Iridium-Catalyzed Asymmetric Allylic Substitution with Enolate Surrogates and Enantioselective Addition of Alkynes to α,α-Dichlorinated Aldehydes

Abstract

Transition metal catalyzed allylic substitutions have been established as a powerful method to generate carbon-carbon and carbon-heteroatom bonds. Among the different transition metals employed for allylic substitutions iridium has appeared as a relevant alternative to palladium due to its complementary regioselectivity. Carbon nucleophiles have been the basis for the study and development of enantioselective Ir-catalyzed allylic substitution reactions. Among all carbon nucleophiles, masked carbonyl and carboxyl enolates have been the most utilized in iridium-catalyzed asymmetric allylic substitutions. However, the direct use of enolates as nucleophiles remains undisclosed. This thesis describes the discovery and development of novel carbon-carbon bond forming reactions with ester, aldehyde and amide enolate surrogates catalyzed by iridium-phosporamidite complex. Trimethyl orthoacetate was found as optimal precursor for the in situ generation of nucleophilic dimethyl ketene acetal, which acts as acetate enolate surrogate. Branched racemic allylic carbonates underwent enantioselective allylic substitution with trimethyl orthoacetat affording the corresponding esters in excellent enantioselectivities (up to >99% ee). The utility of this method has also been demonstrated by its implementation in a formal enantioselective synthesis of the meroterpenoid (+)-conicol. We further extended this strategy to avoid the problems linked to the use highly reactive enolates of aldehydes such as acetaldehyde. The use of ethylene glycol mono-vinyl ether as acetaldehyde enolate surrogate in the presence of the substrate and a chiral iridium catalyst afforded dioxolane-protected aldehydes VIII with high yield (up to 83%) and enantiomeric excess (up to >99% ee). Moreover, morpholine ketene aminal was employed in iridium-catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ-unsaturated β-substituted morpholine amides. The catalytic system employed enabled a kinetic resolution of the allylic carbonates substrates with morpholine ketene aminal as nucleophile. The process was highly selective, affording morpholine amide products in high yield (30–50%) and enantioselectivity (86–98%) along with optically enriched starting materials (27–48% yield, 82–99% ee). Subsequently, the use an achiral ligand led to stereospecific substitution of recovered enantioenriched allylic carbonates with the same nucleophile (93–99% es). The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones and acyl silanes. In the second part of this dissertation, an enantioselective alkyne addition to α,α-dichlorinated aldehydes using Zn(OTf)2 and (+)-N-methylephedrine in presence of triethylamine is documented. The use of a collection of α,α-dichlorinated aldehydes as well as alkynes as substrates for this asymmetric version of the FAVORSKII reaction was described. This approach furnished optically active α,α-dichlorinated propargyl alcohols in useful yields (56–97%) and high enantiocontrol (86–98% ee).