Visible Light Promoted Alkenyl C–H Bond Addition to Dienes and Aldehydes for the Synthesis of Frameworks Relevant to Polyketide Natural Products

Cp*Co-(III)-catalyzed sequential addition of alkenyl C-(sp²)-H bonds to dienes and aldehydes provides products with two additional C-C σ bonds with the simultaneous introduction of contiguous stereogenic centers with high selectivity. Blue LED irradiation is essential for achieving high reaction yields, and under optimized conditions, a broad scope of aromatic and aliphatic aldehydes is observed, including sequential C-H bond additions to chiral aldehydes using acyclic stereocontrol without any epimerization at the racemization prone stereogenic center α to the aldehyde carbonyl. The sequential addition products have carbon frameworks relevant to natural product synthesis applications and can readily be elaborated as demonstrated by the preparation of an intermediate to the macrolide nannocystin Ax and by the efficient asymmetric synthesis of an enantiomerically pure compound incorporating six stereogenic centers. Investigations of the structure and reactivity of allyl cobaltacycle intermediates established pronounced mechanistic differences for the sequential addition of alkenyl versus aromatic C-(sp²)-H bonds to dienes and aldehydes. In particular, for alkenyl C-H bond reactants, cobaltacycle intermediates are formed that have different bonding interactions than for aromatic reactants. Moreover, a facile cobaltacycle isomerization pathway to a more stable, less reactive species can occur that is not possible for aromatic reactants. Characterization of a key unstable cobaltacycle intermediate could only be achieved by structural analysis of microcrystals by MicroEd, highlighting the utility of this method for structural analysis.