A. El Ouarradi et al. / Tetrahedron 64 (2008) 11738–11744
11743
4.3.2.2. 2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-
yl)butyl)phenyl)-2-methyl propanoic acid (1c). Incubation of terfe-
nadine 1a (200 mg, 0.425 mmol) with mycelium of A. corymbifera
LCP 63-1800 obtained in YMS-culture medium (1 L) and suspended
in buffer (1 L), afforded fexofenadine 1c (187 mg, 88%). Mp 193–
Har), 7.59–7.01 (m, 12H, Har), 3.64–3.59 (m, 2H, CHNCH0), 3.22–3.04
(m, 6H, CH2CO, CHNCH0, CH2(CH2)2CO), 2.92–2.84 (m, 1H, CH), 2.11–
2.09 (m, 2H, CH2CH2CO), 1.89–1.79 (m, 4H, CH2CH2N), 1.60 (s, 6H,
CH3); 13C NMR (62.9 MHz, CD3OD):
d¼200.4 (CO), 180.3 (COOH),
152.9, 147.5, 136.6, 129.6, 128.0, 127.7, 127.5, 80.2, 57.8, 54.4, 46.0,
43.1, 36.5, 27.4 (CH3), 25.9, 20.0. HRMS m/z calcd for C32H38NO4
[MþH]þ: 500.2801. Found: 500.2805.
195 ꢂC; 1H NMR (250.13 MHz, CD3OD):
d
¼7.55 (m, 4H, Har), 7.40 (m,
2H), 7.30 (m, 6H, Har), 7.18 (d, 2H, J¼7 Hz, Har), 4.61 (dd, 1H, J¼5.6,
6 Hz, CHOH), 3.32–3.30 (m, 2H, CH2N), 2.90–2.75 (m, 5H), 1.82–1.55
(m, 8H), 1.50 (s, 6H, CH3); 13C NMR (62.9 MHz, CD3OD):
d¼186.3
4.3.2.7. 4-(4-(Benzhydryloxy)piperidin-1-yl)-1-(4-(1-hydroxy-2-meth-
ylpropan-2-yl)phenyl)butan-1-ol (4b). Incubation of ebastol 4a
(70 mg, 0.148 mmol) with cells of Streptomyces platensis NRRL 2364
obtained in YM-culture medium (400 mL) and suspended in buffer
(350 mL) afforded hydroxyebastol 4b (56 mg, 77%) as a white solid.
(COOH), 149.8, 149.3, 145.5, 130.5, 129.0, 128.5, 81.5, 76.0 (CHOH),
59.0, 55.5, 51.3, 44.5, 39.5, 29.9, 27.3, 23.5.
4.3.2.3. 4-(4-(Benzhydryloxy)piperidin-1-yl)-1-(4-(1-hydroxy-2-meth-
ylpropan-2-yl)phenyl)butan-1-one (2b). Incubation of ebastine 2a
(100 mg, 0.213 mmol) with cells of Streptomyces platensis NRRL
2364 obtained in YM-culture medium (500 mL) and suspended in
buffer (500 mL) afforded hydroxyebastine 2b (65 mg, 63%). Mp
Mp 68 ꢂC (decomp.); 1H NMR (250.13 MHz, CDCl3):
d¼7.36–7.24 (m,
14H, Har), 5.50 (s, 1H, CH(Ar)2O), 4.68–4.66 (m, 1H, CHOH), 3.65–
3.61 (m, 1H, CHO), 3.59 (s, 2H, CH2OH), 3.00–2.84 (m, 2H, CHNCH0),
2.75–2.60 (m, 4H, CHNCH0, CH2(CH2)2CHOH), 2.17–2.00 (m, 2H,
CHCH2NCH2CH0), 1.92–1.80 (m, 6H, CHCH2NCH2CH0, CH2CH2CHOH),
52 ꢂC (decomp.); 1H NMR (250.13 MHz, CDCl3):
d
¼7.97 (d,
J¼8.36 Hz, 2H, Har), 7.51 (d, J¼8.36 Hz, 2H, Har), 7.37–7.25 (m, 10H,
Har), 5.55 (s, 1H, CH(Ar)2O), 3.67 (s, 2H, CH2OH), 3.48–3.41 (m, 1H,
CHO), 3.00 (t, J¼7.08 Hz, 2H, CH2CO), 2.80–2.75 (m, 2H, CHNCH0),
2.40 (t, J¼7.10 Hz, 2H, CH2(CH2)2CO), 2.17–2.09 (m, 2H, CHNCH0),
2.00–1.82 (m, 4H, CHCH2NCH2CH0, CH2CH2CO), 1.74–1.62 (m, 2H,
CHCH2NCH2CH0), 1.39 (s, 6H, CH3); 13C NMR (62.9 MHz, CDCl3):
1.34 (s, 6H, CH3); 13C NMR (62.9 MHz, CDCl3):
d
¼145.4, 143.6, 142.9,
128.8, 127.8, 127.4, 126.5, 126.2, 80.8 (CH(Ar)2O), 73.5 (CHOH), 73.4
(CH2OH), 70.7 (CHO), 58.7, 50.3, 40.2, 38.9, 30.2, 25.8 (CH3), 23.5;
MS (ESI): m/z 488 (MþHþ). Anal. Calcd for C32H41NO3$H2O: C 76.00,
H 8.57, N 2.77. Found: C 75.51, H 8.54, N 2.61. HRMS calcd for
C32H42N03 (MþHþ): 488.3165. Found: 488.3165.
