Synthesis of a NO-releasing prodrug of rofecoxib

reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.