title: Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA. gregory-friestad@uiowa.edu
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Friestad
authors.forename: An
authors.initials: A
authors.lastname: Ji
authors.forename: Jonas
authors.initials: J
authors.lastname: Baltrusaitis
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Korapala
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
mesh_terms: D006835:Hydrazones / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry*; D015394:Molecular Structure; D011803:Quinine / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D006835:Hydrazones; D008345:Manganese; D011803:Quinine