This thesis mainly involves CPA-catalyzed desymmetrization of symmetrical oxetanes and acetals. Several interesting and useful catalytic asymmetric reactions have been developed for the synthesis of some heterocyclic compounds. Meanwhile, we have done studies to get insight into the reaction mechanisms.

Chapter 2 describes an oxetane-directed aza-Diels−Alder reaction using indole as the dienophile. Aza-Diels−Alder reactions have been well explored for the efficient synthesis of heterocycles, such as tetrahydroquinolines (THQs), but catalytic asymmetric intermolecular Diels−Alder reactions with indole dienophiles have never been reported before. In this chapter, such a reaction was designed, in which a hydrogen bond acceptor was introduced as a directing group in the diene compo...[ Read more ]

This thesis mainly involves CPA-catalyzed desymmetrization of symmetrical oxetanes and acetals. Several interesting and useful catalytic asymmetric reactions have been developed for the synthesis of some heterocyclic compounds. Meanwhile, we have done studies to get insight into the reaction mechanisms.

Chapter 2 describes an oxetane-directed aza-Diels−Alder reaction using indole as the dienophile. Aza-Diels−Alder reactions have been well explored for the efficient synthesis of heterocycles, such as tetrahydroquinolines (THQs), but catalytic asymmetric intermolecular Diels−Alder reactions with indole dienophiles have never been reported before. In this chapter, such a reaction was designed, in which a hydrogen bond acceptor was introduced as a directing group in the diene component, thus the desired aza-Diels−Alder reaction of indole could proceed not only in high yield but also with excellent stereoselectivity. Moreover, the products contain three key important scaffolds that are widely observed in natural products and studied in medicinal chemistry: indoline, THQ, and tetrahydroisoquinoline (THIQ). These alkaloid-like polycyclic products exhibit moderate anti-cancer activity.

Chapter 3is about the asymmetric synthesis of THIQs with C4 stereocenters and [1,2-a]pyrazins with C2 stereocenters via cascade reaction involving reductive amination and intramolecular oxetane desymmetrization by a nitrogen nucleophile. It is worth highlighting that (a) oxetane as an σ-electrophilecan be successfully activated by CPAs; (b) THIQs with C4 stereocenters and [1,2-a]pyrazins with C2 stereocenterscan be quickly assembled using our methods. THIQs and [1,2-a]pyrazinsare common scaffolds in natural alkaloids and drug lead compounds, whose syntheses with traditional approaches generally require multiple steps. To further demonstrate the utility of our approach, a formal synthesis of natural product (−)-(8S, 13R)-cyclocelabenzine has been accomplished.

Chapter 4 describes an efficient strategy for the installation of both C1 and C4 stereocenters in THIQs in one step in cascade manner with oxetane-tethered aldehydes as substrates. Such scaffolds can be found in many bioactive natural products and drug lead compounds. Few methods are available to synthesize them, most of which require a long sequence and give moderate selectivity. So far there is no direct catalytic asymmetric method available. By utilizing the special chemical properties of oxetane-aldehyde, several cascade reactions were designed to build up such THIQs in one step.

Chapter 5 is a story about asymmetric synthesis of tetrahydrofurans (THFs) and tetrahydropyrans (THPs) bearing C3 all-carbon quaternary stereocenters by intramolecular desymmetrization of anacetal by a diol moiety. THFs and THPs in various oxidation states could be found in many bioactive molecules. Catalytic asymmetric synthesis of all-carbon quaternary centers still remains a challenge in current organic synthesis. Our method provides a concise and useful approach for the synthesis of THFs and THPs with a C3 all-carbon quaternary center. Mechanistic study shows that CPAs could differentiate the two methoxylgroups in the acetal, which might give some clues to rationalize how the chiral information is transferred from the catalyst to the product. More importantly, we also found that the bulk of the CPAs could influence not only stereoselectivity but also chemoselectivity.