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Synlett 2003(2): 0271-0273
DOI: 10.1055/s-2003-36782
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine

Roger Hunter*, Philip Richards
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax: +27(21)6897499; e-Mail: Roger@science.uct.ac.za;
Further Information

Publication History

Received 6 December 2002
Publication Date:
22 January 2003 (online)

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Abstract

A stereoselective synthesis of the tricyclic core in ra­cemic form of the marine alkaloid Lepadiformine is described from 4-methoxy-3-pyrrolin-2-one (methyl tetramate). Key steps involve 5,5-dialkylation of the tetramate, metathesis closure to an A/C 1-azaspirocycle and stereoselective hydrogenation for the trans A/B 1-azadecalin system.

Key words

marine alkaloid - metathesis - silyloxypyrrole alkyl­ation - tetramate reduction - 1-azaspiro[4.5]decane

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The following experimental procedure for conversion of 3b to 4 applies: The substrate 3b (0.73g, 3mmol) was dissolved in anhyd THF (30 mL) under N2 and cooled to -78 °C. A solution of n-BuLi in hexane (2.25 mL of a 1.6 M solution, 3.6 mmol, 1.2 equiv) was added dropwise. After stirring for 30 min at -78 °C TMSCl (0.57 mL, 4.5 mmol, 1.5 equiv) was added dropwise and the solution was stirred for a further 30 min at -78 °C. Trimethyl orthoformate (1.00 mL, 9.0 mmol, 3 equiv) was then added, followed by BF3·OEt2 (0.57 mL, 4.5 mmol, 1.5 equiv). The reaction was allowed to slowly warm to -20 °C over 2 h. Sat. NaHCO3 solution was then added and the THF was removed by evaporation. The remaining aqueous layer was extracted with 3 portions of EtOAc. The organic layers were combined, dried and concentrated to give an oily residue. The product was isolated by column chromatography to give the acetal as an oil that slowly crystallised as a colourless, waxy solid 4 (0.699 g, 2.20 mmol) in 88% yield based on recovered starting material (0.125 g, 0.51 mmol). Data for 4: IR: νmax (CH2Cl2) = 3019, 1669, 1640, 1346 cm-1. Found: M+ (+ H), 318.17144. C18H24NO4 requires M+: 318.17053. 1H NMR (400 MHz, CDCl3): δ = 2.37 (1 H, ddt, J = 1.1, 7.7, 14.7 Hz, CH 2), 2.54 (1 H, dd, J = 6.6, 14.7 Hz, CH 2), 3.27 (3 H, s, OCH 3), 3.32 (3 H, s, OCH 3), 3.75 (3 H, s, OCH 3), 4.21 (1 H, s, OCHO), 4.61 (2 H, s, PhCH 2), 4.84 (2 H, m, CH=CH 2), 5.12 (1 H, s, H-3), 5.18 (1 H, m, CH=CH2), 7.15-7.38 (5 H, m, aromatic). 13C NMR (100 MHz, CDCl3): δ = 33.8 (CH2), 43.6 (PhCH2), 57.8, 57.9 and 58.0 (3 × OCH3), 71.8 (C-5), 95.2 (C-3), 107.6 (OCHO), 118.6 (CH=CH2), 126.6, 128.0 and 128.5 (aromatic), 130.9 (CH=CH2), 139.6 (aromatic), 172.2 (C-4), 174.5 (C=O).

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Prepared from the phosphonium bromide in ref. [17b] by treatment with KOH.