240 Letters in Organic Chemistry, 2011, Vol. 8, No. 4
Mudduluru et al.
(Z)-7-(2-((E)-4-phenoxy-3-hydroxybut-1-enyl)-3,5-
dihydroxycyclopentyl)hept-5-enoicacid (10e)
F=32.3 Hz), 124.25 (q, JC-F=269.3 Hz), 126.84 (q, JC-F=3.8
Hz), 128.82, 129.53, 129.63, 129.74, 135.22, 160.90, 173.40.
Colorless viscous liquid. ESI-MS: m/z 413 ([M+Na]+).
IR(KBr, max, cm-1): 3363, 2929, 1718, 1643, 1557, 1454,
1246, 1031, 972 cm-1. 1H NMR (300 MHz, CDCl3) (ppm):
1.57 – 1.85 (m, 5H), 2.07 – 2.42 (m, 7H), 3.79 – 4.64 (m,
5H), 5.31 – 5.81 (m, 4H), 6.88 – 7.01 (m, 3H), 7.30 (m, 2H).
(Z)-isopropyl7-(2-((E)-4-(4-fluorophenoxy)-3-hydroxybut-
1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (12)
Yellow color viscous liquid. ESI-MS: m/z 473
([M+Na]+). HRMS (ESI): Calcd. for C25H35FO6 Na [M+ Na]+
473.231; found 473.2337. IR (KBr, max, cm-1):3399, 2932,
1725, 1507, 1453, 1375, 1249, 1210, 1108, 971, 829 cm-1. 1H
NMR (300 MHz, CDCl3) (ppm): 1.22 (d, J=6.3 Hz, 6H),
1.52 – 1.84 (m, 4H), 2.05 – 2.43 (m, 6H), 3.82 – 4.00 (m,
3H), 4.20 (br, 1H), 4.52 (br, 1H), 4.99 (m, 1H), 5.37 – 5.42
(m, 2H), 5.61 – 5.79 (m, 2H), 6.85 (m, 2H), 6.97 (m, 2H).
13C NMR (75 MHz, CDCl3) (ppm): 21.70, 24.74, 25.31,
26.50, 33.93, 42.72, 49.94, 55.52, 67.58, 70.92, 72.39,
115.57 (q, JC-F=1.5 Hz), 115.78 (q, JC-F=17.3 Hz), 128.88,
129.62, 130.08, 135.23, 154.60 (q, JC-F=2.3 Hz), 157.33 (q,
JC-F=237.0 Hz), 173.40.
General Procedure for the Synthesis of (±) Travoprost (1)
and its Analogues (11-14)
Compound 10 (1.0 g, 2.18 mmol) in acetone (25.0 mL)
was cooled to -5 °C and DBU (2.0 g, 13.08 mmol) was
added slowly under nitrogen atmosphere at -5 °C. Reaction
mixture temperature was raised to room temperature and
stirred for 30 min. Isopropyl iodide (1.85 g, 10.9 mmol) was
added at room temperature into the reaction mixture and
stirred for 4 h at which TLC indicates completion of the
reaction. Reaction mixture was concentrated under vacuum
to remove acetone and to get residue. Residue was dissolved
in EtOAc (30.0 mL) and washed with 10 % citric acid (20.0
mL) solution followed by 5 % NaHCO3 solution (20.0 mL),
brine (20.0 mL) and dried (Na2SO4) to obtain crude product.
Crude product contains two diastereomers and desired
isomer was separated by column chromatography using
silica gel (230-400 mesh) by eluting EtOAc / hexane (3:7) to
give pure product.
(Z)-isopropyl7-(2-((E)-4-(4-chlorophenoxy)-3-hydroxybut-
1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate(13)
Yellow color viscous liquid. ESI-MS: m/z 489
([M+Na]+). HRMS (ESI): Calcd. for C25H35ClO6 Na [M+
Na]+ 489.2014; found 489.2034. IR(KBr, max, cm-1): 3389,
2931, 1725, 1595, 1479, 1374, 1248, 1107, 1035, 773 cm-1.
1H NMR (300 MHz, CDCl3) (ppm): 1.22 (d, J=6.3 Hz,
6H), 1.55 – 1.84 (m, 4H), 2.09 – 2.40 (m, 8H), 3.88 (dd,
J=9.6, 7.8 Hz, 1H), 4.00 (m, 2H), 4.21 (t, J=4.2 Hz, 1H),
4.52 (m, 1H), 4.99 (m, 1H), 5.40 (m, 2H), 5.61 – 5.78 (d,
2H), 6.80 (ddd, J=8.4, 2.4, 0.9 Hz, 1H), 6.91 – 6.96 (m, 2H),
7.20 (t, J=8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) (ppm):
21.70, 24.74, 25.25, 26.49, 33.94, 42.71, 49.80, 55.38, 67.57,
70.85, 71.85, 72.21, 113.01, 115.03, 121.12, 128.89, 129.58,
130.15, 130.20, 134.74, 135.43, 159.24, 173.44.
