A Short Stereoselective Synthesis of (R)-Salmeterol

David J. Buchanan; Darren J. Dixon; Brian E. Looker

doi:10.1055/s-2005-871927

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Synlett 2005(12): 1948-1950
DOI: 10.1055/s-2005-871927

LETTER

A Short Stereoselective Synthesis of (R)-Salmeterol

David J. Buchanan^a, Darren J. Dixon*^a, Brian E. Looker^b
^a School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Fax: +44(161)2754939; e-Mail: darren.dixon@manchester.ac.uk;
^b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

Further Information

Publication History

Received 4 May 2005
Publication Date:
07 July 2005 (online)

Abstract
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Abstract

A short, highly stereoselective oxy-Michael approach to the total synthesis of the β₂-agonist, (R)-salmeterol is described.

Key words

asymmetric synthesis - oxy-Michael addition - 1,2-amino alcohol - δ-lactol

References

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11

Data for synthetic 1: [α]_D ²⁵ -21.1 (c 1.48, CHCl₃), [lit. [6] [α]_D ²⁵ -20.6 (c 1.46, CHCl₃)]. ¹H NMR (400 MHz, CD₃OD, lit. [5c] ): δ = 7.29 (1 H, s, Ar-CH), 7.23 (2 H, m, Ar-CH), 7.17-7.11 (4 H, m, Ar-CH), 6.75 (1 H, d, J = 8.1 Hz, Ar-CH), 4.68 (1 H, dd, J = 8.7, 4.2 Hz, CHCH₂NH), 4.65 (2 H, s, CH ₂OH), 3.44-3.39 (4 H, m, CH ₂OCH ₂), 3.35 (1 H, s, NH), 3.31 (2 H, s, 2 × OH), 2.77 (1 H, dd, J = 12.1, 8.8 Hz, CHCHHNH), 2.71 (1 H, dd, J = 12.1, 4.3 Hz, CHCHHNH), 2.61 (4 H, m, J = 6.8 Hz, CH₂CH ₂Ph and NHCH ₂CH₂), 1.71-1.56 (8 H, m, 4 × CH₂), 1.37-1.29 (4 H, m, 2 × CH₂). ¹³C NMR (100 MHz, CD₃OD): δ = 154.5 (OAr-1), 142.3 (Ar), 133.6 (Ar), 128.1 (Ar), 128.0 (Ar), 127.9 (Ar), 127.1 (Ar), 125.7 (Ar), 125.3 (Ar), 114.5 (Ar-5), 71.6 (CHCH₂NH), 70.4 (CH₂ °CH₂), 70.3 (CH₂OCH₂), 59.7 (ArCH₂), 56.4 (CHCH₂NH), 50.2 (NHCH₂CH₂), 35.2 (CH₂ CH₂Ph), 30.3 (CH₂), 29.2 (CH₂), 28.9 (CH₂), 27.9 (CH₂), 26.7 (CH₂), 25.7 (CH₂). IR (film): ν_max = 3675 (OH), 2987, 2901, 1452, 1406, 1394 cm^-1. HRMS (ES+): m/z calcd for C₂₅H₃₈NO₄ [M + H]⁺: 416.2795; found: 416.2796. Chiral HPLC was performed on a Sumichiral OA-4100 column (25 cm × 4.6 mm) eluting with hexane-EtOH-CH₂Cl₂-TFA (240:30:130:1), at a flow rate of 1 mL/min, detecting at 276 nm; t _R = 19.26 min, 2.0% [S-isomer]; t _R = 21.84 min, 98.0% [R-isomer].