Chiral phosphoric acid (CPA) catalysis has emerged as a promising area of organocatalysis over the past decade. Numerous interesting and useful asymmetric reactions have been developed in this area. Impressive activation modes as well as transition states have been established. This thesis mainly describes CPA-catalyzed asymmetric ring-opening reactions of strained heterocycles and nucleophilic addition to quinone methides.

Chapter I gives a brief introduction to CPA catalysis. The structural properties of CPAs, typical activation modes and pioneering studies in CPA catalysis based on the activation of different types of functional groups are shown in this chapter.

In Chapter II, the first catalytic asymmetric intermolecular desymmetrization of 3-substituted oxetanes is shown. It...[ Read more ]

Chiral phosphoric acid (CPA) catalysis has emerged as a promising area of organocatalysis over the past decade. Numerous interesting and useful asymmetric reactions have been developed in this area. Impressive activation modes as well as transition states have been established. This thesis mainly describes CPA-catalyzed asymmetric ring-opening reactions of strained heterocycles and nucleophilic addition to quinone methides.

Chapter I gives a brief introduction to CPA catalysis. The structural properties of CPAs, typical activation modes and pioneering studies in CPA catalysis based on the activation of different types of functional groups are shown in this chapter.

In Chapter II, the first catalytic asymmetric intermolecular desymmetrization of 3-substituted oxetanes is shown. It represents a new addition to the small family of asymmetric reactions of oxetanes. This mild process, featuring low catalyst loading and broad functional group compatibility, is also effective for the formation of quaternary chiral centers, including all-carbon quaternary stereocenters. Moreover, the enantioenriched desymmetrization products are versatile precursors to other useful chiral building blocks, suggesting that our method provides an attractive alternative to other known strategies in asymmetric synthesis.

In Chapter III, the first chiral Brønsted acid catalyzed asymmetric nucleophilic ring-opening reaction of meso-epoxides is described. In the presence of a chiral phosphoric acid catalyst, a range of cyclic and acyclic meso-epoxides could undergo smooth ring-opening reactions with moderate to high efficiency and enantioselectivity. The mild reaction conditions can tolerate a range of functional groups. The enantioenriched 1,2-difunctionalized products with vicinal stereocenters are versatile chiral building blocks towards useful molecules, such as chiral free thiols.

In Chapter IV, the first catalytic enantioselective desymmetrization of azetidines is described. Despite the low propensity of azetidine ring-opening and the significant challenge in stereocontrol, the smooth intermolecular desymmetrization of a wide range of 3-substituted azetidines has been achieved with both excellent efficiency and remarkable enantioselectivity, enabled by optimal combination of catalyst, protective group, nucleophile, and reaction conditions. Both tertiary and quaternary stereocenters can be generated efficiently. Mechanistically, only one catalyst molecule is involved in the bond-forming transition state according to kinetic studies and DFT calculations. Although the carbonyl oxygen activation provides a more stable intermediate, the reaction proceeds with lower overall barrier via nitrogen activation, which is consistent with the Curtin-Hammett principle and the observed excellent stereocontrol.

Demonstrated in Chapter V is a new organocatalytic transfer hydrogenation strategy for the efficient asymmetric synthesis of 1,1-diarylethanes, an important family of compounds with broad medicinal and agricultural applications. With suitable design of the substrates by employing a removable ortho-hydroxy group, we were able to achieve excellent reaction efficiency as well as asymmetric induction under mild conditions. Preliminary mechanistic studies confirm the critical importance of the free hydroxy group, which is required for the in-situ generation of the ortho-quinone methide intermediate. DFT calculations provided important insight into the reaction mechanism. The free hydroxy group in the products can be easily removed or converted to other useful functional groups. Furthermore, after careful modifications of the reaction conditions, we have also successfully extended the protocol to the asymmetric transfer hydrogenation of a range of indole-substituted 1,1-diarylethylenes as well as styrenes without a directing group. Further extension of the protocol to asymmetric hydroarylation of 1,1-diarylalkenes with indoles has also been successfully achieved, featuring efficient formation of the intermolecular C−C bonds and the challenging acyclic all-carbon quaternary stereocenters with excellent stereocontrol. Finally, preliminary biological study indicated that the enantioenriched diaryl- and triarylalkanes obtained from our reactions exhibit impressive cytotoxicity against a number of human cancer cell lines.

In Chapter VI, we have developed the chiral Brønsted acid catalyzed asymmetric 1,6-addition to p-quinone methides for the efficient formation of acyclic all-carbon quaternary stereocenters. The reaction features excellent stereocontrol as well as efficient intermolecular C-C bond formation. Preliminary control experiments provides insight into the reaction mechanism. Kinetic studies indicate that only one catalyst molecule is involved in the transition states.