Thio-Claisen rearrangement on pyroglutamates

Terrahedron

0040.4039(95)0173

Thio-Claisen

Sanjay

Medicmal

Jain,

Chemistry

I-3

Rearrangement

Neelima

Divrsion,

Sinha,

Central

Dinesh

Drug

Lerrers, Vol. 36. No. 46, pp. 8467.8468, 1995 Elsevier Science Ltd Printed m Great Britam oao-4039/95 $9.50+0.00

Research

on Pyroglutamates’

K. Dikshit

Institute,

Abstract: S-a//y/ / propargyl / methallyl thioimminium I-benzyl-5-thioxoprolinafe (1) undergoes a facile thio-Claisen an easy access to 4-substituted fhioxoprolinales (2-4).

8 Nitya Anand’

Lucknow

saks derived rearrangement

226001,

India

from methyl which provides

Many natural products and bra-actrve compounds have substituted pyrrolidine skeleton and therefore various approaches for their synthesis are of importance2. Pyroglutamates have recently emerged as useful synthons for chiral synthesis of substituted pyrrolidines and various approaches for C-4 and C-5 functionalisation have been described3. A particularly useful approach for C-4 and C-5 functionalrsation of pyroglutamate is via use of activated lactams and thiolactams4 which has been a subject of our investigations5 In the present communication we describe thio-Claisen rearrangement6 of methyl I-benzyl-5thioxoprolinate which provides a convenient method for the synthesis of C-4 substituted throxoprolinates. give the Thus methyl 1 -benzyl-5thioxoprolrnate 14a reacted with ally1 bromide to corresponding S-ally1 thioimminium salt (not isolated) which on treatment with triethyl amine in underwent facile thio-Claisen rearrangement to give methyl 4-allylchloroform I-benzyl-5thioxoprolinate 2 in 78% yield, as a 1.5.1 mixture of diastereomers (4-a 2a’, 4-p 2b8). The structural assignments were made by ‘H NMR, nOe difference spectroscopy and decoupling experiments.

1 RX w

+

2 CHCIJ / EtaN

S Ci$Ph

Cl$Ph

C+Ph

2-4.a

2-4b

1 2

R=

-CH2CHCH,

3

R=-CHCCH2

4

R = - CH C(Me)

CH>

Similar reactions of 1 with propargyl bromide and methallyl chloride gave the corresponding methyl 4-(allenyl/ methallyl)-I-benzyl-5-throxoprolinate (3-4a & 3-4b) as a mixture of diastereoisomers in 66 and 74% yields respectively. However similar reactions of 1 with cyclohexenyl bromrde, which would have constituted a simple approach for the synthesis of

8468

trams-4-cyclohexyl-l-proltne, a key Intermediate in the synthesis of Fosenopril, an ACE inhibitor, were unsuccessful even when strong bases (DIPEA, DBU) were used. The observed lack of drastereoselectivity at C-4 in such thio-Claisen rearrangement is not surprising as similar low order of selectivity has also been reported in reactions of Lithium enolates of pyroglutamatesg with electrophiles at C-4 Typical procedure: A mixture of 1 [50 mmol] and ally1 bromide [50 mmol] was stirred at 30°C for 0.5lh. Dry chloroform (50 ml) was added to this mixture, followed by triethyl amine (52 mmol] and the reaction mrxture was stirred at 30°C for 15 min. The reaction mixture was washed with water and brtne, dried (Na2S04) and concentrated to give 2, as a mixture of diastereoisomers which were separated by column chromatography on a silica gel column using hexane - ethyl acetate as eluant. Acknowledgement: We are grateful to the CSIR for financial support for this work and for Research Associateship to SJ. We thank Dr PK. Misra for the NMR spectral data.

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