Darren L. Riley

Formal synthesis of (5R,8R,8aS)-indolizidine 209I via enaminones incorporating Weinreb amides

A formal enantioselective synthesis of the amphibian alkaloid (5R,8R,8aS)-(-)-indolizidine 2091 (6) is reported. Control of the absolute stereochemistry at C-5 resulted from application of the Davies procedure, which entails stereoselective conjugate addition of (R)-(+)-N-benzyl-1-phenylethylamine to tert-butyl (E)-hex-2-enoate. The resulting chiral adduct 26 was converted in eight steps into a pivotal enaminone incorporating a Weinreb amide, the inherent nucleophilicity of which was exploited in a cyclisation that yielded the key bicyclic intermediate (5R)-N-methoxy- N-methyl-5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxamide (38). Stereoselective catalytic hydrogenation of the alkene bond, reaction of the Weinreb amide with ethylmagnesium bromide, and epimerisation of the resulting ketone completed the formal synthesis of the target alkaloid.

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.

Design and synthesis of ring C opened analogues of α-santonin as potential anticancer agents

Here we describe ring opening reaction of a novel halo triene derivative viz., (3S, 5aS)-8-chloro-3a, 4, 5, 5a-tetrahydro-3, 5a, 9-trimethylnaphtho [1, 2-b] furan-2(3H)-one of α-santonin upon nucleophillic attack with alcohols. Halo-triene was synthesized from α-santonin upon reaction with vilsmeier reagent. The synthesized compounds from ring opening reaction were evaluated for anticancer activity against a panel of four human cancer cell lines (A-549, THP-1, HCT-15, and IMR-13). Most of the compounds exhibited promising anticancer activity against all cancer cells in vitro; however compound. 3d with benzyl substitution showed most potent anticancer activity with an IC50 value of 0.3, 0.51, 0.6 and 0.23 μM against A-549, THP-1, HCT-116 and IMR-13 cell lines respectively.

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

We recently reported a novel hybrid batch–flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow conditions using sodium dithionite. We now report the expansion of this method to include the reduction of aldehydes. The method developed affords yields which are comparable to those under batch conditions, has a reduced reaction time and improved space-time productivity. Furthermore, the approach allows the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process.