Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin. / Yorkshire Cancer Research

Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.

Studies toward the total synthesis of (+)-providencin (1), a highly oxygenated cembranoid dipterpene with a unique bicyclo[12.2.0]hexadecane skeleton and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 320 and 332 which contain all of the carbon atoms of 1. In a first generation approach toward 1, a zirconium-mediated deoxygenative ring contraction of furanose 177 was used to furnish enantiopure cyclobutanol 176. Olefination of furan aldehyde 197 with phosphonate 214 completed cyclobutylfuran segment 215. A second generation approach toward cyclobutylfuryl subunit 221 via ring-closing metathesis of diene 237 was unproductive, but the iodolactone subunit 228 needed for 1 was prepared successfully using carbometallation-iodination of alkyne 231. Nucleophilic substitution of tosylate 230 with the dianion of phenylselenyl acetic acid (252) followed by acid-catalyzed lactone formation was employed for construction of the γ-lactone moiety of 228. A third generation route to the cyclobutylfuryl subunit of 1 involved a tin(II) chloride-mediated stereoselective allenol synthesis by reaction of aldehyde 302 with propargyllic bromide 264. A silver-catalyzed allenone-to-furan isomerization of 309 completed the synthesis of cyclobutylfuran subunit 288. Attempts to couple the two major fragments, 228 and 288, using palladium-catalyzed C-H activation of the furan component were unsuccessful, but linkage of two major subunits was achieved at the C12-C13 bond via an intermolecular aldol reaction to give 332 and at the C6-C7 bond using intermolecular palladium-catalyzed cross-coupling to afford 320. / Graduation date: 2012