I. Total synthesis of bistratamide D. II. Investigations of chiral non-racemic 5,7-bicyclic lactams

Abstract

I. Due to a continued interest shown by the Meyers group in the construction of nitrogen-containing heterocycles, the synthesis of bistratamide D was undertaken. The synthetic strategy involved the convergent assembly of enantiomerically pure oxazole, thiazole, and oxazoline segments, which were derived from amino acid starting materials. Carbodiimide-mediated peptide coupling was utilized to synthesize an oxazole-thiazole tetrapeptide, as well as oxazoline-oxazole-thiazole and oxazolethiazole-oxazoline hexapeptide sequences. The title compound was prepared in fair yield by macrolactam ization of either of these two hexapeptide sequences utilizing O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (HATU). II. The synthesis and utility of a novel class of compounds, the 5,7-bicyclic lactams, are described. Compounds produced by the cyclodehydration of (R)-phenylglycinol with ω-keto acids were obtained as separable diastereomeric mixtures (~2:1 at the angular center) in low yields (~40%). Higher chemical yields (65-87%) were realized through either the use of a keto acid conformationally constrained by a cis-aikene (cyclodehydration method), or by the use of a ring closing metathesis strategy to synthesize the bicyclic structure. Neither modification, however, provided improvement in the product diastereoselection. Stereoselective reductions of the 5,7-bicyclic lactams occurred with the use of alane or lithiumaluminum hydride, affording amino alcohols of the R configuration at the 2-position, in good to moderate yields (50-88%). Selectivity was also observed in the diisobutylaluminum hydride reduction of the endo lactam epimers, affording amino alcohols of the opposite configuration at C-2. Rationalization for the selectivity in both cases was described to derive from an intramolecular transfer of hydride from the precoordinated aluminum reagent to the angular center before complete planarity of the iminium ion was realized. Complexation of the reagent to the less congested face of the bicyclic systems results in "retention" of the relative stereochemistry at this chiral center. Lastly, hydrogenolytic cleavage of the benzyl moiety afforded chiral 2-substituted perhydroazepines in good yields, and good enantiomeric excesses (84-94%).