Palladium-catalyzed alkylative enyne cyclizations and their application to the synthesis of vitamin D analogs

The scope of palladium-catalyzed alkylative enyne cyclization reactions was investigated. This methodology has been expanded to include the use of vinyl triflates as cyclization initiators. The employment of a halide additive (e.g. tetra-n-butylammonium bromide) was found to be mandatory for this cyclization process with the exception of the vitamin D system. Two different modes of cyclization--"normal" and "abnormal"--were observed depending on the type of enyne substrates utilized. In the "normal"-mode cyclizations, 1,6-enynes gave rise to both 5-exo and 6-endo cyclization products; 1,7-enynes gave rise to only 6-exo cyclization products. Vinyl triflates derived from aldehydes and ketones and bearing different alkyl substitution patterns were tolerated. A common occurrence in these cyclization reactions is the subsequent 1,7-hydrogen sigmatropic shift of the initial cyclization product leading to mixtures of double bond isomers. In the "abnormal"-mode cyclizations, 1,6-enynes and 1,7-enynes gave rise to only endo-type cyclization products. Enynes bearing terminal and internal alkyne moieties, as well as reactive functionalities (i.e. enones, allylic ethers) were tolerated. Vinyl triflates derived from ketones, enones, and lactones were also tolerated. A common observation in these cyclization reactions is the mixture of E/Z exocyclic double bond isomers generated from competing pathways of cyclization (i.e. exo-trig vs. endo-trig). Several cases exist in which only the E-exocyclic double bond isomer was obtained; this isomer derives from the kinetically preferred 5-exo-trig cyclization pathway.; This cyclization methodology using vinyl triflates was applied successfully to the synthesis of two vitamin D analogs. The two requisite components were obtained through partial and total syntheses. A stereoselective synthesis of a vinyl triflate CD fragment from Grundmann's alcohol was achieved. A scalemic synthesis of the other requisite component, an enyne A-ring precursor, from ethyl vinyl ether was accomplished. Utilizing the palladium-catalyzed alkylative enyne cyclization reaction, two vitamin D analogs were synthesized in good yields (ca. 60-70%).