Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α- Methylidene-β-Lactams

Transcription

1 SI - 1 Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α- Methylidene-β-Lactams Marek Humpl, Jiří Tauchman, Nikola Topolovčan, Jan Kretschmer, Filip Hessler, Ivana Císařová, Martin Kotora * and Jan Veselý *

2 SI - 2 Contents I. General Experimental 2 II. X-ray Structure Analysis 3 III. References 4 IV. HPLC analysis 5 V. 1 H and 13 C Spectra 9 I. General Experimental Chemicals and solvents were either purchased (puriss p.a.) from commercial suppliers or purified by standard techniques. 1-Phenylbut-3-en-1-ol (2k), 1 1-phenylbut-3-en-1-yl acetate (2l), 2 1-[(1-phenylbut-3-enyloxy)methyl]benzene (2m), 3 1-phenyl-but-3-en-1-yloxy(tbutyl)dimethylsilane (2n) 4 and (S)-[1-(4-fluorophenyl)but-3-en-1-ol 5 were synthesized according to the previously literature procedures. Thin-layer chromatography (TLC) was performed on aluminium plates coated with 60 F 254 silica. Plates were visualized by irradiation with UV light (254 nm) and/or by treatment with a solution of phosphomolybdenic acid (25 g), Ce(SO 4 ) 2 H 2 O (10 g), conc. H 2 SO 4 (60 ml), and H 2 O (940 ml) followed by heating. Flash column chromatography was performed on Kieselgel 60 silica (particle size mm). Melting points are uncorrected. Selected characteristic peaks are reported in cm -1. NMR spectra were recorded on a 300 MHz ( 1 H at 300 MHz, 13 C at 75 MHz), 400 MHz ( 1 H at 400 MHz, 13 C at 100 MHz) and 600 MHz ( 1 H at 600 MHz, 13 C at 151 MHz) rt in the deuterated solvent stated. Chemical shifts (δ/ppm) are given relative to the residual peak of the NMR solvent (CHCl 3 -d 1 : δ H = 7.26 ppm, δ C = ppm) and coupling constants J are given in Hz. 19 F NMR spectra were referenced to internal instrument standard CF 3 CO 2 H. High resolution mass spectra were obtained with LTQ Orbitrap XL spectrometer. IR spectra were recorded using an ATR module.

3 SI - 3 II X-ray Structure Analysis Single-crystal X-ray diffraction data for 3aa and 3aj were obtained from single crystal diffractometer by monochromatized MoKα radiation (λ = Å) at 150(2)K. The structure was solved by direct methods (SHELXS, Sheldrik, 2008) and refined by full-matrix least squares based on F 2 (SHELXL97). 6 The hydrogen atoms were fixed into idealized positions (riding model) and assigned temperature factors H iso (H) = 1.2 U eq (pivot atom). Crystal data for 3aa: C 22 H 17 NO, M r = , Monoclinic, P2 1 /c (No 14), a = (4), Å, b = (10) Å, c = (12) Å, β = (3), V = (19) Å 3, Z = 4, D x = Mg m -3, colourless crystal of dimensions mm, multi-scan absorption correction (µ = 0.08 mm -1 ) T min = 0.960, T max = 0.988; a total of 8944 measured reflections (θ max = 26 ), from which 3156 were unique (R int = 0.028) and 2270 observed according to the I > 2σ(I) criterion. The refinement converged ( /σ max < 0.001) to R = for observed reflections and wr(f 2 ) = 0.097, GOF = 1.02 for 217 parameters and all 3156 reflections. The final difference map displayed no peaks of chemical significance ( ρ max = 0.17, ρ min e.å -3 ). Crystal data for 3aj: C 23 H 19 NO, M r =325.39, Triclinic, P1 (No 1), a = (4)Å, b = (5) Å, c = (11) Å, α = (2), β = (2), γ = (2), V = (9) Å 3, Z = 4, D x = Mg m -3, colourless crystal of dimensions mm, multi-scan absorption correction (µ = 0.08 mm -1 ) T min = 0.939, T max = 0.991; a total of 8912 measured reflections (θ max = 26 ), from which 5753 were unique (R int = 0.016) and 5335 observed according to the I > 2σ(I) criterion. The refinement converged ( /σ max < 0.001) to R = for observed reflections and wr(f 2 ) = 0.104, GOF = 1.03 for 390 parameters and all 5753 reflections. The final difference map displayed no peaks of chemical significance ( ρ max = 0.28, ρ min e.å -3 ). Crystallographic data (excluding structure factors) for the structure has been deposited with the Cambridge Crystallographic Data Centre with CCDC numbers for 3aa and for 3aj. Copies of the data can be obtained, free of charge, on application to Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0) or deposit@ccdc.cam.ac.uk).

