Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.

Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5'-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.

The potent antitumor agent mucocin (1) was isolated from the leaves of Rollinia mucosa (jacq.) Baill. (Annonaceae) by McLaughlin and co-workers in 1995. 1-3 This agent has exquisite selectivity for the inhibition of A-549 (lung cancer) and PACA-2 (pancreatic cancer) solid tumor cell lines with potency 10,000 times that of adriamycin (doxorubicin). Annonaceous acetogenins selectively inhibit cancerous cells through the blockage of the mitochondrial complex I (NADH-ubiquinone oxidoreductase), and the inhibition of the plasma membrane NADH oxidase, which depletes ATP and induces apoptosis (programmed cell death) in malignant cells. 4In a program directed toward the construction of nonadjacent tetrahydrofuran containing acetogenins, we have developed a new approach to the construction of C 2 -symmetrical 1,4-diols, using a temporary silicon-tethered (TST) ring-closing metathesis (RCM) homo-coupling reaction. 5 Herein, we now describe a novel and expeditious synthesis of mucocin (1), which utilizes the TST-RCM cross-coupling reaction (Scheme 1). 6,7 This approach capitalizes on the localized C 2 -symmetry and thereby permits the construction of 2 and 3 from a common synthetic intermediate, the known homoallylic epoxide 5. 8 We further envisioned that the C4-C5 bond could be formed by enantioselective addition of the alkyne 3 to the aldehyde 4, thereby providing a new strategic disconnection for this class of biologically important molecules. 9 The key feature of this approach is the utilization of a triply convergent strategy, that can be adapted to facilitate the synthesis of related annonaceous acetogenins, resulting in one of the most expeditious syntheses of a complex acetogenin developed to date.The synthesis of the 3-hydroxy-2,6-disubstituted tetrahydropyran 2 was accomplished using the novel six-step strategy outlined in Scheme 2. Mitsunobu inversion of the allylic alcohol 5 using p-methoxyphenol afforded the requisite aryl ether. 10 Regiospecific ring opening of the epoxide with the homoenolate equivalent 11 derived from tert-butyldimethylsilyl protected divinyl carbinol, followed by an in situ protection of the resultant secondary alcohol, afforded the differentially protected triene 7 in 96% overall yield. Chemoselective Sharpless asymmetric dihydroxylation of the triene 7 using AD-mix-β furnished the hydroxy ketone 8 in 70% yield (ds ≥99:1 by HPLC), after recycling the recovered triene 7 (2×). 12 The alkyl side chain was then introduced via the conjugate addition of the cuprate derived from octylmagnesium bromide and copper cyanide to furnish the ketone 9 and thereby set the stage for the reductive etherification. Treatment of 9 with bismuth tribromide and tert-butyldimethylsilane in acetonitrile, followed by in situ protection of the secondary alcohol, furnished the tertbutyldimethylsilyl ether 10 in 93% yield (ds ≥19:1 by NMR). 13 Finally, the p-methoxyphenyl Note Added after ASAP. In the version posted 11/5/O3, in Scheme 2 the absolute configuration for the secondary tert-butyldimethylsilyl ether in 7,...

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Treatment of 2-(1-alkynyl)phenyl isocyanates 6 with the iminophosphorane 14 produced in situ the benzoenynyl carbodiimides 15. Thermolysis of 15 under refluxing p-xylene furnished the 6H-indolo[2,3-b][1,6]naphthyridines 5, which could be regarded as the 5-aza analogues of ellipticine alkaloids. Similarly, condensation of 6 with the iminophosphorane 20 led to the formation of the 6H-indolo[2,3-b][1,5]naphthyridines 25 as the major isomer and the 10H- indolo[2,3-b][1,7]naphthyridines 26 as the minor isomer. The indolonaphthyridines 32, 33, and 34 having a methoxyl substituent were likewise synthesized. Treatment of the diisocyanate 43 with 2 equiv of the iminophosphorane 7 furnished 45 having two indoloquinoline units incorporated in a seven-fused-ring system.