Stereocontrolled Syntheses of Kainoid Amino Acids from 7-Azabicyclo[2.2.1]heptadienes Using Tandem Radical Addition-Homoallylic Radical Rearrangement

Abstract

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Kainate has a 2-carboxypyrrolidine-3-acetic acid backbone, and analogs containing this backbone, known as kainoids (Sonnenberg et al, 1996;Hodgson et al, 2005;Sagot et al, 2008;Bunch and Krogsgaard-Larsen, 2009), include domoic acid (Hampson et al, 1992;Alt et al, 2004) and acromelic acid (Kwak et al, 1992;Smith and McIlhinney, 1992). Agonist potency and efficacy are subunit-specific, because kainate and domoic acid are potent agonists of GluK1 and GluK2 but show low potency at GluK3 receptors (Table 6; Jane et al, 2009).…”

Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives

“…152,153 Another application aimed at the stereocontrolled syntheses of kainoid aminoacids is illustrated in Scheme 52. 154 In the latter case, the aminocyclopropane moiety is not part of the starting material but …”

“…Scheme 52. Stereocontrolled syntheses of kainoid aminoacids, relying on the radical ringclosure and ring-opening of an aminocyclopropane moiety 154. …”

“…Cyclopropane ringopening takes place under typical radical deoxygenation conditions to generate the radical 76, stabilised by the nitrogen atom. Two main types of reactivity are eventually observed: either direct trapping by Bu 3 SnH to produce 2-azabicyclo[2.2.1]hept-5-enes or a further β-fragmentation to produce the radical 77, which finally abstracts a hydrogen atom from Bu 3 SnH to give a dihydropyridine compound(Scheme 50, top) 152,153,154,155,156. The latter reaction pathway operates only when the starting radical precursor bears a radical-stabilising group R 1 (e.g.…”

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

“…Although 6 was shown 20 to not retain the kainate-type selectivity, it was recognized as an agonist of the N-methyl-D-aspartate (NMDA) receptor. 19 Whereas several strategies have been proposed for the asymmetric total syntheses of kainoid amino acids 2,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and other unnatural kainoids, [37][38][39][40][41][42][43][44][45] only a few asymmetric syntheses of optically active 6 with complete control of the stereochemistry have been proposed. [45][46][47][48][49][50] Biotransformations are a powerful tool to control the configuration of chiral centers in stereoselective synthesis, 51 although to our knowledge, this powerful synthetic approach has not been used in the asymmetric synthesis of CPAA 6.…”