A Concise Formal Synthesis of Unnatural (+)-Aphanorphine from (2S,4R)-4-Hydroxyproline

Zhiqiang Ma; Hongbin Zhai

doi:10.1055/s-2006-956499

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Synlett 2007(1): 0161-0163
DOI: 10.1055/s-2006-956499

LETTER

A Concise Formal Synthesis of Unnatural (+)-Aphanorphine from (2S,4R)-4-Hydroxyproline

Zhiqiang Ma^a, Hongbin Zhai*^a,b
^a Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
^b The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Road, Beijing 100083, P. R. of China
Fax: +86(21)64166128; e-Mail: zhaih@mail.sioc.ac.cn;

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Publication History

Received 19 September 2006
Publication Date:
20 December 2006 (online)

Abstract
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Abstract

(-)-Aphanorphine methyl ether was synthesized in ten steps from commercially available (2S,4R)-4-hydroxyproline, featuring the C-2 configuration inversion of an intermediate amide and intramolecular Friedel-Crafts reaction. The present work constitutes a formal synthesis of unnatural (+)-aphanorphine.

Key words

aphanorphine - configuration inversion - intramolecular Friedel-Crafts - marine alkaloid - synthesis

References and Notes

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8

8: colorless solid; mp 70-72 °C; [α]²⁶ _D +95.7 (c = 0.91, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.70-2.20 (m, 2 H), 2.55-3.05 (m, 1.5 H), 3.08-3.24 (m, 1.5 H), 3.50-3.60 (m, 1 H), 3.78 (s, 3 H), 4.00-4.30 (m, 1 H), 4.40-4.60 (m, 1 H), 6.55-6.70 (m, 1 H), 6.87 (d, J = 8.1 Hz, 1.5 H), 7.20 (d, J = 7.8 Hz, 1.5 H), 7.35-7.50 (m, 5 H). ¹³C NMR (75 MHz CDCl₃): δ = 37.0, 37.8, 55.1, 57.0, 57.6, 69.2, 113.6, 126.2, 127.1, 128.1, 130.1, 130.6, 136.4, 158.0, 170.0. MS (ESI): m/z = 312 (100) [M + H], 333 (73) [M + Na - H], 366 (15) [M + MeOH + Na], 645 (21) [2 × M + Na]. HRMS (EI): m/z calcd for C₁₉H₂₁NO₃: 311.1521; found: 311.1518.

12

11: colorless oil; [α]²⁸ _D +76.2 (c = 1.53, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.48 (s, 2 H), 1.59 (s, 1 H), 1.90-2.10 (m, 2 H), 2.81 (s, 0.67 H), 2.98 (dd, J = 2.4, 17.1 Hz, 0.67 H), 3.30-3.54 (m, 2.66 H), 3.76 (s, 2 H), 3.80 (s, 1 H), 4.32-4.37 (m, 0.33 H), 4.85-4.91 (m, 0.67 H), 6.70-6.80 (m, 1.65 H), 6.86 (d, J = 2.4 Hz, 0.35 H), 6.97 (d, J = 8.4 Hz, 0.35 H), 7.07 (d, J = 8.4 Hz, 0.65 H), 7.30-7.37 (m, 3.25 H), 7.41-7.48 (m, 1.75 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.6, 20.8, 34.8, 37.3, 40.0, 41.0, 41.9, 42.2, 54.7, 54.9, 55.0, 56.4, 61.5, 64.1, 109.4, 109.5, 111.4, 111.5, 124.0, 125.3, 126.1, 126.5, 127.8, 128.1, 129.1, 129.2, 129.9, 130.2, 136.7, 137.2, 144.7, 145.6, 157.5, 157.9, 168.7, 169.8. MS (ESI): m/z = 308 (100) [M + H], 330 (6) [M + Na], 362 (19) [M + MeOH + Na]. HRMS (EI): m/z calcd for C₂₀H₂₁NO₂: 307.1572; found: 307.1570.

14

(-)-Aphanorphine methyl ether 12: colorless oil; [α]²⁸ _D -10.38 (c = 1.36, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.46 (s, 3 H, CH₃), 1.83 (d, J = 11.1 Hz, 1 H, 0.5 × CH₂), 2.01 (dd, J = 6.0, 11.1 Hz, 1 H, 0.5 × CH₂), 2.46 (s, 3 H, NCH₃), 2.74 (d, J = 6.0 Hz, 1 H, 0.5 × CH₂), 2.81 (s, 1 H, 0.5 × CH₂), 2.84 (s, 1 H, 0.5 × CH₂), 3.02 (d, J = 16.8 Hz, 1 H, 0.5 × CH₂), 3.37-3.40 (m, 1 H, NCH), 3.75 (s, 3 H, OCH₃), 6.67 (dd, J = 2.1, 8.4 Hz, 1 H, CH), 6.77 (s, 1 H, CH), 7.00 (d, J = 8.4 Hz, 1 H, CH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.2, 35.3, 41.3, 41.4, 42.9, 54.9, 61.1, 71.0, 109.1, 110.8, 125.6, 129.9, 147.6, 157.5. MS (EI): m/z = 218 (18) [M + H], 217 (48) [M], 202 (100), 159 (64), 144 (28), 115 (38). HRMS (EI): m/z calcd for C₁₄H₁₉NO: 217.1467; found: 217.1460.