Full Papers
1-(3-Bromophenyl)-2,2,2-trifluoroethanol (6c). 1H-NMR (CDCl3,
300.13 MHz): δ 2.88 (brs, 1H), 5.02 (q, 3JHF =6.7 Hz, 1H), 7.03 (t, 3JHH
General procedure for the sequential transformation towards (R)-
2,2,2-trifluoro-1-[4’-methylsulfonyl-(1,1’-biphenyl)-4-yl]ethanol (2)
at 500 mM of reactants. Na2CO3 (228 mg, 2.15 mmol) was dissolved
in a KPi buffer 1.0 M, pH 8 (3.2 mL) and 4-(methylsulfonyl) phenyl-
boronic acid (9, 318 mg, 1.59 mmol), 1-(4-bromophenyl)-2,2,2-
trifluoroethanone (8a, 402 mg, 1.59 mmol,) and PdCl2(PPh3)2
(22 mg, 0.032 mmol) were added. The mixture was stirred for 24 h
1
2
3
4
5
6
7
8
9
=
3
3
7.8 Hz, 1H), 7.43 (d, JHH =7.7 Hz, 1H), 7.57 (d, JHH =7.8 Hz, 1H), 7.73
(s, 1H) ppm. 13C-NMR (CDCl3, 75.5 MHz): δ 72.2 (q, 2JCF =32.3 Hz, CH),
122.8 (C), 124.1 (q, 1JCF =282.3 Hz, C), 126.3 (q, 4JCF =1.4 Hz, CH),
3
130.3 (CH), 130.6 (q, 4JCF =1.2 Hz, CH), 132.8 (CH), 136.1 (q, JCF
=
=
3
1.2 Hz, C) ppm. 19F-NMR (CDCl3, 282.35 MHz): δ À 78.35 (d, JHF
6.7 Hz) ppm. HRMS (ESIÀ , m/z) (C8H5BrF3O)À (MÀ H)À : calculated
252.9481, found 252.9468. [α]D20 =À 23.5 (c 1, CH2Cl2, >99% ee (R)-
6c); lit. [α]D20 =À 7.3 (c 0.11, CH2Cl2, 51% ee).[28]
at 60 C obtaining a pH of 8 at the end of the first reaction step.
°
Next, 1,4-dioxane (300 μL), NADP+ (2.5 mg, 1 mM), GDH (5 mg,
220 U), glucose (347 mg, 550 mM) and the lyophilized enzyme
crude of Ras-ADH (150 mg, ratio 1:3.5 enzyme:10 w/w) and stirred
1-(2-Bromophenyl)-2,2,2-trifluoroethanol (6d). 1H-NMR (CDCl3,
300.13 MHz): δ 2.95 (brs, 1H), 5.67 (q, 3JHF =6.3 Hz, 1H), 7.31 (td,
3JHH =7.8, 4JHH =1.7 Hz, 1H), 7.45 (td, 3JHH =7.6, 4JHH =1.0 Hz, 1H),
°
at 40 C for 24 h. The product was extracted in a Falcon centrifuge
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32
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57
tube using EtOAc (4×20 mL), the combined organic phases were
washed with water (2×20 mL) and filtered through a silica gel path.
The mixture was dried over Na2SO4, filtered and the solvent
evaporated under reduced pressure, obtaining alcohol (R)-2
(430 mg, 82% overall yield).
3
4
3
7.65 (dd, JHH =8.0, JHH =1.2 Hz, 1H), 7.73 (d, JHH =7.7 Hz, 1H) ppm.
13C-NMR (CDCl3, 75.5 MHz): δ 71.3 (q, JCF =32.5 Hz, CH), 124.0 (C),
2
1
4
124.4 (q, JCF =282.9 Hz, C), 128.0 (CH), 129.4 (q, JCF =1.5 Hz, CH),
131.1 (CH), 133.1 (CH), 133.8 (q, 3JCF =1.2 Hz, C) ppm. 19F-NMR
(CDCl3, 282.35 MHz): δ À 77.62 (d, 3JHF =6.3 Hz) ppm. HRMS (ESIÀ , m/
z): (C8H5BrF3O)À (MÀ H)À : calculated 252.9481, found 252.9491. [α]D
20
À 15.4 (c 0.5, CH2Cl2, >99% ee (R)-6d).
