Enantioselective synthesis of anhydrogukulenin A C2-acetate

We report an enantioselective synthesis of anhydrogukulenin A C2-acetate (31), a potential precursor to the antiproliferative bis(tropolone) metabolites known as the gukulenins. Key steps in the synthetic sequence include a directed C–H arylation of an exo-2-norbornyl picolinamide using a hindered, electron-rich arene coupling partner, a tandem Grob fragmentation–diastereoselective α-methylation to establish the highly-substituted cyclopentane rings of the target, a novel one-carbon ring expansion of an α-iodo-ortho-benzoquinone monoketal, a two-fold Stille coupling using the novel linchpin reagent (E)-1,2-di(tributylstannyl)-1-ethoxyethylene (15), and late-stage, diastereoselective addition of an α-tropolone to an α-acetoxy aldehyde, which may mirror the biosynthesis of the metabolite. We present the first evidence supporting the formation of carbinolamides (–)-gukulenins C (3) and D (4) from the parent metabolite (–)-gukulenin A (1) by the addition of ammonia to the α-acetoxy aldehyde. This work provides a platform to elucidate the structure–function relationships and mechanism of action of the gukulenins, and, with further development, may provide access to the targets themselves.