DEVELOPMENT OF AN ASYMMETRIC APPROACH TO THE 3,8-DIAZABICYCLO[3.2.1]OCTANE MOIETY OF QUINOCARCIN VIA INTERMOLECULAR 1,3-DIPOLAR CYCLOADDITIONS OF PHOTOCHEMICALLY GENERATED AZOMETHINE YLIDES

Exploratory work culminating in an enantioselective approach to the DNA-reactive alkaloid quinocarcin (1) is detailed. The key step involves auxiliary-controlled dipolar cycloaddition between photochemically generated azomethine ylides such as 11 and Oppolzer's chiral acryloyl sultam (-)-32 to assemble the 6-exo-substituted 3,8-diazabicyclo[3.2.1]octane core of 1. The synthetic sequence begins with condensation of the benzylamines 3 and maleic anhydride to give the N-alkylated maleimides 6. Triazoline formation (MeN3) followed by photolytic (lambda > 3000 angstrom) extrusion of nitrogen leads to the corresponding aziridines 10. Upon irradiation at 2537 angstrom, these aziridines undergo electrocyclic ring-opening to give azomethine ylides 11, which can be trapped with (-)-32 to give the 6-exo-substituted cycloadduct 33 (diastereoselectivity, ds > 25:1). These results stand in sharp contrast to cycloadditions of 11 with (achiral and chiral) acrylate ester dipolarophiles as well as acrylonitrile, which proceed with no appreciable facial selectivity. The expected re-face selectivity of (-)-32 was confirmed in one case by X-ray crystallographic analysis of endo-adduct 35a. Removal (and recovery) of the chiral sultam auxiliary can be effected by titanium (IV)-mediated alcoholysis to give ester derivatives of the cycloadducts.