Azabicyclic Amino Acids by Stereoselective Dearomatizing Cyclization of the Enolates of N-Nicotinoyl Glycine Derivatives

Abstract

[Structure: see text] On activation by pyridine N-acylation, enolates of N-nicotinoyl and N-isonicotinoyl glycine and alanine derivatives cyclize to yield 6,5-azabicyclic or 6,4-azaspirocyclic lactams. With an N-alpha-methyl-p-methoxybenzyl group the cyclization is diastereoselective; hydrogenation and deprotection yields azabicyclic amino acids in 94:6 er.

Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

“…We assume, in line with previous results [39], that cyclisation occurs only after the addition of the electrophilic trap (which, precedent suggests, attacks the pyridine lone pair and activates the ring as an acylpyridinium species even in the presence of the lithium enolate). Attempts to use bases with a sodium or potassium counter ion led instead to a high yield of the Claisen product 6 (R = Me), presumably because the sodium and potassium enolates are more reactive than the lithium enolate and compete too well with N-acylation.…”

“…However, immediate hydrogenation at ambient pressure using the conditions developed by Arnott for related 3,4-fused dihydropyridines [39] gave 15 in 45% yield after chromatography as an inseparable mixture of two diastereoisomers in a ratio of approximately 6:1. A slightly improved yield of 48% was obtained by the use of an H-cube flow hydrogenation apparatus at 40 bar and 30 °C.…”

“…While reactive carbanions derived from allyl or benzyllithiums will undergo dearomatising addition even into relatively electron rich rings [35–38], the scope of the dearomatisation can be extended to much less reactive nucleophiles with a more electron deficient aromatic acceptor [39–41]. Thus enolates of glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substituents cyclise readily to yield bicyclic amino acid derivatives 2 (Scheme 1 for example) [39].…”

“…Thus enolates of glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substituents cyclise readily to yield bicyclic amino acid derivatives 2 (Scheme 1 for example) [39]. Even greater reactivity towards intramolecular nucleophilic attack is exhibited by isonicotinamides when activated by N-sulfonation [40–41].…”

Synthesis and reactivity of spiro-fused β-lactams

“…The cyclisation of enolates from glycine derivatives 75 (R 3 = H), generated from N-nicotinoyl and N-isonicotinoyl glycine, and the corresponding alanine derivatives (R 3 = Me) took place with dearomatisation of the pyridine ring forming 2-azetidinones 76 spiro-fused to a dihydropyridine moiety (Scheme 24). 42 These reactions occur with a benzylic group at the amide nitrogen as well. Baran's approach to synthesise chartelline started from a simple -amino ester 88, which was transformed into a complex amide 89 through a number of steps.…”