A NOVEL STEREOSPECIFIC REARRANGEMENT OF 3-SUBSTITUTED B-HOMO 5-AZASTEROIDS TO THEIR A-NOR ANALOGS - PREPARATION, STEREOCHEMISTRY, AND CONFORMATIONAL STUDIES

The novel 3-alpha- and 3-beta-hydroxy-B-homo-5-azasteroid lactams 4 and 5 were prepared from testosterone. When the hydroxyl group in these compounds is converted into a leaving group, rearrangement to the corresponding A-nor azasteroids occurs under a variety of conditions, along with competing substitution with inversion of configuration at C-3. The rearrangements proceed with complete stereospecificity and are faster and more efficient in the 3-alpha-series. The observed stereochemistry, as well as the results of molecular modeling, low-temperature NMR, and X-ray crystallographic studies support a mechanism involving neighboring-group participation by the nitrogen atom in the departure of the nucleofuge from C-3 via the formation of aziridinium ion intermediates. Compounds in the 3-alpha-series require prior ring-flipping to the A-boat conformation, while those in the 3-beta-series react through the corresponding A-chairs. The differences in the free energies of the A-boat and A-chair forms are greater in the 3-beta-compounds (1.6-3.4 kcal/mol) than in the corresponding 3-alpha-isomers (0.1-1.3 kcal/mol). The 3-alpha-chloro derivative 19 exists mainly as the A-chair in solution (DELTA-G = 0.3 kcal/mole; DELTA-G* = 12.2 kcal/mol), but crystallizes in the A-boat conformation. Molecular modeling studies of several 3-substituted derivatives and X-ray investigations of 19 and its 3-beta-isomer 20 also reveal separate flip forms of the B-rings associated with the A-chair and A-boat conformations in each case. Relief of steric hindrance between one of the hydrogen atoms at C-19 and the beta-hydrogen at C-7 (this H-H contact is only 1.98 angstrom in the crystal structure of 19) in the A-boat conformations of the 3-alpha-series enhances anchimeric assistance to the departure of the leaving group and facilitates the rearrangements of these compounds relative to their 3-beta-counterparts.