d
¼200.2 (CO), 152.5, 143.2, 135.5, 128.7, 128.6, 127.7, 127.5, 126.8,
80.4, 73.1 (CH2OH), 72.2, 58.1, 51.5, 40.9, 36.7, 31.7, 25.6 (CH3), 22.4;
MS (ESI): m/z 486 (MþHþ). Anal. Calcd for C32H39NO3$0.5H2O: C
77.70, H 8.15, N 2.83. Found: C 77.81, H 8.41, N 2.66. HRMS m/z calcd
for C32H40NO3 [MþH]þ: 486.3008. Found: 486.2995.
4.3.2.8. 2-(4-(4-(4-(Benzhydryloxy)piperidin-1-yl)-1-hydroxybutyl)-
phenyl)-2-methylpropanoic acid (4c). Incubation of ebastol 4a
(82 mg, 0.174 mmol) with mycelium of A. corymbifera LCP 63-1800
obtained in YMS-culture medium (500 mL) and suspended in
buffer (410 mL), afforded 4c (46.4 mg, 52%) as a slightly coloured
4.3.2.4. 2-(4-(4-(4-(Benzhydryloxy)piperidin-1-yl)butanoyl)phenyl)-
2-methylpropanoic acid (2c). Incubation of ebastine 2a (100 mg,
0,21 mmol) with mycelium of A. corymbifera LCP 63-1800 obtained
in YMS-culture medium (500 mL) and suspended in buffer
(500 mL), afforded carebastine 2c (84 mg, 80%). Mp 173–175 ꢂC; 1H
solid. Mp 119–120 ꢂC; 1H NMR (250.13 MHz, CD3OD):
d¼7.41–7.26
(m, 14H, Har), 5.62 (s, 1H, CH(Ar)2O), 4.71–4.67 (m, 1H, CHOH),
3.81–3.70 (m, 1H, CHO), 3.37–3.22 (m, 2H, CHNCH0), 3.14–3.02 (m,
4H, CHNCH0, CH2(CH2)2CHOH), 2.02–1.96 (m, 4H, CH2CH2N), 1.85–
1.76 (m, 4H, CH2CH2CHOH), 1.53 (s, 6H, CH3); 13C NMR (62.9 MHz,
NMR (250.13 MHz, CDCl3):
d
¼7.75 (d, J¼8.45 Hz, 2H, Har), 7.57 (d,
CDCl3):
d
¼181.2 (COOH), 145.3, 142.9, 142.4, 128.9, 128.1, 127.2,
J¼8.46 Hz, 2H, Har), 7.36–7.24 (m, 10H, Har), 5.48 (s, 1H, CH(Ar)2O),
3.73 (m, 1H, CHO), 3.05–3.02 (m, 2H, CHNCH0), 2.77–2.66 (m, 4H,
CH2CH2CH2CO), 2.20–2.07 (m, 2H, CHCH2NCH2CH0), 2.00–1.81 (m,
4H, CHCH2NCH2CH0, CH2CH2CO), 1.58 (s, 6H, CH3); 13C NMR
126.2, 126.1, 81.4 (CH(Ar)2O), 72.9 (CHOH), 67.8 (CHO), 57.3, 48.8,
46.9, 36.1, 28.0, 27.1 (CH3), 21.1; HRMS calcd for C32H40N04 (MHþ):
502.2957. Found: 502.2946.
(62.9 MHz, CDCl3):
128.9, 128.1, 128.0, 127.2, 126.7, 81.2, 69.0, 56.6, 48.6, 48.0, 36.0, 28.7,
27.1, 19.3.
