Cyclic β-amino acid derivatives: synthesis via lithium amide promoted tandem asymmetric conjugate addition–cyclisation reactions

Abstract

The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-beta-amino ester (derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-beta-amino ester derivative (derived from double conjugate addition) in high de. The introduction of a protected nitrogen functionality into the diester skeleton facilitates, after conjugate addition and intramolecular enolate cyclisation, the asymmetric construction of piperidines in high de; variation in the N-protecting group indicates that the highest stereoselectivity is observed with alpha-branched N-substituents. Tandem conjugate addition-aldol reactions can also be achieved stereoselectively, with lithium amide conjugate addition to epsilon- and zeta-oxo-alpha,beta-unsaturated esters giving the corresponding five and six membered cyclic beta-amino esters in high de. N-deprotection by hydrogenolysis of the products arising from these reactions furnishes a range of polyfunctionalised transpentacin and transhexacin derivatives in high de and ee.

Concise Pathway to New Multifunctionalized Constrained Pentacin Derivatives by Means of Two Stereospecific Tandem Reactions

“…Introduction of an α,β-unsaturated ester at this position leading to the creation of a suitable ε-oxo-α,β-unsaturated ester sequence was crucial at this stage when the goal was to achieve subsequent conjugate addition/cyclization (MIRC). This methodology is well documented on acyclic α,β-diunsaturated diesters and also on ε-and ζ-formyl-α,β-unsaturated esters, [25] and we thought that the reaction could be extended to cyclic ketones to provide access to bicyclic pentacin structures. Instead of homochiral lithium N-benzyl-N-α-methylbenzylamide, our synthetic route involved achiral amines reacting on a chiral unit.…”

“…[25] To promote the tandem Michael addition and cyclization reaction, ε-oxo-α,β-unsaturated ester 4a previously prepared was heated at reflux in ethanol in the presence of benzylamine. A mixture of isomers 5a_1 and 5a_2 was obtained in an overall yield of 80 %, after back recovery of the starting material.…”

“…In the perspective of stereoselective synthesis of cyclic β-amino acids synthesis, the MIRC (Michael-initiated ring closure) reaction, a tandem conjugate addition/aldol reaction on ε-oxo-α,β-unsaturated esters, is probably the most extensively applicable. Initiated by Yamamoto et al [29][30][31] and developed by Davies et al, [25] nucleophilic addition to α,β-unsaturated esters is followed by subsequent intramolecular cyclization of the resulting enolate onto an internal electrophilic entity. Aiming at the synthesis of rigid pentacin derivatives, we have applied this relevant reaction to a suitable chiral synthon fashioned from a regioselective and stereospecific tandem reaction: the transannular rearrangement of activated lactams (TRAL)/alkylation (Scheme 2).…”

Synthesis of Carbocyclic and Heterocyclic β-Aminocarboxylic Acids

“…Similarly to the transformations presented above, enantiomerically pure 5-and 6-hydroxylated cyclopentane-and cyclohexanecarboxylic acids (93) were obtained (Scheme 16). 21 The parallel kinetic resolution of substituted unsaturated esters is an interesting application of chiral amide conjugate addition. Addition of a 1:1 mixture of a pseudoenantiomeric mixture of (S)-80 and (R)-98 ( Figure 7) to racemic 5-tris(phenylthio)methylcyclopent-1-enecarboxylate (95, derived from 94) provided tris(phenylthio)amino ester derivatives 96 and 97 with de higher than 98% (Scheme 17).…”

“…Starting from a diene dicarboxylate, conjugate addition followed by ring closure by using chiral lithium amide (S)-80 proceeded with high diastereoselectivity to give the corresponding aminocyclohexanecarboxylates. 21 Hydroxy-functionalized cyclopentane or cyclohexane β-amino acids were prepared by applying the conjugate addition−ring closure procedure. Unsaturated formyl carboxylates (91) served as suitable starting materials for this purpose.…”