Total Synthesis of (−)-(α)-Kainic Acid via a Diastereoselective Intramolecular [3 + 2] Cycloaddition Reaction of an Aryl Cyclopropyl Ketone with an Alkyne

Abstract

An enantioselective synthesis of (-)-(α)-kainic acid in 15 steps with an overall yield of 24% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with complete diastereoselectivity via an unprecedented SmI2-catalyzed intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone and an alkyne. Double bond isomerization was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis

“…A particularly impressive example, the enantioselective synthesis of (´)-α-kainic acid (60), in which Zhou and Li et al present a unique SmI 2 -catalyzed [3 + 2] intramolecular cycloaddition reaction with excellent diastereoselectivity, is summarized in Scheme 12 [37,38]. The key precursor, cyclopropane 56, was synthesized from D-serine methyl ester HCl (55) using conventional protocols.…”

SmI2-catalysed cyclization cascades by radical relay

“…Key to the catalytic radical process is the spring-loaded nature of ketyl radical I which is formed by reversible SET from SmI 2 to substrate 1a. Ketyl radical I fragments 32,33 to give distal radical II. Cyclization then generates radical III which rebounds by addition to the Sm(III)-enolate moiety, regenerating new ketyl radical IV.…”

Recent Progress in the Stereoselective Synthesis of (−)‐α‐Kainic Acid

“…[11] In 2012, Li and co-workers reported the synthesis of (À )-α-kainic acid in enantiopure form in 15 linear steps from inexpensive D-serine methyl ester hydrochloride, using a SmI 2 catalyzed intramolecular [3 + 2] radical cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne as the key step (Scheme 2). [12] Initially, the commercially available D-serine was transformed into key olefin 6 by following the classical synthetic sequence. Cyclopropanation of olefin 6 with Me 3 SOI followed by N-alkylation with 1-bromo-2-butyne delivered the key precursor 7.…”

“…In 2012, Li and co‐workers reported the synthesis of (−)‐α‐kainic acid in enantiopure form in 15 linear steps from inexpensive D ‐serine methyl ester hydrochloride, using a SmI 2 catalyzed intramolecular [3+2] radical cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne as the key step (Scheme 2). [12] …”