Scope of Stereoselective Mn-Mediated Radical Addition to Chiral Hydrazones and Application in a Formal Synthesis of Quinine

Stereocontrolled Mn-mediated addition 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 6a–d as radical precursors, or using multifunctional chiral N-acylhydrazones 26a–d as radical
acceptors. These were included among Mn-mediated radical additions
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 addition of 6d to chiral N-acylhydrazone 22b, which
generated a key C–C bond with complete stereochemical 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 calculations 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 (21b), completing a formal synthesis
of quinine.