d
¼198.5 (CO), 181.7 (COOH), 154.2, 142.6, 134.3,
4.3.2.9. 1-(4-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-4-(piperidin-
1-yl)butanone (5b). Incubation of 5a (200 mg, 0.696 mmol) with
mycelium of Cunninghamella echinulata ATCC 9245 obtained in
YMS-culture medium (1 L) and suspended in buffer (1 L) afforded
5b (74 mg, 35%) as a yellow oil. 1H NMR (250.13 MHz, CDCl3):
4.3.2.5. 1-(4-(1-Hydroxy-2-methylpropan-2-yl)phenyl)-4-(4-(hydroxy-
diphenylmethyl)piperidin-1-yl)butan-1-one (3b). Incubation of
terfenadone 3a (200 mg, 0.426 mmol) with mycelium of A. cor-
ymbifera LCP 63-1800 obtained in YM-culture medium (1 L) and
suspended in buffer (1 L), afforded 3b (101.2 mg, 49%) as a white
solid. Mp 149–151 ꢂC (lit.34 135–137 ꢂC); 1H NMR (250.13 MHz,
d
¼7.93 (d, J¼8.35 Hz, 2H, Har), 7.51 (d, J¼8.36 Hz, 2H, Har), 3.66 (s,
2H, CH2OH), 3.12 (t, J¼6.54 Hz, 2H, CH2CO), 2.92–2.85 (m, 6H,
CH2N), 2.24–2.15 (m, 2H, CH2CH2CO), 1.91–1.88 (m, 4H, CH2CH2N),
1.59–1.57 (m, 2H, CH2CH2CH2N), 1.36 (s, 6H, CH3); 13C NMR
(62.9 MHz, CDCl3):
d
¼199.1 (CO), 153.4, 134.7, 128.5, 127.0, 72.8
CD3OD):
d
¼7.95 (d, J¼8.38 Hz, 2H, Har), 7.57–7.14 (m, 12H, Har),
(CH2OH), 57.4, 53.8, 40.9, 36.0, 25.6, 23.8, 23.0, 19.3; MS (ESI): m/z
304 (MþHþ); HRMS: calcd for C19H30N02 (MHþ): 304.2277. Found:
304.2268.
3.62 (s, 2H, CH2OH), 3.24–3.19 (m, 2H, CHNCH0), 3.08 (t, J¼6.60 Hz,
2H, CH2CO), 2.72–2.66 (m, 3H, CH(CH2)2N, CH2(CH2)2CO), 2.45–2.37
(m, 2H, CHNCH0), 2.04–1.92 (m, 2H, CH2CH2CO), 1.73–1.62 (m, 4H,
CH2CH2N), 1.35 (s, 6H, CH3); 13C NMR (62.9 MHz, CD3OD):
d
¼201.7
Acknowledgements
(CO), 155.3, 148.0, 136.2, 129.4, 128.1, 127.8, 127.6, 80.6, 73.0
(CH2OH), 58.8, 55.1, 44.8, 41.8, 36.6, 27.0, 26.2 (CH3), 21.7. MS (ESI)
m/z 486 (MþHþ), 468, 219. HRMS calcd for C32H40N03 (MHþ):
486.3008. Found: 486.3012.
We thank Mrs. A. Triclin for technical assistance, and Drs. Pierre
Lafite, Patrick Dansette and Dr. Chantal Blandin for fruitful discus-
sions. Part of this work was financially supported by RDR2 ‘Aller vers
´
une Chimie ecocompatible’.
4.3.2.6. 2-(4-(4-(4-(Hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)-
phenyl)-2-methylpropanoic acid (3c). Incubation of terfenadone 3a
(200 mg, 0.426 mmol) with cells of Streptomyces platensis NRRL
2364 obtained in YM-culture medium (1 L) and suspended in buffer
(1 L) afforded 3c (106 mg, 50%) as a pale yellow solid. Mp 164–
References and notes
1. Yun, C. H.; Okerholm, R. A.; Guengerich, F. P. Drug Metab. Dispos. 1993, 21, 403–
166 ꢂC; 1H NMR (250.13 MHz, CD3OD):
d¼7.98 (d, J¼8.56 Hz, 2H,
409.