Expeditious amide-forming reactions using thiol esters

Article abstract of DOI:10.1016/S0040-4039(99)02132-2

The reaction of a 2-pyridylthiol ester with a dimethylaluminum amide leads to the rapid formation of the corresponding amide. The tolylthiol esters can be activated with silver trifluoroacetate and coupled even with poorly reactive amino compounds. (C) 20

Full text of DOI:10.1016/S0040-4039(99)02132-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 591–594
Expeditious amide-forming reactions using thiol esters
∗
Michio Kurosu
Department of Chemistry, The Florida State University, Tallahassee, Florida 32306, USA
Received 5 October 1999; revised 11 November 1999; accepted 12 November 1999
Abstract
The reaction of a 2-pyridylthiol ester with a dimethylaluminum amide leads to the rapid formation of the
corresponding amide. The tolylthiol esters can be activated with silver trifluoroacetate and coupled even with
poorly reactive amino compounds. © 2000 Elsevier Science Ltd. All rights reserved.
The direct conversion of esters into amides is an ideal method in the syntheses of peptides in
terms of the reduction of the deprotection step(s) at the C-terminus needed for usual peptide-forming
reactions. Thiol esters are versatile intermediates in natural product syntheses; e.g. Lewis acid-catalyzed
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2
3
4
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asymmetric aldol-type reactions, kinetic resolutions, synthesis of aldehydes, esters, lactons, and
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ketones. However, application of thiol esters in peptide-forming reactions has not been thoroughly
investigated. In peptide synthesis, it is essential to prevent base-catalyzed racemization during coupling
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reactions. The conditions to circumvent this problem are: (1) reducing the lifetime of the racemization
prone species; and (2) omission of tertiary amines from the reaction mixture.
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-Pyridylthiol esters are stable to Brønsted acids (e.g. TFA in CH Cl at 0°C to deprotect N-Boc
2 2
groups), as well as to Lewis acids (e.g. diethylaluminum chloride in CH Cl ). They are highly reactive
2
2
with nucleophiles under basic conditions.
Taking advantage of the nature of trimethylaluminum, which reacts with primary or secondary amines
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with the evolution of methane to give dimethylaluminum amides, the reactivity of 2-pyridylthiol ester
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1
to the dimethylaluminum amide generated from H-L-Phe-OMe (3) was examined. This reaction was
completed at 0°C within 10 min to afford Z-L-Val-L-Phe-OMe (4). The expeditious peptide-formation
observed would result in the dual activation of amino group and 2-pyridylthiol ester by aluminum
species. Interestingly, the dimethylaluminum amide of 3 did not react with tolylthiol ester 2 under the
same conditions. On the other hand, tolylthiol ester 211 could be coupled with H-L-Phe-OMe (3) in the
presence of silver trifluoroacetate in toluene at 60°C within 20 min to afford dipeptide 4. In a competition
reaction between 2-pyridylthiol ester 1 and tolylthiol ester 2 with the dimethylaluminum amide of 3,
after 1 was completely consumed, 95% of 2 was recovered. In the same competition reaction using
AgOCOCF , 1 was recovered in 90% yield after the reaction (Scheme 1).
3
∗
Corresponding author. Fax: (850) 644-2333; e-mail: kurosu@chem.fsu.edu (M. Kurosu)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02132-2
tetl 16060

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Scheme 1.
These competition reaction studies are given to show the applicability of thiol esters as a protecting
group for the C-terminus of amino acids and the utility of this rapid and simple method for the formation
of peptide bond under mild conditions. More conveniently, Me Al promoted coupling reactions were
3
accomplished by the addition of two equivalents of Me Al into a mixture of the amino acid ester
3
hydrochloride and the 2-pyridylthiol ester. The peptide formation with thiol esters of urethane-protected
amino acids was verified and is summarized in Table 1.12
Table 1
The usefulness of these protocols was demonstrated by the synthesis of tripeptide 7 as illustrated in
Scheme 2. The coupling reaction between Z-L-Val-SPy (1) and H-L-Phe-STol (5) with one equivalent
of Me Al at 0°C for 10 minutes afforded dipeptide 6 in 75%, which was subsequently coupled with
3
H-L-Phe-OMe (3) using AgOCOCF at 60°C to give tripeptide 7 in 90% yield.
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13,14
In order to assess how powerful these peptide-forming reactions are, H-N-OBn-L-Ala-OEt (8)
was
chosen as an acceptor amino acid. 2-Pyridylthiol ester 1 and 8, using Me Al, did not afford the coupling
3
product 9; starting material was recovered after the reaction. In contrast, tolylthioester 2 reacted with
H-N-OBn-L-Ala-OEt in the presence of AgOCOCF to afford the desired dipeptide 9 in 55% yield when
3
2
equivalents of 8 were used (Scheme 3). N-Hydroxy-α-amino acids show no reactivity to conventional

