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Synlett 2008(18): 2821-2822  
DOI: 10.1055/s-0028-1083498
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Formal Asymmetric Synthesis of (-)-Aphanorphine via Ring-Closing Metathesis Reaction

Xiaobao Yanga,b, Bin Chengb, Zhong Li*a, Hongbin Zhai*b
a Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. of China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
e-Mail: zhaih@mail.sioc.ac.cn;
Further Information

Publication History

Received 15 July 2008
Publication Date:
15 October 2008 (online)

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Abstract

We have developed an asymmetric route to (-)-aphanorphine from O-Me-d-tyrosine methyl ester hydrochloride salt, available from d-tyrosine in four steps. The tricyclic framework of (-)-aphanorphine was assembled stereoselectively by intramolecular Friedel-Crafts reaction of the corresponding bicyclic precursor, which was in turn generated via ring-closing metathesis reaction.

Key words

aphanorphine - asymmetric synthesis - ring-closing metathesis reaction - tyrosine

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10

Compound 8: white solid; mp 136-138 ˚C (Lit.5a 137-138 ˚C); [α]D ²5 -16.9 (c 0.89, CHCl3) {Lit.5a [α]D ²0 -13.4 (c 0.97, CHCl3); Lit.5b [α]D ²0 -14.3 (c 0.93, CHCl3)}. ¹H NMR (300 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.41-1.49 (m, 1 H), 1.79 (d, J = 11.1 Hz, 1 H), 2.43 (s, 3 H), 2.91-3.16 (m, 2 H), 3.03 (d, J = 8.4 Hz, 1 H), 3.41 (d, J = 8.7 Hz, 1 H), 3.80 (s, 3 H), 4.40 (t, J = 3.3 Hz, 1 H), 6.74 (dd, J = 8.4, 2.4 Hz, 1 H), 6.79 (d, J = 2.7 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H). ¹³C NMR (75.47 MHz, CDCl3): δ = 20.8, 21.6, 38.3, 41.8, 42.4, 55.4, 58.0, 63.1, 110.3, 111.9, 125.5, 127.3, 129.8, 130.6, 135.9, 143.4, 145.1, 158.2. ESI-MS: m/z = 380 [M + Na], 358 [M + H]. ESI-HRMS: m/z calcd for C20H23NO3S + H: 358.1477; found: 358.1473. ESI-HRMS: m/z calcd for C22H23NO3S + Na: 380.1296; found: 380.1308.