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TRANSCRIPT
SUPPORTING INFORMATION
Papain-catalyzed aldol reaction for the synthesis of trifluoromethyl
carbinol derivatives
Jun-Tao Guo, Yang Xiang, Zhi Guan*, Yan-Hong He*
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, PR China
E-mails: [email protected] (for Z. Guan); [email protected] (for Y.-H. He)
Table of contents
1. Effect of some reaction conditions on the papain-catalyzed aldol reaction..................................22. Characterization of aldol products................................................................................................33. 1H NMR, 13C NMR, HRMS and HPLC spectra for aldol products...............................................84. References...................................................................................................................................27
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1. Effect of some reaction conditions on the papain-catalyzed aldol reaction
(a) Effect of mole ratio of substrates on the papain-catalyzed aldol reaction a
Entry Molar ratio (1a:2a) Yield(%) b Ee (%) c
1 1:5 91 26
2 1:7.5 95 28
3 1:10 98 28
4 1:15 98 28
5 1:20 99 28
6 1:25 98 29
7 1:30 99 28a The reaction conditions were as follows: trifluoromethyl ketone (0.6 mmol), acetone (3.0-18.0 mmol), papain
(160 U), DMF (0.95 mL), deionized water (0.05 mL) at 25 °C for 72 h.
b Yield of the isolated product after silica gel chromatography.
c Ee was determined by HPLC analysis using a chiral column (OD-H).
(b) Effect of pH on the papain-catalyzed aldol reaction a
Entry Buffer pH Yield (%) b Ee (%) c
1 4.7 85 26
2 5.9 86 26
3 6.5 90 28
4 7.4 94 29
5 8.5 97 27
6 9.6 99 29
7 10.2 98 26
8 11.1 90 28
9 None (deionized water) 98 29a The reaction conditions were as follows: trifluoromethyl ketone (0.6 mmol), acetone (6.0 mmol), papain (96 U),
DMF (0.95 mL), phosphate buffer (NaH2PO4-Na2HPO4, 0.05 mL) at 25 °C for 72 h.
b Yield of the isolated product after silica gel chromatography.
c Ee was determined by HPLC analysis using a chiral column (OD-H).
(c) Effect of solvent volume on the model reaction a
Entry Solvent volume (mL) Yield (%) b Ee (%) c
1 0.25 98 28
2 0.50 98 28
3 0.75 98 29
4 1.00 98 29
2
5 1.25 99 29
6 1.50 98 30
7 1.75 99 30
8 2.00 95 29a The reactions conditions were as follows: trifluoromethyl ketone (0.6 mmol), acetone (6.0 mmol), papain (96 U),
DMF:H2O = 95:5 (v/v), total volume (0.25-2.00 mL) at 25 °C for 72 h.
b Yield of the isolated product after silica gel chromatography.
c Ee was determined by HPLC analysis using a chiral column (OD-H).
2. Characterization of aldol products
5,5,5-trifluoro-4-hydroxy-4-phenylpentan-2-one (3a)1
CF3
HO
O
Yield 97%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 7.6 Hz, 2H), 7.38 (m, 3H),
5.44 (s, 1H), 3.35 (d, J = 17.2 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.18 (s, 3H). 13C NMR (150
MHz, CDCl3): δ = 208.8, 137.5, 128.8, 128.5, 126.1, 124.5 (q, J = 285.3 Hz), 76.0 (q, J = 29.0
Hz), 45.2, 32.0. HPLC analysis: Chiralcel OD-H, n-hexane / i-PrOH = 97 : 3, flow rate 1.0 mL /
min, λ = 210 nm, tmajor = 15.87 min, tminor = 9.39 min.
5,5,5-trifluoro-4-(4-fluorophenyl)-4-hydroxypentan-2-one (3b)1
CF3
HO
O
F
Yield 90%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.56 - 7.58 (m, 2H), 7.07 - 7.11 (m,
2H), 5.55 (s, 1H), 3.33 (d, J = 17.3 Hz, 1H), 3.23 (d, J = 17.3 Hz, 1H), 2.21 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 208.8, 162.9 (d, J =247.7 Hz), 133.4 (d, J = 3.2 Hz), 128.1 (d, J = 8.2 Hz),
124.4 (q, J = 285.3 Hz), 115.4 (d, J = 21.5 Hz), 75.7 (q, J = 29.3 Hz), 45.1, 31.9.
