Stereoselective Formal Synthesis of (+)-Allokainic Acid <i>via</i> Thiol-Mediated Acyl Radical Cyclization

Abstract

Stereoselective formal synthesis of (؉)-allokainic acid was accomplished starting from L-glutamate by using a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly diastereoselective manner to give trans-4,5-disubstituted pyrrolidin-3-one without the production of the cis-isomer. The pyrrolidinone was then converted into the established synthetic intermediate of (؉)-allokainic acid via the iron-catalyzed coupling reaction with an isopropenyl Grignard reagent.

Iron-promoted C–C bond formation in the total synthesis of natural products and drugs

“…53 Yamada also reported in their formal total synthesis of (+)-allokainic acid the use of an iron-catalysed coupling between a vinyl Grignard and a secondary bromoalkyl derivative 78, although the yield of 79 remained low (36%) due to competitive opening of the pyrrolidine ring (Scheme 29). 54 Iodocholestene was successfully reacted with an alkynyl Grignard reagent 80 under iron(II)-catalysis to afford the natural product derived compound 81 in moderate yield (50%) and selectivity favouring retention of conguration (dr ¼ 7 : 1) (Scheme 30). 55 In 2015, an important breakthrough was reported by Nakamura who performed a Fe-catalysed enantioselective crosscoupling of racemic a-chloroesters with aryl Grignard reagents in presence of a C 2 -symmetric bisphosphine ligand.…”

Photophysical/Photochemical, Kinetic, and Migration Stability Studies of One‐Component Polymerizable Thioxanthone‐Based Photoinitiators

“…Moreover, the intramolecular free radical conjugated additions have been widely demonstrated as the useful tools in the construction of cyclic molecules. [ 37–39 ] Thus, it implied the possibility of the formation of cyclic molecules or intermediates in our case.…”

High‐Performance and Low Migration One‐Component Thioxanthone Visible Light Photoinitiators

“…As the mechanism aforementioned, once the aminoalkyl radical yielded, it was transferred to acryloxy group and the propagation of radical occurred. The intramolecular free radical conjugated additions have been widely demonstrated as the useful tools in the construction of cyclic molecules . Thus, it implied the possibility of the formation of the cyclic molecules or intermediates in our case.…”