Novel concepts and methodologies in pseudo natural product chemistry

Abstract

Natural products (NPs) are an inspiring source for chemical biology and drug discovery research, featuring complex and diverse structures. However, the chemical space explored by nature is limited by the biosynthetic precursors and machineries available in NP-producing organisms. To explore the vast chemical space of biological relevance, pseudo natural product design is proposed to unprecedentedly recombine NP fragments from different sources. This thesis aims to develop novel concepts and methodologies in pseudo natural product design to supply structurally complex and diverse compound collections for biological study. To answer the question whether varying connections between two fragments can lead to diverse biological performance, a systematic recombination of alkaloid-derived NP fragments pyrrolidine and tetrahydroquinoline is disclosed in Chapter 3. Efficient and concise methodologies are developed to afford a library of 123 members and 7 scaffolds varying the connectivity patterns, positions and saturation states. To improve the synthetic efficiency, a previously neglected Rh(III)-catalyzed reaction between benzhydroxamate and diazooxindole is presented in Chapter 4. Besides varying connections between two fragments, ring distortion and pseudo natural product design are conceptually combined where sesquiterpene lactones are converted to diverse scaffolds via ring distortion followed by incorporation of alkaloid-derived pyrrolidine fragments yielding pseudo sesquiterpenoid alkaloids in Chapter 5. To increase the diversity of the compound collection, a stereodivergent 1,3-dipolar cycloaddition is developed to afford stereocomplementary pyrrolidines.