5,5,5-trifluoro-4-(3-fluorophenyl)-4-hydroxypentan-2-one (3c)
3
CF3
HO
O
F
Yield 95%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.32-7.39 (m, 3H), 7.06-7.09 (m, 1H),
5.59 (s, 1H), 3.33 (d, J = 17.3 Hz, 1H), 3.23 (d, J = 17.3 Hz, 1H), 2.22 (s, 3H). 13C NMR (150
MHz, CDCl3): δ = 208.7, 162.8(d, J = 244.8 Hz), 140.2 (d, J = 7.0 Hz), 130.0 (d, J = 8.1 Hz),
124.6 (d, J = 283.3 Hz), 115.8 (d, J = 20.9 Hz), 113.8 (d, J = 23.8 Hz), 75.7(q, J =29.1 Hz), 45.0,
31.8. HRMS (ESI) calc. for C11H10O2F4 (M-H)-: 249.0544, found: 249.0537.
4-(4-chlorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-one (3d)1
CF3
HO
O
Cl
Yield 96%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.5 Hz, 2H), 7.39 (d, J =
8.7 Hz, 2H), 5.54 (s, 1H), 3.32 (d, J = 17.3 Hz, 1H), 3.22 (d, J = 17.3 Hz, 1H), 2.21 (s, 3H). 13C
NMR (150 MHz, CDCl3): δ = 208.7, 136.1, 135.0, 128.7, 127.7, 124.3 (q, J = 285.9 Hz), 75.8 (q, J
= 29.5 Hz), 45.0, 31.9.
4-(4-bromophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-one (3e)1
CF3
HO
O
Br
Yield 94%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 8.6 Hz, 2H), 7.46 (d, J =
8.5 Hz, 2H), 5.54 (s, 1H), 3.31 (d, J = 17.3 Hz, 1H), 3.22 (d, J = 17.3 Hz, 1H), 2.21 (s, 3H). 13C
NMR (150 MHz, CDCl3): δ = 208.7, 136.7, 131.7, 127.9, 127.1, 125.2, 123.2, 121.4, 75.9 (q, J =
29.3 Hz), 44.9, 31.9.
5,5,5-trifluoro-4-hydroxy-4-(p-tolyl)pentan-2-one (3f)1
CF3
HO
O
4
Yield 97%; White solid, mp = 61-63 °C; 1H NMR (600 MHz, CDCl3): 1H NMR (600 MHz,
CDCl3) δ = 7.43 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 5.38 (s, 1H), 3.35 (d, J = 17.1 Hz,
1H), 3.16 (d, J = 17.1 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 209.1,
138.7, 134.5, 129.2, 126.1, 124.5 (q, J = 286.9 Hz), 76.0 (q, J = 29.2 Hz), 45.2, 32.0, 21.0.
5,5,5-trifluoro-4-hydroxy-4-(perfluorophenyl)pentan-2-one (3g)1
CF3
HO
OF
F
FF
F
Yield 42%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 4.85 (s, 1H), 3.82 (dt, J = 18.3, 2.4 Hz,
1H), 3.16 (dt, J = 18.3, 3.6 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 206.6, (148.0-
110.0) (m), 76.5 (q, J = 31.0 Hz), 46.5 (t, J = 6.0 Hz), 30.5.
5,5,6,6,6-pentafluoro-4-hydroxy-4-phenylhexan-2-one (3h)2
CF2CF3
HO
O
Yield 95%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.60 (d, J = 7.4 Hz, 2H), 7.48 – 7.32
(m, 3H), 5.66 (s, 1H), 3.40 (d, J = 16.9 Hz, 1H), 3.26 (d, J = 16.9 Hz, 1H), 2.16 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 209.4, 137.7,(134.8 - 104.2) (m), 128.7, 128.4, 126.2, 76.9 (q, J = 29.4
Hz), 45.2, 32.1.
