Rogers, Joseph Nathan
(2009)
Biomimetic studies towards the polycyclic diterpene bielschowskysin.
PhD thesis, University of Nottingham.
Abstract
Thesis describes synthetic studies directed towards evaluating the biosynthetic relationships between several novel polycyclic diterpenes, including bielschowskysin 1, verrillin 2, plumarellide 3 and intricarene 4, and their probable furanobutenolide -based cembrane precursors, e.g. bipinnatin J (5) and bipinnatin G (6). These interesting natural products have all been isolated from marine corals in recent years.
The Introduction describes a general overview of biologically active compounds isolated from natural sources, followed by the isolation, structure and biological profile of the aforementioned marine natural products.
The Discussion section introduces the family of furanobutenolide - based cembrane natural products and then discusses the structures of bielschowskysin 1, verrillin 2, plumarellide 3 and intricarene 4 and their proposed biogenetic origins from simple furanocembranes via transannular pericyclic cycloaddition processes. A synthetic study towards the model bielschowskysin structures 106 and 132 from rubifolide analogues, i.e. 102 and 125 is then described. Difficulties with the stabilities of various substrates led to abandonment of this route, but an alternative strategy produced the 14-membered furanocembrane structure 142 which lacked a delta11,12-alkene bond. Further manipulation of 142 into the modified bielschowskysin structure 125 could not be achieved, due to the dearth of material.
The oxidation chemistry of 2-alkenylfurans was next studied. Model studies established that treatment of the alkenylfuran 162 with peroxy reagents led to the Zdienedione 163. When 163 was left in the presence of p-TSA in THF-H20 it was first converted into the beta-hydroxyketone 165 and then into the vicinal diol 178, presumably via the transient enol ether species 166. In complementary studies, treatment of the Z-dienedione 163 with K2C03 in THF-H20 led to the 4-hydroxycyclopent-2-enone 193 (53%), and isomerisation in the presence of iodine gave the corresponding E-isomer 194 (90%). These observations may have significance for the origins of coralloidolide F (195) and the macrocyclic Edienedione 196 from furanocembrane precursors in corals.
A brief review of the syntheses of furanobutenolide - based cembranes is presented and then two synthetic approaches towards deoxybipinnatin G (188b/ 188e), using Aldol/Stille/Nozaki-Hiyama-Kishi (NHK) and ring-closing metathesis (RCM)/StilieINHK reactions, are presented. The RCM/StillelNHK approach produced the macrocyclic precursor 275b which, unfortunately, upon exposure to CrCh in THF, produced the acyclic intermediate 318. In contemporaneous studies, attempts were made to form the furanobutenolide - based cembrane bis-deoxylopholide 319 en route to plumarellide 3, via a ReM approach. Unfortunately, exposure of the vinyl furan 322 to Grubbs 2nd generation catalyst in refluxing DCM only led to the phenylvinylfuran 338 and to the dimer 339.
In a separate study, treatment of isoepilophodione B (159), derived from bipinnatin J (5) via rubifolide 49, with p- TSA in THF-H20 led to the novel and unusual 19-hydroxyrubifolide 353, presumably via the enol ether intermediate 354 and allylic transposition.
The Experimental section contains full details of the preparative work carried out, and collects together spectroscopic and analytical data for all the new compounds described.
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