Asymmetric synthesis of 2-alkyl-perhydroazepines from [5,3,0]-bicyclic lactams

The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the cyclodehydration of (R)-phenylglycinol with omeg a -keto acids, lactams 4-6 were obtained as separable diastereomeric mixtur es (similar to2:1) in low yields (similar to 40%). Higher chemical yield (u p to 61%) was realized tia an alternate route involving ring closure metath esis of 2-allyl-N-acroyl oxazolidines, 8. Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a, occurred with the use of alane or lithium aluminum hydride, affording azepine alcohols, 11a and;15a, of the R configu ration at the 2-position, in good to moderate yields (50-88%). High selecti vity was also observed in the diisobutylaluminum hydride reduction of the e pimeric anti lactams, 4b and 5b, affording azepine alcohols, 11b and 15b, o f the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiet y afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric excesses (84-94%).