5,5,6,6,7,7,7-heptafluoro-4-hydroxy-4-phenylheptan-2-one (3i)2
CF2CF2CF3
HO
O
Yield 96%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 7.6 Hz, 2H), 7.44 – 7.35
(m, 3H), 5.71 (s, 1H), 3.36 (d, J = 16.8 Hz, 1H), 3.28 (d, J = 16.8 Hz, 1H), 2.15 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 209.4, 137.6, (136.1 - 106.9) (m), 128.7, 128.3, 126.2, 77.3 (q, J = 29.2
Hz), 45.5, 32.1.
5-chloro-5,5-difluoro-4-hydroxy-4-phenylpentan-2-one (3j)1
5
CF2Cl
HO
O
Yield 99%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.58 (d, J = 7.4 Hz, 2H), 7.39 – 7.34
(m, 3H), 5.55 (s, 1H), 3.44 (d, J = 17.0 Hz, 1H), 3.24 (d, J = 17.0 Hz, 1H), 2.17 (s, 3H). 13C NMR
(150 MHz, CDCl3): δ = 209.1, 138.0, 130.2 (t, J =299.1 Hz), 128.8, 128.3, 126.6, 79.5 (t, J = 25.5
Hz), 45.6, 32.1.
5,5,5-trifluoro-4-hydroxy-4-(thiophen-2-yl)pentan-2-one (3k)3
CF3
HO
O
S
Yield 92%; Colorless oil; 1H NMR (600 MHz, CDCl3) : δ = 7.37 – 7.33 (m, 1H), 7.12 (d, J = 3.5
Hz, 1H), 7.03 (dd, J = 4.9, 3.8 Hz, 1H), 5.92 (s, 1H), 3.34 (d, J = 17.1 Hz, 1H), 3.17 (d, J = 17.1
Hz, 1H), 2.22 (s, 3H). 13C NMR (150 MHz, CDCl3) δ = 208.8, 141.7, 127.2, 126.5, 125.8, 124.8,
122.9, 121.0, 75.7 (q, J = 29.7 Hz), 45.8, 31.9.
3,4-Dihydroxy-8-phenyl-4-(trifluoromethyl)octan-2-one (3l)2
CF3
HO
OHO
Yield 70%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.69 (dd, J = 12.4, 5.7 Hz, 4H), 7.50 –
7.41 (m, 6H), 4.85 (s, 1H), 4.66 (s, 1H), 3.91 (s, 1H), 3.88 (d, J = 6.1 Hz, 1H), 2.19 (s, 3H), 1.59
(s, 3H). 13C NMR (150 MHz, CDCl3): δ = 207.9, 206.1, 134.2, 134.0, 129.5, 129.3, 128.9, 128.5,
126.5, 126.0, 124.6 (q, J = 287.8 Hz), 124.6 (q, J = 288.2 Hz), 78.4 (q, J = 25.6 Hz), 77.9 (q, J
=27.4 Hz), 29.7, 28.1.
6,6,6-trifluoro-5-hydroxy-5-phenylhexan-3-one (3m)1
CF3
HO
O
Yield 72%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 7.6 Hz, 2H), 7.41 (dd, J =
15.4, 7.7 Hz, 3H), 5.68 (s, 1H), 3.33 (d, J = 16.9 Hz, 1H), 3.21 (d, J = 16.9 Hz, 1H), 2.54 - 2.58
6
(m, 1H), 2.45–2.41 (m, 1H), 1.01 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 211.8,
137.6, 128.8, 128.4, 126.1, 124.5 (q, J = 284.9 Hz), 75.9 (q, J = 29.0 Hz), 44.1, 38.1, 7.0.
1,1,1-trifluoro-2-hydroxy-2-phenylheptan-4-one (3n)1
CF3
HO
O
Yield 75%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.59 (d, J = 7.4 Hz, 2H), 7.41 (dd, J =
15.2, 7.4 Hz, 3H), 5.65 (s, 1H), 3.33 (d, J = 17.0 Hz, 1H), 3.19 (d, J = 17.0 Hz, 1H), 2.54 – 2.47
(m, 1H), 2.44 – 2.37 (m, 1H), 1.54 - 1.59 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ = 211.3, 137.6, 129.0, 128.4, 126.1, 124.6 (q, J = 285.9 Hz), 76.1 (q, J = 29.1 Hz), 46.8,
44.4, 16.6, 13.3.
