric syntheses of a-mercapto carboxylic acid
derivatives through dynamic resolution of N-methyl
pseudoephedrine a-bromo esters. The simple protocol
with mild conditions and the easy removal of chiral
auxiliary without detectable racemization suggests fur-
ther development of this methodology. Current work is
aimed at understanding mechanistic details of these
processes and expanding the utility of this
methodology.
and 2c were assigned by analogy to the formation of
(aR)-2b. We have found that the a-position of 2b is
configurationally stable under the reaction condition (1.0
equiv. of Et3N in CH3CN).
5. (aS)-1 epimer was assigned as a major isomer by compari-
son to the 1H NMR of authentic epimer obtained from the
coupling of (S,S)-N-methyl pseudoephedrine and (S)-2-
bromobutanoic acid obtained from commercially available
(S)-2-aminobutyric acid.
6. General procedure for the asymmetric preparation of (R)-2-
tritylthiobutanol (15) and methyl (R)-2-tritylthiopropanoic
ester (16): To a solution of (aRS)-1 (or (aRS)-5) in
CH3CN (ca. 0.1 M) at room temp. was added Et3N (1.0
equiv.). The resulting reaction mixture was stirred at room
temperature for 24 h (or 2 h), and then trityl thiol (1.2
equiv.) was added. After 5 h, the solvent was evaporated
and the crude material was purified by column chromatog-
raphy to give 2b and 11 in 65 and 80% yield, respectively.
(a) After the addition of LiAlH4 (1.5 equiv.) to 2b in THF,
the mixture was stirred at rt for 18 h and then quenched
with EtOAc and water. Extractive workup and column
chromatography gave (R)-15 in 73% yield. 1H NMR
(CDCl3, 400 MHz) 7.54–7.19 (m, 15H), 3.14 (br, 1H), 2.91
(dd, J=5.3 and 5.3 Hz, 1H), 2.33 (m, 1H), 1.56 (m, 3H),
0.84 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
145.5, 130.0, 128.3, 127.1, 67.7, 63.4, 49.7, 25.5, 11.7. The
enantiomeric ratio of 15 was determined to be 96:4 in
favor of the R enantiomer by CSP-HPLC using racemic
material as a standard. (Chiralcel OD column; 5% 2-
propanol in hexane; 0.5 mL/min; the R-enantiomer
(major) had a retention time of 15.7 min, and the S-enan-
tiomer (minor) had a retention time of 16.8 min). (b) The
mixture of 11 and p-toluenesulfonic acid (0.1 equiv.) in
methanol were refluxed for 24 h. The solvent was evapo-
rated and the crude material was purified by column
chromatography to give (R)-16 in 88% yield. 1H NMR
(CDCl3, 400 MHz) 7.45–7.19 (m, 15H), 3.46 (s, 3H), 2.98
(q, J=7.4 Hz, 1H), 1.19 (d, J=7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) 174.4, 144.8, 130.1, 128.3, 127.2, 68.6,
52.5, 42.8, 19.2. The enantiomeric ratio of 16 was deter-
mined to be 97:3 in favor of the R enantiomer by CSP-
HPLC using racemic material as a standard. (Chiralcel
OD column; 10% 2-propanol in hexane; 0.5 mL/min; the
R-enantiomer (major) had a retention time of 9.7 min, and
the S-enantiomer (minor) had a retention time of 10.3
min). For the conversion of 16 to 2-mercapto propanoic
acid, 16 was treated with 1:1 mixture of 0.5 M NaOH and
dioxane for 5 h at room temperature. After acidic workup,
the organic phase was concentrated. The residue was
dissolved in 1:1 mixture of methylene chloride and trifl-
uoroacetic acid and Et3SiH (1.0 equiv.) was added. After
stirring for 1 h at room temperature, the reaction mixture
was concentrated and chromatographed on SiO2 to give
the trityl deprotected 2-mercapto propanoic acid in 93%
yield. [h]2D4=+24.0° (c=0.13, CHCl3).
Acknowledgements
This paper was supported by Konkuk University in
2002.
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