Download PDF
Synlett 2006(18): 2965-2968  
DOI: 10.1055/s-2006-944193
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Enantioselective Access to an Anthracycline AB Synthon by a ­Desymmetrizing Heck Cyclization

Martin Oestreich*, Fernando Sempere-Culler, Axel B. Machotta
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
Fax: +49(761)2036100; e-Mail: martin.oestreich@orgmail.chemie.uni-freiburg.de;
Further Information

Publication History

Received 31 January 2006
Publication Date:
29 June 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

A group-selective intramolecular Heck reaction of an acyclic prochiral cyclization precursor provides an entry into the catalytic asymmetric synthesis of the AB bicyclic skeleton of ­anthracyclines. Enantiotopic group selection is strongly influenced by the hydroxylation pattern relative to the triflate moiety of the B ring (47% ee for 3,6-dimethoxy, 76% ee for 3-methoxy, and 92% ee without substitution).

Key words

asymmetric synthesis - catalysis - cyclizations - Heck ­reaction - palladium

    References and Notes

  • 1 Minotti G. Menna P. Salvatorelli E. Cairo G. Gianni L. Pharmacol. Rev.  2004,  56:  185 ; and references cited therein
    CrossrefGoogle Scholar
  • 2 For tetracycline antibiotics, see: Charest MG. Lerner CD. Brubaker JD. Siegel DR. Myers AG. Science  2005,  308:  395 
    CrossrefGoogle Scholar
  • 3a Krohn K. Angew. Chem., Int. Ed. Engl.  1986,  25:  790 ; Angew. Chem. 1986, 98, 788
    Google Scholar
  • 3b Krohn K. Tetrahedron  1990,  46:  291 
    Google Scholar
  • 4a Wong CM. Popien D. Schwenk R. Te Raa J. Can. J. Chem.  1971,  49:  2712 
    CrossrefGoogle Scholar
  • 4b Arcamone F. Bernardi L. Patelli B. Giardino P. Di Marco A. Casazza AM. Soranzo C. Pratesi G. Experientia  1978,  34:  1255 
    CrossrefGoogle Scholar
  • For recent total syntheses of aglycone 3, see:
  • 5a Allen JG. Hentemann MF. Danishefsky SJ. J. Am. Chem. Soc.  2000,  122:  571 
    CrossrefGoogle Scholar
  • 5b Achmatowicz O. Szechner B. J. Org. Chem.  2003,  68:  2398 
    CrossrefGoogle Scholar
  • Sharpless asymmetric epoxidation/kinetic resolution:
  • 6a Rama Rao AV. Yadav JS. Bal Reddy K. Mehendale AR. Tetrahedron  1984,  40:  4643 
    CrossrefGoogle Scholar
  • 6b Holland HL. Viski P. J. Org. Chem.  1991,  56:  5226 
    CrossrefGoogle Scholar
  • Sharpless asymmetric epoxidation:
  • 6c Sodeoka M. Iimori T. Shibasaki M. Tetrahedron Lett.  1985,  26:  6497 
    CrossrefGoogle Scholar
  • 6d Sodeoka M. Iimori T. Shibasaki M. Chem. Pharm. Bull.  1991,  39:  323 
    CrossrefGoogle Scholar
  • Sharpless asymmetric dihydroxylation:
  • 6e Nakajima M. Tomioka K. Koga K. Tetrahedron  1993,  49:  10807 
    CrossrefGoogle Scholar
  • 6f Badalassi F. Crotti P. Di Bugno C. D’Arata F. Favero L. Ramacciotti A. Tetrahedron: Asymmetry  2001,  12:  3155 ; and references cited therein
    CrossrefGoogle Scholar
  • 7 Catalytic asymmetric ring-opening of a meso-epoxide: Sekine A. Ohshima T. Shibasaki M. Tetrahedron  2002,  58:  75 
    CrossrefGoogle Scholar
  • For recent reviews, see:
  • 8a Intramolecular Heck reactions: Link JT. In Organic Reactions   Vol. 60:  Overman LE. Wiley; New York: 2002.  p.157 
    Google Scholar
  • 8b Catalytic asymmetric Heck reactions: Shibasaki M. Vogl EM. Ohshima T. Adv. Synth. Catal.  2004,  346:  1533 
    Google Scholar
  • 8c Heck reactions in total synthesis: Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 
    Google Scholar
  • For desymmetrizing Heck cyclizations, see:
  • 9a Ohrai K. Kondo K. Sodeoka M. Shibasaki M. J. Am. Chem. Soc.  1994,  116:  11737 
    Article in Thieme ConnectGoogle Scholar
  • 9b Imbos R. Minnaard AJ. Feringa BL. J. Am. Chem. Soc.  2002,  124:  184 
    Article in Thieme ConnectGoogle Scholar
  • 9c Lautens M. Zunic V. Can. J. Chem.  2004,  82:  399 
    Article in Thieme ConnectGoogle Scholar
  • 9d Bräse S. Synlett  1999,  1654 
    Article in Thieme ConnectGoogle Scholar
  • 10 Oestreich M. Sempere-Culler F. Machotta AB. Angew. Chem. Int. Ed.  2005,  44:  149 ; Angew. Chem. 2005, 117, 152
    CrossrefGoogle Scholar
  • 11 For related work, see: Coogan MP. Pottenger MJ. J. Organomet. Chem.  2005,  690:  1409 
    CrossrefGoogle Scholar
  • 13 Oestreich M. Eur. J. Org. Chem.  2005,  783 
    CrossrefGoogle Scholar
  • For neighboring group effects in intermolecular Heck reactions, see:
  • 14a Díaz Buezo N. Alonso I. Carretero JC. J. Am. Chem. Soc.  1998,  120:  7129 
    CrossrefGoogle Scholar
  • 14b Nilsson P. Larhed M. Hallberg A. J. Am. Chem. Soc.  2003,  125:  3430 
    CrossrefGoogle Scholar
  • 15 Baeyer-Villiger oxidation of the corresponding benzaldehyde afforded the phenol in high yield: Wriede U. Fernandez M. West KF. Harcourt D. Moore HW. J. Org. Chem.  1987,  52:  4485 
    CrossrefGoogle Scholar
  • 16 Applications of the 2-tetrahydropyranyl ether as an ortho-directing group are scarce: Geneste H. Schäfer B. Synthesis  2001,  2259 
    Article in Thieme ConnectGoogle Scholar
  • 17 Snieckus V. Chem. Rev.  1990,  90:  879 
    Google Scholar
  • 18 Velkov J. Mincheva Z. Bary J. Boireau G. Fujier C. Synth. Commun.  1997,  27:  375 
    CrossrefGoogle Scholar
  • 19 Oestreich M. Sempere-Culler F. Chem. Commun.  2004,  692 
    CrossrefGoogle Scholar
  • 20 Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 
    CrossrefGoogle Scholar
  • 22a

