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Abstract

The asymmetric synthesis of nitiol was proposed. We employed a convergent approach where the 12-membered B-ring was constructed at a late stage via the sequential coupling of two cyclopentane fragments. For the A-ring fragment, the initial stereochemistry was set using the Sharpless asymmetric epoxidation (94%ee) and the quaternary center was formed through a stereoselective siloxyepoxide rearrangement. The contiguous stereocenters were established using a Pauson-Khand [2+2+1] cycloaddition/ Norrish Type I photofragmentation sequence. This approach utilized the conformational bias of a bicyclic system to affect stereochemical relay over the three contiguous stereocenters. For the C-ring fragment, the initial stereocenter was set using a Sharpless kinetic resolution (92%ee). The chiral allylic alcohol was converted to the allylic ester and a diastereoselective Ireland Claisen rearrangement set the two contiguous stereocenters. Elaboration of the resulting acid followed by ringclosing metathesis furnished the cyclopentenone and the vinyl triflate was accessed through a conjugate reduction with concomitant enolate trapping. The A-ring and C-ring fragments were coupled using a Cu-mediated Stilletype cross-coupling reaction. Several macrocyclization options were investigated and eventually the Nozaki-Hiyama-Kishi macrocyclization was successful. Despite our best efforts, the deoxygenation of the resulting allylic alcohol was not achieved. Consequently, this research has resulted in the asymmetric syntheses of (1/?)- and (IS)-hydroxynitiol, in 29 steps (longest linear sequence) with a 5.1% over-all yield (2.55% of each diastereomer). [Chemical Diagrams]