Chemoenzymatic Total Synthesis of (+)-Codeine by Sequential Intramolecular Heck Cyclizations via C-B-D Ring Construction

Abstract

An enzymatically generated diene diol was utilized as homochiral starting material in the total synthesis of (+)-codeine featuring a Mitsunobu inversion and two intramolecular Heck ­cyclizations.

enzymatic dihydroxylation - sequential intramolecular Heck reactions - hydroamination - codeine

References and Notes

<A NAME="RS05007ST-1">1</A>

To whom correspondence should be addressed.

<A NAME="RS05007ST-2A">2a</A> Gates M. Tschudi G. J. Am. Chem. Soc.  1952,  74:  1109 

<A NAME="RS05007ST-2B">2b</A> Gates M. Tschudi G. J. Am. Chem. Soc.  1956,  78:  1380 

For reviews of morphine syntheses, see:

<A NAME="RS05007ST-3A">3a</A> Zezula J. Hudlicky T. Synlett  2005,  388 

<A NAME="RS05007ST-3B">3b</A> Blakemore PR. White JD. Chem. Commun.  2002,  1159 

<A NAME="RS05007ST-3C">3c</A> Hudlicky T. Reed JW. Mulzer J. Trauner D. Curr. Org. Chem.  2000,  4:  343 

<A NAME="RS05007ST-3D">3d</A> Hudlicky T. Butora G. Fearnley S. Gum A. Stabile M. In Studies in Natural Products Chemistry   Vol. 18:  . Elsevier; Amsterdam: 1996.  p.43-154  

<A NAME="RS05007ST-4">4</A> Uchida K. Yokoshima S. Kan T. Fukuyama T. Org. Lett.  2006,  8:  5311 

<A NAME="RS05007ST-5A">5a</A> Taber DF. Neubert TD. Rheingold AL. J. Am. Chem. Soc.  2002,  124:  12416 

<A NAME="RS05007ST-5B">5b</A> Sondergaard K. Kristensen JL. Palner M. Gillings N. Knudsen GM. Roth BL. Begtrup M. Org. Biomol. Chem.  2005,  3:  4077 

<A NAME="RS05007ST-6A">6a</A> Stabile MR. Hudlicky T. Meisels ML. Tetrahedron: Asymmetry  1995,  6:  537 

<A NAME="RS05007ST-6B">6b</A> For large-scale (15 L) fermentation protocol, see: Endoma MA. Bui VP. Hansen J. Hudlicky T. Org. Process Res. Dev.  2002,  6:  525 

<A NAME="RS05007ST-7A">7a</A> Trost BM. Tang W. J. Am. Chem. Soc.  2002,  124:  14542 

<A NAME="RS05007ST-7B">7b</A> Trost BM. Tang W. J. Am. Chem. Soc.  2005,  127:  14785 

<A NAME="RS05007ST-8A">8a</A> Butora G. Hudlicky T. Fearnley SP. Gum AG. Stabile MR. Abboud KA. Tetrahedron Lett.  1996,  37:  8155 

<A NAME="RS05007ST-8B">8b</A> Butora G. Hudlicky T. Fearnley SP. Stabile MR. Gum AG. Gonzalez D. Synthesis  1998,  665 

<A NAME="RS05007ST-9A">9a</A> Frey DA. Duan C. Hudlicky T. Org. Lett.  1999,  1:  2085 

<A NAME="RS05007ST-9B">9b</A> Frey DA. Duan C. Ghiviriga I. Hudlicky T. Coll. Czech. Chem. Commun.  2000,  65:  561 

<A NAME="RS05007ST-10A">10a</A> Parker KA. Fokas D. J. Am. Chem. Soc.  1992,  114:  9688 

<A NAME="RS05007ST-10B">10b</A> Parker KA. Fokas D. J. Org. Chem.  1994,  59:  3927 

<A NAME="RS05007ST-10C">10c</A> Parker KA. Fokas D. J. Org. Chem.  1994,  59:  3933 

<A NAME="RS05007ST-10D">10d</A> Parker KA. Fokas D. J. Org. Chem.  2006,  71:  449 

<A NAME="RS05007ST-11">11</A> Nagata H. Miyazawa N. Ogasawara K. Chem. Commun.  2001,  1094 

<A NAME="RS05007ST-12">12</A> Zylstra GJ. Gibson DT. J. Biol. Chem.  1989,  264:  14940 

<A NAME="RS05007ST-13A">13a</A> Matsumoto M. Kuroda K. Tetrahedron Lett.  1980,  21:  4021 

<A NAME="RS05007ST-13B">13b</A> For experimental procedure, see: Michel P. Gennet D. Rasat A. Tetrahedron Lett.  1999,  40:  8575 

<A NAME="RS05007ST-14">14</A>

We are very grateful to Dr. Weiping Tang (University of Wisconsin) for supplying us with detailed description of the experiments performed in Trost’s group as well as experimental and spectral information used in monitoring the progress of the reaction. In spite of these details we were never successful in detecting codeine in the reaction mixtures and had to resort to alternative ways of performing the C-9 amination.

<A NAME="RS05007ST-15">15</A> White JD. Hrnciar P. Stappenbeck F. J. Org. Chem.  1999,  64:  7871