Studies toward total synthesis of iriomoteolide-2a and 4β-acetoxyprobotryanes

Total synthesis of natural products is an important part of organic chemistry and has an impact on life sciences. Utilization of natural products in combating against human diseases has a long history and total synthesis has become an essential approach to get access to limited supply of rare natural products and its derivatives nowadays. Besides, total synthesis enables exploration and discovery of many unprecedented and novel reactivities and efficient synthetic strategies. This thesis research deals with total synthesis studies on two different types of natural products. The first target molecule is the proposed structure of iriomoteolide-2a, whose C6–C18 fragment has been synthesized in this thesis work. The second type of target molecule is 4β-acetoxyprobotryane-9β,15α-diol and the congeners, which contain a strained trans-[3.3.0]octane core. A novel methodology for the construction of the strained core was explored and total synthesis 4β-acetoxyprobotryane-9β,15α-diol has been accomplished. Iriomoteolide-2a was the first 23-membered macrolide with significant bioactivity and structural novelty. But its bioactivity was limited as increasing dosage did not give a better activity, suggesting the demand for structural modifications. In Chapter 1, a brief background of iriomoteolides family of marine macrolides, including isolation, bioactivity, and reported synthetic studies, is provided. Chapter 2 presents the results of the synthesis of the C6–C18 bis-tetrahydrofuran (bis-THF) fragment of the proposed structure of iriomoteoldie-2a via stepwise double SN2 cyclization reaction. The C9–C12 THF ring was first constructed through an AD–SN2 cascade sequence while the C13–C16 THF ring was then installed via an intramolecular SN2 reaction of a chiral propargylic mesylate. Asymmetric transfer hydrogenation of propargylic ketones was demonstrated as a powerful synthetic tool to secure the stereogenic centers of the C16-propargylic carbon a