First Synthesis of (+)-Pteroenone: A Defensive Metabolite of the Abducted Antarctic Pteropod Clione antarctica

Yoko Nakamura; Hiromasa Kiyota; Bill J. Baker; Shigefumi Kuwahara

doi:10.1055/s-2005-862389

LETTER

First Synthesis of (+)-Pteroenone: A Defensive Metabolite of the Abducted Antarctic Pteropod Clione antarctica

Yoko Nakamura^a, Hiromasa Kiyota*^a, Bill J. Baker^b, Shigefumi Kuwahara^a
^a Department of Applied Bioorganic Chemistry, Division of Bioscience & Biotechnology for Future Bioindustry, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Fax: +81(22)7178783; e-Mail: kiyota@biochem.tohoku.ac.jp;
^b Department of Chemistry, University of South Florida, 4202 E. Fowler Ave SCA400, Tampa, FL 33620, USA
Fax: +1(813)9741733;

Abstract

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Abstract

(+)-Pteroenone, a defensive metabolite of the abducted antarctic pteropod Clione antarctica, was firstly and efficiently synthesized by employing anti-selective aldol reaction as the key step.

Key words

pteroenone - defensive metabolite - Clione antarctica - marine natural products - anti-aldol reaction

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References

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5

At first, we tried shortcut routes (Scheme [2] ). The chiral auxiliary was removed by transamidation to afford Weinreb amide 10, accompanied by undesired ring-opening compound 11. A variety of conditions were tried but formation of 11 could not be suppressed, and all attempts to convert 11 into 10 or 1 failed. Amide 10 was treated with excess n-PrMgBr without protecting the hydroxy group to give the desired compound 1, but only in 10% yield. The major impurities were retro-aldol reaction products. Although the hydroxy group was protected, the corresponding TES ether 12 also gave the ketone 9 in low yield, accompanied by the over-reacted tertiary alcohol.

Scheme 2 Other synthetic routes to (+)-1. Reagents and conditions: a) Me(MeO)NH·HCl (3 equiv), AlCl₃ (3 equiv), CH₂Cl₂, -20 °C to 20 °C; b) n-PrMgBr (3 equiv), THF, 0 °C; c) TESOTf (1.2 equiv), 2,6-lutidine (1.2 equiv), CH₂Cl₂, -55 °C; d) n-PrLi (3 equiv), THF, -78 °C.

6 Damon RE. Coppola GM. Tetrahedron Lett. 1990, 31: 2849

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10

Determined by HPLC analysis (98% ee and 96% de): column, Daicel Chiralcel^® OJ (4.6 × 250 mm); solvent, hexane-i-PrOH (100:1) 0.5 mL/min, 20 °C; detection, 234 nm; t _R = 18.9, 19.6 (diastereomers, Σ = 2%), 22.6 (enantiomer, 1%) and 24.7 [(+)-1, 97%] min. These retention times of the peaks were identified by the separate synthesis of other three diastereomers.

11

Compound (+)-1: colorless oil, [α]_D ²⁶ +47 (c 0.30, hexane) {Lit.², [α]_D +48 (c 0.6, hexane)}. ¹H NMR (500 MHz, C₆D₆): δ = 0.82 (3 H, d, J = 7.5 Hz, 5-Me), 0.84 (1 H, t, J = 7.5 Hz, H-1), 1.58 (3 H, d, J = 7.0 Hz, H-11), 1.62 (2 H, sextet, J = 7.5 Hz, H-2), 1.65 (3 H, s, 9-Me), 1.67 (1 H, d, J = 3.5 Hz, OH), 1.71 (3 H, s, 7-Me), 2.19 (1 H, td, J = 7.3, 17.5 Hz, H-3), 2.31 (1 H, td, J = 7.3, 17.5 Hz, H-3), 2.60 (1 H, qd, J = 7.0, 9.5 Hz, H-5), 4.07 (1 H, dd, J = 2.5, 9.0 Hz, H-6), 5.40 (1 H, q, J = 6.7 Hz, H-10), 5.78 (1 H, s, H-8). All the signals were fully assigned by HH-COSY, HSQC and HMBC spectra. In the ¹H NMR, signal at δ = 2.31 ppm was misdescribed in ref.² as 2.21 ppm. ¹³C NMR (125 MHz in C₆D₆): δ = 12.5 (7-Me), 13.7 (C-1), 13.9 (C-11), 14.1 (5-Me), 16.5 (9-Me), 17.0 (C-2), 45.6 (C-3), 48.8 (C-5), 81.3 (C-6), 124.9 (C-10), 132.4 (C-8), 133.2 (C-9), 134.5 (C-7), 213.2 (C-4). HRMS (EI) [M⁺]: m/z calcd for C₁₄H₂₄O₂: 224.1776; found: 224.1779.