Progress towards the development of a new strategy for the highly stereoselective synthesis of alkene-containing macrocyclic ring systems by organocuprate oxidation

Abstract

Macrocyclic ring systems incorporating geometrically defined alkenes are the structural cores of a large number of biologically active molecules and thus represent targets of significant interest for chemical biology studies. Catalytic ring-closing metathesis (RCM) is undoubtedly the most widely used method for the synthesis of such scaffolds and represents an exceptionally powerful general synthetic tool. However, there are some drawbacks associated with typical RCM methods in this context. From the perspective of bioactivity, perhaps the most significant of these is that control of the stereochemistry of the resulting olefin is problematic when typical reaction conditions are employed. In general, RCM reactions of unhindered alkenes using standard conditions to form medium/large rings tend to give mixtures of the (E )- and (Z )- configured cyclic olefins. As the stereochemical identity of the alkene can be critical to the biological activities of such molecules, such mixtures may be undesirable and it is often the case that the isomers are very difficult to separate. Thus the exploration of alternative, non-RCM-based strategies for the stereoselective synthesis of alkene-containing large-ring systems is warranted. Herein progress towards the development of a new strategy for the highly stereoselective synthesis of alkene containing macrocyclic ring systems, which is based around the use of organocuprate oxidation chemistry, is presented. As a proof-of-principle, the highly stereoselective synthesis of a 12-membered (Z)- configured cyclic olefin by intramolecular cyclisation, without recourse to high dilution conditions, is reported. This demonstrates the feasibility of the new strategy and provides a springboard for further studies.

Keywords: Macrocycles, organocuprates, alkenes, ring-closing, stereoselectivity.