An Efficient Synthesis of a Cyclopentannulated Pyrrolidine Derivative

Abstract

A racemic cyclopentannulated pyrrolidine derivative was synthesized utilizing ruthenium oxidation and borane reduction as the key steps. Ruthenium oxidation reaction of the 1,2-dibromoalkene moiety in an N-Boc-protected tetrabromonorbornyl derivative afforded a tricyclic α-hydroxy ketone, which on alkaline hydrogen peroxide cleavage furnished a bicyclic lactam in excellent yield. Borane reduction of the N-Boc-protected bicyclic lactam gave an unexpected product as a single diastereomer resulting from the reduction of not only the lactam and ester moieties but also the ketal to the corresponding methyl ether. A plausible mechanism involving an oxocarbenium ion is discussed.

Key words

bicyclic pyrrolidine - ruthenium oxidation - borane reduction - Diels-Alder cycloaddition - hydrodehalogenation

References

• 1a Ranatunga S. Valle JRD. Tetrahedron Lett.  2009,  50:  2464 
• 1b Obst U. Betschmann P. Lerner C. Seiler P. Diederich F. Helv. Chim. Acta  2000,  83:  855 
• 1c Kolodziej SA. Nikiforovich GV. Skeean R. Lignon M.-F. Martinez J. Marshall GR. J. Med. Chem.  1995,  38:  137 
• 2a Martín R. Alcón M. Pericás MA. Riera A. J. Org. Chem.  2002,  67:  6896 
• 2b Sebahar PR. Williams RM. J. Am. Chem. Soc.  2000,  122:  5666 
• 2c Denhart DJ. Griffith DA. Heathcock CH. J. Org. Chem.  1998,  63:  9616 
• 2d Overman LE. Tellew JE. J. Org. Chem.  1996,  61:  8338 
• 2e Sisko J. Henry JR. Weinreb SM. J. Org. Chem.  1993,  58:  4945 
• 3a Lombardo M. Fabbroni S. Trombini C. J. Org. Chem.  2001,  66:  1264 
• 3b Dondoni A. Perrone D. Tetrahedron Lett.  1999,  40:  9375 
• 3c Blanco M.-J. Sardina FJ. J. Org. Chem.  1998,  63:  3411 
• 3d Wong C.-H. Provencher L. Porco JA. Jung S.-H. Wang Y.-F. Chen L. Wang R. Steensma DH. J. Org. Chem.  1995,  60:  1492 
• 3e Lundt I. Madsen R. Daher SA. Winchester B. Tetrahedron  1994,  50:  7513 
• 3f Thompson DK. Hubert CN. Wightman RH. Tetrahedron  1993,  49:  3827 
• 3g Liu KKC. Kajimoto T. Chen L. Zhong Z. Ichikawa Y. Wong CH. J. Org. Chem.  1991,  56:  6280 
• 3h Card PJ. Hitz WD. J. Org. Chem.  1985,  50:  891 
• 4a Bunch L. Nielsen B. Jensen AA. Bräuner-Osborne H. J. Med. Chem.  2006,  49:  172 
• 4b Ennis MD. Hoffman RL. Ghazal NB. Old DW. Mooney PA. J. Org. Chem.  1996,  61:  5813 
• 4c Yan M. Jacobsen N. Hu W. Gronenberg LS. Doyle MP. Colyer JT. Bykowski D. Angew. Chem. Int. Ed.  2004,  43:  6713 
• 4d Feldman KS. Iyer MR. J. Am. Chem. Soc.  2005,  127:  4590 
• Reviews of the use of pyrrolidine derivatives in enamine catalysis, see:
• 5a Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 5b Notz W. Tanaka F. Barbas CF. Acc. Chem. Res.  2004,  37:  580 
• 5c List B. Acc. Chem. Res.  2004,  37:  548 
• 6 Khan FA. Das BP. Dash J. J. Prakt. Chem.  2000,  342:  512 ; and references therein
• 7a Khan FA. Prabhudas B. Dash J. Sahu N. J. Am. Chem. Soc.  2000,  122:  9558 
• 7b Khan FA. Sahu N.
  J. Catal.  2005,  231:  438 
• For selected list of publications on the applications of norbornyl derivatives from our laboratory, see:
• 8a Khan FA. Rao CN. Tetrahedron Lett.  2006,  47:  7567 
• 8b Khan FA. Dash J. Sudheer Ch. Sahu N. Parasuraman K.
  J. Org. Chem.  2005,  70:  7565 
• 8c Khan FA. Dash J. Eur. J. Org. Chem.  2004,  2692 
• 8d Khan FA. Dash J. Sudheer Ch. Chem. Eur. J.  2004,  10:  2507 
• 8e Khan FA. Satapathy R. Dash J. Savitha G. J. Org. Chem.  2004,  69:  5295 
• 8f Khan FA. Dash J. Sahu N. Sudheer Ch.
  J. Org. Chem.  2002,  67:  3783 
• 8g Khan FA. Sahu N. Dash J. Prabhudas B. J. Indian Inst. Sci.  2001,  81:  325 
• 9a Khan FA. Rout B. J. Org. Chem.  2007,  72:  7011 
• 9b Khan FA. Rout B. Tetrahedron Lett.  2006,  47:  5251 
• 10 Khan FA. Upadhyay SK. Tetrahedron Lett.  2008,  49:  6111 
• 11 Köhling P. Schmidt AM. Eilbracht P. Org. Lett.  2003,  5:  3213 
• 12 Khan FA. Prabhudas B. Tetrahedron Lett.  1999,  40:  9289 
• 13a Anastasia M. Allevi P. Ciuffreda P. Fiecchi A. Scala A. J. Chem. Soc., Perkin Trans. 1  1986,  2117 
• 13b Borch RF. Bernstein MD. Durst HD. J. Am. Chem. Soc.  1971,  93:  2897 
• 15 Hwu JR. Jain ML. Tsay S.-C. Hakimelahi GH. Tetrahedron Lett.  1996,  37:  2035 
• 16a Brown HC. Murray KJ. Tetrahedron  1986,  42:  5497 
• 16b Maryanoff BE. McComsey DF. Nortey SO. J. Org. Chem.  1981,  46:  355 
• 17 Rathore R. Weigand U. Kochi JK. J. Org. Chem.  1996,  61:  5246 
• 18 Fleming B. Bolker HI. Can. J. Chem.  1974,  52:  888 
• 19a Fu Y.-Q. Li Z.-C. Ding L.-N. Tao J.-C. Zhang S.-H. Tang M.-S. Tetrahedron: Asymmetry  2006,  17:  3351 
• 19b Tzeng Z.-H. Chen H.-Y. Reddy RJ. Huang C.-T. Chen K. Tetrahedron  2009,  65:  2879 
• 20 Perrin DD. Armarego WLF. Perrin DR. Purification of Laboratory Chemicals   2nd ed.:  Pergamon Press; Oxford: 1980. 

14

The original endo/exo ratio in 11 was slightly altered in favor of exo product perhaps due to epimerization of aldehyde group in 10 under reaction conditions. On the other hand, addition of relatively bulky groups such as allyl to 10 with similar endo/exo composition exclusively furnished the endo addition product due to the unfavorable steric interaction of the syn-OMe group of the ketal offsetting the balance in favor of the endo product^8e via epimerization of aldehyde group.