Abstracts Chemistry

Total Synthesis of (–)-Chromodorolide B and Origins of Diastereoselectivity for Conjugate Additions of Trisubstituted Acetonide Radicals

by Daniel James Tao

In Chapter 1, the rearranged spongian diterpene class of natural products is discussed. The biological effects of the natural product family on the Golgi apparatus are highlighted along with previous completed total syntheses of members in the family. Early efforts by the Overman group towards the chromodorolide natural products are also discussed, as these model system studies revealed several key insights in developing a second-generation approach. In Chapter 2, the synthetic routes to (3aS,7aS)-4,4,7a-trimethyloctahydro-1H-inden-1-one are reported. This chiral fragment is embedded within the hydrophobic subunit of the chromodorolides and is surprisingly difficult to access enantioenriched on multi-gram scale using previously reported routes. Chapter 2 discusses the multiple approaches that have been developed by other research groups and ours to access this compound. In particular, a novel route using reductive transposition proved nearly thrice as high yielding relative to previously reported methods in preparing to (3aS,7aS)-4,4,7a-trimethyloctahydro-1H-inden-1-one. In Chapter 3, the total synthesis of (–)-chromodorolide B is described. The first section discusses an unsuccessful approach to the chromodorolides using a formal [3+2] radical cycloaddition as a novel method to couple highly oxygenated nucleophiles. The second section discusses a revised synthetic strategy using a radical addition/cyclization/fragmentation (ACF) cascade to form two C–C bond and four stereocenters in a single step. Using this key transformation, (–)-chromodorolide B was completed in 21 steps by the longest linear sequence. In Chapter 4, the diastereoselectivities observed in the ACF cascade are examined. As the cyclization step disfavored the desired C8 stereochemistry, strategies to synthesize α-substituted butenolides are reported. The stereoselection of the coupling reactions with trisubstituted acetonide radicals is also discussed as the couplings typically occurred with diastereoselectivity from the contrasteric face. Detailed experimental and computational studies are reported which reveal several parameters that govern the facial selectivity for the conjugate addition of trisubstituted acetonide radicals.