5,5,5-trifluoro-4-hydroxy-1-methoxy-4-phenylpentan-2-one (3o)
CF3
HO
O
O
Yield 56%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 7.57 (d, J = 7.6 Hz, 2H), 7.37 (dt, J =
20.8, 7.1 Hz, 3H), 5.26 (s, 1H), 3.89 (d, J = 2.1 Hz, 2H), 3.50 (d, J = 16.9 Hz, 1H), 3.37 (s, 3H),
3.21 (d, J = 16.9 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 208.8, 137.2, 128.9, 128.5, 127.3,
126.3, 125.5, 123.6, 121.7, 78.0, 76.1 (q, J = 29.4 Hz), 59.4, 41.6. HRMS (ESI) calc. for
C12H13O3F3 (M+Na)+: 285.0709, found: 285.0714.
ethyl-3-hydroxy-5-oxo-3-(trifluoromethyl)hexanoate (3p)2
F3C O
OHOO
Yield 58%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 5.75 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H),
3.01 (d, J = 16.2 Hz, 1H), 2.95 (d, J = 16.2 Hz, 1H), 2.83 (d, J = 15.4 Hz, 1H), 2.77 (d, J = 15.4
Hz, 1H), 2.29 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ = 208.1, 170.4,
124.9 (q, J =286.0 Hz), 73.8 (q, J = 29.0 Hz), 61.4, 43.2, 37.3, 32.2, 13.9.
ethyl-2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (3q)4
7
F3CO
O
OHO
Yield 67%; Colorless oil; 1H NMR (600 MHz, CDCl3): δ = 4.34 (dd, J = 7.1, 5.6 Hz, 2H), 4.23 (s,
1H), 3.24 (d, J = 17.1 Hz, 1H), 3.14 (d, J = 17.1 Hz, 1H), 2.19 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C
NMR (150 MHz, CDCl3): δ = 203.1, 168.5, 123.1 (q, J = 284.0 Hz), 74.9 (q, J = 28.2 Hz), 63.6,
44.8, 30.4, 13.7.
3. 1H NMR, 13C NMR, HRMS and HPLC spectra for aldol products
3a-1H NMR
3a-13C NMR
8
3b-1H NMR
3b-13C NMR
9
10
3c-1H NMR
3c-13C NMR
11
3d-1H NMR
3d-13C NMR
12
3e-1H NMR
3e-13C NMR
13
3f-1H NMR
3f-13C NMR
14
3g-1H NMR
3g-13C NMR
15
3h-1H NMR
3h-13C NMR
16
3i-1H NMR
3i-13C NMR
17
3j-1H NMR
3j-13C NMR
18
3k-1H NMR
3k-13C NMR
19
3l-1H NMR
3l-13C NMR
20
3m-1H NMR
3m-13C NMR
21
3n-1H NMR
3n-13C NMR
22
3o-1H NMR
3o-13C NMR
23
3p-1H NMR
3p-13C NMR
24
3q-1H NMR
3q-13C NMR
25
HRMS of 3c
HRMS of 3o 10:39:25 30-Dec-2015GJT
m/z150 175 200 225 250 275 300 325 350 375 400 425
%
0
100YDC-750 4 (0.074) AM (Cen,4, 80.00, Ht,5000.0,0.00,1.00); Sm (Mn, 2x3.00); Cm (1:4)
1.02e3285.0714
274.2734
199.0866163.1282 231.0328
286.0750
318.3022413.1395362.3282
26
HPLC of 3a
3a-racemic
3a-asymmetric
27
4. References
1. H. Zong, H.-Y. Huang, G.- L. Bian, L. Song. J. Org. Chem., 79 (2014) 11768-11773. 2. C. G. Kokotos, J. Org. Chem., 77 (2012) 1131-1135. 3. N. Hara, R. Tamura, Y. Funahashi, S. Nakamura, Org. Lett., 13 (2011) 1662-1665.4. K. Mikami,Y. Kawakami, K, Akiyama, K. Aikawa, J. Am. Chem. Soc., 129 (2007) 12950-
12951.
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