Chemoselective Staudinger Strategy in the Practical, Fit for Purpose, Gram-Scale Synthesis of an HCV RNA Polymerase Inhibitor

Abstract

The use of a late-stage selective Staudinger reaction in the preparation of the novel HCV RNA polymerase inhibitor is described.

Staudigner - nucleoside - 7-deaza-adenosine - azide - HCV NS5B

References and Notes

For a general review on HCV therapeutics, see:

1a Brown NA. Expert Opin. Invest. Drugs  2009,  18:  709 

1b Tan SL. Pause A. Shi Y. Sonenberg N. Nat. Rev. Drug Discovery  2002,  1:  867 

2a Smith DB. Kalayanov G. Sund C. Winqvist A. Pinho P. Maltseva T. Morisson V. Leveque V. Rajyaguru S. Le Pogam S. Najera I. Benkestock K. Zhou X.-X. Maag H. Cammack N. Martin JA. Swallow S. Johansson NG. Klumpp K. Smith M.
J. Med. Chem.  2009,  52:  219 

2b Klumpp K. Leveque V. Le Pogam S. Ma H. Jiang W.-R. Kang H. Granycome C. Singer M. Laxton C. Hang JQ. Sarma K. Smith DB. Heindl D. Hobbs C. Merrett JH. Symons J. Cammack N. Martin JA. Devos R. Najera I. J. Biol. Chem.  2006,  281:  3793 

2c McCown MF. Rajyaguru S. Le Pogam S. Ali S. Jiang W.-R. Kang H. Symons J. Cammack N. Najera I. Antimicrob. Agents Chem.  2008,  52:  1604 

3 For a review on multiple classes of NS5B inhibitors, see: Beaulieu PL. Expert Opin. Ther. Pat.  2009,  19:  145 

4 Avolio S, Di Francesco ME, Pompei M, and Summa V. inventors; PCT Int. Appl., WO  2010/026153. 

5a Li J. Chiang F.-I. Chen H.-N. Chang C.-WT. J. Org. Chem.  2007,  72:  4055 

5b Li J. Chen H.-N. Chang H. Wang J. Chang C.-WT. Org. Lett.  2005,  7:  3061 

5c Chapyshev SV. Synlett  2009,  1 

5d Nyffeler PT. Liang C.-H. Koeller KM. Wong C.-H. J. Am. Chem. Soc.  2002,  124:  10773 

6 Perrone P. Daverio F. Valente R. Rajyaguru S. Martin JA. Leveque V. Le Pogam S. Najera I. Klumpp K. Smith DB. McGuigan C. J. Med. Chem.  2007,  50:  5463 

7

At higher temperatures, aromatic Finkelstein displacement of the Cl group was observed and elimination of the alkyl iodide proved sluggish requiring 2 d to proceed to 100% conversion. Increased heating resulted in decomposition of the sensitive vinyl ether product.

8

The beneficial effect of the large TBS protecting group on reactions at C4′ might result from a preferred conformation alignment. Further mechanistic investigation is ongoing and will be reported in due course.

9 For a discussion on the limitations of DMDO use on scale, see: Ferrer M. Gibert M. Sánchez-Baeza F. Messeguer A. Tetrahedron Lett.  1996,  37:  3585 

10 Epoxidation of 4′,5′-unsaturated nucleosides exhibits high selectivity. The low dr in this case results from ring opening, see: Haragushi K. Takeda S. Tanaka H. Org. Lett.  2003,  5:  1399 

11 Connolly TJ, Durkin K, Sarma K, and Zhu J. inventors; PCT Int. Appl., WO  2005/000864. 

12 Wolfe JP. Åhman J. Sadighi JP. Singer RA. Buchwald SL. Tetrahedron Lett.  1997,  38:  6367 

This protocol is known to be sensitive to ortho substitution:

13a Lee S. Jørgensen M. Hartwig JF. Org. Lett.  2001,  3:  2729 

13b Huang X. Buchwald SL. Org. Lett.  2001,  3:  3417 

14

Palladium-catalyzed hydrogenolysis and metal-mediated reductions (Zn, Mg, Fe) gave unsatisfactory results. Reduction with TMS₂S resulted only in partial conversion.

15 Gololobov YG. Kasukhin LF. Tetrahedron  1992,  48:  1353 

16 The exquisite selectivity might arise from both steric and electronic influences. For recent work dealing with relative rates of azides in Staudinger reactions, see: Lin FL. Hoyt HM. Van Halbeek H. Bergman RG. Bertozzi CR. J. Am. Chem. Soc.  2005,  127:  2686 

17 Poupon J.-C. Boezio AA. Charette AB. Angew. Chem. Int. Ed.  2006,  45:  1415 

18

Separation of the product from triphenylphosphine oxide was very tedious via traditional silica gel chromatography. With SCG-PPh₃ a simple workup and precipitation procedure was devised: The reaction was concentrated and taken into CH₂Cl₂. This solution was then washed with sat. aq NaHCO₃ and brine. The crude CH₂Cl₂ solution was then concentrated to a minimum amount of solvent required for complete solubilization. To this stirring solution was then added MTBE dropwise which resulted in precipitation of the SCG-phosphine oxide. The filtrate was concentrated to afford the reduced amine in >90% purity by HPLC.