Stereoselective synthesis of a potent human NK1 receptor antagonist via acyl-Claisen rearrangement

Synlett

Volumn , Issue 4, 2006, Pages 600-604

  Raubo, Piotr ^a   Giuliano, Claudio ^b   Hill, Alastair W ^a   Huscroft, Ian T ^a   London, Clare ^a   Reeve, Austin ^a   Seward, Eileen M ^a   Swain, Christopher G ^a   Kulagowski, Janusz J ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b Merck Research Laboratories   (Italy)

Author keywords

Acyl Claisen rearrangement; Asymmetric synthesis; NK1 receptors; Stereoselectivity; Total synthesis

Indexed keywords

NEUROKININ 1 RECEPTOR; NEUROKININ 1 RECEPTOR ANTAGONIST; TETRAHYDROPYRAN DERIVATIVE;

ARTICLE; CHIRALITY; CLAISEN REARRANGEMENT; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; STEREOCHEMISTRY;

EID: 33645013791     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2006-932489     Document Type: Article

References (23)

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18. 3): 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).
19. 3, 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).
20. 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.
21. Diasteromeric excess was determined by HPLC analysis. The absolute stereochemistry of C3 centre of tetrahydrofuran ring was determined by X-ray analysis of close analogue of 1.
22. 3): 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).
23. Cascieri, M. A.; Ber, E.; Pong, T. M.; Sadowski, S.; Bansal, A.; Swain, C. J.; Seward, E. M.; Frances, B.; Burns, D.; Strader, C. D. Mol. Pharmacol. 1992, 47, 458.