Indole alkaloids and their derivatives are among the largest families of natural products and bioactive molecules. Many of them exhibit significantly biological and physiological activities and are used as therapeutic agents for various diseases. The medicinal value has driven the indoles research including chemical synthesis, which plays an important role in drug discovery and development. Although the chemical synthesis of indole alkaloids advances tremendously in the past decades, it remains challenging from the perspective of green chemistry and efficiency. This thesis is to address these two issues by developing new green protocol for catalytic oxidation of indoles (Chapter 1) and new synthetic strategy for collective total synthesis of indole alkaloid natural products.

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Indole alkaloids and their derivatives are among the largest families of natural products and bioactive molecules. Many of them exhibit significantly biological and physiological activities and are used as therapeutic agents for various diseases. The medicinal value has driven the indoles research including chemical synthesis, which plays an important role in drug discovery and development. Although the chemical synthesis of indole alkaloids advances tremendously in the past decades, it remains challenging from the perspective of green chemistry and efficiency. This thesis is to address these two issues by developing new green protocol for catalytic oxidation of indoles (Chapter 1) and new synthetic strategy for collective total synthesis of indole alkaloid natural products.

The chapter one describes the development of two green protocols for catalytic green oxidation of indoles to 2-oxindoles. 2-Oxindoles have been found as privileged structural motif in many bioactive natural products and pharmaceutical agents, and the chemical oxidation of indoles is an important and straightforward method to prepare 2-oxindoles. However, the existing oxidants including m-CPBA, NBS, t-BuOCl, and Pb(OAc)₄ for the indole oxidation are toxic ad hazardous and thus pose significant health and environment concerns. To address this safety and environmental issue, we developed a green oxone-halide systems for the oxidation of indoles to provide spirooxindoles (oxidative rearrangement) and 2-keto acetanilides (witkop cleavage). The oxone-halide oxidation protocol features (1) generation of K₂SO₄ as the only byproducts from the oxidant, (2) low cost and non-toxic and (3) simple operation with high yield and broad substrate scope. Although the oxone-halide systems solve the major safety and environmental problem in the oxidation of indoles, we envisioned that hydrogen peroxide (H₂O₂) or molecule oxygen (O₂) might be used as an ideal terminal oxidant (instead of oxone) for green oxidation of indoles to 2-xoindoles, which mimics enzymatic oxidation of indoles with H₂O₂ or O₂ as terminal oxidants. The notable specificity of enzymatic oxidation lies on the very narrow substrate scope with 1000 times dilute reaction concentration. In continuation of our interest and previous works in green oxidation of indoles, we develop our second-generation of green oxidation of indoles by using H₂O₂ as the oxidant in the presence of FeBr₂ or CeBr₃ catalyst which represents the first example of Fenton chemistry for the oxidative rearrangement of indoles through mimicking haloperoxidase to oxidize bromide with hydrogen peroxide to generate in situ reactive brominating species under neutral condition.

Indole alkaloids natural products are an important source of therapeutic agents and therefore attract intensive synthetic interest in academia and industrial sectors. Tetrahydro-β-carbolines (THβCs) is a subclass of indole alkaloids that possess interesting biological activities with great potential to be developed into new drugs. The chapter two describes the development of approaches for syntheses of chiral C1-alkynyl THβCs through asymmetric alkynylation of 3,4-dihydro-β-carbolinium (DHβC) ions up to 96% yield and 99% ee. The utility of the newly established method for asymmetric C1-alkynylation was demonstrated by collective syntheses of seven indole alkaloids including harmicine, eburnamonine, desthyleburnamonine, larutensin, geissoschizol, geissochizine, and akuammicine. Notably, two complementary optimal approaches were developed for the preparation of 3,4-dihydro-β-carbolinium (DHβC) ions for enantiomerically C1-alkynylation. The first approach relies on a CuI-catalyzed redox isomerization to in situ generate the DHβC ions and the substrate scope of this redox isomerization-alkynylation approach was examined with 23 examples, however only aromatic aldehyde can be employed for this approach, which substantially limitsits applications in organic synthesis and medicinal chemistry. To overcome this limitation, we developed an alternative approach for the generation of 3,4-dihydro-β-carbolinium (DHβC) ions: N-alkynylation of 3,4-dihydro-β-carbolines, and the optimal reaction condition of this approach was identified. The second approach greatly expands the availability of different optically active C1-alkynyl tetrahydro-β-carbolines. These two approaches constitute the first example of asymmetric synthesis of C1-alkynyl THβCs with high enantioselectivity and excellent yield. It is expected that these two catalytic asymmetric alkynylation approaches will find wide applications in the chemical synthesis of bioactive indole alkaloids.