Synthesis of complex bioactive polycyclic natural products via samarium(II) folding cascades

Abstract

Radical cyclisations are privileged processes for the regio- and stereocontrolled construction of molecular complexity. In particular, cyclisations triggered by single-electron transfer (SET) reduction of carbonyl compounds using the archetypal SET reducing agent samarium diiodide (SmI2), offer a radical umpolung strategy that couples carbonyl moieties with unsaturated functionalities delivering highly functionalised cyclic structures. Thus, it offers "go-to" solutions for the synthesis of otherwise challenging high-profile natural products and other bioactive molecules. Guaiane-type sesquiterpenes have long been known for their enhanced bioactivity. Among these compounds, the recently extracted phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, herein we describe the first enantioselective total synthesis of phaeocaulisin A (Chapter 2). Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by SmI2, the lactone intermediate was submitted to two sequential SmI2-mediated cyclisations to stereoselectively construct the polycyclic core of the natural product. Crucially, we devised a steric blocking strategy by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes. Despite significant progress in the area of carbonyl reduction using SmI2 to form ketyl radicals from difficult to reduce functionalities, acyclic esters have long been considered to be unreactive to SmI2. Our aim was to develop the first SmI2-mediated radical cyclisation of "unusual" ketyl radicals, delivered from acyclic esters, with pendant alkenes. Our reactivity design built on the understanding of conformational stabilisation of ketyl radicals derived from delta-lactones and the highly reducing SmI2-H2O system. An alkyl substituent in the C6 position of delta-lactones proved to be key, ultimately delivering 1,4-ester migration products (Chapter 3). Our collaborative efforts delivered the first example of a SmI2-mediated C-C bond forming ketyl-olefin coupling of acyclic esters.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Procter (Supervisor) & Daniele Leonori (Supervisor)