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Scheme 2.
peptide forming reactions using DCC or BOP.15 This method is shown to be a powerful peptide forming
reaction. It is especially useful for the reaction of amino acids having the diminished nucleophilicity on
nitrogen.
Scheme 3.
In conclusion, it has been demonstrated that the reactions of thiol esters (2-pyridylthiol ester and
tolylthiol ester) with different promoters (trimethylaluminum and silver trifluoroacetate, respectively)
constitute an efficient method for rapid synthesis of peptides. Significantly, the generated peptides from
two different types of thiol amino acid esters can be utilized directly to the next coupling reaction. The
application of these protocols for the synthesis of apoptosis-inducing cyclic depsipeptide polyoxypeptin
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A
is in progress.
General Procedure for Z-L-Val-L-Phe-OMe. Method A (Me Al promoted coupling reaction): To a
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stirred suspension of Z-L-Val-SPy (100 mg, 0.279 mmol) and HCl·H-L-Phe-OMe (120 mg, 0.558 mmol)
in CH Cl (2 mL) at 0°C was added Me Al (0.558 mL, 1.116 mmol, 2 M in toluene). After 10 min at
2
2
3
0°C, the reaction mixture was quenched with t-butanol and acidified with 0.1N HCl. The aqueous layer
was extracted with CH Cl . The combined extracts were dried over Na SO , filtered, and concentrated in
2
2
2
4
vacuo. The crude dipeptide was purified by silica gel chromatography (2:1:1, hexanes:EtOAc:CH Cl )
2
2
to afford Z-L-Val-L-Phe-OMe (89.2 mg, 75%). Method B (AgOCOCF promoted coupling reaction):
3
To a stirred solution of Z-L-Val-STol (100 mg, 0.283 mmol) and H-L-Phe-OMe (101 mg, 0.566 mmol)
in toluene (2 mL) was added AgOCOCF (62.5 mg, 0.283 mmol). The reaction mixture was warmed
3
to 60°C. After 20 min, the reaction mixture was cooled, and quenched with aqueous NH OH. The
4
aqueous layer was extracted with CH Cl . The combined extracts were dried over Na SO , filtered, and
2
2
2
4
concentrated in vacuo. Purification by the same conditions as Method A afforded Z-L-Val-L-Phe-OMe
108 mg, 90%).
(
Acknowledgements
The author is grateful to Professors Y. Kishi (Harvard University), M. Schwartz, R. Holton and M.
Krafft (The Florida State University) for their guidance and encouragement. Financial support was
provided by The Florida State University.

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1
1
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1. The esterification reactions of tolylthiol ester with secondary or tertiary alcohols are approximately two times faster than
those of benzenethiol ester with silver trifluoroacetate. These results indicate that alkyl substitution in para position of aryl
group enhances the reactivity toward the thiophilic reagents.
1
12. In order to examine the extent of racemization, a diastereomixture of Boc-DL-Tyr(Me)-L-Phe-OMe was synthesized from
Boc-DL-Tyr(Me)-SPy and HCl·H-L-Phe-OMe using Me
OMe, synthesized from Boc-L-Tyr(Me)-SPy and HCl·H-L-Phe-OMe in the same manner, using H NMR revealed that no
detectable racemization occurred. Boc-L-Tyr(Me)-L-Phe-OMe synthesized by the AgOCOCF promoted peptide-forming
3
Al. Comparison of this mixture with Boc-L-Tyr(Me)-L-Phe-
1
3
1
reaction with Boc-L-Tyr(Me)-STol and H-L-Phe-OMe showed a single diastereomer by H NMR.
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A. A.; Caldwell, C. G. Tetrahedron Lett. 1990, 31, 1237. (b) Wang, Q. X.; Phanstiel, O, IV. J. Org. Chem. 1998, 68, 1491.
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1
1
1
1
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