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

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.

lactam - spirocyclic imine - shellfish toxin - gymnodimin­e - spirolides

References

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<A NAME="RD20603ST-19">19</A>

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).

<A NAME="RD20603ST-20">20</A> Typical Procedure for Metathesis Reaction:2-Azaspiro[5.5]undec-8-en-1-one (14) - To a stirred solution of dialkylated lactam 8 (0.58 g, 3 mmol) in anhyd CH₂Cl₂ (30 mL) was added benzylidene-bis-(tricyclohexyl-phosphine)-dichlororuthenium (0.12 g, 0.15 mmol) at 23 °C and the reaction mixture stirred for 3 h. DMSO (0.5 mL) was added and stirring continued for 12 h. The solvents were removed under reduced pressure and bicyclic lactam 14 (0.45 g, 90%) was obtained as a colourless oil after purification of the residue by column chromatography.FTIR (thin film): 2948, 1650, 1489, 1265, 729, 704 cm^-1. ¹H NMR (300 MHz, CDCl₃): 5.93 (br s, 1 H, NH); 5.68-5.58 (m, 2 H, 2 × CH); 3.29-3.26 (m, 2 H, NHCH₂); 2.60-2.56 (m, 1 H, CHH); 2.14-1.54 (m, 9 H, 4 × CH₂ and CHH). ¹³C NMR (75 MHz, CDCl₃): 178.2 (C=O), 125.3, 124.6 (CH), 39.7 (C), 42.6, 33.3, 30.1, 28.9, 21.3, 19.0 (CH₂).HRMS (EI): m/z for C₁₀H₁₅NO: 165.1154, found: 165.1155 [M]⁺.MS (EI): m/z = 165 (100%) [M]⁺, 136 (80)

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<A NAME="RD20603ST-25">25</A>

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=O_amide), 155.3 (C=O_carbamate), 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).

<A NAME="RD20603ST-26">26</A>

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).