In the Ward Group, stereoselective aldol reactions of thiopyran derived templates play an important role in polypropionate natural product syntheses. Central to this approach is the diastereo- and enantioselective synthesis of all possible aldol adducts 3 arising from tetrahydro-4H-thiopyran-4-one (1) and 1,4-dioxa-8-thiaspiro[4.5] decane-6- carboxaldehyde (2). There are four possible diastereomers of 3 indicated by the relative configurations at positions 3 and 1’ (syn or anti) and positions 1’ and 6’ (syn or anti). Up to date, the asymmetric aldol reaction of 1 with 2 catalyzed by L-proline or its tetrazole analogue 12 provides efficient access to 3,1’-anti-1’,6’-syn-3 (3-AS) without need for chromatography (>40 g scale; 75% yield, >98% ee) and 3,1’-syn-1’,6’-syn-3(3-SS) (via isomerization of 3-AS; >75% yield, 2 cycles); however, the preparation of enantiopure 3,1’-anti-1’,6’-anti-3 (3-AA) and 3,1’-anti-1’,6’-syn-3 (3-SA) still requires the use of enantiopure aldehyde 2 in a diastereoselective synthesis. Without a simple and scalable route, access to enantioenriched iterative aldol adducts and polypropionate natural products that are based on 3-AA and 3-SA skeletons are hindered. It was observed that conducting the asymmetric aldol synthesis of 3-AS on large scale gave enantioenriched 3-AA as a very minor product. This observation triggered the hypothesis of using L-proline to resolve racemic 3-AA via a retro-aldol reaction.In this thesis, the development, optimization, and application of an unprecedented L-proline catalyzed enantioselective retro-aldol reaction is described. Interesting mechanistic insights were uncovered. An unexpected isomerization process between 3-AA and 3-SA occurs in parallel with the retro-aldol process. The method was demonstrated to be a robust, flexible, and readily scalable process to access highly enantioenriched 3-AA (ee > 95%) and 3-SA (ee > 95%). To the best of our knowledge, this reaction represents the only reported enantioselective retro-aldol reaction catalyzed by L-proline.

Muamvatin (30) is a polypropionate natural product isolated from Siphonaria normalis by Ireland et al. in 1986. Muamvatin (30) is made from eight propionate units and contains an extraordinary trioxaadamantane ring system. This ring system exists in only one other naturally occurring polypropionate known as caloundrin B. Regarding the rare muamvatin trioxaadamantane ring system, it was hypothesized this ring system may not be formed via an enzymatic process and the actual natural product could be the linear precursor ent-71 which cyclizes to muamvatin (30) during isolation. The first total synthesis of muamvatin (30) by Paterson et al. confirmed its absolute and relative configuration, but the ambiguity regarding the origin of the trioxaadamantane ring system in this molecule remains unresolved. This work describes two approaches to make the linear precursor ent-71 from triol ketone 153. The carbon skeleton of muamvatin was synthesized through two iterative diastereoselective aldol reactions. In the first approach, “the thiopyran route”, the diene moiety of aldehyde 73 required protection to avoid reduction during desulfurization. Although use of the tircarbonyliron complex was successful, the trihydroxy ketone revealed upon desulfurization was unstable and spontaneously cyclized to bicyclic acetal 156. Molecular mechanics revealed that the relative configurations embedded in C3, C7, and C8 dramatically effected the stability of the corresponding bicyclic acetal. With that lesson learned, the fully assembled linear precursor 197 was made in our second approach “the acyclic route”. The oxidation state of the backbone oxygens were manipulated via an unusual chemoselective double Swern oxidation. Finally, revealing the sensitive 5-hydroxy-3,7,9-trione functionality formed the precursor 202. Efficient cyclization of precursor 202 and removal of the protecting group at C11-OH produced the desired natural product 30. The cyclization conditions tested on the linear precursor 202, suggested that although the cyclization to the trioxaadamantane is strongly favored thermodynamically, the process is very slow and unlikely to occur during the isolation process. Thus, formation of the trioxaadamantane ring system could be an enzyme-mediated process as was concluded for caloundrin B.

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.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors. / text

Le portentol est un polypropionate qui possède une structure spirocyclique très originale. Cette molécule, dont il n'existe encore aucune synthèse totale, a été isolée du lichen Rocella portentosa à la fin des années 1960. Dans le but d'accéder au squelette du portentol, nous avons développé une méthodologie visant à synthétiser des spirotétrahydropyranes fonctionnalisés via une cyclisation de Prins. Au cours de ce travail, un phénomène de dédoublement cinétique dynamique a aussi été mis en évidence. La stachybotrine C, isolée à partir de la bactérie Stachybotrys parvispora, possède des propriétés neurotrophiques et neuroprotectrices très intéressantes. Deux voies de synthèse ont été envisagées pour préparer ce produit naturel. La première voie repose sur une réaction d'hydroarylation d'un éther propargylique catalysée à l'or, suivie d'une oxydation régiosélective du chromène résultant. La seconde voie fait intervenir une étape clé d'époxydation/cyclisation d'un alkénylphénol obtenu suite à un réarrangement de Claisen. Ces travaux nous ont permis d'accomplir la synthèse totale de la stachybotrine C, de réviser sa structure et de déterminer sa configuration absolue. / Portentol is a polypropionate with an unusual spirocylic structure. This natural product, which has never been synthesized, has been isolated from the lichen Rocella portentosa. To access the spiranic moiety of the portentol, we have developed a methodology to synthesize spirotetrahydropyranes through a Prins cyclization. Through the study of the scope of this reaction, an usual dynamic kinetic resolution has been highlighted. Stachybotrin C, isolated from the bacteria Stachybotrys parvispora, exhibits interesting neuritogenic and neuroprotective properties. To prepare this natural product, two synthetic routes have been investigated. The first one is based on a gold-catalyzed hydroarylation of a propargyllic ether followed by a regioselective oxidation of the resulting chromene. The second pathway involves as a key step an epoxydation/cyclisation of a phenol prepared via a Claisen rearrangment. We accomplished the synthesis of stachybotrin C, revised its structure and established its absolute configuration.

Leiodolide A is a unique natural product isolated from Pacific marine sponges which has provided an interesting target for total synthesis due to its complex structure and undefined stereochemistry. Although synthetic work towards the synthesis of sister compound leiodolide B has been published, the total synthesis of leiodolide A is yet to be achieved but remains an important target due to high potency against leukaemia, non-small lung and ovarian cancers. The convergent strategy towards the synthesis of leiodolide A involved the synthesis of three subunits; a synthetic route to the C21-C25 vinyl stannane is described, and efforts towards the synthesis of the bidirectional C11-C20 subunit are detailed. Asymmetric vinylogous aldol methodology was developed for the installation of the 1,2-syn propionate motif found in the C1-C10 subunit and in other polypropionate natural products, and was shown to be applicable to a range of substrates in moderate diastereoselectivity and excellent enantioselectivity.