Asymmetric Catalysis: From Atroposelective Organocatalysis to Iridium-Catalyzed Generation of Central Chirality

Abstract

Thesis Abstract: This thesis, entitled as “Asymmetric Catalysis: From Atroposelective Organocatalysis to Iridium-Catalyzed Generation of Central Chirality” is divided into three chapters. Chapter 1, highlights the progression of atropisomerism. The widespread occurrence of atropisomerism in ligands, natural products, and bioactive compounds has driven significant progress in this field. The chapter provides a comprehensive overview of key advances in the synthesis and understanding of C−N axial chirality. Chapter 1A, outlines the first atroposelective desymmetrization of prochiral N-aryl maleimides through its conversion to axially chiral phthalimides developed by applying a de novo arene construction strategy. Catalyzed by bis(3,5-dimethylphenyl)prolinol TMS ether, this reaction proceeds through oxidative [4 + 2]-cycloaddition with α,β-unsaturated aldehydes to generate only a chiral C−N axis remote from the reaction sites with excellent enantioselectivity. In Chapter 1B, we addressed challenges associated with atroposelective phthalimide synthesis through modified alkoxy-directed dienamine catalysis. Due to high HOMO energy of in situ generated alkoxy-substituted dienamine over its classical variants, there is an improvement in the rate of [4+2]-cycloaddition reaction, and also eliminates the requirement of a nitro substituent on N-aryl maleimides. Ultimately, the modified alkoxy-directed dienamine showed high reactivity compared to Danishefsky’s diene. In Chapter 2, we present the first atroposelective formal C(sp²)–H alkylation and alkenylation of quinones using a Takemoto urea as a bifunctional catalyst. This strategy utilizes readily available, inexpensive, and air-stable nitroalkanes as both alkylating and alkenylating agents and proceeds efficiently at ambient or lower temperatures. The method provides access to atropoisomeric quinones with low rotational barriers, affording products in good to excellent yields and high enantioselectivities. In Chapter 3, an allylic substitution with difluoroenoxysilanes as the nucleophile is accomplished for the enantioselective synthesis of α-allylic α,α-difluoroketones. Despite its emergence as a reliable synthon of α,α-difluoroketones during the past decade, the applicability of difluoroenoxysilane has been hampered by its low nucleophilicity. We successfully surmounted this challenge by employing a highly reactive allylic electrophile to develop an enantioselective allylic substitution with difluoroenoxysilanes as the nucleophile. With racemic branched allylic alcohols as the easily accessible allylic electrophile, this branch-selective and enantioconvergent allylic alkylation reaction is catalyzed by an Ir(I)/(P,olefin) complex and overcomes the low nucleophilicity of difluoroenoxysilanes to furnish β-chiral α,α-difluoroketones in moderate to good yields with high enantioselectivity