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Synthesis 2006(18): 3015-3018  
DOI: 10.1055/s-2006-942547
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Stereoselective Anti-Aldol Route to (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Ligand for a New Generation of HIV Protease Inhibitors

Arun K. Ghosh*, Jianfeng Li, Ramu Sridhar Perali
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
Fax: +1(765)4961612; e-Mail: akghosh@purdue.edu;
Further Information

Publication History

Received 27 April 2006
Publication Date:
02 August 2006 (online)

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Abstract

A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step.

Key Words

antiviral agents - asymmetric synthesis - chiral auxiliary - aldol reactions - fused-ring systems

    References

  • 1 . 2004 Report on the Global HIV/AIDS Epidemic   4th Global Report; New York, USA: 2004. 
    Google Scholar
  • 2a Flexner C. N. Engl. J. Med.  1998,  338:  1281 
    Google Scholar
  • 2b Cihlar T. Bischofberger N. Annu. Rep. Med. Chem.  2000,  35:  1777 
    Google Scholar
  • 3a Grabar S. Pradier C. Le Corfec E. Lancer R. Allavena C. Bentata M. Berlureau P. Dupont C. Fabbro-Peray P. Poizot-Martin I. Cosatagliola D. AIDS  2000,  14:  141 
    CrossrefGoogle Scholar
  • 3b Richman DD. Nature  2001,  410:  995 
    CrossrefGoogle Scholar
  • 4a Ghosh AK. Shin DW. Swanson L. Krishnan K. Cho H. Hussain KA. Walters DE. Holland L. Buthod J. Farmaco  2001,  56:  29 
    CrossrefGoogle Scholar
  • 4b Ghosh AK. Kincaid JF. Cho W. Walters DE. Krishnan K. Hussain KA. Koo Y. Cho H. Rudall C. Holland L. Buthod J. Bioorg. Med. Chem. Lett.  1998,  8:  687 
    CrossrefGoogle Scholar
  • 4c Koh Y. Nakata H. Maeda K. Ogata H. Bilcer G. Devasamudram T. Kincaid JF. Boross P. Wang Y.-F. Tie Y. Volarath P. Gaddis L. Harrison RW. Weber IT. Ghosh AK. Mitsuya H. Antimicrob. Agents Chemother.  2003,  47:  3123 
    CrossrefGoogle Scholar
  • 4d Yoshimura K. Kato R. Kavlick MF. Nguyen A. Maroun V. Maeda K. Hussain KA. Ghosh AK. Gulnik SV. Erickson JW. Mitsuya H. J. Virol.  2002,  76:  1349 
    CrossrefGoogle Scholar
  • 5a De Meyer S. Peeters M. Conference on Retroviruses and Opportunistic Infections (11th CROI), Feb 8-11   San Francisco, USA: 2004. Abstracts 533 and 620
    CrossrefGoogle Scholar
  • 5b Surleraux DLNG. Tahri A. Verschueren WG. Pille GME. de Kock HA. Jonckers THM. Peeters A. De Meyer S. Azijn H. Pauwels R. de Bethune M.-P. King NM. Prabu-Jeyabalan M. Schiffer CA. Wigerinck PBTP. J. Med. Chem.  2005,  48:  1813 
    CrossrefGoogle Scholar
  • 5c Sorbera LA. Castaner J. Bayes M. Drugs Future  2005,  30:  441 
    CrossrefGoogle Scholar
  • 7 Miller JF. Andrews CW. Brieger M. Furfine ES. Hale MR. Hanlon MH. Hazen RJ. Kaldor I. McLean EW. Reynolds D. Sammond DM. Spaltenstein A. Tung R. Turner EM. Xu RX. Sherrill RG. Bioorg. Med. Chem. Lett.  2006,  16:  1788 
    CrossrefPubMedGoogle Scholar
  • 8a Ghosh AK. Kincaid JF. Walters DE. Chen Y. Chaudhuri NC. Thompson WJ. Culberson C. Fitzgerald PMD. Lee HY. McKee SP. Munson PM. Duong TT. Darke PL. Zugay JA. Schleif WA. Axel MG. Lin J. Huff JR. J. Med. Chem.  1996,  39:  3278 
    CrossrefGoogle Scholar
  • 8b Ghosh AK. Chen Y. Tetrahedron Lett.  1995,  36:  505 
    CrossrefGoogle Scholar
  • 8c Ghosh AK. Leshchenko S. Noetzel M. J. Org. Chem.  2004,  69:  7822 
    CrossrefGoogle Scholar
  • 9 Quaedflieg PJLM. Kesteleyn BRR. Wigerinck PBTP. Goyvaerts NMF. Vijn RJ. Liebregts CSM. Kooistra JHMH. Cusan C. Org. Lett.  2005,  7:  5917 
    CrossrefPubMedGoogle Scholar
  • For recent ester enolate-based anti-aldol procedures, see:
  • 10a Ghosh AK. Kim J. Org. Lett.  2003,  5:  1063 
    CrossrefPubMedGoogle Scholar
  • 10b Ghosh AK. Fidanze S. Org. Lett.  2000,  2:  2405 
    CrossrefPubMedGoogle Scholar
  • 10c Ghosh AK. Onishi M. J. Am. Chem. Soc.  1996,  118:  2527 
    CrossrefPubMedGoogle Scholar
  • 11a Ghosh AK. Bischoff A. Cappiello J. Eur. J. Org. Chem.  2003,  821 
    CrossrefPubMedGoogle Scholar
  • 11b Ghosh AK. Bischoff A. Cappiello JJ. Org. Lett.  2001,  3:  2677 
    CrossrefPubMedGoogle Scholar
  • 13 Dale JA. Dull DL. Mosher HS. J. Org. Chem.  1969,  34:  2543 
    CrossrefGoogle Scholar
6

On June 23, 2006, the FDA approved a new HIV treatment for patients who do not respond to existing drugs; see: www.fda.gov/bbs/topics/NEWS/2006/NEW01395.html.

12

The Mosher ester was formed by the reaction of Mosher acid and alcohol 3 with EDCI in the presence of DMAP. The 19F NMR analysis of the Mosher ester13 revealed an enantiomeric purity of >99%.