STUDIES ON VITAMIN-D (CALCIFEROL) AND ITS ANALOGS .38. [1,7]-SIGMATROPIC HYDROGEN SHIFTS OF A-NORVITAMIN-D ANALOGS - RING SIZE AND SUBSTITUENT EFFECTS ON THE PREVITAMIN-D VITAMIN-D EQUILIBRIUM

The [1,7]-sigmatropic hydrogen shift of the 11-alpha-OH-A-norprevitamin D analogue 9 and its 11-beta-epimer 10 to the vitamin forms 24 and 25, respectively, was determined to be approximately 20 and approximately 10 times faster than that of previtamin D3 (1) to vitamin D3 (2). In addition, the location or absence of the hydroxyl group relative to the triene moiety of A-norprevitamins 9-12 was determined to have diverse effects on the position of the previtamin-vitamin equilibrium. Together with the results for the oxa analogues 53/54 and 55/56 and our earlier results for 3/4, 5/6, and 7/8, it appears that the smaller A-ring size favors the previtamin structure and the larger A-ring favors the vitamin form, but small structural changes can readily influence the equilibrium (e.g., the 11-OH group in the A-nor series 9/24 and 10/25). While the observed equilibrium changes can be rationalized on the basis of nonbonded substituent steric effects superimposed upon ring size (strain) effects, the origin of the observed rate enhancements of the [1,7]-shift in the A-nor series compared to the six-membered A-ring, natural series is less clear.