Acknowledgements
2,2,2-Trifluoro-1-(naphthalene-1-yl)etanol (6e). 1H-NMR (CDCl3,
300.13 MHz): δ 2.90 (brs, 1H), 5.89 (q, 3JHF =6.5 Hz, 1H), 7.50-7.61 (m,
Financial support of this work by the Spanish Ministerio de
Economía y Competitividad ( MINECO, CTQ-2013-44153-P project)
is gratefully acknowledged. D.G.-M. thanks also Asturian Regional
Government for a predoctoral fellowship. we also thank Prof.
Wolfgang Kroutil for the donation of overexpressed alcohol
dehydrogenases.
3H), 7.84 (d, 3JHH =7.3 Hz, 1H), 7.89–7.95 (m, 2H), 8.05 (d, JHH
=
3
8.2 Hz, 1H) ppm. 13C-NMR (CDCl3, 75.5 MHz): δ 69.0 (q, 2JCF =32.3 Hz,
CH), 122.9 (CH), 124.8 (q, 1JCF =283.0 Hz, C), 125.3 (CH), 125.9 (q,
4JCF =1.4 Hz, CH), 126.1 (CH), 127.0 (CH), 129.1 (CH), 130.1 (q, JCF
=
3
1.0 Hz, C), 130.3 (CH), 131.2 (C), 133.8 (C) ppm. 19F-NMR (CDCl3,
282.35 MHz): δ À 76.85 (d, 3JHF =6.4 Hz) ppm. [α]D20: À 17.8 (c 1,
CH2Cl2, 99% ee (R)-6e); lit. [α]D20 =À 14.6 (c 0.47, CH2Cl2, 60% ee).[28]
2,2,2-Trifluoro-1-(naphthalen-2-yl)etanol (6f). White solid. Mp=
96–98 C. 1H-NMR (CDCl3, 300.13 MHz): δ 2.93 (brs, 1H), 5.19 (q,
°
Conflict of Interest
3JHF =6.7 Hz, 1H), 7.50–7.61 (m, 3H), 7.84-7.91 (m, 3H), 7.95 (s, 1H)
ppm . 13C-NMR (CDCl3, 75.5 MHz): δ 73.1 (q, 2JCF =32.1 Hz, CH), 124.4
The authors declare no conflict of interest.
1
(CH), 124.5 (q, JCF = 282.3 Hz, C), 126.7 (CH), 127.0 (CH), 127.5 (CH),
127.9 (CH), 128.4 (CH), 128.6 (CH), 131.4 (C), 133.0 (C), 133.9 (C)
3
ppm. 19F-NMR (CDCl3, 282.35 MHz): δ À 76.05 (d, JHF =6.8 Hz) ppm.
Keywords: Alcohol dehydrogenase · Asymmetric synthesis ·
Bioreduction · Cascade reactions · Odanacatib
[α]D20 =À 35.8 (c 1, CH2Cl2, 98% ee (R)-6f); À 23.7 (c 0.16, CH2Cl2,
71% ee).[27]
General procedure for the sequential transformation towards (R)-
2,2,2-trifluoro-1-[4’-methylsulfonyl-(1,1’-biphenyl)-4-yl]ethanol (2)
at 100 mM of reactants. In a tube, 4-(methylsulfonyl) phenyl-
boronic acid (9, 13 mg, 0.065 mmol), 1-(4-bromophenyl)-2,2,2-
trifluoroethanone (8a, 0.06 mmol, 15 mg) and PdCl2(PPh3)2
(0.0012 mmol, 0.8 mg) were dissolved in a KPi solution 1.0 M,
[1] J. Y. Gauthier, N. Chauret. W. Cromlish, S. Desmarais, L. T. Duong, J.-P.
