Download PDF
Synlett 2003(13): 2042-2046  
DOI: 10.1055/s-2003-41481
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Spirocyclic Imines: Key Pharmacophores in the Shellfish Toxins Spirolides and Gymnodimine

Michael Trzoss, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: m.brimble@auckland.ac.nz;
Further Information

Publication History

Received 14 August 2003
Publication Date:
08 October 2003 (online)

    Permissions and Reprints All articles of this category

Abstract

The efficient synthesis of several spirocyclic imines of similar structure to that present in the shellfish toxins, the spirolides and gymnodimine, is described. The key steps involved double α-alkylation of simple lactam starting materials, Grubbs’ ring closing metathesis of the resultant bis-alkylated lactams and LiEt3BH reductio­n of the TEOC protected lactams to imines.

Key words

lactam - spirocyclic imine - shellfish toxin - gymnodimin­e - spirolides

19

Typical Dialkylation Procedure (Method A):3-Allyl-3-(3-butenyl)tetrahydro-2(1 H )-pyridinone (8): To a stirred solution of δ-valerolactam (0.49 g, 5 mmol) in anhyd THF (30 mL) was added dropwise n-BuLi (1.6 M solution in hexane, 3.28 ml, 5.25 mmol) at -78 °C. After stirring for 15 min at -78 °C trimethylsilyl chloride (0.67 mL, 5.25 mmol) was added dropwise and stirring continued for 30 min while the solution was allowed to warm to 0 °C. The reaction mixture was then cooled to -78 °C and transferred (via cannula) to a solution of freshly prepared LDA (5 mmol) in anhyd THF (20 mL) at -78 °C. After stirring for 30 min at -78 °C, 4-bromo-1-butene (0.53 mL, 5.25 mmol) was added dropwise and stirring continued for 1 h while the solution was allowed to warm to 0 °C. The reaction mixture was then cooled to -78 °C and transferred to a solution of freshly prepared LDA (5.5 mmol) in anhyd THF (20 mL) at -78 °C. After stirring for 45 min at -78 °C, allyl iodide (0.57 ml, 6.25 mmol) was added dropwise and stirring continued for 3 h while the solution was allowed to warm to 23 °C. The reaction mixture was quenched by the addition of sat. aq NH4Cl solution and extracted with Et2O. The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure and dialkylated lactam 8 (0.78 g, 4.05 mmol, 81%) was obtained as a colorless oil after purification of the residue by column chromatography.
FTIR (thin film): 3211, 3074, 2942, 1659, 1489, 1448, 997, 911 cm-1.
1H NMR (300 MHz, CDCl3): δ = 6.00 (br s, 1 H, NH), 5.84-5.73 (m, 2 H, 2 × CH), 5.09-4.91 (m, 4 H, 2 × CH=CH2), 3.28-3.23 (m, 2 H, NHCH2), 2.53-2.47 (m, 1 H, CHH), 2.25-2.19 (m, 1 H, CHH), 2.15-1.99 (m, 2 H, CH2), 1.84-1.67 (m, 5 H, 2 × CH2 and CHH), 1.57-1.47 (m, 1 H, CHH).
13C NMR (75 MHz, CDCl3): δ = 176.4 (C=O), 138.6, 134.3 (CH), 118.1, 114.4 (CH=CH2), 44.4 (C), 43.0, 42.7, 37.6, 29.3, 28.7, 19.7 (CH2).
HRMS (EI): m/z for C12H19NO: 193.1467, found: 193.1468 [M]+.
MS (EI): m/z = 193 (4%) [M]+, 139(100).

25

Typical Procedure for TEOC-Protection:2-(Trimethylsilyl)ethyl 1-oxo-2-azaspiro[5.5]undec-8-ene-2-carboxylate (20): To a stirred solution of bicyclic lactam 14 (0.49 g, 3 mmol) in anhyd THF (30 mL) was added dropwise a 1.6 M solution of n-BuLi in hexane (1.97 mL, 3.15 mmol) at -78 °C. After stirring for 30 min at -78 °C a solution of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate (0.98 g, 3.45 mmol) in anhyd THF (5 mL) was added dropwise and stirring continued for 1.5 h while the solution was allowed to warm up to 23 °C. The reaction mixture was quenched by the addition of sat aq NH4Cl solution and extracted with Et2O. The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure and TEOC protected lactam 20 (0.90 g, 97%) was obtained as a white solid after purification of the residue by column chromatography.
FTIR (thin film): 3025, 2952, 2899, 1769, 1713, 1438, 1379, 1295, 1268, 1237, 1162, 1049, 944, 860, 838 cm-1.
1H NMR (300 MHz, CDCl3): 5.69-5.58 (m, 2 H, 2 × CH), 4.34-4.28 (m, 2 H, OCH2), 3.76-3.60 (m, 2 H, NHCH2), 2.65-2.57 (m, 1 H, CHH), 2.12-1.62 (m, 9 H, 4 × CH2 and CHH); 1.13-1.06 (m, 2 H, CH2Si); 0.03 (s, 9 H, SiMe3).
13C NMR (75 MHz, CDCl3): 177.8 (C=Oamide), 155.3 (C=Ocarbamate), 125.4, 124.5 (CH), 65.4 (OCH2), 43.3 (C), 47.4, 33.6, 30.7, 29.7, 21.6, 19.4 (CH2), 17.5 (CH2Si), -1.6 (SiMe3).
HRMS (EI): m/z for C16H27NO3Si: 309.1760 (-0.8 ppm error), found: 309.1763 [M]+.
MS (EI): m/z = 309 (1%) [M]+, 281(30), 73(100).

26

Typical Procedure for Imine Preparation:
2-Azaspiro[5.5]undeca-1,8-diene (26): To a stirred solution of TEOC protected lactam 20 (0.31 g, 1 mmol) in anhyd THF (10 mL) was added dropwise a 1 M solution of LiEt3BH in THF (1.2 mL, 1.2 mmol) at -78 °C. After stirring for 45 min at -78 °C the reaction mixture was quenched by dropwise addition of water followed by aqueous work up and extraction of the aq phase with Et2O. The combined organic layers were dried over MgSO4 and the solvents removed under reduced pressure. The crude residue was dissolved in THF (10 mL) and treated with a 1 M solution of TBAF in THF (2 ml, 2 mmol). After stirring for 12 h at 23 °C toluene (10 mL) was added and all solvents removed under reduced pressure. Spiroimine 26 (0.13 g, 86%) was obtained as a colorless oil after purification of the residue by column chromatography.
FTIR (thin film): 3023, 2923, 2852, 1649, 1438, 1047, 923 cm-1.
1H NMR (300 MHz, CDCl3): δ = 7.52 (br s, 1 H, CHN), 5.73-5.70 (m, 1 H, CH), 5.63-5.57 (m, 1 H, CH), 3.61-3.43 (m, 2 H, NCH2); 2.11-1.99 (m, 3 H, CH2 and CHH); 1.89-1.82 (m, 1 H, CHH); 1.72-1.39 (m, 6 H, 3 × CH2).
13C NMR (75 MHz, CDCl3): δ = 169.6 (C=N), 126.3, 124.0 (CH), 34.8 (C), 49.9, 33.4, 31.1, 29.6, 21.2, 19.0 (CH2).
HRMS (EI): m/z for C10H15N: 149.1205, found: 149.1204 [M]+.
MS (EI): m/z = 149 (95%) [M]+, 120(100).