Total Synthesis of (-)-Neoechinulin A

Toshiaki Aoki; Shinji Kamisuki; Masaaki Kimoto; Kensuke Ohnishi; Yoichi Takakusagi; Kouji Kuramochi; Yoshifumi Takeda; Atsuo Nakazaki; Kenji Kuroiwa; Takashi Ohuchi; Fumio Sugawara; Takao Arai; Susumu Kobayashi

doi:10.1055/s-2006-933113

LETTER

Total Synthesis of (-)-Neoechinulin A

Toshiaki Aoki^a,b, Shinji Kamisuki^c, Masaaki Kimoto^c, Kensuke Ohnishi^a,b, Yoichi Takakusagi^a,b, Kouji Kuramochi^c, Yoshifumi Takeda^a,b, Atsuo Nakazaki^a, Kenji Kuroiwa^c, Takashi Ohuchi^c, Fumio Sugawara^a,c, Takao Arai^c, Susumu Kobayashi*^a,b
^a Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Fax: +81(4)71213671; e-Mail: kobayash@rs.noda.tus.ac.jp;
^b Frontier Research Center for Genome and Drug Discovery, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda, Chiba 278-8510, Japan
^c Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

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Abstract

A total synthesis of neoechinulin A was accomplished with high enantiomeric excess. Our total synthesis of neoechinulin A established the absolute configuration of natural neoechinulin A. The synthetic route features aldol condensation of a 3-formyl indole derivative and intramolecular cyclization.

Key words

natural product - total synthesis - alkaloid - aldol reaction - cyclization

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References and Notes

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All new compounds were fully characterized on the basis of spectral data (IR, ¹H NMR, ¹³C NMR, and HRMS).
Compound 4: yellow oil, [α]_D ²⁵ -66.8 (c 0.62, MeOH). IR (neat): 3465, 1690, 1630, 1460 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 1.55 (s, 6 H), 1.59 (d, J = 7.0 Hz, 3 H), 2.64 (s, 3 H), 3.40 (s, 3 H), 5.06 (d, J = 17.5 Hz, 1 H), 5.12 (q, J = 7.0 Hz, 1 H), 5.14 (d, J = 10.6 Hz, 1 H), 5.52 (s, 2 H), 6.19 (dd, J = 10.6, 17.5 Hz, 1 H), 7.16-7.19 (m, 3 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.47 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.0, 27.0, 29.75, 29.81, 40.7, 52.8, 55.7, 75.2, 105.4, 110.6, 112.3, 117.6, 118.6, 121.7, 123.3, 124.9, 125.5, 138.1, 146.6, 166.3, 172.0. ESI-MS: m/z calcd for C₂₃H₂₇N₃O₄Na [M + Na]⁺: 432.1893; found: 432.1905.
Compound 5: white solid, mp 180-182.5 °C (EtOAc-hexane); [α]_D ²⁶ -15.5 (c 0.61 MeOH). IR (KBr): 3200, 3060, 2970, 2930, 2870, 1670, 1635 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 1.58 (d, J = 7.0 Hz, 3 H), 1.59 (s, 6 H), 3.39 (s, 3 H), 4.28 (dq, J = 1.6, 7.0 Hz 1 H), 5.05 (d, J = 17.5 Hz, 1 H), 5.12 (d, J = 10.6 Hz, 1 H), 5.50 (s, 2 H), 6.18 (dd, J = 10.6, 17.5 Hz, 1 H), 6.68 (br, 1 H), 7.16 (t, J = 7.2 Hz, 1 H), 7.21-7.25 (m, 2 H), 7.32 (br, 1 H), 7.42 (d, J = 7.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 29.7, 40.5, 51.6, 55.6, 75.1, 105.1, 110.3, 112.1, 113.1, 118.9, 121.3, 123.1, 125.2, 125.4, 138.0, 143.2, 146.8, 159.5, 165.6. ESI-MS: m/z calcd for C₂₁H₂₅N₃O₃Na [M + Na]⁺: 390.1788; found: 390.1794.
Compound 10: yellow amorphous; [α]_D ²⁵ +20.6 (c 1.85 MeOH). IR (KBr): 3320, 3055, 2975, 2940, 1710, 1630, 1505, 1440, 1375 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 1.13 (d, J = 7.0 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.57 (s, 6 H), 4.32 (dq, J = 1.4, 7.1 Hz, 2 H), 4.46 (m, 2 H), 5.18-5.28 (m, 4 H), 5.86 (m, 1 H), 6.10 (dd, J = 10.6, 6.7 Hz, 1 H), 7.07 (t, J = 7.2 Hz, 1 H), 7.14 (t, J = 7.2 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.33 (br, 1 H), 7.72 (s, 1 H), 8.26 (br, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 18.3, 27.46, 27.52, 39.2, 50.4, 61.4, 65.7, 106.3, 111.1, 113.1, 117.7, 120.2, 120.4, 122.0, 122.5, 126.1, 126.2, 132.5, 134.1, 144.3, 144.5, 155.5, 164.8, 170.0. ESI-MS: m/z calcd for C₂₅H₃₁N₃O₅Na [M + Na]⁺: 476.2155; found: 476.2173.
Neoechinulin A: white needle crystal, mp 272-275 °C; [α]_D ²³ -55 (c 0.59 MeOH; 93% ee). IR (KBr): 3300, 3060, 2970, 2925, 1680, 1630 cm^-1. ¹H NMR (600 MHz, DMSO-d ₆): δ = 1.37 (d, J = 6.9 Hz, 3 H), 1.47 (s, 6 H), 4.17 (dq, J = 6.9, 1.7 Hz, 1 H), 5.02 (d, J = 17.8 Hz, 1 H), 5.05 (d, J = 11.0 Hz, 1 H), 6.07 (dd, J = 11.0, 17.8 Hz, 1 H), 6.88 (s, 1 H), 7.00 (t, J = 7.4 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 8.37 (s, 1 H), 8.77 (s, 1 H), 11.07 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.8, 27.7, 39.2, 50.7, 103.6, 110.3, 110.7, 111.8, 119.1, 119.5, 120.9, 125.1, 126.2, 135.3, 144.1, 145.3, 160.1, 166.6. ESI-MS: m/z calcd for C₁₉H₂₁N₃O₂Na [M + Na]⁺: 346.1525; found: 346.1531.