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Asymmetric Synthesis of 2-Alkyl-Perhydroazepines from [5,3,0]-Bicyclic Lactams

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journal contribution
posted on 24.01.2001, 00:00 by A. I. Meyers, Susan V. Downing, Michael J. Weiser
The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the cyclodehydration of (R)-phenylglycinol with ω-keto acids, lactams 46 were obtained as separable diastereomeric mixtures (∼2:1) in low yields (∼40%). Higher chemical yield (up to 61%) was realized via an alternate route involving ring closure metathesis of 2-allyl-N-acroyl oxazolidines, 8. Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a, occurred with the use of alane or lithiumaluminum hydride, affording azepine alcohols, 11a and 15a, of the R configuration at the 2-position, in good to moderate yields (50−88%). High selectivity was also observed in the diisobutylaluminum hydride reduction of the epimeric anti lactams, 4b and 5b, affording azepine alcohols, 11b and 15b, of the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiety afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric excesses (84−94%).