Synthesis of chiral building blocks by hydrogen bonding catalysis

Abstract

Asymmetric organocatalysis is a powerful tool for enantioselective synthesis of chiral building blocks, where chiral hydrogen bonding catalysts, such as chiral phosphoric acids (CPAs) and chiral thioureas (CTs), are widely used. In the past, efforts in chiral phosphoric acid catalysis include developing novel CPAs, achieving new enantioselective reactions with such catalysts, expanding capability of CPAs in activating inert substrates, and synthesizing important chiral building blocks with this strategy. My research focuses on employing CPAs for asymmetric synthesis of vital bioactive molecules and investigating novel unsaturated conjugated electron-deficient systems. While the primary focus of the research is on CPA catalysis, during my research I also found that CTs could be better catalysts in some reactions that are difficult to achieve with CPAs. In this thesis work, I have successfully realized a CPAs-catalyzed oxidative rearrangement of indoles to synthesize chiral spirooxindoles, a family of important bioactive compounds. In addition, a series of addition and rearrangement reactions of functionalized propargylic alcohols have also been developed for the construction of various building blocks. Along the line of hydrogen bonding catalysis, an efficient asymmetric O–H insertion of sulfonium ylides was achieved, leading to the synthesis of α-oxygen-substituted ketones bearing a tertiary stereogenic center. CTs were found to be the optimal catalysts in this reaction. Chapter 1 gives a general overview of organocatalysis and hydrogen-bonding catalysis. In Chapter 2, a CPA-catalyzed enantioselective oxidative rearrangement of indoles to synthesize spirooxindoles is described. The transformation provides rapid access to a range of enantioenriched spirooxindoles with high enantioselectivity controlled by dynamic kinetic resolution. In Chapter 3, the power of CPA catalysis was further demonstrated by asymmetric synthesis of axially chiral tetrasubstituted allenes and their derivatives, including diverse spirocyclic heterocycles. High enantioselectivity was achieved from the easily accessible propargylic alcohols. Interestingly, regiodivergence was also observed with different indole nucleophiles. In Chapter 4, catalyst-controlled divergent reactions of 2,3-disubstituted indoles with propargylic alcohols were developed for the first time. In the presence of TsOH or B(C₆F₅)₃ as catalyst, 2,3-disubstituted indoles react smoothly with functionalized propargylic alcohols to afford benzo[b]azepines by selective C2(sp²)–C3(sp²) ring expansion of indoles. In contrast, decreasing the catalyst activity interrupted the cascade reactions, affording axially chiral tetrasubstituted allenes bearing an adjacent chiral quaternary carbon stereocenter. In Chapter 5, the first organocatalyzed synthesis of C(sp²)–N atropisomer by C(sp²)–O amination was developed. The conversion of C–O bonds to C–N bonds proceeded through an interesting rearrangement. The kinetic product Z-isomer and the thermodynamic product E-isomer could be obtained simultaneously by adjusting the strength of acid and reaction time. Mechanistically, this rearrangement is believed to involve a highly active hemiaminal intermediate with a six-membered ring. In Chapter 6, a new catalytic asymmetric synthesis of chiral α-oxygen-substituted ketones was developed. This is the first enantioselective O–H bond insertion of sulfonium ylides. A chiral thiourea was used as catalyst to control the enantioselectivity of the reaction, opening a new platform for the synthesis of chiral α-oxygen-substituted ketones, a family of versatile building blocks in organic synthesis.

Date of Award	2023
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Jianwei SUN (Supervisor) & Pengfei Li (Supervisor)