A Stereoselective Synthesis of (±)-3-Aryl-6-phenyl-1-oxa-7-azaspiro[4.5]-decanes

Abstract

A novel stereoselective synthesis of the 3-aryl-6-phenyl-1-oxa-7-azaspiro[4.5]decane ring is reported. Palladium(0)-mediated cyclocarbonylation of γ-iodoallylic alcohol is a key step in the formation of the spirocyclic ring.

Key words

spirocyclic compounds - lactones - stereoselective synthesis - regioselective lithiation - substance P (NK₁ receptor) antagonist

References

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10

Experimental Procedure for the Preparation of 3: A solution of EtMgBr in THF (1 M, 4.1 mL, 4.1 mmol) was added dropwise to a stirred solution of 5 (1.0 g, 4.1 mmol) in THF (10 mL) at r.t. After 30 min, the mixture was cooled to 0 °C and a solution of 4 (1.07 g, 3.9 mmol) in THF (10 ml) was added dropwise over 5 min. The mixture was stirred at 0 °C for 2 h and at r.t. overnight. After quenching with sat. aq NH₄Cl, the mixture was extracted into 2-methylpentane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (2-methylpentane-Et₂O) to give the alcohol 3 (1.17 g, 62%). ¹H NMR (360 MHz, CDCl₃): δ = 0.78-0.90 (m, 4 H), 1.32 (s, 9 H), 1.80 (m, 1 H), 2.00-2.15 (m, 2 H), 2.14 (s, 1 H), 2.22 (m, 1 H), 3.11 (m, 1 H), 3.78 (m, 1 H), 4.15 (dd, J = 5.6, 13.4 Hz, 1 H), 5.48 (s, 1 H), 7.15 (dd, J = 2.0, 9.2 Hz, 1 H), 7.17-7.40 (m, 6 H), 7.55 (d, J = 7.2 Hz, 2 H). Relative stereochemistry was assigned by ¹H NMR experiments. [6a]

11

Experimental Procedure for the Preparation of 8: A solution of Red-Al^® in toluene (0.9 mL, 3.1 mmol) was added dropwise to a stirred solution of 3 (1.17 g, 2.25 mmol) in anhyd Et₂O (15 mL) at 0 °C. The ice bath was removed and the reaction mixture was stirred at r.t. for 2.5 h. The mixture was cooled to -78 °C and a solution of I₂ (1 g, 4 mmol) in anhyd Et₂O (10 mL) was added over 5 min. The reaction mixture was allowed to warm to r.t. over 2 h and quenched with sat. aq Na₂SO₃. The mixture was extracted into Et₂O. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (2-methylpentane-Et₂O) to give the iodide 8 (1.14 g, 78%). ¹H NMR (360 MHz, CDCl₃): δ = 0.80-0.90 (m, 4 H), 1.34 (s, 9 H), 1.74-1.90 (m, 2 H), 2.05 (m, 1 H), 2.31 (dt, J = 5.2, 13.2 Hz, 1 H), 2.63 (s, 1 H), 3.18 (ddd, J = 5.8, 11.3, 13.6 Hz, 1 H), 3.78 (m, 1 H), 4.10 (m, 1 H), 5.39 (s, 1 H), 6.35 (s, 1 H), 7.06 (d, J = 2.8 Hz, 1 H), 7.20 (dd, J = 2.3, 8.5 Hz, 1 H), 7.22 (d, J = 8.9 Hz, 1 H), 7.25-7.40 (m, 4 H), 7.52 (d, J = 7.2 Hz, 2 H).

14

Experimental Procedure for the Preparation of 2: A solution of hydrazine in THF (0.07 mL, 0.07 mmol) was added, under an atmosphere of CO, to a stirred mixture of 8 (320 mg, 0.5 mmol), (Ph₃P)₂PdCl₂ (50 mg, 0.07 mmol), K₂CO₃ (138 mg, 1 mmol) and THF (5 mL). The mixture was stirred at 50 °C for 5 d. After cooling to r.t., the mixture was diluted with Et₂O and filtered through a pad of Celite. The filtrate was concentrated and the residue purified on silica gel (2-methylpentane-EtOAc) to give the lactone 2 (184 mg, 68%). ¹H NMR (360 MHz, CDCl₃): δ = 0.76-0.94 (m, 4 H), 1.39 (s, 9 H), 1.82-2.04 (m, 3 H), 2.30 (m, 1 H), 3.20 (dt, J = 4.8, 13.7 Hz, 1 H), 3.82 (m, 1 H), 4.22 (dd, J = 5.6, 13.4 Hz, 1 H), 5.25 (s, 1 H), 7.19 (dd, J = 1.4, 9.2 Hz, 1 H), 7.22-7.33 (m, 4 H), 7.39 (d, J = 7.3 Hz, 1 H), 7.98 (d, J = 2.9 Hz, 1 H), 8.08 (s, 1 H).

16

The spectral data exhibited by 1 was identical to reported. [15]