Stereoselective Pyrrolidine Synthesis and Approaches to Cyclic Tetrapeptides

This thesis describes the synthesis of a family of amino acids containing a ketone functionalised side-chain (I, II, III), which are analogues of one of the amino acids found in the cyclic tetrapeptide apicidin (IV). Cross metathesis of the alkenes (V, VI, VII) with a range of unsaturated ketones, followed by hydrogenation, gave the target amino acids in excellent yields. The required alkenes were prepared in moderate to good yield by the copper-catalysed allylation of the homologous organozinc reagents (VIII, IX, X) with allyl chloride. In initial cross-metathesis experiments using the alkene (V), a highly diastereoselective cyclisation to give the trans-pyrrolidines (XIb) was observed. After careful study, it was established that the cyclisation occurred on standing in CDCl3, and that it could also be achieved in a more controlled way by using catalytic amounts of dry HCl in ether. The alkene (VI) was incorporated into the linear tetrapeptide (XII), which was then cyclised to give the cyclic tetrapeptide (XIII) along with the cyclic octapeptide (XIV). Cross metathesis of the cyclic tetrapeptide (XIII) with methyl vinyl ketone and propyl vinyl ketone, followed in each case by hydrogenation, gave the two modified cyclic peptides (XV) and (XVI) in good yield, demonstrating the feasibility of the cross-metathesis/hydrogenation strategy for the preparation of analogues of apicidin.