S-4-Methoxytrityl mercapto acids: Synthesis and application

Article abstract of DOI:10.1016/S0040-4039(01)01423-X

4-Methoxytrityl (Mmt)-mercapto acids were obtained either by the reaction of mercapto acids with Mmt-chloride or by the reaction of halo acids with Mmt-thiol. The derivatives obtained were used in the solid-phase synthesis of small libraries of mercaptoacylamino acids and mercaptoacyl peptides. The removal of the Mmt-group was performed by treatment with trifluoroacetic acid (TFA) in dichloromethane (DCM) using triethylsilane (TES) as scavenger.

Full text of DOI:10.1016/S0040-4039(01)01423-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6965–6967
S-4-Methoxytrityl mercapto acids: synthesis and application
Spyros Mourtas, Dimitrios Gatos, Vagiani Kalaitzi, Christina Katakalou and Kleomenis Barlos*
Department of Chemistry, University of Patras, Patras, Greece
Received 1 June 2001; revised 23 July 2001; accepted 2 August 2001
Abstract—4-Methoxytrityl (Mmt)-mercapto acids were obtained either by the reaction of mercapto acids with Mmt-chloride or by
the reaction of halo acids with Mmt-thiol. The derivatives obtained were used in the solid-phase synthesis of small libraries of
mercaptoacylamino acids and mercaptoacyl peptides. The removal of the Mmt-group was performed by treatment with
trifluoroacetic acid (TFA) in dichloromethane (DCM) using triethylsilane (TES) as scavenger. © 2001 Elsevier Science Ltd. All
rights reserved.
Mercapto acids are constituents of important drugs
such as the enzyme inhibitors captopril 11,2 and thior-
phane 23,4 and the radio- and chemoprotective agent
tiopronine 3. In addition, mercaptoacyl dipeptides are
strong dual peptidase inhibitors.5 For the development
of new drugs using solid-phase combinatorial methods,
suitably S-protected mercapto acid derivatives are
required.
chloride or by the reaction of alkyl halides with
Trt-thiol.7,8 The removal of the S-Trt-group requires
treatment with concentrated TFA and is reversible. In
contrast, the S-Mmt-group is very acid-labile and can
be removed by 1% TFA selectively in the presence of
protecting groups of the tert-butyl-type.9 To obtain
very acid labile protected derivatives of mercapto acids,
we synthesised the corresponding S-Mmt-derivatives.10
Thus, we treated the mercapto acids 5 with Mmt-chlo-
ride 4 and 90% of the calculated equimolar amount of
diisopropylethylamine (DIPEA) in DCM/dimethylfor-
mamide (DMF) (1:1) for 1 h at rt (Scheme 1). Under
these conditions no concurrent tritylation of the car-
boxy group was observed. We obtained the S-Mmt
protected linear chain acids 6 in 75–85% yield and
The trityl (Trt) group is an effective protecting group
for mercaptans and especially for the thiol-group of
cysteine.6 The synthesis of Trt-mercaptans can be per-
formed by treatment of mercapto-compounds with Trt-
>98% purity, D,L-thiolactic acid 7 and mercaptomethyl-
benzoic acids 8 and 9 in 75–80% yield and >97% purity.
For the preparation of the S-Mmt butyric acid the
corresponding sodium salt was used.
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01423-X

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S. Mourtas et al. / Tetrahedron Letters 42 (2001) 6965–6967
ple, the mixture of the Mmt-protected mercaptopropi-
onyl (Mpr)-amino acid library 14 was prepared by
coupling a threefold molar excess of Mmt-Mpr-OH 6b
to the resin-bound library 12 using diisopropylcarbodi-
imide (DIC)/1-hydroxybenzotriazole (HOBt) as the
condensing agent (Scheme 4). The reaction was com-
plete in 90 min at rt as determined by the Kaiser test,
indicating a similar coupling behaviour of S-Mmt-mer-
capto acids and N-protected amino acids. The library
14 was cleaved quantitatively from the resin by treating
13 with acetic acid (AcOH)/trifluoroethanol (TFE)/
DCM (1:2:7) for 15 min at rt. This left the S-Mmt
protection unaffected. The product mixture obtained
was analysed by RP-HPLC (Fig. 1). The individual
components were separated by semipreparative HPLC
and were identified by ES-MS.
Mercapto acids are of limited commercial availability
and they are usually prepared from the corresponding
halo acids. To avoid the reaction step required for the
conversion of the halo to the corresponding mercapto
acid, we reacted halo acids or esters with Mmt-thiol 10.
This was obtained as a crystalline compound (mp:
98–101°C) in 74% yield by the reaction of Mmt-chlo-
ride with hydrogen sulfide in DCM/DMF (1:1) for 3 h
at rt (Scheme 2).
For the preparation of the S-protected mercapto acids
we reacted halo acids or esters 11 with Mmt-thiol and
excess DIPEA in DMF for 4 h at rt (Scheme 3). No
by-products were detected in the reaction mixtures by
TLC and HPLC analysis. The S-Mmt esters were
hydrolysed with aqueous NaOH in dioxane/H2O (1:1)
for 2 h at rt, to yield the corresponding Mmt-mercapto
acids. Extractive work up of the reaction mixtures gave
6 as crystalline compounds in 75–85% yield and >96%
purity. Compounds 7, 8 and 9 were also obtained in
crystalline form by the reaction of Mmt-thiol 10 with
the corresponding halo acids in high yield and >98%
purity.
In contrast to the treatment with acetic acid, the S-
Mmt-function is very sensitive towards TFA. Thus
treatment of 6–9 with 1 and 5% TFA in DCM/TES
(95:5) for 45 and 5 min, respectively, at rt, effected
complete cleavage of the Mmt-group.
In a further application Mmt-mercaptobenzoic acid
(Mba) 9 was coupled with the resin bound 95–101
fragment 15 of prothymosin a (ProTa) (Scheme 5). The
S-Mmt protected peptide 17 was obtained by treating
16 with AcOH/TFE/DCM (1:2:7) for 15 min.
To examine the utility of the Mmt-derivatives 6–9 in
solid-phase synthesis we coupled them with small
amino acid libraries esterified on 2-chlorotrityl resin.11
The amino acids were chosen to enable the separation
of the products by semipreparative HPLC. As an exam-
Scheme 2.
Figure 1. Analytical HPLC of the crude library of 14a–e;
Column: Lichrospher RP-8, 5 mm; 4×150 mm; gradient from
20 to 100% B within 30 min; eluant A: 0.1% TFA in water,
eluant B: 0.1% TFA in acetonitrile; flow rate 1 ml/min;
detection at 254 nm.
Scheme 3.
Scheme 4.

S. Mourtas et al. / Tetrahedron Letters 42 (2001) 6965–6967
6967
Scheme 5.
Figure 2. (a) Analytical HPLC of 17 in DMF; Column: Nucleosil C8, 5 mm; 4×125 mm; gradient: from 50 to 100% acetonitrile
in water within 30 min; flow rate 1 ml/min; detection at 254 nm. (b) Analytical HPLC of 18 in DMF (conditions as in Fig. 2a).
(c) ES-MS analysis of purified 18 at 30 V.
Cleavage with 1% TFA in DCM/TES (95:5) gave the
selectively S-deprotected peptide 18, while cleavage
with 65% TFA in DCM/TES (95:5) for 1 h at rt, gave
the fully deprotected peptide 19. Peptides 17–19 were
precipitated from ether and their purity was detected by
HPLC analysis. Their correct mass was identified by
ES-MS (Fig. 2).
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Acknowledgements
We thank CBL-Patras for financial support.
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