Total syntheses of aogacillins A and B

Abstract

Total synthesis of natural products is a flagship and pivot of organic synthetic chemistry. Not only does it serve for structural identification and elucidation, but also as an enabling endeavor for the inspiration of novel methodology and strategy in chemistry and their potential societal impact to chemical biology and other disciplines. Lactone moiety is a common structural subunit present in many natural products, including those isolated from insects, fungi, marine organisms, and plants. Natural products containing the δ-lactone framework have been shown to exhibit a wide range of biological activity. In recent years, multi-substituted lactones are of particular synthetic significance due to their capacity as synthetic intermediates toward complex molecules. The structure of spiro-δ-lactones and their derivatives have gained much attention. Aogacillins A and B were isolated by Shiomi and co-workers in 2013 from a culture broth of Simplicillium sp. FKI-5985 and have been found to be capable of overcoming arbekacin resistance in methicillin-resistant Straphylococcus aureus (MRSA). Structurally, Aogacillins represent an unusual δ-lactone with spiro-fused 2-ethyl-6-methylcyclohexane and their highly dense functionalities on the δ-lactone pose a major challenge for their chemical synthesis. A brief introduction of the structures of lactones and spiro-lactones, and the reported natural products including lactones and spiro-lactones are given in chapter 1. It is followed by an overview of construction method of spiro-lactones ring and its application in total synthesis. These serve as the background information for the proposed research in this thesis work. Chapter 2 discusses the background of aogacillins A and B, including their isolation, structural features and biological activity against methicillin-resistant Straphylococcus aureus (MRSA). And there is also a plausible biosynthetic pathways for aogacillins A and B. Chapter 3 summarizes our results on total synthesis towards aogacillins A and B. The first total syntheses of (±)-aogacillin B have been achieved in 16 steps from cis-2-methylcyclohexanone and simple furan compound. The key features of our synthesis include Achmatowicz rearrangement to install the highly functionalized dihydropyranone acetal. However, in aspect of aogacillin A synthesis, the late stage dehydration posed synthetic challenges and could not afford target natural product. Moreover, in terms of enantionselective synthesis, the furan coupling resulted in partial epimerization for achieving fully enantiopure substance eventually. The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. Copies of original ¹H and ¹³C NMR spectra of key compounds in the total synthesis towards Aogacillin A and B.

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