First chemoenzymatic synthesis of (+)‐2‐carboxypyrrolidine‐3‐acetic acid, the nucleus of kainoid amino acids

Abstract

The distinctive nucleus of kainoid amino acids, (2S,3R)-(+)-2-carboxypyrrolidine-3-acetic acid 6, was synthesized by a chemoenzymatic process, exploiting the diastereomeric cis/trans methyl pyroglutamate derivatives 10a-c/11a-c as key intermediates. These mixtures, when subjected to a kinetic resolution mediated by α-chymotrypsin, reacted diastereo-, regio-, and enantioselectively to give the trans derivatives (+)-10a-c possessing the correct (2S,3R) configuration. Subsequently, the desired product (2S,3R)-(+)-6 could be obtained after well-established transformations.

Design and Synthesis of 2,3-trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

“…Due to the limited availability of commercial vinyl bromides and the lengthy synthesis, we set out to find a more general and convenient procedure. Several other methods for the preparation of 3a have been reported, however none of these would allow for readily modification of the substituent on the ε-carbon. − We envisioned enone 10 as a suitable key intermediate for conjugate additions of different substituted malonates. Clearly, this strategy comes with the loss of absolute stereochemical control, which we accepted as the cost for a more feasible access to new analogues for a more comprehensive study of the structure–activity relationship (SAR).…”