(Z)-6-(3,5-dihydroxy-2-((E)-3-hydroxy-4-(3-
(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl)hex-4-
enyl isobutyrate ((±)Travoprost) (1) [10d]
Pale yellow color viscous liquid. ESI-MS: m/z 523
([M+Na]+). HRMS (ESI): Calcd. for C26H35F3O6 Na [M+
Na]+ 523.2278; found 523.2299. IR (KBr, max, cm-1): 2980,
1
2935, 1719, 1492, 1450, 1330, 1126, 1061, 793 cm-1. H
(Z)-isopropyl7-(3,5-dihydroxy-2-((E)-3-hydroxy-4-
phenoxybut-1-enyl)cyclopentyl)hept-5-enoate(14)
NMR (300 MHz, CDCl3) (ppm): 1.21 (d, J=6.3 Hz, 6H),
1.50 – 1.83 (m, 5H), 2.04 – 2.44 (m, 7H), 3.91 – 4.04 (m,
3H), 4.19 (t, J=3.9 Hz, 1Ha), 4.54 (m, 1Hb), 4.98 (m, 1H),
5.35 – 5.42 (m, 2H), 5.66 (dd, J=15.3, 5.7 Hz, 1H), 5.76 (dd,
J=15.3, 5.7 Hz, 1H), 7.08 (dd, J=8.1, 2.1 Hz, 1H), 7.14 (br,
1H), 7.22 (d, J=7.8 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H). 13C
NMR (75 MHz, CDCl3) (ppm): 21.67, 24.71, 25.27, 26.47,
33.90, 42.69, 49.89, 55.48, 67.61, 70.85, 71.86, 72.34,
111.40 (q, JC-F=3.8 Hz), 117.61 (q, JC-F=4.5 Hz), 117.95,
123.79 (q, JC-F=270.8 Hz), 128.83, 129.64, 129.93, 130.01,
131.74 (q, JC-F=32.3 Hz), 135.48, 158.60, 173.48.
Yellow color viscous liquid. ESI-MS: m/z 455
([M+Na]+). HRMS (ESI): Calcd. for C25H36O6 Na [M+ Na]+
455.2404; found 455.2394. IR(KBr, max, cm-1): 3369, 2928,
2859, 1726, 1634, 1599, 1496, 1375, 1246, 1108, 1040, 970
1
cm-1. H NMR (300 MHz, CDCl3) (ppm): 1.21 (d, J=6.3
Hz, 6H), 1.64 – 1.83 (m, 4H), 1.98 – 2.30 (m, 8H), 3.91 (dd,
J=9.3, 7.5 Hz, 1H), 3.97 – 4.02 (m, 2H), 4.19 (t, J=4.2 Hz,
1H), 4.53 (m, 1H), 4.99 (m, 1H), 5.41 (m, 2H), 5.70 (m, 2H),
6.87 – 7.00 (m, 3H), 7.30 (m, 2H). 13C NMR (75 MHz,
CDCl3) (ppm): 21.71, 24.77, 25.41, 26.50, 29.56, 33.95,
50.09, 55.65, 58.44, 67.49, 70.90, 71.71, 72.42, 114.54,
120.95, 129.03, 129.37, 129.49, 130.19, 135.12, 158.50,
173.32.
(Z)-isopropyl7-(3,5-dihydroxy-2-((E)-3-hydroxy-4-(4-
(trifluoromethyl)phenoxy)but-1-enyl)cyclopentyl) hept-5-
enoate (11)
Pale yellow color viscous liquid. ESI-MS: m/z 523
([M+Na]+). HRMS (ESI): Calcd. for C26H35F3O6 Na [M+
Na]+ 523.2278; found 523.2295. IR (KBr, max, cm-1): 3393,
2980, 2934, 1724, 1615, 1520, 1375, 1330, 1259, 1111, 837
CONCLUSION
1
cm-1. H NMR (300 MHz, CDCl3) (ppm):1.21 (d, J=6.3
The advanced racemic key intermediate (2) was
successfully converted in to (±) travoprost and its analogs
establishing the generality of the synthetic approach.
Hz, 6H), 1.53 – 1.84 (m, 5H), 2.05 – 2.41 (m, 7H), 3.90 –
4.06 (m, 3H), 4.21 (t, J=3.9 Hz, 1H), 4.55 (m, 1H), 4.99 (m,
1H), 5.36 – 5.44 (m, 2H), 5.63 – 5.80 (m, 2H), 6.98 (d, J=8.7
Hz, 2H), 7.54 (d, J=8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3)
(ppm):21.69, 24.74, 25.42, 26.50, 33.90, 42.80, 50.26,
55.78, 67.61, 70.67, 71.85, 72.71, 114.50, 123.22 (q, JC-
ACKNOWLEDGEMENT
The authors thank Dr. C. Satyanarayana, CEO, Aptuit
Laurus Private Ltd. for his encouragement.