Falgueyret, D. B. Kimmel, S. Lamontagne, S. Léger, T. LeRiche, C. S. Li, F.
Massé, D. J. McKay, D. A. Nicoll-Griffith, R. M. Oballa, J. T. Palmer, M. D.
Percival, D. Riendeau, J. Robichaud, G. A. Rodan, S. B. Rodan, C. Seto, M.
Thérien, V.-L. Truing, M. C. Venuti, G. Wesolowski, R. N. Young, R.
[2] a) L. Tu, K. Rui, H. Feng, Z. Wang, Int. J. Clin. Exp. Med. 2017, 10, 5977–
5984; b) X. Chen, J. Jiang, P. Hu, S. Zajic, W. Liu, J. McCrea, F. Liu, W.
744–750; c) J. A. Stone, J. B. McCrea, R. Witter, S. Zajic, S. A. Stoch, Br. J.
[4] H. Ovaa, M. W. E. Mons, S. Van Boeckel (Academic Ziekenhuis Leiden),
WO2019112426A1 2019.
[5] P. D. O‘Shea, C.-Y. Chen, D. Gauvreau, F. Gosselin, G. Hughes, C. Nadeau,
R. P. Volante, J. Org. Chem. 2009, 74, 1605–1610.
[6] a) J. Limanto, A. Shafiee, P. N. Devine, V. Upadhyay, R. A. Desmond, B. R.
2372–2375; b) M. D. Truppo, D. J. Pollard, J. C. Moore, P. N. Devine,
Catalysis on Industrial Scale, 2nd Edition (Eds. H.-U. Blaser, H.-J. Federsel).
Wiley-VCH, Weinheim, 2010. Chapter 22, pp 397–414.
°
pH 9.0 (600 μL) and stirred at 40 C for 24 h. Once the first step was
finished, a pH measurement of 8 was obtained in the reaction
medium so 1,4-dioxane (60 μL, 10% v/v), NADP+ (0.4 mg, 1 mM),
GDH (0.4 mg, 18 U), glucose (16 mg, 100 mM) and E. coli/ Ras-ADH
(6.5 mg, 1:3 ratio enzyme:10 w/w) and stirred for another 4 h
°
keeping the temperature at 40 C. The product was recovered after
extracting with EtOAc (3×3 mL) and the combined organic phases
washed with water (5 mL), dried over Na2SO4, filtered and the
solvent evaporated under reduced pressure, obtaining the alcohol
(R)-2 as a yellow solid (19 mg, 97% overall yield). Rf (50% EtOAc/
1
°
hexane): 0.35. Mp: 153.8-154.9 C. H-NMR (THF-d8, 300.13 MHz): δ
3
3.05 (s, 3H), 5.06-5.16 (m, 1H), 5.96 (d, JHH =5.1 Hz, 1H), 7.60–7.66
(m, 2H), 7.70–7.73 (m, 2H), 7.84–7.89 (m, 2H), 7.98–8.03 (m, 2H)
ppm. 13C-NMR (THF-d8, 75.5 MHz): δ 44.4 (CH3), 72.5 (q, JCF
=
2
1
30.7 Hz, CH), 126.1 (q, JCF =282.9 Hz, C), 128.1 (2CH), 128.6 (2CH),
128.9 (2CH), 129.3 (2CH), 137.4 (C), 140.7 (C), 141.5 (C), 146.3 (C)
ppm. 19F-NMR (THF-d8, 282.35 MHz): δ À 80.83 (d, 3JHF =7.1 Hz) ppm.
[α]D20 =À 27.2 (c 1.5, THF, >99% ee for (R)-2).
19–29; b) R. O. Lopes, J. B. Ribeiro, A. S. de Miranda, G. V. V. de Silva,
L. S. M. Miranda, I. C. R. Leal, R. O. M. A. de Souza, Tetrahedron 2014, 70,
ChemCatChem 2019, 11, 1–9
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