Chiral pool approach for the total synthesis of bis THF C15 acetogenins - notoryne, laurefurenynes A/B, laurendecumenyne B and a chloroenyne from laurencia majuscula and synthesis of eribulin fragment C14 to C29

Abstract

The problem associated with the structural assignment of natural products having poor crystallinity/liquid nature is prevalent even today and is faced by the isolation/synthetic groups throughout the globe. Till date, the structural assignment is mainly done by the careful analysis of the 13C NMR chemical shift values of the related isomers of natural products. Substituted tetrahydrofuran ring is one of the most common scaffolds, found in many natural products or drugs. Structure elucidation of such THF containing compounds is done particularly by XRD (if it is a solid with a proper crystalline nature) or an extensive 2D NMR analysis. However, a major drawback of the assignment using 2D NMR analysis is the difficulty faced due to the overlapping methine (CHO) signals in the 1H NMR spectrum, and thus, in such cases analysis by 13C NMR chemical shift values remains the only feasible solution for structure prediction. In this thesis, we have generated a number of 2-halo/hydroxy THF compounds to take advantage of the small but revealing differences in the 13C NMR chemical shift values to analyze and study those differences to help us in the structure assignment. Chapter 1, covers the total synthesis of bis-THF C15 acetogenins and is divided into two sections. Section A describes the total synthesis of Notoryne by confirming its absolute configuration with the help of its four diastereomers, while section B deals with the total syntheses of other bis-THF C15 acetogenins: Laurefurenynes A/B, Chloroenyne from L. Majuscula, Laurendecumenyne B and (formal synthesis) (E/Z)-Elatenynes. The stereochemistry of these natural products/intermediates has been predicted mainly by 13C NMR chemical shift values analysis with the assistance of 2D NMR spectra. Chapter 2, deals with the synthesis of three different fragments {C14 to C28, C19 to C35 and C14 to C29} of the breast cancer drug Eribulin Mesylate. Two key approaches viz. [Au]-catalyzed cycloisomerisation/Kishi reduction approach and Sharpless asymmetric dihydroxylation/cycloetherification approach have been employed to synthesize the targeted fragments. In this case too, the intermediates as well as the target compounds have been assigned their respective configurations after being characterized with the help of thorough 2D NMR as well as 13C NMR analysis.