    Analytical Data for Trifluoromethanesulfonic Acid ( E , E )-2-[2-Hydroxy-5-phenyl-2-(3-phenyl-2-propenyl)-4-pentenyl]-3,6-dimethoxyphenyl Ester ( 9a).
    IR (CHCl3): 3627 (w), 3033 (s), 3016 (s), 2976 (m), 2897 (w), 1521 (m), 1492 (m), 1420 (m), 1238 (s), 1225 (s), 1211 (s), 1083 (m), 1047 (m) cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 1 H, OH), 2.38 (dd, J = 14.1 Hz, J = 7.3 Hz, 2 H), 2.45 (dd, J = 14.1 Hz, J = 7.3 Hz, 2 H), 3.09 (s, 2 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 6.32 (ddd, J = 15.9 Hz, J = 7.3 Hz, J = 7.3 Hz, 2 H), 6.44 (d, J = 15.9 Hz, 2 H), 6.83 (m, 1 H), 7.12-7.35 (m, 11 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.1, 43.9, 56.4, 56.6, 75.8, 110.4, 111.1, 118.8 (q, J = 319 Hz), 122.0, 125.7, 126.2, 127.1, 128.5, 129.1, 133.5, 137.7, 146.0, 152.0 ppm. MS (CI with NH3): m/z = 580 [M + NH4]+. Anal. Calcd for C29H29F3O6S: C, 61.91; H, 5.20; S, 5.70. Found: C, 62.13; H, 5.37; S, 5.58.

  • 22b

    Analytical Data for ( E , E )-4-Benzylidene-5,8-dimethoxy-2-(3-phenyl-2-propenyl)-1,2,3,4-tetrahydro-2-naphthol ( 8a).
    [α]D 20 -10.8 (c 1.09, CHCl3) for 52% ee. IR (CHCl3): 3628 (w), 3016 (s), 2977 (m), 2899 (w), 1521 (m), 1477 (m), 1437 (m), 1234 (s), 1216 (s), 1087 (m), 1046 (m) cm-1. 1H NMR (500 MHz, CDCl3): δ = 1.87 (s, 1 H, OH), 2.34 (ddd, J = 13.8 Hz, J = 8.1 Hz, J = 1.1 Hz, 1 H), 2.48 (ddd, J = 13.8 Hz, J = 6.9 Hz, J = 1.4 Hz, 1 H), 2.72 (dd, J = 13.0 Hz, J = 0.9 Hz, 1 H), 2.86 (d, J = 13.0 Hz, 1 H), 2.88 (s, 2 H), 3.78 (s, 3 H), 3.80 (s, 3 H), 6.08 (ddd, J = 15.8 Hz, J = 8.1 Hz, J = 6.9 Hz, 1 H), 6.39 (d, J = 15.8 Hz, 1 H), 6.71 (d, J = 8.9 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 7.10-7.38 (m, 10 H), 7.76 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 37.3, 39.4, 44.5, 55.8, 56.2, 71.3, 109.0, 109.9, 125.3, 125.7, 125.9, 126.2, 126.5, 127.2, 128.3, 128.5, 129.4, 131.0, 133.5, 134.0, 137.4, 138.5, 151.6, 151.8 ppm. MS (EI): m/z = 412 [M+]. HRMS (EI): m/z calcd for C28H28O3: 412.2044; found: 412.2039.

12

Machotta, A. B.; Sempere-Culler, F.; Straub, B. F.; Oestreich, M. manuscript in preparation.

21

General Procedure for Heck Reaction.
A base-washed and flame-dried sealed tube equipped with a magnetic stir bar is charged with Pd(OAc)2 (5.0 mol%), (R)-BINAP (7.5 mol%), and K2CO3 (4.0 equiv) or TMP (4.0 equiv). Then a solution of triflate 9 and degassed toluene (0.1 M) is subsequently added. The resulting suspension is vigorously stirred at r.t. until the formation of a red homogeneous solution except for the solid base. The tube is sealed and heated at the indicated temperature for 18 h. After cooling to r.t., silica gel is added and the solvent is evaporated under reduced pressure. The crude product 8 on silica gel is subjected to flash column chromatography on silica gel using cyclohexane-tert-butylmethylether solvent mixtures.