An Improved Synthesis of (-)-Martinellic Acid via Radical Addition-Cyclization-Elimination Reaction of Chiral Oxime Ether

Okiko Miyata; Atsushi Shirai; Shintaro Yoshino; Yoshifumi Takeda; Makiko Sugiura; Takeaki Naito

doi:10.1055/s-2006-939046

LETTER

An Improved Synthesis of (-)-Martinellic Acid via Radical Addition-Cyclization-Elimination Reaction of Chiral Oxime Ether

Okiko Miyata, Atsushi Shirai, Shintaro Yoshino, Yoshifumi Takeda, Makiko Sugiura, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax: +81(78)4417556; e-Mail: taknaito@kobepharma-u.ac.jp;

Abstract

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Abstract

A concise formal synthesis of (-)-martinellic acid has been accomplished by preparing optically active dipyrroloquinoline as a key synthetic intermediate, which was prepared via the radical addition-cyclization-elimination of oxime ether carrying an unsaturated ester followed by two chemoselective reductions of the carbonyl groups.

Key words

martinellic acid - radical reaction - oxime ether - asymmetric synthesis - pyrroloquinoline

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References

References and Notes

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In addition to 15a, three stereoisomers, which are (3aR,3bS,11bR)-15b (12%), (3aS,3bS,11bS)-15c (9%), and (3aS,3bS,11bR)-15d (6%) were obtained after purification of the reaction mixture by column chromatography.
Compound 15a: mp >260 °C (acetone, MeOH). IR: ν_max = 1694, 3433 cm^-1. ¹H NMR (500 MHz): δ = 1.72-1.80 (1 H, m), 2.22 (1 H, d, J = 17.0 Hz), 2.40-2.71 (4 H, m), 2.80 (1 H, dd, J = 17.0, 7.5 Hz), 3.71 (1 H, dt, J = 11.5, 7.5 Hz), 4.83 (1 H, d, J = 5.5 Hz), 6.48 (1 H, br s), 7.16 (1 H, td, J = 8.0, 2.0 Hz), 7.29 (1 H, dd, J = 8.0, 2.0 Hz), 7.37 (1 H, td, J = 8.0, 2.0 Hz), 8.50 (1 H, dd, J = 8.0, 2.0 Hz). ¹³C NMR (125 MHz): δ = 22.8, 31.2, 34.1, 40.5, 53.4, 55.8, 120.2, 123.8, 124.5, 129.22, 129.24, 135.7, 173.2, 175.1. HRMS: m/z calcd for C₁₄H₁₄N₂O₂ [M⁺]: 242.1055; found: 242.1067; Anal. Calcd for C₁₄H₁₄N₂O₂: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.16; H, 5.80; N, 11.48. [α]_D ²⁷ +44.5 (c 0.26, CHCl₃).

Column chromatography of the reaction mixture gave (3aR,3bS,11bS)-dipyrroloquinoline 6a (29%), (3aR,3bS,11bR)-6b (8%), (3aS,3bS,11bS)-6c (4%), and (3aS,3bS,11bR)-6d (4%), respectively.
Compound 6a: mp 165-168 °C (acetone, MeOH). IR: ν_max = 1702, 3428 cm^-1. ¹H NMR (500 MHz): δ = 1.75-1.83 (1 H, m), 2.26 (1 H, d, J = 17.0 Hz), 2.45-2.56 (2 H, m), 2.59-2.74 (2 H, m), 2.82 (1 H, dd, J = 17.0, 7.5 Hz), 3.77 (1 H, td, J = 11.0, 7.5 Hz), 3.93 (3 H, s), 4.86 (1 H, d, J = 5.5 Hz), 5.93 (1 H, br s), 7.99 (1 H, d, J = 2.0 Hz) 8.02 (1 H, dd, J = 8.5, 2.0 Hz), 8.67 (1 H, d, J = 8.5 Hz). ¹³C NMR (125 MHz): δ = 23.1, 31.4, 34.0, 40.3, 52.3, 53.2, 55.8, 119.6, 123.5, 125.7, 130.7, 131.1, 139.8, 166.2, 173.8, 174.6. HRMS: m/z calcd for C₁₆H₁₆N₂O₄ [M⁺]: 300.1110; found: 300.1128. Anal. Calcd for C₁₆H₁₆N₂O₄: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.85; H, 5.25; N, 9.25. [α]_D ²⁸ +100.7 (c 0.235, CHCl₃).

Optical purity of 21 was determined to be >93% ee by
¹H NMR spectroscopic analysis of the corresponding
(-)-MTPA ester which was derived from 21 by esterification using (-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride.

Compound 7: IR: ν_max = 1695, 3526 cm^-1. ¹H NMR (300 MHz): δ = 1.56 (4 H, br s), 2.12 (1 H, br s), 2.30 (1 H, m), 2.72 (1 H, m), 3.58 (3 H, m), 3.93 (4 H, br s), 4.75 (1 H, br s), 5.35 (1 H, br s), 7.39 (1 H, br s), 8.03 (1 H, br d, J = 8.5 Hz), 8.44 (1 H, br s). ¹³C NMR (125 MHz): δ = 28.6, 29.7, 30.1, 30.8, 46.0, 52.4, 57.7, 58.6, 61.9, 116.3 (q, COCF₃), 125.3, 129.9, 130.4, 133.6, 137.8, 157.1 (q, COCF₃), 165.8. HRMS: m/z calcd for C₂₀H₂₀F₆N₂O₅ [M⁺]: 482.1276. Found: 482.1273. [α]_D ¹⁶ +64.0 (c 0.99, CHCl₃) {lit.^2a,2b [α]_D ²⁰ +65.1 (c 0.97, CHCl₃)}.