Abstract
Ph.D.
The first part of the research described in this thesis involves the development of a new methodology for the synthesis of N-hydroxy pyrrolidines, starting from carbohydrates as building blocks. The products were identified as possible synthons for the stereocontrolled synthesis of isosteric analogues of polyhydroxylated indolizidine alkaloids. The consecutive reduction and cyclisation of selectively protected 5-0-mesyl hexose O-(tert-butyldiphenylsilyl) oximes to afford chiral N-hydroxy pyrrolidines is discussed. The mechanism involves a cascade of neighbouring group participation steps by the O-benzoyl protecting groups. This protocol gave rise to novel chiral N-hydroxy pyrrolidines in good overall yield. The choice of leaving group as well as a labile oxime protecting group proved to be of great import in the outcome of the cyclisation reactions.
The second part of the research concerns the ongoing development in our laboratories of the synthesis of analogues of biologically active compounds. In this regard, we were interested in synthesising the aza analogues of f3-C-nucleosides and f3-C-glycosides. Our strategy involves the synthesis of a D-ribose derived chiral cyclic nitrone as the key synthon. A facile route
towards cyclic nitrones was developed starting from suitably protected hemiacetals of Dribofuranose. Readily available tri-O-benzyl-D-ribofuranose was allowed to react with hydroxylamine hydrochloride to afford an acyclic oxime. Selective silylation followed by iodonation at C-5 (with inversion of configuration) furnished the cyclisation precursor. Anhydrous TBAF-mediated desilylation and subsequent intramolecular nucleophilic attack afforded a cyclic nitrone in excellent yield. Following the same protocol, 2,3-isopropylidene-5- 0-trityl-D-ribofuranose was converted into the corresponding nitrone.
The 1,3-dipolar cycloaddition reaction of a nitrone to an alkene is an extremely powerful synthetic method for the creation of complex heterocyclic structures. The reaction of the Dribose derived nitrones with a,(3-unsaturated carbonyl compounds furnished the corresponding cycloadducts in good diastereomeric excess. The exo-product was isolated as the major isomer in each case. The reaction of a variety of carbon nucleophiles, including a Grignard reagent, with the nitrones led to the formation of interesting p-C-glycoside analogues. One of the carbohydrate nitrones was also converted into its thymine C-nucleoside analogue. This work clearly shows that the construction of chiral cyclic nitrones from D-ribose derivatives is an extremely efficient and simple procedure.
The final part of the work described in this thesis involve the construction of CD-ring analogues of the natural metabolite, streptonigrin. The use of metalation and palladium catalysed cross-coupling reactions were investigated for the synthesis of highly functionalised biaryls. The synthesis and crystal structure determination of [3-(tert-butoxycarbonylamino)-4- pyridyl]-trimethyltin(IV) is discussed. The Stille cross-coupling reaction between an electron rich arylstannane and an electron poor aryl halide proved to be the most successful. The use of co-catalytic copper(I) had a dramatic effect on the overall yield and rate of this Stille crosscoupling reaction. This methodology would , in principle, allow the construction of the natural product and appropriate structural analogues.