Stereocontrol through Catalytic Enantioselective C(sp2)−H and C(sp3)−H Alkylation: From Bifunctional Organocatalysis to Iridium-Catalysis

Abstract

This thesis, entitled “Stereocontrol through Catalytic Enantioselective C(sp2)−H and C(sp3)−H Alkylation: From Bifunctional Organocatalysis to Iridium-Catalysis” primarily deals with the development of various catalytic enantioselective C(sp2)− and C(sp3)− alkyl and allyl bond forming reactions. In Chapter 1, we have described a new and general approach for the enantioselective synthesis of monosubstituted norbornenoquinones based on C(sp2)−H alkylative desymmetrization of meso norbornenoquinones. Catalyzed by a bifunctional tertiary amino(thio)urea derivative, and utilizing air-stable and inexpensive nitroalkanes as the alkylating agents, this operationally simple protocol delivers synthetically versatile benzoquinone-fused tricyclic compounds, containing at least four contiguous stereogenic centers remote from the reaction site, with excellent enantioselectivities (up to 99:1 er). In Chapter 2, we have discussed the development of the first Ir-catalyzed enantioselective vinylogous allylic alkylation of a coumarin derivative. This Ir/phosphoramidite catalyzed reaction utilizes easily accessible linear allylic carbonates as the allylic electrophile to install an unfunctionalized allyl group. This protocol delivers synthetically versatile -allylcoumarins in exclusively branched-selective manner generally in high yields with an excellent level of enantioselectivity (up to 99:1 er). In Chapter 3, we have shown the first enantioselective vinylogous allylic alkylation of 4-methylquinolones. This iridium-catalyzed reaction introduces an allyl group at the γ-position of 4-methyl-2-quinolones with exclusive branched selectivity and excellent level of enantioselectivity (up to 99:1 er). This in turn allows for the enantioselective synthesis of γ-allylquinolines and related nitrogenous heterocycles. This is the first application of 4-methylquinolones in an enantioselective transformation. In addition to these reactions, we have also developed the first enantioselective α-C(sp2)–H allylic alkylation of α,β-unsaturated carbonyl compounds under cooperative Lewis base and iridium-catalysis. Using linear allylic carbonates as the allylic electrophile, this reaction, catalyzed by cinchonidine and an in situ generated cyclometalated Ir/phosphoramidite complex, makes use of the latent enolate character of the coumalate ester to introduces an allyl group at its α position in a branched-selective manner with good to excellent enantioselectivities (up to 98:2 er). The results of this investigation are detailed in Chapter 4.