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

The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide to dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-β-amino ester (derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-β-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 α-branched N-substituents. Tandem conjugate addition aldol reactions can also be achieved stereoselectively, with lithium amide conjugate addition to ε- and ζ-oxo-α,β- unsaturated esters giving the corresponding five and six membered cyclic β-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.