A study of alkylation reactions α- to nitrogen for application in alkaloid synthesis

Doctoral Thesis


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University of Cape Town

This thesis begins with a review (Chapter 1) of methodologies for carbon-carbon bond formation a to nitrogen of relevance to alkaloid synthesis, from which a specific structural motif for study in this thesis is identified. In the first phase of the research component (Chapter 2) relating to benzylic secondary aza stereogenic centres, a study has been undertaken of the stereoselective synthesis of tetrahydropyrido[2, 1-a]isoindolones, via radical and carbanionic cyclisation of a Ntethered α-sulfanyl lactam incorporating an enoate ester as the acceptor and an allylic tertbutyldiphenylsilyloxy group (OTBDPS) as stereocontrol element. The product stereochemistries have successfully modelled the required cis-stereochemistry of the DIE ring fusion of the indole alkaloid tacamonine in which the pyrido and indolo rings of the natural product have been replaced by pyrrolo and phenyl respectively. The N-tether was constructed in a high-yielding sequence from (S)-malic acid. The radical cyclisation occurred with good diastereoselectivity, to afford of the four possible diastereomers, a major product(~ 50%) with the hydrogens of the two new stereocentres in a cis relationship. Similarly the carbanionic cyclisation gave a major product in even higher diastereoselectivity (~80%), which could be desulfurised with retention of configuration to give the other cis diastereomer. These results complement the radical approach, providing the required stereochemistry for the Tacaman alkaloid DIE ring fusion. A transition-state model is presented for the radical cyclisation in which the acceptor substituent adopts a pseudoaxial configuration in the transition-state as a result of the imposing steric effect of the OTB DPS group. This is in stark contrast to other 6-exo-trig cyclisations in which the acceptor group is normally pseudoequatorial.

Includes bibliographical references.