Synthesis of 1-Azaspiroundecane Ring System via Thorpe-Ziegler Annulation of 2-Cyano-2-(4-Cyano-Tethered) Arylpiperidines

Abstract

An efficient stereocontrolled route to the 1-azaspiro[5.5]undecan framework of the histrionicotoxin alkaloids, employing anodic cyanation and Thorpe-Ziegler cyclization as key steps, is described. In the process of gaining information concerning the hydrolysis of the cyanoenamine function in 8, an unexpected intramolecular Friedel-Crafts type reaction provided the aza-fluorene 10.

spiro compounds - stereoselective synthesis - lithiation - annulation - nitriles

References

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Crystallographic data for the structures 3d, 8-10 reported in this paper have been deposited at the Cambridge Crystallographic Data Center as supplementary publication no: 179964(3d), 179965(8), 179966(9), 179967(10). Copies of the data can be obtained free of charge on application to The Director CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax: int. code+44(1221)336033, e-mail: [e-mail]].

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6: IR(neat) 2216, 2246 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ 1.35-1.90 (11 H, m), 2.00 (1 H, dm, J = 10.6 Hz), 2.15 (2 H, t, J = 6.5 Hz), 2.95 (1 H, dm, J = 12.0 Hz), 3.12 (1 H, tm, J = 12.0 Hz), 7.15-7.35 (5 H, m). [13] C NMR (50 MHz, CDCl₃): δ 17.34, 22.25, 23.16, 25.69, 26.20, 36.03, 38.13, 53.35, 61.52, 119.81, 120.64, 127.03, 127.52, 129.58, 149.35. C₁₇H₂₁N₃: calcd 267.1736, found 267.1737 (MS). C₁₇H₂₁N_3: calcd. C 76.37, H 7.92, N 15.72; found C 76.11, H 8.02, N 15.56.

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25

A solution (20 mL, THF) of 6 (0.5 g, 1.87 mmol) was cooled to -30 °C and treated dropwise (by syringe) with a 2 M solution of LDA (0.94 mL, 1.87 mmol). The solution was allowed to warm to -20 °C and maintained at that temperature for 1 h, before being stirred at r.t. for 3 h. The reaction mixture was quenched with water and extracted with CH₂Cl₂. The organic phases were combined, dried over MgSO₄, and concentrated in vacuo. The crude material was purified over a silica column (diethyl ether-petroleum ether, 1:1) to afford 8 (0.433 g, 87%).