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Allylic Sulfones in Solid-Phase Synthesis:  Preparation of Cyclobutylidenes

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journal contribution
posted on 12.11.1999, 00:00 by Wei-Chieh Cheng, Chris Halm, Jerry B. Evarts, Marilyn M. Olmstead, Mark J. Kurth
Polymer-bound allyl sulfones (cf. 9) were utilized in geminal cycloalkylations with epichlorohydrin to generate a cis-phenylsulfonylcyclobutanol derivative (cf. 11) in one step. In the final step of this solid-phase synthetic sequence, cuprate, organomolybdenum, and organopalladium reagents were screened to obtain an optimal protocol for “traceless” cleavage of cyclobutylidene products from the resin. Among these, palladium-catalyzed allylic alkylation was the most efficient. In addition, highly regioselective nucleophilic attack at the less hindered terminus of the allyl fragment (i.e., overall SN2‘ sulfinate displacement) was observed. Cyclobutylidene diversification was demonstrated by incorporating different allylic substituents, O-functionalizations, and C-nucleophiles to prepare a demonstration library of eight cyclobutylidene derivatives (i.e., derivatives of 4) in four steps and 30−38% overall yield from lithium polystyrene/divinylbenzene sulfinate.