Stereoselective Synthesis of a Potent Human NK₁ Receptor Antagonist via Acyl-Claisen Rearrangement

Abstract

Stereoselective synthesis of the tetrahydropyran derivative 1 is reported. Diastereoselective acyl-Claisen rearrangement was employed for formation of C3 and C4 chiral centres on the ­tetrahydropyran ring.

acyl-Claisen rearrangement - asymmetric synthesis - ­total synthesis - stereoselectivity - NK₁ receptors

References and Notes

1 Seward EM. Swain CJ. Expert Opin. Ther. Pat.  1999,  9:  571 

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 

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For recent advances, see:

4a Shaw D. Chicchi GG. Elliott JM. Kurtz MM. Morrison D. Ridgill MP. Szeto N. Watt AP. Williams AR. Swain CJ. Bioorg. Med. Chem. Lett.  2001,  11:  3031 

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9

Experimental Procedure for the Preparation of 18a.
Methanesulphonyl chloride (0.12 mL, 1.5 mmol) was added dropwise to an ice-bath-cooled, stirring mixture of 13a (280 mg, 1 mmol), Et₃N (0.4 mL, 2.8 mmol) and CH₂Cl₂ (2 mL). The mixture was stirred for 90 min and (R)-2-(methoxy-methyl)pyrrolidine (0.2 mL, 1.6 mmol) was added. The mixture was stirred for 2 h and poured onto a sat. aq solution of NaHCO₃. The mixture was extracted into CH₂Cl₂. The organic extract was dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (CH₂Cl₂-2 M NH₃ in MeOH, 0-10%) to give the amine 18a (230 mg, 61%). ¹H NMR (360 MHz, CDCl₃): δ = 0.04 (6 H, s), 0.90 (9 H, s), 1.61-1.77 (3 H, m), 1.86-2.01 (1 H, m), 2.21 (1 H, q, J = 8.5 Hz), 2.67 (1 H, m), 2.95 (1 H, d, J = 13.2 Hz), 3.04 (1 H, m), 3.25 (1 H, dd, J = 7.4, 9.1 Hz), 3.35 (3 H, s), 3.46 (1 H, dd, J = 4.5, 9.3 Hz), 3.74 (1 H, d, J = 13.1 Hz), 4.26 (2 H, s), 6.58 (1 H, s), 7.29-7.31 (5 H, m).

10

Experimental Procedure for the Preparation of 20a.
TiCl₄-THF₂ (33 mg, 0.1 mmol) was added to a stirred mixture of 18a (375 mg, 1 mmol), i-Pr₂EtN (0.3 mL, 1.7 mmol) at -10 °C followed by 10 (510 mg, 1.5 mmol). The mixture was stirred at -10 °C for 30 min and warmed to 10 °C over 1 h. The mixture was treated with 1 M aq NaOH and the mixture was extracted into CH₂Cl₂. The organic extract was dried (Na₂SO₄) and concentrated. The residue (a mixture of 20a:20b:20c:20d in the ratio 18:3:5:2) was purified on silica gel (i-hexane-EtOAc, 5-35%) to give the amide 20a (390 mg, 58%, 5:1 mixture of rotamers). ¹H NMR (400 MHz, CDCl₃, a major rotamer): δ = -0.07 (3 H, s),
-0.06 (3 H, s), 0.83 (9 H, s), 1.31 (3 H, d, J = 6.4 Hz), 1.64-2.00 (4 H, m), 3.26 (1 H, m), 3.29 (3 H, s), 3.33 (1 H, dd, J = 6.5, 9.3 Hz), 3.52 (1 H, m), 3.83-3.97 (3 H, m), 4.20 (1 H, m), 4.36 (1 H, d, J = 9.3 Hz), 4.55 (1 H, q, J = 6.6 Hz), 4.97 (1 H, s), 5.15 (1 H, s), 7.20-7.26 (5 H, m), 7.44 (2 H, s), 7.74 (1 H, s).

11

Diastereomeric products of the acyl-Claisen reaction were separable by flash chromatography and converted into the corresponding lactones 17a-d as outlined in Scheme [4] .

12

Diasteromeric excess was determined by HPLC analysis. The absolute stereochemistry of C3 centre of tetrahydro-furan ring was determined by X-ray analysis of close analogue of 1.

13

Experimental Procedure for the Preparation of 1.
Sodium triacetoxyborohydride (91 mg, 0.43 mmol) was added to a stirred mixture of 24 (100 mg, 0.215 mmol) and 28 (73 mg, 0.216 mmol) and DCE (0.5 mL). The mixture was stirred for 60 min and treated with a sat. aq solution of NaHCO₃ and extracted with CH₂Cl₂. The organic extract was dried (Na₂SO₄) and concentrated. The mixture was treated with MeOH (2 mL) and 4 M aq NaOH (0.3 mL) was added dropwise. The mixture was stirred for 15 min, diluted with H₂O and extracted into CH₂Cl₂. The organic extract was dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (CH₂Cl₂-MeOH, 0-10%) to give 1 (66 mg, 50%). ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (3 H, d, J = 6.4 Hz), 1.38-1.50 (3 H, m), 1.77 (1 H, dd, J = 3.0, 12.5 Hz), 1.81 (1 H, m), 1.97 (1 H, t, J = 10.7 Hz), 2.01-2.11 (2 H, m), 2.12-2.20 (1 H, m), 2.30 (1 H, t, J = 10.6 Hz), 2.40 (1 H, m), 3.12 (1 H, t, J = 11.5 Hz), 3.25 (1 H, t, J = 10.8 Hz), 3.42 (1 H, dt, J = 4.7, 9.8 Hz), 3.52 (1 H, AB, J = 8.6 Hz), 3.57 (1 H, AB, J = 8.6 Hz), 3.64 (1 H, dd, J = 2.2, 10.1 Hz), 3.88 (1 H, m), 4.01 (1 H, dd, J = 4.6, 10.1 Hz), 4.21 (1 H, dd, J = 4.5, 11.8 Hz), 4.25 (1 H, dd, J = 4.6, 11.0 Hz), 4.27 (1 H, q, J = 6.5 Hz), 6.83 (2 H, t, J = 8.9 Hz), 6.93 (2 H, m), 7.20 (2 H, s), 7.66 (1 H, s).

14 Cascieri MA. Ber E. Fong TM. Sadowski S. Bansal A. Swain CJ. Seward EM. Frances B. Burns D. Strader CD. Mol. Pharmacol.  1992,  47:  458