A Short Stereoselective Synthesis of (R)-Salmeterol

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

• 1a Adderley NJ. Buchanan DJ. Dixon DJ. Lainé DI. Angew. Chem. Int. Ed.  2003,  42:  4241 
• 1b Buchanan DJ. Dixon DJ. Scott MS. Lainé DI. Tetrahedron: Asymmetry  2004,  15:  195 
• 1c Buchanan DJ. Dixon DJ. Hernández-Juan FA. Org. Biomol. Chem.  2004,  2:  2932 
• 2a Bradshaw J. Brittain RT. Coleman RA. Jack D. Kennedy I. Lunts LHC. Skidmore IF. Brit. J. Pharm.  1987,  92:  590P 
• 2b Ullman A. Svedmyr N. Thorax  1988,  43:  674 
• 3 Johnson M. Butchers PR. Coleman RA. Nials AT. Strong P. Summer MJ. Vardey CJ. Whelan CJ. Life Sci.  1993,  52:  2131 
• 4a Procopiou PA. Morton GE. Todd M. Webb G. Tetrahedron: Asymmetry  2001,  12:  2005 
• 4b Goswami J. Bezbaruah RL. Goswami A. Borthakur N. Tetrahedron: Asymmetry  2001,  15:  3343 
• 5a Hett R. Stare R. Helquist P. Tetrahedron Lett.  1994,  35:  9375 
• 5b Coe DM. Perciaccante R. Procopiou PA. Org. Biomol. Chem.  2003,  1:  1106 
• 5c Bream RN. Ley SV. McDermott B. Procopiou PA. J. Chem. Soc., Perkin Trans. 1  2002,  2237 
• 6 Bream RN. Ley SV. Procopiou PA. Org. Lett.  2002,  4:  3793 
• 7 Skidmore IF, Lunts LHC, Finch H, and Naylor A. inventors; US  4992474. 
• 8 Evans B. inventors; EP-A  422889. 
• 9 Amann A, Koenig H, Thieme PC, and Giertz H. inventors; Ger. Offen.  2,310,140. 
• 10a Nose A. Kudo T. Chem. Pharm. Bull.  1981,  29:  1159 
• 10b Nose A. Kudo T. Chem. Pharm. Bull.  1988,  36:  1529 
• 10c Nose A. Kudo T. Chem. Pharm. Bull.  1989,  37:  816 
• 10d Osby JO. Ganem B. Tetrahedron Lett.  1985,  26:  6413 

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].