Use of trityl thiol for stereoselective thioester synthesis: A new preparation of (S)-thiolactic acid

Article abstract of DOI:10.1016/S0040-4039(00)00249-5

Trityl thiol is found to be a convenient reagent for the enantioselective preparation of (S)-thiolactic acid and a muramic acid thioester. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00249-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2729–2731
Use of trityl thiol for stereoselective thioester synthesis:
a new preparation of (S)-thiolactic acid
Ross L. Harding and Timothy D. H. Bugg ∗
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Received 10 December 1999; accepted 9 February 2000
Abstract
Trityl thiol is found to be a convenient reagent for the enantioselective preparation of (S)-thiolactic acid and a
muramic acid thioester. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: thiols; thioesters; enzyme reactions.
Peptide thioesters are convenient reagents for the assay of a wide range of protease and peptidase
enzymes, via release of a thiol equivalent and reaction with a chromogenic thiol reagent such as 5,50-
dithiobis(2-nitrobenzoic acid) (DTNB).1 For endo-peptidases which require an oligopeptide substrate
containing a central thioester linkage, such thioester substrates must incorporate a functionalised thiol
component, which may contain one or more chiral centres. Few methods are available for the stereo-
selective introduction of sulphur, the most widely used reagent being thioacetic acid, a noxious liquid
whose acyl protecting group is prone to hydrolysis under basic conditions.2
(S)-Thiolactic acid, a useful starting material for synthesis of anti-platelet activating factor agents,3
has previously been prepared using thioacetic acid via a selective enzymatic deprotection method.4
In the course of the preparation of peptide thioester substrates for the enzyme N-acetyl-muramyl-
L-alanine amidase,5 we have developed a method for the convenient introduction of sulphur in a
stereoselective fashion using trityl (triphenylmethyl) thiol, a reagent which has not previously been used
for stereoselective synthesis.6 We report here its application for the synthesis of (S)-thiolactic acid and
its incorporation into a complex thioester.
Trityl thiol (1) was prepared by the method of Balfe et al. via reaction of triphenylmethanol with
hydrogen sulfide in acidic solution, in quantitative yield.7 Reaction of trityl thiol with (R)-ethyl chloro-
propionate (2) in the presence of sodium methoxide proceeded cleanly to give the protected thioether (3)
(Scheme 1). A sample of (3) was deprotected by treatment with 0.5 M aqueous sodium hydroxide:1,4-
dioxane (1:1),8 then trifluoroacetic acid/triethylsilane to give (S)-thiolactic acid, which was found to be
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00249-5
tetl 16529

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enantiomerically pure upon treatment with chiral shift reagent Eu(hfc)3, compared with a sample of
racemic thiolactic acid.
Scheme 1.
The absolute configuration of (3) was confirmed by synthetic conversion to the dipeptide derivative
(5). The methyl ester of (3) was deprotected by treatment with 0.5 M aqueous sodium hydroxide:1,4-
dioxane (1:1)8 to give acid (4) (Scheme 2). DCC coupling with either D-alanine diphenylmethyl ester
or D-alanine amide gave the dipeptide analogues (5) or (6), respectively. Crystals of dipeptide ester (5)
grown by vapour diffusion from isopropanol/water were suitable for X-ray diffraction, and determination
of the X-ray crystal structure confirmed that the thiolactyl chiral centre has the S configuration. Analysis
1
of the H NMR spectrum of dipeptide amide (6) showed no evidence of epimerisation at the sulphur
centre. The lack of racemisation upon hydrolysis is noteworthy, and is precedented for trityl-protected
cysteine derivatives.8
Scheme 2.
Deprotection of the trityl thioether was achieved by treatment of (6) with trifluoroacetic acid in the
presence of triethylsilane (2 equiv.), which gave the deprotected thiol (7) in quantitative yield. Coupling
with a protected muramic acid derivative then formed the thioester linkage in 62% yield.9
Thus, trityl thiol can be used for the clean SN2 displacement of a secondary halide, which proceeds
with inversion of configuration. The trityl thioether product can be deprotected selectively at sulphur
under acidic conditions, or at a carboxyl terminus under basic conditions. Trityl thiol offers practical
advantages over reagents such as thioacetic acid, being an odourless crystalline solid which can be
prepared in quantitative yield and is easily stored. It is of sufficient reactivity to be of use for the
preparation of a variety of complex sulphides and thioesters. The preparation and biological evaluation
of peptide thioester substrates for N-acetyl-muramyl-L-alanine amidase will be reported in due course.

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Acknowledgements
We thank EPSRC for the provision of a studentship (R.L.H.).
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