Modern organic chemistry strives to achieve rapid molecular complexity from simple achiral substrates. One method by which this may be achieved is with enolate formation followed by attack on an electrophile which can generate one, two or even more new stereocentres in one step. However regioselective generation of an enolate in the presence of several enolisable sites has always proved problematical. A partial answer to this problem has been provided by the development of the reductive aldol reaction. The first part of this thesis is concerned with describing a highly diastereoselective Co(II)-catalysed reductive aldol reaction between α,β-unsaturated amides and ketones. The reaction proceeds using substoichiometric quantities of cobalt(II) in the presence of a stoichiometric quantity of the reductant diethylzinc. Using both N,Ndimethyl and morpholine amides, the reactions are tolerant of substituted aromatic ketones as well as aliphatic ketones. The reaction also proceeded well when the β-carbon was substituted with both aromatic and aliphatic groups resulting in improved diastereoselection. The racemic work is followed by the development of an asymmetric version of the reaction using oxazolidinone chiral auxiliaries that impart high levels of diastereofacial selectivity. The reaction was found to proceed with a variety of aromatic ketones and once again, substitution of the β-carbon resulted in improved diastereoselectivity. Finally work on formal homo aldol cyclisations using substoichiometric quantities of Ni(II) also in the presence of a stoichiometric quantity of diethylzinc is described. This work aims to develop methodology that involves double cyclisations with the formation of up to five contiguous stereocentres. Although unsuccessful, useful conclusions for future work were made as well as the serendipitous discovery of a apparent base catalysed alternative cyclisation pathway that successfully generated two new rings and four contiguous stereocentres.

A highly diastereoselective nickel-catalysed reductive aldol cyclisation is described. Using Ni(acac)2 as a precatalyst and diethylzinc as a stoichiometric reductant, various α,β-unsaturated carbonyl compounds tethered through an amide or ester linkage to a ketone electrophile underwent efficient cyclisation to afford β-hydroxylactams and β-hydroxylactones respectively. The scope of this process is broad with variation in the α,β-unsaturated carbonyl component, ketone and, where applicable, the nitrogen protecting group all tolerated. A series of experiments, including deuterium-labelling studies, were carried out in an attempt to gain insight into the possible reaction mechanisms that might be operative. II. Development of Novel Methodologies for the Silylation and Stannylation of Base-Sensitive Cyclopropenes Two distinct approaches to the synthesis of silyl- and stannylcyclopropenes are described. Using substoichiometric quantities of Cu(acac)2 and 1,2-bis(diphenylphosphino)ethane in combination with (trifluoromethyl)trimethylsilane, a diverse range of 1,3,3-trisubstituted cyclopropenes underwent direct silylation to afford the corresponding 1-silylcyclopropenes in good to excellent yield. Attempts to adapt these conditions to synthesise the corresponding stannylcyclopropenes proved unsuccessful. However, by employing (pentafluoroethyl)tributylstannane and stoichiometric potassium fluoride, it was possible to access 1-stannylcyclopropenes in comparable yields. It was also demonstrated that both the stannyl- and silylcyclopropene derivatives synthesised using these methodologies were able to serve as precursors for a variety of novel molecules that might otherwise be difficult to access using alternative methods.

Aldol reactions are widely used in forming new carbon-carbon bonds. Since the discovery of the aldol condensation, controlling the relative and absolute stereochemistry in aldol chemistry has been a major interest in organic chemistry. Efforts in achieving diastereoselectivity in aldol reactions via chelation of Lewis acids to chiral aldehydes are reviewed. The following chapters discuss the diastereoselectivities of hydrogen-mediated reductive aldol reactions. Herein, a highly diastereoselective reductive aldol coupling reactions with broad substrate scope using rhodium catalysts ligated to (2-furyl)₃P were studied. It was demonstrated that the coupling of enones with alpha-amino aldehydes proceeds with high diastereoselectivity via chelation control. The second topic deals with phosphine-mediated furan ring formation. Derivatives of furan are often found in natural products and therapeutic agents. To provide a more facile route to substituted furans, we have developed a phosphine mediated reductive cyclization of gamma-acyloxy butynoates. In this reaction, phosphine is involved in both the reductive formation of allenyl ketones from acyloxy butynoates and the subsequent catalytic cyclization. / text

The biological activity of the pharmaceutical drugs often depends on how it fits with a receptor making stereochemistry a key component. Selective reactions can limit or avoid the mixture of enantiomers obtained. One such reaction is the selective reduction of a carbon-carbon double bond in the presence of a carbonyl. Although efficient, current asymmetric synthesis methods have limitations such as harsh reaction conditions, the high costs of chiral catalysts and the toxicity of the metal-based catalysts. Catalysts derived from small organic molecules have become an attractive alternative which have been explored more rigorously in recent years. Using a BINOL-derived boro-phosphate catalyst, we have developed a methodology that selectively reduces the carbon-carbon double bond of linear α, β-unsaturated ketones, exclusively giving the corresponding saturated ketone. To the best of our knowledge, this reaction is the first of its kind to accomplish this transformation and results give high yields of >93% and enantioselectivities >90% at room temperature. Furthermore, the products of this novel reaction can be subjected to a choice electrophile, in example benzaldehyde, to afford diastereoselective tertiary alcohol products with enantioselectivities of >88% and diastereoselectivities of up to 99:1.