Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine.

Stereocontrolled Mn-mediated addn. of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond constructions at the stereogenic centers of chiral amines. Applying this strategy to quinine suggested complementary synthetic approaches to construct C-C bonds attached at the nitrogen-bearing stereogenic center using multifunctional alkyl iodides, e.g, I, as radical precursors, or using multifunctional chiral N-acylhydrazones, e.g., II, as radical acceptors. These were included among Mn-mediated radical addns. of various alkyl iodides to a range of chiral N-acylhydrazone radical acceptors, leading to the discovery that pyridine and alkene functionalities are incompatible. In a revised strategy, these functionalities are avoided during the Mn-mediated radical addn. of I to chiral N-acylhydrazone II, which generated a key C-C bond with complete stereochem. control at the chiral amine carbon of quinine. Subsequent elaboration included two sequential cyclizations to complete the azabicyclo[2.2.2]octane ring system. Group selectivity between two 2-iodoethyl groups during the second cyclization favored an undesired azabicyclo[3.2.1]octane ring system, an outcome that was found to be consistent with transition state calcns. at the B3LYP/6-31G(d) level. Group differentiation at an earlier stage enabled an alternative regioconvergent pathway; this furnished the desired azabicyclo[2.2.2]octane ring system and afforded quincorine, completing a formal synthesis of quinine. [on SciFinder(R)]