Enantioselective Synthesis of Axially Chiral Spiro[3.3]heptanes by Site-Selective C–H Functionalization

High Resolution Image Download MS PowerPoint Slide The enantioselective synthesis of axially chiral 2,6-disubstituted spiro[3.3]heptanes is challenging because the differentiating functionalities are far apart from each other. The known enantioselective methods to generate these compounds have relied on the use of enzymatic processes. The current study achieves a highly regio-, diastereo-, and enantioselective entry to the 2,6-disubstituted spiro[3.3]heptanes by desymmetrizing 2-substituted spiro[3.3]heptanes using rhodium-catalyzed C–H functionalization by donor/acceptor carbenes derived from aryldiazoacetates and styryldiazoacetates. The optimum catalyst is dirhodium tetrakis(4,4′-(3,5-ditertbutylphenyl)-6,6′-dichlorobinaphthylphosphate) (Rh 2 ( S -MegaBNP) 4 ), which adopts a D 4 -symmetric structure. The optimum functionality on the spiro[3.3]heptane is the N -phthalimido group, which is ideally suited for further derivatization to a range of amine and amide derivatives. Under the optimized conditions, the C–H functionalization products can be generated in up to 92% yield, >20:1 rr, >20:1 dr, and 99% ee. Computational studies revealed that the catalyst is relatively rigid and both the orientation of the bound carbene and the approaching substrate are controlled by their necessary alignment in hydrophobic grooves between tert -butyl groups of adjacent ligands. The diastereoselectivity is controlled by selective C–H functionalization of one of the equilibrating enantiomers of the 2-substituted spiro[3.3]heptane, hence achieving conformation sorting. These studies reveal that bowl-shaped dirhodium catalysts are capable of subtle site selectivity caused by secondary noncovalent interactions with the catalyst wall.