The evolution of the synthesis of oseltamivir phosphate (Tamiflu ® ), used for the oral treatment and prevention of influenza virus infections (viral flu) is described. Oseltamivir phosphate is the ethyl ester prodrug of the corresponding acid, a potent and selective inhibitor of influenza neuraminidase. The discovery chemistry route and scalable routes used for kilo laboratory production as well as the technical access to oseltamivir phosphate from (-)-shikimic acid proceeding via a synthetically well-developed epoxide building block followed by azide transformations are reviewed. Synthesis and process research investigations towards azide-free conversions of the key epoxide building block to oseltamivir phosphate are discussed. The search for new routes to oseltamivir phosphate independent of shikimic acid including Diels-Alder approaches and transformations of aromatic rings employing a desymmetrization concept are presented in view of large-scale production requirements.

Total syntheses from pyridine precursors of 5,10-dideazaaminopterin (1) and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin (2) are described. These compounds exhibit significant in vivo activity against L1210 leukemia that is comparable to that observed with methotrexate.

An efficient synthesis of 4-bromo-l-tosylii>dole (10) based on the Pd(II)-catalyzed cyclization of an o-ethénylaniline p-toluehesulfonamide has been developed. A Pd(0) oxidative addition-olefin insertion-/S-hydride elimination cycle converted 10 to a number of 4-substituted 1-tosylindóles. Selective electrophilic substitutions at the 3-position of 10 provided access to the 3-(chloromercurio)-( 18) and 3-iodo-l-tosylindoles ( 22). Transmetalation to palladium and allyl chloride insertion converted 18 to 3-allyl-4-bromo-1-tosylindole (20) which could be cyclized to the benz[c,d]indoline 21. A Pd(0) oxidative addition-olefin insertion-j3-hydride elimination cycle converted the 3-iodo compound 22 to a number of 4-bromo-3-substituted 1-tosylindoles including 24, a potential precursor to optically active tryptophans.

A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride-amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladiumcatalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35-38% for two previous processes, respectively, to 61%.

thia-crowns, and it can be used to rationalize the following experimentally observed order of gauche preference: C-S » C-C > C-O. Prediction of conformation in -(C-C-E)"crown-type ligands can be accomplished by the following: (1) maximizing the number of C-S bonds in gauche placement; (2) minimizing the number of C-0 (or secondary C-N) bonds in gauche placement; (3) minimizing the number of C-C bonds in gauche placement. The application of these considerations to design of macrocyclic ligands is apparent.