Total synthesis of (-)-morphine.

We have developed an efficient total synthesis of (-)-morphine in 5% overall yield with the longest linear sequence consisting of 17 steps from 2-cyclohexen-1-one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki-Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6-addition. Furthermore, mild deprotection conditions to remove the 2,4-dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N-methyl-DNs-amide moiety.

[1]  T. Hudlický,et al.  Chemoenzymatic enantiodivergent total syntheses of (+)- and (−)-codeine , 2009 .

[2]  V. Lynch,et al.  Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative. , 2009, Journal of the American Chemical Society.

[3]  G. Schulte,et al.  Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system. , 2009, Journal of the American Chemical Society.

[4]  B. Iorga,et al.  Diastereoselective total synthesis of (+/-)-codeine. , 2008, Chemistry.

[5]  Yuta Suzuki,et al.  Second-generation total synthesis of haterumalide NA using B-alkyl Suzuki-Miyaura coupling. , 2008, Organic letters.

[6]  N. Chida,et al.  Formal synthesis of (−)-morphine from d-glucal based on the cascade Claisen rearrangement , 2008 .

[7]  T. Kan,et al.  Total synthesis of (+/-)-morphine. , 2006, Organic letters.

[8]  Demosthenes Fokas,et al.  Enantioselective synthesis of (-)-dihydrocodeinone: a short formal synthesis of (-)-morphine. , 2006, The Journal of organic chemistry.

[9]  B. Trost,et al.  Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine. , 2005, Journal of the American Chemical Society.

[10]  C. Tanyeli,et al.  Chemoenzymatic synthesis of a '- and a-acetoxylated cyclic ketones , 2004 .

[11]  T. Kan,et al.  Ns strategies: a highly versatile synthetic method for amines. , 2004, Chemical communications.

[12]  J. Yeo,et al.  The intramolecular Baylis-Hillman reaction: easy preparation of versatile substrates, facile reactions, and synthetic applications. , 2004, Chemical communications.

[13]  B. Trost,et al.  Enantioselective synthesis of (-)-codeine and (-)-morphine. , 2002, Journal of the American Chemical Society.

[14]  A. Rheingold,et al.  Synthesis of (-)-morphine. , 2002, Journal of the American Chemical Society.

[15]  T. Kan,et al.  Highly Versatile Synthesis of Nitrogen-Containing Compounds by Means of Nitrobenzenesulfonamides , 2001 .

[16]  P. Parsons,et al.  A general approach to the galanthamine ring system , 2001 .

[17]  K. Ogasawara,et al.  Diastereoselective synthesis of 3,4-dimethoxy-7-morphinanone: a potential route to morphine. , 2000, Organic letters.

[18]  J. Liou,et al.  Total synthesis of (±)-desoxycodeine-d: a novel route to the morphine skeleton , 2000 .

[19]  L. Overman,et al.  A Suzuki Coupling Method for Directly Introducing a Protected β-Aminoethyl Group into Arenes and Alkenes. Convenient Synthesis of Phenethyl and Homoallylic Amines , 1999 .

[20]  D. Trauner,et al.  Synthesis of Enantiomerically Pure Morphine Alkaloids: The Hydrophenanthrene Route. , 1998, The Journal of organic chemistry.

[21]  G. Butora.  Toward a Practical Synthesis of Morphine. The First Several Generations of a Radical Cyclization Approach , 1998 .

[22]  T. Kan,et al.  2,4-Dinitrobenzenesulfonamides: A simple and practical method for the preparation of a variety of secondary amines and diamines , 1997 .

[23]  James D White,et al.  Asymmetric Synthesis of (+)-Morphine. The Phenanthrene Route Revisited , 1997 .

[24]  Norio Miyaura,et al.  Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds , 1995 .

[25]  L. Overman,et al.  Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (-)- and (+)-dihydrocodeinone and (-)- and (+)-morphine , 1993 .

[26]  Demosthenes Fokas,et al.  Convergent Synthesis of (+/-)-Dihydroisocodeine in 11 Steps by the Tandem Radical Cyclization Strategy - a Formal Total Synthesis of (+/-)-Morphine , 1992 .

[27]  M. Tius,et al.  A novel approach to the synthesis of morphine alkaloids: the synthesis of (d,l)-thebainone-A , 1992 .

[28]  G Shams,et al.  Synthesis of halogenated trimetoquinol derivatives and evaluation of their beta-agonist and thromboxane A2 (TXA2) antagonist activities. , 1992, Journal of medicinal chemistry.

[29]  J. Toth,et al.  Studies culminating in the total synthesis of (dl)-morphine , 1988 .

[30]  N. Schore,et al.  Two approaches to angularly fused triquinanes via intramolecular Pauson-Khand cyclization , 1987 .

[31]  J. Toth,et al.  Morphine support studies. 2. Formation of the neopinone/codeinone ring system via intramolecular 1,6-addition of an amino moiety to a dienyl ketone , 1986 .

[32]  D. Dess,et al.  Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones , 1983 .

[33]  W. Moos,et al.  CODEINE ANALOGS. SYNTHESIS OF 4A‐ARYLDECAHYDROISOQUINOLINES CONTAINING NITROGEN RING FUNCTIONALITY AND OF OCTAHYDRO‐1H‐INDENO(1,2,3‐EF)ISOQUINOLINES. A TOTAL SYNTHESIS OF CODEINE , 1983 .

[34]  C. Mitch,et al.  Studies directed towards the total synthesis of morphine alkaloids , 1982 .

[35]  O. Mitsunobu.  The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products , 1981 .

[36]  K. Rice.  Synthetic opium alkaloids and derivatives. A short total synthesis of (.+-.)-dihydrothebainone, (.+-.)-dihydrocodeinone, and (.+-.)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners , 1980 .

[37]  O. Mitsunobu,et al.  Preparation of Esters of Carboxylic and Phosphoric Acid via Quaternary Phosphonium Salts , 1967 .

[38]  R. Grewe,et al.  Die Cyclisierung von Octahydro‐isochinolinderivaten durch Morphinan‐Ringschluß. Synthese des Dihydrothebainons , 1967 .

[39]  M. Gates,et al.  The Synthesis of Morphine , 1952 .

[40]  K. Ogasawara,et al.  A concise route to (−)-morphine , 2001 .

[41]  K. Rice.  A rapid, high-yield conversion of codeine to morphine. , 1977, Journal of medicinal chemistry.

[42]  D. Ginsburg,et al.  THE SYNTHESIS OF MORPHINE , 1954 .