A Chemo-enzymatic Approach for the Rapid Assembly of Tetrahydroisoquinoline Alkaloids and Their Analogs

Abstract

The utilization of enzymes that catalyze sequential reactions to construct highly functionalized skeletons in a single step could expedite the total synthesis of natural products and allow more precise control of chemo-, regio-, stereo- and enantio-selectivity while minimizing the use of protecting groups. In this chapter, we describe the development of a chemo-enzymatic hybrid synthetic process for a series of complex antitumor natural products, the bis-tetrahydroisoquinoline (THIQ) alkaloids. The approach integrates the precise chemical synthesis of hypothetical biosynthetic intermediates with an enzymatic one-pot conversion to assemble the intricate pentacyclic scaffold, enabling the efficient total synthesis of saframycin A, jorunnamycin A, and N-protected saframycin Y3. We exploited synthetic substrate analogs to implement a versatile chemo-enzymatic synthetic approach to generate variants of THIQ alkaloids, by systematic modification of the substituents and functional groups. Subsequent chemical manipulation allowed the expeditious total synthesis of THIQ alkaloids. Section 7.2 discusses the biosynthesis of THIQ alkaloids, while Sect. 7.3 shifts the focus to chemo-enzymatic hybrid synthesis. Section 7.3.1 examines the impact of long-chain fatty acid side chains on enzymatic conversions by SfmC. In Sect. 7.3.2, the conversion efficiencies of substrates with ester or allyl carbamate linkages replacing amide bonds are sequentially addressed. Sections 7.3.3 and 7.3.4 delve into the chemo-enzymatic total synthesis of THIQ alkaloids. Finally, Sect. 7.3.5 discusses prospective expansion of the substrate scope for broader synthetic applications.