A wide variety of natural products have been isolated from Didemnum species of ascidians, and a survey of such compounds is presented. The didemnaketals are the only spiroacetal containing natural products to be elaborated by this genus, with didemnaketal A showing the greatest activity against HIV-1 protease. General synthetic approaches to the spiroacetal moiety are discussed, and then applied in retrosynthetic analyses of the spiroacetal portion of didemnaketal A. Synthesis towards this spiroacetal portion is reported, with the products being characterised by detailed 2D NMR spectroscopy and other methods. The relative stereochemistry at C12, C14, C16, C18 and C20 in the natural product is established. Further extensions of the synthesis are discussed. Two models of the E,F bicyclic portion of the shellfish poison, pinnatoxin D, are synthesised, and characterised by detailed 2D NMR analysis. The relative stereochemistry at C27, C29 and C30 is established by this synthetic work, and is in agreement with that based only on NMR analyses. This work has been published. {Suthers, B.D., Jacobs, M.F., Kitching, W. Tetrahedron Letters 39, 2621-2624 (1998)}

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

In recent decades the emergence of marine polypropionate natural products as compounds of diverse structural complexity and intriguing biological activity has influenced the advancement of asymmetric synthesis and predicated detailed studies of marine ecology. The introductory chapter of this thesis explores the nature of marine natural products, including their structure, biological activity and biosynthesis. Additionally, a brief review of the aldol reaction is presented. This well established biomimetic chemical transformation underpins polyketide synthesis and was utilised extensively in the research contributing to this dissertation. Chapter Two describes the first asymmetric total synthesis of the two marine polypropionates isolated from specimens of Siphonaria australis by Hochlowski et al. in 1984. Spectroscopic analysis revealed hemiacetal 22 and ester 23 to be identical to the secondary metabolites extracted from the marine pulmonate. The synthetic approach to hemiacetal 22 utilised lactate derived ketone (S)-67 to control the configuration of the C7 and C8 stereocentres and involved the discovery of a mild protocol for the synthesis of trimethylsilyl enol ether 109, which was employed for a Mukaiyama aldol homologation reaction. Additionally, ester 23 was synthesised from hemiacetal 22 via a retro-Claisen fragmentation. The retro-Claisen approach utilised in the synthesis of ester 23 was extended in Chapter Three to serve as the pivotal transformation in an attempted total synthesis of the unusual marine polypropionate dolabriferol (30). The strategy toward dolabriferol (30) involved an iterative homologation of chiral ketone (S)-67 to install all but one of the requisite stereocentres in the natural product. Chemoselective deprotection of acyclic precursor 160 gave the elaborate 2,4,6-trioxaadamantane 167, whose participation as a protecting group mimic lead to the formation of ester 169 after reaction of the polycycle 167 with base. The synthesis of ester 169, which represents a direct precursor to dolabriferol (30), was achieved in 16 steps with an overall yield of 24%. Unfortunately, a robust protecting group on ester 169 prohibited a synthesis of dolabriferol (30), but intriguingly in one deprotection of ester 169 with aqueous hydrofluoric acid, spiroacetal 172 was isolated. Chapter Four describes the first total synthesis of cytotoxic marine polypropionate auripyrone A (78) and establishes the absolute configuration of this important natural product as that depicted for compound 78. The requisite C8-C12 stereopentad of auripyrone A (78) was formulated from Evans� dipropionate equivalent 53 in a double stereodifferentiating aldol reaction, followed by syn-reduction to give diol 206. Differentiation of the secondary alcohols in compound 206 was achieved by migration of the PMB protecting group and protection at C11 with the requisite acyloxy group of auripyrone A (78). Differential protection was critical to achieving selective spiroacetalisation to afford the unique spiroacetal dihydropyrone core of the natural product. The utility of LiHMDS for highly selective double stereodifferentiating aldol homologations of sensitive fragments is also discussed. This mild aldol protocol was pivotal to forming the carbogenic skeleton of auripyrone A, in particular, elaborate adduct 278.