No description available.

No description available.

No description available.

No description available.

Cyanohydrins are a group of compounds that are widely used in industry as common building blocks for asymmetric synthesis. In this thesis, novel methods of synthesizing chiral cyanohydrins are investigated using complexes of transition metals complexed to salen ligands. To start the project, alternative sources of cyanide were investigated. Unfortunately, this investigation could not uncover a new cyanide source that was more effective than trimethylsilyl cyanide as a substrate for titanium(salen) based catalysts. However, this research has led to the finding that KCN / 18-Crown-6 can be used as a co-catalyst in the addition of ethyl cyanoformate to various aldehydes. This has led to a huge reduction in the amount of catalyst that is required to achieve the same enantiomeric excess. In addition, the diastereoselective synthesis of cyanohydrin derivatives using chiral cyanoformates was made possible for the first time. Some of the cyanohydrins synthesized by the new ethyl cyanoformate route were taken a step further, and their use as chiral building blocks was also studied. By using a palladium based catalyst, α,β,-unsaturated cyanohydrins were converted into amides via a two-step reaction. Research into the Strecker reaction was also carried out using vanadium(V)(salen) complexes as catalysts. In this field, the use of phenols as co-catalysts was discovered, and this has led to a world leading enantiomeric excess.

No description available.

Lactonizations are important steps in many synthetic sequences. Substrate-controlled reactions that use chiral auxiliaries or chiral alkenes have already been studied in depth. This study focuses on stereoselective reagent-controlled iodolactonizations, by application of a new method that uses complexes of iodine monochloride and various donor molecules. (/)-l,2,3,4-Tetrahydro-l-naphthylamine and other amines with similar structures were synthesized and found to be efficient in the iodocyclization of 4-aryl-4-pentenoic acids and other similar substrates. Calculations were performed on complexes of ( )-l,2,3,4-tetrahydro-l-naphthylamine with XC1 (X=I, H) to identify possible reactive species in these iodocyclizations. Various levels of theory were employed, including B3LYP/6-31+G (d,p) using a modified SDD basis set for iodine.

This thesis describes the development of diastereotopic group selective processes allowing the desymmetrisation of 1,4-cyclohexadiene derivatives and their application to target synthesis. Chapter 1 discusses some of the benefits that may be derived by the use of desymmetrisation, and demonstrates some of the ways in which it has recently been applied in compounds based on 1,4-cyclohexadiene. Chapter 2 describes a novel use of the Prins reaction to desymmetrise cyclohexadiene derivatives with high diastereoselectivity, and the optimisation of this resulting in an effective, practical and straightforward procedure. Chapter 3 details the investigation into desymmetrisation through diastereoselective iodocyclisation reactions, much higher stereoselectivity is observed than found previously in cyclohexadiene based substrates and an explanation is suggested by examination of structural differences. Chapter 4 reviews some of the previous synthetic approaches to members of the fawcettimine group of Lycopodium alkaloids. This is followed by the results of our first approach to the core tetracyclic ring system of lycoposerramine A, based on the discovery of a novel base induced diastereotoselective cyclisation reaction. Chapter 5 describes our revised approach, leading to the construction of a closely related tetracycle, although not permitting the construction of the target. Chapter 6 discusses the synthesis of the core tricyclic system of lycoposerramine S by a different strategy. NMR spectra obtained from the final product are found to closely match those obtained from the natural product.

Chiral interactions of compounds with therapeutic interest and its study predicting and interpreting transport process across biological barriers represents one of the most important topics in research. This thesis is devoted to the study of chiral ion transfer at the interface between two immiscible electrolytes solutions (ITIES), as a promising method of simplifying chiral detection and separation. As a proof of concept, for the study of chiral compounds at liquid|liquid interface, three different approaches were used: i) chiral stationary phases based on modified cyclodextrins, AcαCD and AcβCD, ii) chiral acute phase protein, α1-acid-glycoprotein (AGP) and iii) thick film electrode modified with an ethylated cyclodextrin ferrocene (EtCDFc). The chiral selectors used, AcαCD, AcβCD, AGP and EtCDFc display complex three-dimensional structures that are capable of recognising specifically the enantiomers of a drug molecule, with different affinity. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were used to investigate the enantioselective interaction between the chiral molecules. In the study of chiral ion transfer using AcαCD and AcβCD, as a chiral organic phase, it was observed that the two lipophilic CDs facilitated the transfer of ephedrine ions by the formation of inclusion complexes. The enantioselectivity was achieved as the complexes between the protonated ephedrine ions and the CDs lead two different signal responses as a result of different affinities in the complex formation. Furthermore, the positive enantiomer (+)EPH+ showed to be consistently the cation being transferred at less positive potentials suggesting that it binds preferentially with the chiral selectors, in comparison with (-)EPH+, indicating that its transfer is more facile. The difference in stability constant between the (+)EPH+ and (-)EPH+ complexes was found to be 1.41±0.1 for AcβCD and 1.20±0.1 for AcαCD. When investigating the chiral interactions between the AGP and the three basic drugs (propranolol, lidocaine and procaine hydrochloride), it was found, that the plasma protein binds to the protonated drugs with clear different affinities. The formation of a complex between the drugs and AGP was shown as a decrease in the CV and DPV responses, corresponding to the reduction in the transfer of the cationic drugs, as only the unbound (free) drug was able to be transferred across the liquid|liquid interface. The bound and unbound drug concentration was estimated in a different range of concentrations based on the responses obtained in the presence and absence of the protein. The differences in current responses, observable in the measurements, lead to chiral discrimination between R- and S-propranolol. Scatchard analysis was employed to calculate the association constant and the number of binding sites of the drugs with AGP. The calculated association constants were 2.7x105 M-1 for S- and 1.3x105 M-1 for R-propranolol, which were significantly higher than those for lidocaine, 1.2x104 M-1, and for procaine,8.4x103 M-1. This showed that AGP has more affinity for R- and S-propranolol than lidocaine or procaine hydrochloride. A thick film modified electrode with a chiral redox probe, ethylated ferrocene cyclodextrin (EtCDFc) was used to study chiral ion transfer across the liquid|liquid interface coupled to a redox reaction. EtCDFc has a dual role, a redox active moiety and a cyclodextrin moiety which is able to form chiral complexes. Thus, the redox reaction of EtCdF was accompanied by the complexation of mandelic acid enantiomers with the cyclodextrin part of EtCDFc, with the two reactions mutually influencing each other. In addition the thick film ensured that the generated product of the molecular probe was within the diffusion layer and away from the aqueous|organic solvent interface, so that the charge neutrality of the organic film was only maintained by the presence of ions from the aqueous phase.

No description available.