Total Syntheses of (–)‐α‐Kainic Acid

Abstract

Kainoid amino acids are a unique group of non‐proteinogenic pyrrolidinedicarboxylic acids. The parent member, (–)‐α‐kainic acid (originally known as digenic acid), has attracted considerable interest, largely because of its neuroexcitatory properties, as well as its pronounced insecticidal and anthelmitic activities. Because these activities are strongly due to its stereochemistry, (–)‐α‐kainic acid represents a considerable synthetic challenge, and many groups have therefore reported syntheses of kainic acids, as well as of kainoid analogues. This article is intended to review the total synthesis of kainic acid from 1996 until the end of 2011.

Scalable Biosynthesis of the Seaweed Neurochemical, Kainic Acid

“…[9] In fact, kainic acid was important in the initial discovery and characterization of several classes of iGluRs,s uch as the eponymous kainate receptor, [10] and has been exploited to create mouse model systems to study neurological diseases, [11] particularly temporal lobe epilepsy. [14] These syntheses employ diverse methods to produce the kainoid ring pharmacophore such as ring opening followed by cyclization, [15] ene-cyclization, [16] or radical formation. [14] These syntheses employ diverse methods to produce the kainoid ring pharmacophore such as ring opening followed by cyclization, [15] ene-cyclization, [16] or radical formation.…”

“…[12,13] In the 50 years since kainic acid was isolated, over 70 synthetic routes have been established ( Figure 1). [14] These syntheses employ diverse methods to produce the kainoid ring pharmacophore such as ring opening followed by cyclization, [15] ene-cyclization, [16] or radical formation. [17] Unfortunately,c hallenges in generating the three contiguous stereocenters often limit these approaches to low yields or many steps.I nc ontrast to the synthetic work, little progress has been made on elucidating how kainic acid is constructed by seaweeds.R ecently,w ee stablished the biosynthetic logic for domoic acid production in microalgal Pseudo-nitzschia multiseries diatoms through the discovery of af our-gene cassette (dabA-D)a nd the confirmation of their in vitro enzymatic functions ( Figure 2A).…”

A Short Scalable Route to (−)‐α‐Kainic Acid Using Pt‐Catalyzed Direct Allylic Amination

“…The huge demand for (−)‐α‐kainic acid ( 1 ) in the neuroscience field and its limited supply from natural sources has resulted in a worldwide shortage and a high price of 1 8. Although 1 is a potential target for total synthesis, the construction of three contiguous stereogenic centers in the pyrrolidine ring, especially the thermodynamically less favorable C3–C4 cis configuration, is highly challenging 9. Since the pioneering achievement of the enantioselective synthesis of 1 by Oppolzer and Thirring,10 several efficient total syntheses of 1 have been reported 11.…”

A Unified Strategy for Kainoid Synthesis

“…[11i,11j] Synthetic routes to the kainoids have been extensively explored, not only as a result of their importance in the field of neuroscience, but also due to their unique struc-4-position of the pyrrolidine ring, starting from the common intermediate and appropriate acetic acid derivatives. [12][13][14] To date, more than 50 syntheses of kainic acid, and several syntheses of domoic acid, [15] the isodomoic acids, [16] and the acromelic acids, [9a,17] have been reported. tures.…”