Asymmetric synthesis of chiral organofluorine compounds: Use of nonracemicfluoroiodoacetic acid as a practical electrophile and its application to the synthesis of monofluoro hydroxyethylene dipeptide isosteres within a novel series of HIV protease inhibitors

Two stereoselective routes to a series of diastereomeric inhibitors of 1HIV protease, monofluorinated analogues of the Merck HIV protease inhibitor in dinavir, are described. The two routes feature stereoselective construction of the fluorinated core subunits by asymmetric alkylation reactions. The f irst-generation syntheses were based on the conjugate addition of the lithi um enolate derived from pseudoephedrine alpha -fluoroacetamide to nitroalke ne 12, a modestly diastereoselective transformation. A more practical secon d-generation synthetic route was developed that is based on a novel method for the asymmetric synthesis of organofluorine compounds, by enolate alkyla tion using optically active fluoroiodoacetic acid as the electrophile in co mbination with a chiral amide enolate. Resolution of fluoroiodoacetic acid with ephedrine provides either enantiomeric form of the electrophile in gre ater than or equal to 96% ee. Alkylation reactions with this stable and sto rable chiral fluorinated precursor are shown to proceed in a highly stereos pecific manner. With the development of substrate-controlled syn- or anti-s elective reductions of alpha -fluoro ketones 44 and 45 (diastereomeric rati os 12:1-84:1), efficient and stereoselective routes to each of the four tar geted inhibitors were achieved. The optimized synthetic route to the most p otent inhibitor, (syn,syn-4, K-i = 2.0 nM) proceeded in seven steps (87% av erage yield per step) from aminoindanol hydrocinnamide 40 and (S)-fluoroiod oacetic acid, and allowed for the preparation of more than 1 or of this com pound. The inhibition of HIV-1 protease by each of the fluorinated inhibito rs was evaluated in vitro, and the variation of potency as a function of in hibitor stereochemistry;is discussed.