An Efficient Synthesis of (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine. A Formal Synthesis of (-)-Aphanorphine

Abstract

We report a highly efficient synthesis of (1R,4S)-1-methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine in six steps from 5. The present work constitutes a new formal synthesis of marine alkaloid (-)-aphanorphine.

aphanorphine - benzazepine - Friedel-Crafts alkylation - marine alkaloid - synthesis

References

<A NAME="RU16903ST-1">1</A> Gulavita N. Hori A. Shimizu Y. Laszlo P. Clardy J. Tetrahedron Lett.  1988,  29:  4381 

<A NAME="RU16903ST-2">2</A> Palmer DC. Strauss MJ. Chem. Rev.  1977,  77:  1 

<A NAME="RU16903ST-3">3</A> Shiotani S. Kometani T. Mitsuhashi K. Nozawa T. Kurobe A. Fitsukaichi O. J. Med. Chem.  1976,  19:  803 

<A NAME="RU16903ST-4A">4a</A> Takano S. Inomata K. Sato T. Ogasawara K. J. Chem. Soc., Chem. Commun.  1989,  1591 

<A NAME="RU16903ST-4B">4b</A> Takano S. Inomata K. Sato T. Takahashi M. Ogasawara K. J. Chem. Soc., Chem. Commun.  1990,  290 

<A NAME="RU16903ST-4C">4c</A> Honda T. Yamamoto A. Cui YS. Tsubuki M. J. Chem. Soc., Perkin Trans. 1  1992,  531 

<A NAME="RU16903ST-4D">4d</A> Hume AN. Henry SS. Meyers AI. J. Org. Chem.  1995,  60:  1265 

<A NAME="RU16903ST-4E">4e</A> Meyers AI. Schmidt W. Santiago B. Heterocycles  1995,  40:  525 

<A NAME="RU16903ST-4F">4f</A> Fadel A. Arzel P. Tetrahedron: Asymmetry  1995,  6:  893 

<A NAME="RU16903ST-4G">4g</A> Hallinan KO. Honda T. Tetrahedron  1995,  51:  12211 

<A NAME="RU16903ST-4H">4h</A> Node M. Imazato H. Kurosaki R. Kawano Y. Inoue T. Nishide K. Heterocycles  1996,  42:  811 

<A NAME="RU16903ST-4I">4i</A> Shiotani S. Okada H. Nakamata K. Yamamoto T. Sekino F. Heterocycles  1996,  43:  1031 

<A NAME="RU16903ST-4J">4j</A> Fadel A. Arzel P. Tetrahedron: Asymmetry  1997,  8:  283 

<A NAME="RU16903ST-4K">4k</A> Fadel A. Arzel P. Tetrahedron: Asymmetry  1997,  8:  371 

<A NAME="RU16903ST-4L">4l</A> Shimizu M. Kamikubo T. Ogasawara K. Heterocycles  1997,  46:  21 

<A NAME="RU16903ST-4M">4m</A> Tamura O. Yangimachi T. Kobayashi T. Ishibashi H. Org. Lett.  2001,  3:  2427 

<A NAME="RU16903ST-4N">4n</A> Fuchs JR. Funk RL. Org. Lett.  2001,  3:  3923 

<A NAME="RU16903ST-4O">4o</A> Tanaka K. Taniguchi T. Ogasawara K. Tetrahedron Lett.  2001,  42:  1049 

<A NAME="RU16903ST-4P">4p</A> El Azab AS. Taniguchi T. Ogasawara K. Heterocycles  2002,  56:  39 

<A NAME="RU16903ST-4Q">4q</A> Zhai H. Luo S. Ye C. Ma Y. J. Org. Chem.  2003,  68:  ASAP ; MS No. JO0348726

For the preparation of compound 5, see:

<A NAME="RU16903ST-5A">5a</A> Han G. LaPorte MG. Folmer JJ. Werner KM. Weinreb SM. J. Org. Chem.  2000,  65:  6293 

<A NAME="RU16903ST-5B">5b</A> Westwood NB. Walker RT. Tetrahedron  1998,  54:  13391 

<A NAME="RU16903ST-6">6</A> For Swern oxidation, see: Anthory JM. Debra SB. Daniel S. J. Org. Chem.  1979,  44:  4148 

<A NAME="RU16903ST-7">7</A> Steele M. Watkinson M. Whiting A. J. Chem. Soc., Perkin Trans. 1  2001,  588 

For reduction with triethylsilane, see:

<A NAME="RU16903ST-8A">8a</A> Orfanopoulos M. Smonou I. Synth. Commun.  1988,  18:  833 

<A NAME="RU16903ST-8B">8b</A> Smonou I. Orfanopoulos M. Tetrahedron Lett.  1988,  29:  5793 

For methylation of similar pyrrolidinones, see:

<A NAME="RU16903ST-9A">9a</A> Blanco M.-J. Sardina FJ. J. Org. Chem.  1998,  63:  3411 

<A NAME="RU16903ST-9B">9b</A> Moulines J. Bats J.-P. Hautefaye P. Nuhrich A. Lamidey A.-M. Tetrahedron Lett.  1993,  34:  2315 

<A NAME="RU16903ST-10">10</A>

Compound 2, a colorless solid: mp 137-138 °C; 99.8% ee; [α]_D ²⁰ -13.4 (c 0.969, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.41 (s, 3 H, CH₃), 1.46 (ddd, J = 11.1, 6.3, 1.5 Hz, 1 H, 0.5CH₂), 1.79 (d, J = 11.1 Hz, 1 H, 0.5CH₂), 2.43 (s, 3 H, benzylic CH₃), 2.93 (dd, J = 16.6, 2.8 Hz, 1 H, 0.5 CH₂), 3.02 (d, J = 8.7 Hz, 1 H, 0.5 CH₂), 3.12 (d, J = 16.8 Hz, 1 H, 0.5 CH₂), 3.40 (dd, J = 8.6, 1.4 Hz, 1 H, 0.5 CH₂), 3.79 (s, 3 H, OCH₃), 4.39-4.45 (m, 1 H. NCH), 6.72 (dd, J = 8.6, 2.8 Hz, 1 H, CH), 6.78 (d, J = 2.1 Hz, 1 H, CH), 6.98 (d, J = 8.1 Hz, 1 H, CH), 7.28 (d, J = 8.1 Hz, 2 H, 2 CH), 7.69 (d, J = 8.4 Hz, 2 H, 2 CH). ¹³C NMR (75 MHz, CDCl₃): δ = 20.7, 21.5, 38.2, 41.7, 42.3, 55.3, 57.8, 62.9, 110.0, 111.7, 125.2, 127.1, 129.6, 130.4, 135.6, 143.1, 144.9, 157.9. MS (EI): 357 (18) [M⁺], 202 (15), 173 (100). Anal. Calcd for C₂₀H₂₃NO₃S: C, 67.20; H, 6.49; N, 3.92. Found: C, 67.18; H, 6.55; N, 3.80.