The studies to be conducted under this grant fall in three major areas: 1) complete work on the total synthesis of the hypoglycemic agent Saudin (1); test 1 and its precursors to identify the pharmacophore, and determine if possible the mechanism by which the hypoglycemic effects are elicited (in collaboration with Sandoz Research Institute); prepare appropriate analogues as warranted by the preceding studies; 2) continue work directed at the application of Lewis acid catalyzed asymmetric [2+2] cycloaddition reactions and asymmetric SN2' substitutions as general methods to access the chiral vinylcyclobutane precursors for (+)-Laurencin (2) and (+)-Laurenyne (3). To employ the novel retro-Claisen rearrangement to create the required oxocene ring system in enantiomerically pure form. 3) investigate the mechanism, scope, and limitations of the novel TiC14 catalyzed Claisen rearrangement of endocyclic vinyl allyl ethers. This process permits modification of the stereochemical outcome of the process relative to the thermal rearrangement. The hypothesis that an internal chelate of suitably disposed oxygen functions permits the modification of the ring conformation from half-chair to half-boat will be tested.
