Bicyclic glutamic acid derivatives

For the second‐generation asymmetric synthesis of the trans‐tris(homoglutamic) acids via Strecker reaction of chiral ketimines, the cyanide addition as the key stereodifferentiating step produces mixtures of diastereomeric α‐amino nitrile esters the composition of which is independent of the reaction temperature and the type of the solvent, respectively. The subsequent hydrolysis is exclusively achieved with concentrated H2SO4 yielding diastereomeric mixtures of three secondary α‐amino α‐carbamoyl‐γ‐esters and two diastereomeric cis‐fused angular α‐carbamoyl γ‐lactams as bicyclic glutamic acid derivatives, gained from in situ stereomer differentiating cyclisation of the secondary cis‐α‐amino α‐carbamoyl‐γ‐esters. Separation was achieved by CC. The pure secondary trans‐α‐amino α‐carbamoyl‐γ‐esters cyclise on heating and treatment with concentrated H2SO4, respectively, to diastereomeric cis‐fused angular secondary α‐amino imides. Their hydrogenolysis led to the enantiomeric cis‐fused angular primary α‐amino imides. The configuration of all compounds was completely established by NMR methods, CD‐spectra, and by X‐ray analyses of the (αR,1R,5R)‐1‐carbamoyl‐2‐(1‐phenylethyl)‐2‐azabicyclo[3.3.0]octan‐3‐one and of the trans‐αS,1S,2R‐2‐ethoxycarbonylmethyl‐1‐(1‐phenylethylamino)cyclopentanecarboxamide. Chirality, 2006. © 2006 Wiley‐Liss, Inc.