4 SI - 4 Figure 1. View of the molecule 3aa (left) and of the one of two symmetrically independent molecules 3aj (right) with atom numbering scheme. The displacement ellipsoids are drawn with 30% probability level. III. References Demir, A. S.; Akhmedov, I. M.; Sesenoglu, O.; Alpturk, O.; Apaydin, S.; Gercek, Z.; Ibrahimzade, N. J. Chem. Soc., Perkin Trans. 1, 2001, 1, Phukan, P. Tetrahedron Lett. 2004, 45, Seayad, J.; Seayad, A. M.; Chai, C. L. L. Org. Lett. 2010, 12, Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron 2007, 63, Jain, P.; Antilla, J. C. J. Am. Chem. Soc. 2010, 132, Sheldrick, G. M. Acta Cryst. 2008, A64,

5 SI - 5 IV HPLC analysis Compound 1b (racemic) HPLC analysis using Chiralpak IC column (99/1 heptane/i-proh, flow rate 1.0 ml/min. Compound (R)-1b (enriched) The ee was determined by HPLC analysis using Chiralpak IC column (99/1 heptane/i-proh, flow rate 1.0 ml/min; λ max = 288 nm, t major = 15.0 min; t minor = 16.5 min.) (72% ee)

6 SI - 6 Compound (S)-2o The ee was determined by HPLC analysis of the corresponding alcohol using Chiralpak IA column (99/1 heptane/i-proh, flow rate 0.5 ml/min; λ = 190 nm, t minor = 46.8 min; t major = 48.5 min.)

7 SI - 7 Ezetimibe, 6 Enantiomeric purity of 6 was confirmed by comparison of HPLC analysis of 6 with the sample obtained from commercial supplier (Molekula, 99% ee) using chiralpak AD column (50/50 heptane/i-proh, flow rate 0.4 ml/min; λ = 235 nm, t = 13.4 min. Enantiomeric purity of 6 was also confirmed by comparison of optical rotation. The sample obtained from commercial supplier (Molekula): [α] D = (c = 0.50, MeOH). Compound 6: [α] D = (c = 0.50, MeOH). Ezetimibe (Molekula) Ezetimibe (6)

8 Ezetimibe (Molekula)/6 = ratio 1:1 SI - 8

9 SI - 9 V Copies of 1 H, 13 C and 19 F Spectra

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19 2n SI - 19

20 (S)-2o SI - 20

21 (S)-2o SI - 21

22 (S)-2o SI - 22

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25 3ac SI - 25

26 3ac SI - 26

27 3ad SI - 27

28 3ad SI - 28

29 SI ad

30 3ae SI - 30

31 3ae SI - 31

32 3af SI - 32

33 3af SI - 33

34 3ag SI - 34

35 3ag SI - 35

36 3aj SI - 36

37 3aj SI - 37

38 3an SI - 38

39 3an SI - 39

40 (7S)-3bo SI - 40

41 (7S)-3bo SI - 41

42 (7S)-3bo SI - 42

43 (4R,7S)-3bo SI - 43

44 (4R,7S)-3bo SI - 44

45 (4R,7S)-3bo SI - 45

46 SI - 46 (3R,4R, 7S)-4 (3S,4S,7S)-4

47 SI - 47 (3R,4R,7S)-4 (3S,4S,7S)-4

48 SI - 48 (3R,4R,7S)-4 (3R,4S,7S)-4 (3S,4S,7S)-4

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52 (3R,4S,7S)-5 SI - 52

53 (3R,4S,7S)-5 SI - 53

54 (3R,4S,7S)-5 SI - 54

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