Palladium-Catalyzed Alkylation, Arylation and Dehydrogenation of Unactivated Carbon-Hydrogen bonds. Syntheses of the Tetracyclic Aminoquinone Moiety of Marmycin A, (+/-)-Nosyberkol (Isotuberculosinol, Revised Structure of Edaxadiene), and (+/-)-Tuberculos

An unprecedented, anion-directed Pd-insertion into sp3 beta-C-H bonds in simple aliphatic acids has been observed. Organoboron reagents were used as coupling partners to achieve monoselective alkylation and arylation of sp2 and sp3 C-H bonds in carboxylic acids. The utility of carboxyl-directed C-H activation was further explored by the arylation of beta-C-H bonds in aliphatic acids using ArI.;Using a removable auxiliary approach to direct C-H activation, we have established reaction conditions for the Pd(OAc)2-mediated dehydrogenation of ethyl and propyl groups in carboxylic acid derivatives. Although dehydrogenation of these simple acids is stoichiometric in PdII, a catalytic dehydrogenation protocol for cyclopentylcarboxamides was also developed.;While studying the ability of a number of optically active ligands to effect asymmetric C-H activation, we discovered that mono-protected alpha-amino acids were surprisingly effective ligands for the PdII-catalyzed enantioselective C-H activation of pyridine derivatives bearing prochiral C-H bonds. The coordination of a chiral nitrogen atom to the metal center is believed to be crucial for asymmetric induction, and a working model for the asymmetric C-H activation event has been established. This model should allow for the development of enantioselective C-H activation reactions with broad substrate scope.;An efficient four-step route to the tetracyclic aminoquinone moiety of marmycin A from 5-nitro-1,4-naphthoquinone that proceeds in 41% overall yield has been developed. This will facilitate the preparation of marmycin analogues for biological evaluation. A Diels-Alder reaction of 5-nitro-1,4-naphthoquinone and 5-methyl-1-vinylcyclohex-1-ene gave exclusively the desired Diels-Alder adduct that is favored by steric considerations rather than the adduct favored by electronic considerations. Some interesting internal redox chemistry was also observed when a nitro group served as an oxidant in the oxidation of the Diels-Alder adduct to a quinone and aromatic E-ring of the angucycline.;The structure of edaxadiene has been revised to that of nosyberkol (isotuberculosinol). The efficient routes to nosyberkol (six steps, 19% overall yield) and tuberculosinol (seven steps, 17% overall yield) make these compounds readily available for further biological evaluation. The syntheses of nosyberkol and tuberculosinol feature an exo-selective Diels-Alder reaction of N-tigloyloxazolidinone and 6,6-dimethyl-1-vinylcyclohexene that provides the complete carbon skeleton of both systems in a single step.