PDF icon Download PDF
Synlett 2006(4): 0600-0604  
DOI: 10.1055/s-2006-932489
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Piotr Raubo*a, Claudio Giulianob, Alastair W. Hilla, Ian T. Huscrofta, Clare Londona, Austin Reevea, Eileen M. Sewarda, Christopher G. Swaina, Janusz J. Kulagowskia
a Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, CM20 2QR, UK
Fax: +44(1279)440187; e-Mail: piotr_raubo@merck.com;
b Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare (IRBM) P. Angeletti, Merck Research Laboratories, Rome, Italy
Further Information

Publication History

Received 1 December 2005
Publication Date:
20 February 2006 (online)

   Permissions and Reprints All articles of this category
Preview

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.

Key words

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

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).