Synthesis of bicyclic ether, total synthesis of cinanthrenol A, and total syntheses and structural revision of uprolide G acetate and uprolide F diacetate

Abstract

This PhD thesis was composed of three chapters: a new synthetic method for bicyclic ether was developed in chapter 1, a short synthesis of the bioactive Cinanthrenol A was described in chapter 2, and a full story about total syntheses of uprolide F diacetate and uprolide G acetate was given in chapter 3. After these chapters, the appendix containing NMR spectra was attached. Chapter 1 discusses the synthesis of bicyclic ether and our development of a novel double cascade synthetic strategy for the diastereoselective syntheses of cis-fused bicyclic ethers through Achmatowicz/spiroketalization and spiroketal reduction/oxa-Michael cyclization with a wide substrate scope. Significantly, we have achieved the chemo-, regio- and diastereoselective reduction of the highly functionalized spiroketal dihydropyranone and subsequent oxa-Michael cyclization. The double cascade processes would provide a concise route to diastereoselective synthesis of cis-fused cyclic ethers present in halichondrins and other (non-) natural products. And the diastereoselective synthesis of trans-fused bicyclic ether was also achieved via Kishi reduction/hydroxy ketone reductive cyclization sequence. Chapter 2 described the first, concise total synthesis of Cinanthrenol A in a longest linear sequence of 13 steps from commercially available materials. The synthetic strategy was enabled by i) 6π electrocyclization/aromatization to construct the phenanthrene framework and ii) hydroxyl-directed Simmons-Smith cyclopropanation to construct the spirocyclopropyl subunit. Chapter 3 gave an acount of our synthetic studies on uprolide F diacetate and uprolide G acetate. Firstly, we have achieved the first, asymmetric total synthesis of the purported structure of uprolide G acetate (UGA) in 43 steps, and discovered that spectral properties of our synthetic compound clearly differed from those reported for natural UGA. On the basis of comprehensive analysis of the NMR data, we proposed two possible structures for the natural UGA and achieved their total synthesis, which led to identification and confirmation of the correct structure and absolute configuration of the natural UGA. Some features of our synthetic strategy included i) Cascade Sharpless asymmetric dihydroxylation/lactonization to stereoselectively install the γ-lactone, and ii) ring closing metathesis (RCM) to build the 14-membered cembranolide framework. Then, we proposed a similar structural revision for the natural uprolide F diacetate (UFD). And we achieved its asymmetric total synthesis of the revised UFD in 30 steps, which confirmed that our revised structure correctly represents the natural UFD and its absolute configuration. Our synthesis was enabled by a highly efficient and stereoselective NHK macrocyclization/lactonization and a rarely explored translactonization.

Date of Award	2015
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology