Synthesis of (±)-1-Phenyl-2-azabicyclo[2.2.1]heptane Derivatives - Novel NK₁ Receptor Ligands

Abstract

The synthesis of the 1-phenyl-2-azabicyclo[2.2.1]heptane derivative 2, a potential NK₁ receptor ligand, is reported. Ring-closing metathesis of diene 10 and regio- and stereoselective opening of the oxirane ring in 14 are key steps in the synthetic sequence.

Key words

bicyclic compounds - ring-closing olefin metathesis - McMurry coupling - opening of epoxides - NK₁ receptor

References and Notes

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• 2 Kramer MS. Cutler N. Feighner J. Shrivastava R. Carman J. Sramek JJ. Reines SA. Liu G. Snavely D. Wyatt-Knowles E. Hale JJ. Mills SG. MacCoss M. Swain CJ. Harrison T. Hill RG. Hefti F. Scolnick EM. Cascieri MA. Chicchi GG. Sadowski S. Williams AR. Hewson L. Smith D. Carlson EJ. Hargreaves RJ. Rupniak NMJ. Science  1998,  281:  1640 
• 3 Snider RM. Constantine JW. Lowe JA. Longo KP. Lebel WS. Woody HA. Drozda SE. Desai MC. Vinick FJ. Spencer RW. Hess H.-J. Science  1991,  251:  435 
• For recent advances, see:
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8

Experimental Procedure for the Preparation of 11.
Ozone was passed through a stirred mixture of 10 (30.5 g, 124 mmol), MeOH (1.4 mL) and CH₂Cl₂ (350 mL) at -70 °C to -65 °C until the reaction mixture turned blue. Then, DMS (90 mL, 1.24 mol) was added keeping the temperature of the reaction mixture below -60 °C. The mixture was slowly warmed up to r.t. and stirred for an additional 48 h. Then the mixture was filtered through a pad of Celite^® and concen-trated. The residue was purified on silica gel (i-hexane-EtOAc, 0-30%) to give the keto aldehyde 11 as an oil (19.5 g, 63%). ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (3 H, t, J = 7.1 Hz), 2.81 (1 H, ddd, J = 1.0, 5.4, 18.2 Hz), 2.99 (1 H, ddd, J = 1.0, 6.2, 18.1 Hz), 3.25 (1 H, dd, J = 8.1, 19.4 Hz), 3.48-3.54 (2 H, m), 4.16 (2 H, q, J = 7.2 Hz), 7.46 (2 H, m), 7.58 (1 H, m), 7.96 (2 H, m), 9.80 (1 H, s).

9

Experimental Procedure for the Preparation of 12.
TiCl₄ (15.5 mL, 140 mmol) was added dropwise to THF (800 mL) to form a yellow slurry. Zinc dust (21 g, 325 mmol) was added in one portion to this slurry. The resulting mixture was stirred for 1 h and pyridine (13 mL, 160 mmol) was added. The mixture was stirred for 30 min and a solution of 11 (19.3 g, 78 mmol) in THF (30 mL) was added. The resulting black mixture was stirred at reflux overnight. After cooling to r.t., Et₃N (75 mL) and EtOH (75 mL) were added and the mixture stirred for 30 min. Then, H₂O (15 mL) and EtOAc (800 mL) were added and the mixture was stirred until a white solid was formed. This mixture was filtered through a pad of Celite^® and concentrated. The residue was purified on silica gel (i-hexane-Et₂O, 0-30%) to give the cyclopentene 12 as an oil (10.8 g, 64%). ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (3 H, t, J = 7.2 Hz), 2.83 (2 H, m), 2.97-3.11 (2 H, m), 3.28 (1 H, m), 4.18 (2 H, q, J = 7.2 Hz), 6.08 (1 H, m), 7.23 (1 H, m), 7.31 (2 H, m), 7.42 (2 H, m).

10

Experimental Procedure for the Preparation of 14.
MCPBA (60%, 5 g) was added to a stirred mixture of 12 (1.62 g, 7.5 mmol), Na₂HPO₄ (5 g, 35 mmol) and CH₂Cl₂ (50 mL). The mixture was stirred for 30 min and a solution of Na₂SO₃ (10 g) in H₂O (50 mL) was added. The mixture was extracted into i-hexane (150 mL) and an organic layer was washed with 2 M aq NaOH solution and brine, then dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (i-hexane-Et₂O, 0-20%) to give the epoxide 14 (1.1 g, 63%) and the epoxide 13 (0.33 g, 18%). ¹H NMR of 14 (400 MHz, CDCl₃): δ = 1.28 (3 H, t, J = 7.2 Hz), 2.08 (1 H, dd, J = 10.2, 14.0 Hz), 2.45 (1 H, dd, J = 8.0, 14.0 Hz), 2.53 (2 H, d, J = 9.2 Hz), 2.86 (1 H, pent., J = 9.2 Hz), 3.61 (1 H, s), 4.17 (2 H, q, J = 7.1 Hz), 7.26-7.39 (5 H, m). Relative stereochemistry of 14 was assigned by ¹H NMR/NOE experiments. ¹H NMR of 13 (400 MHz, CDCl₃): δ = 1.27 (3 H, t, J = 7.1 Hz), 2.06 (1 H, dd, J = 8.5, 14.5 Hz), 2.44 (1 H, dd, J = 8.8, 14.0 Hz), 2.81 (1 H, d, J = 14.4 Hz), 2.84 (1 H, m), 2.91 (1 H, d, J = 14.1 Hz), 3.56 (1 H, s), 4.16 (2 H, q, J = 7.1 Hz), 7.27-7.37 (5 H, m).

12

Relative stereochemistry of 17 was assigned by ¹H NMR/NOE experiments. ¹H NMR (400 MHz, CDCl₃): δ = 1.11 (9 H, s), 1.67 (1 H, m), 1.88 (1 H, br), 2.08-2.13 (3 H, m), 2.52 (1 H, m), 3.19 (1 H, dd, J = 1.6, 9.3 Hz), 3.50 (1 H, dt, J = 2.5, 9.4 Hz), 4.56 (1 H, d, J = 6.2 Hz), 7.25 (1 H, m), 7.32 (2 H, m), 7.58 (2 H, m).