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Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange
Author(s) -
Martínez Verónica,
Villamil Valentina,
Duarte Diego,
Saiz Cecilia,
Davyt Danilo,
Fontana Carolina,
Veiga Nicolás,
Mahler Graciela
Publication year - 2020
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201901677
Subject(s) - chemistry , iminium , imine , aldehyde , thiazolidine , metathesis , bond cleavage , enamine , combinatorial chemistry , stereochemistry , cleavage (geology) , organic chemistry , catalysis , polymer , geotechnical engineering , fracture (geology) , engineering , polymerization
Bisthiazolidines (BTZ) are bicyclic compounds considered as penicillin analogs that inhibit the full range of Metallo‐β‐Lactamases (MBLs) and potentiate β‐lactam activity against resistant bacteria. Herein, we present a new methodology to prepare 2‐substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranging from 31 to 75 %. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments, and a key imine 1b‐II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b‐III by i) a N‐assisted N–C bond cleavage, and ii) a thiol‐mediated 5 endo ‐trig cyclization followed by a C–N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b‐III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b‐V .