Synlett 2010(19): 2923-2927  
DOI: 10.1055/s-0030-1259015
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Synthesis of Bengamide E and Analogues via E-Selective Cross-Metathesis Olefination

Safiul Alam, Hamid Dhimane*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris cedex 06, France
Fax: +33(1)42864050; e-Mail: [email protected];
Further Information

Publication History

Received 2 September 2010
Publication Date:
03 November 2010 (online)


A modular, eight-step synthesis of bengamide E and six analogues from a common chiral pool has been developed. The key step in this approach is a cross-metathesis coupling of various commercial terminal olefins and a common alkene bearing the required stereogenic centers of bengamides lateral chain, which was easily derived from α-d-glucoheptonic-γ-lactone. Complete E-selectivity, and up to 92% yield were achieved for this crucial cross-metathesis step.

    References and Notes

  • 1a Quiñoà E. Adamczeski M. Crews P. Bakus G.
    J. Org. Chem.  1986,  51:  4494 
  • 1b Adamczeski M. Quiñoà E. Crews P. J. Am. Chem. Soc.  1989,  111:  647 
  • 1c Adamczeski M. Quiñoà E. Crews P. J. Org. Chem.  1990,  55:  240 
  • 1d D’Auria MV. Giannini C. Minale L. Zampella A. Debitus C. Frostin M. J. Nat. Prod.  1997,  60:  814 
  • 2 Thale Z. Kinder FR. Bair KW. Bontempo J. Czuchta AM. Versace RW. Phillips PE. Sanders ML. Wattanasin S. Crews P. J. Org. Chem.  2001,  66:  1733 
  • 3a For recent review (up to early 2001), see: Kinder FR. Org. Prep. Proced. Int.  2002,  34:  559 
  • 3b Banwell MG. McRae KJ. J. Org. Chem.  2001,  66:  6768 
  • 3c Liu W. Szewczyk JM. Waykole L. Repic O. Blacklock TJ. Tetrahedron Lett.  2002,  43:  1373 
  • 3d Boeckman RK. Clark TJ. Shook BC. Org. Lett.  2002,  4:  2109 
  • 3e Sarabia F. Sánchez-Ruiz A. J. Org. Chem.  2005,  70:  9514 ; and references cited therein
  • 3f Liu G. Ma Y.-M. Tai W.-Y. Xie C.-M. Li Y.-L. li J. Nan F.-J. ChemMedChem  2008,  3:  74 
  • 4 Kinder FR. Versace RW. Bair KW. Bontempo JM. Cesarz D. Chen S. Crews P. Czuchta AM. Jagoe CT. Mou Y. Nemzek R. Phillips PE. Tran LD. Wang R. Weltchek S. Zabludoff S. J. Med. Chem.  2001,  44:  3692 
  • 5 Towbin H. Bair KW. DeCaprio JA. Eck MJ. Kim S. Kinder FK. Morollo A. Mueller DR. Schindler P. Song HK. van Oostrum J. Versace RW. Voshol H. Wood J. Zabludoff S. Phillips PE. J. Biol. Chem.  2003,  278:  52964 
  • For recent reviews, see:
  • 6a Bernier SG. Taghizadeh N. Thompson CD. Westlin WF. Hannig G. J. Cell. Biochem.  2005,  95:  1191 
  • 6b Selvakumar P. Lakshmikuttyamma A. Dimmock J. Sharma RK. Biochim. Biophys.  2006,  1765:  148 
  • 6c Frottin F. Martinez A. Peynot P. Mitra S. Holz RC. Giglione C. Meinel T. Mol. Cell. Proteomics  2006,  5:  2336 
  • 6d Wiltschi B. Merkel L. Budisa N. ChemBioChem  2009,  10:  217 
  • 7 Hu X. Dang Y. Tenney K. Crews P. Tsai CW. Sixt KM. Cole PA. Liu JO. Chem. Biol.  2007,  14:  764 
  • 8a Levraud C. Calvet-Vitale S. Bertho G. Dhimane H. Eur. J. Org. Chem.  2008,  1901 
  • 8b David M. Dhimane H. Synlett  2004,  1029 
  • 9 Xu DD. Waykole L. Calienni JV. Ciszewski L. Lee GT. Liu W. Szewczyk J. Vargas K. Prasad K. Repic O. Blacklock TJ. Org. Process Res. Dev.  2003,  7:  856 
  • 12a Grank G. Eastwood FW. Aust. J. Chem.  1964,  17:  1392 
  • 12b Ando M. Ohhara H. Takase K. Chem. Lett.  1986,  879 
  • 14 Chatterjee AK. Choi R.-L. Sanders DP. Grubbs RH. J. Am. Chem. Soc.  2003,  125:  11360 
  • 16a Maynard HD. Grubbs RH. Tetrahedron Lett.  1999,  40:  4137 
  • 16b Edwards SD. Lewis T. Raylor RJK. Tetrahedron Lett.  1999,  40:  4267 
  • 16c Bourgeois D. Pancrazi A. Ricard L. Prunet J. Angew. Chem. Int. Ed.  2000,  39:  725 
  • 17 Fürstner A. Thiel OR. Ackermann L. Schanz H.-J. Nolan SP. J. Org. Chem.  2000,  65:  2204 
  • For review, see:
  • 18a Schmidt B. Eur. J. Org. Chem.  2004,  1865 
  • 18b Alcaide B. Almendros P. Chem. Eur. J.  2003,  9:  1259 
  • 19a Cadot C. Dalko PI. Cossy J. Tetrahedron Lett.  2002,  43:  1839 
  • 19b Maishal TK. Sinha-Mahapatra DK. Paranjape K. Sarkar A. Tetrahedron Lett.  2002,  43:  2263 
  • 20 Courchay FC. Sworen JC. Ghiviriga I. Aboud KA. Wagener KB. Organometallics  2006,  25:  6074 ; and references cited therein
  • 21 Hong SH. Sanders DP. Lee CW. Grubbs RH. J. Am. Chem. Soc.  2005,  127:  17160 
  • 23 Boyle WJ. Sifniades S. van Peppen JF. J. Org. Chem.  1979,  44:  4841 
  • 24 Liu W. Xu DD. Repic O. Blacklock TJ. Tetrahedron Lett.  2001,  42:  2439 

Aldehyde 3 is highly hygroscopic and sensitive to both acid and base; it should be freshly prepared and dehydrated by azeotropic evaporations with i-PrOAc prior to its use.


Our initial attempt to carry out the Julia-Kocienski methylenation of aldehyde 3 led to the required olefin 4 in poor yields (<10%).


Use of PTSA as catalyst in toluene at 80 ˚C gave similar yields; however, in large-scale batches, we observed transprotection of the acetonide, thus leading to the corresponding bisorthoester. Orthoester 6 was found to be stable at r.t. in the solid state; however, it undergoes gradual hydrolysis (into methyl formiate and diol 2) on standing in CDCl3.


The CM adducts 5 could not be quantitatively recovered from the reaction mixtures; aromatic compounds 5e-g could not be fully separated from substrate 4, while the aliphatic ones 5a-d were always contaminated with the substrate isomer 4′.


No CM reaction was observed with: H2C=CHTMS, H2C=CHO-t-Bu, H2C=CHOAc, H2C=CHSO2Me, N-vinylimidazole.