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Through the advantages conferred in the speed of synthesis, combinatorial chemistry is making a significant impact on the process of drug discovery. The mix-and-split paradigm has been an effective method for the production of compound mixtures, although there is now a need for new, fast library approaches to generate well-characterised single compounds. Having already demonstrated the successful preparation and application of library mixtures, we have now developed a novel combinatorial method for the production of single compounds.

Simmons-Smith type methylenation of allylsilanes, followed by protodesilylation, can be used to achieve overall the S E 2' replacement of the silyl group by a methyl group. The regioselectivity is good for protonation on the methylene carbon of the cyclopropylmethylsilanes 11, 17, 20 and 23, but the low stereoselectivity in the formation of the cyclopropylmethylsilane 26 and its failure to undergo clean protodesilylation make the method of limited use

5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Through the advantages conferred in the speed of synthesis, combinatorial chemistry is making a significant impact on the process of drug discovery. The mix-and-split paradigm has been an effective method for the production of compound mixtures, although there is now a need for new, fast library approaches to generate well-characterised single compounds. Having already demonstrated the successful preparation and application of library mixtures, we have now developed a novel combinatorial method for the production of single compounds.

A propargylic alcohol 24 with the propynyl group exo on the norbornene framework was used in a stereospecific synthesis of the mixture of allylsilanes 27 and 28. The stereospecific reaction of this mixture with peracid gave, with a high level of stereocontrol, the norbornenol 25 having the alkenyl group endo on the norbornene framework. This substrate underwent an oxyanion accelerated Cope rearrangement setting up all four stereocentres in a synthesis of (±)-dihydronepetalactone 6.