A Facile and Efficient Synthesis of (15R)-Latanoprost from Chiral Precursor Corey Lactone Diol

Article abstract of DOI:10.1007/s12039-015-0963-2

An efficient asymmetric synthetic route for the synthesis of anti-glaucoma agent, (15R)-latanoprost using Corey lactone diol as chiral substrate under Swern oxidation, allylic reduction and Wittig reaction conditions has been developed. In this method, reduction of keto and alkene functional groups has been achieved in a single step using low cost catalyst NiCl₂/NaBH₄ in methanol. This new synthetic protocol is a good alternative for the synthesis of latanoprost with high stereo selectivity and improved yield. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-015-0963-2

c
J. Chem. Sci. Vol. 127, No. 11, November 2015, pp. 2023–2028. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-0963-2
A Facile and Efficient Synthesis of (15R)-Latanoprost from Chiral
Precursor Corey Lactone Diol
K VIJENDHARa,b, B SRINIVASb and SATHYANARAYANA BOODIDAa,∗
aDepartment of Chemistry, JNTUH College of Engineering Jagtial, Karimnagar 505 501, India
bR&D Division, Aspen Bio Pharma Labs Pvt. Ltd, Genome Vally, Turkapally, Hyderabad 500 078, India
e-mail: bs14@jntuh.ac.in
MS received 29 June 2015; revised 1 September 2015; accepted 3 September 2015
Abstract. An efficient asymmetric synthetic route for the synthesis of anti-glaucoma agent, (15R)-latanoprost
using Corey lactone diol as chiral substrate under Swern oxidation, allylic reduction and Wittig reaction condi-
tions has been developed. In this method, reduction of keto and alkene functional groups has been achieved in a
single step using low cost catalyst NiCl2/NaBH4 in methanol. This new synthetic protocol is a good alternative
for the synthesis of latanoprost with high stereo selectivity and improved yield.
Keywords. Latanoprost; Corey lactone diol; Swern oxidation; Allylic reduction; Wittig reaction.
1. Introduction
The synthetic prostaglandin (figure 1) misoprostol
(1) doses are effective and high enough to reduce gas-
tric acid secretion5 whereas tafluprost (2) is used as eye
drops to control the progression of glaucoma and ocular
hypertension.6 On the other hand, latanoprost (3) which
relates structurally to PGF2α, is one of the prostaglandin
analogues that continue to hold key positions in the
treatment of glaucoma. The novel structure and bio-
logical profile of latanoprost has attracted the interest
of synthetic community and reported various synthetic
approaches for the synthesis of latanoprost.7 Recently,
Martynow and co-workers have synthesized from (-)-
Corey lactone8 and Vidari and co-worker synthesized
using Corey aldehyde.9
In view of the biological importance of latanoprost,
the present study focused on the development of a
new efficient, alternative route10 for the synthesis of
latanoprost (3). This synthetic approach has been devel-
oped with high stereo selectivity and good yield using
LiOH/MTBE and Swern oxidation, Witting Hornor
reaction conditions as key steps. In the earlier method,
the reduction of keto and alkene functional groups
was achieved in two steps using expensive catalysts
R-methyl oxazaborolidine in toluene/borane di methyl
sulfide in THF and platinium oxide respectively11
whereas the present method illustrates a single step
reaction using low cost NiCl2/NaBH4 catalyst in
methanol. We also developed an efficient and enan-
tio selective synthesis of optically active latanoprost
with good yield employing flash purification method
using acetonitrile/water mixture with an entirely differ-
ent strategy. This strategy involves a concise divergent
Prostaglandins are a class of naturally occurring lipid
compounds. The active prostaglandins produced in
vivo are: prostaglandin (PGE2), prostacyclin (PGI2),
prostaglandin D2 (PD2) and prostaglandin F2α (PGF2α).
Prostaglandin (PGE2), is most widely characterized
in animal species, and exhibits versatile biological
activities under physiological conditions. Prostacyclin
(PGI2), affects many organ systems in human body and
inhibits platelet activation and deposition of platelet on
vascular surfaces. Prostaglandin D2 (PGD2) functions
as a neuromodulator as well as trophic factor in the cen-
tral nervous system and it is also involved in smooth
musclar contraction or relaxation.1 Prostaglandin F2α
(PGF2α), functions in contraction and relaxation of
smoother muscles and used for induction of abortions
and also glaucoma.2 These prostaglandins are very
promising moieties for the development of new thera-
peutic agents due to their strong physiological effects.
Prostaglandins play key role in the generation of the
inflammatory response and contribute to the develop-
ment of the cardinal signs of acute inflammation.3
The initial treatment of glaucoma usually involves
pilocarpine or epinephrine drugs and if treatment
is not effective with these topically applied drugs,
prostaglandins are employed for the treatment of glau-
coma. Hence, latanoprost is the most widely used PG
drug for effective treatment of glaucoma.4
∗For correspondence
2023

2024
K Vijendhar et al.
dried over anhydrous Na2SO4 and concentrated under
HO
O
COOH
COOiPr
HO
reduced pressure. The residue was dissolved in pet ether
and kept in refrigerator for 5 h. The solid was filtered to
afford compound 5 as a white solid (72 g, 93.98%). 1H
NMR (300 MHz, CDCl3): δ2.9 (q, 4H), 3.8 (s, 2H), 7.2
(m, 3H), 7.3 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ29.87, 34.24, 41.38, 126.34 (2C), 128.28 (2C), 128.57,
140.29, 201.18.
O
F
F
OH
OH
(1)
(2)
O
O
HO
2.2b Synthesis of dimethyl 2-oxo-4-phenylbutylphos-
phonate (6): To a degassed stirred solution of 5 (80 g,
1 mmol) in acetone (480 mL), was added sodium iodide
(63 g, 1.2 mmol) and stirred at room temperature for
12 h. After completion of the reaction, reaction mix-
ture was filtered and washed with acetone (200 mL).
Then the filtrate was evaporated in vacuo and obtained
crude product was dissolved in dichloromethane (800
mL), washed with water (500 mL) and brine solu-
tion (500 mL), dried over anhydrous Na2SO4. The col-
lected organic solution was concentrated under reduced
pressure to get iodo compound (90 g).
To a solution of iodo compound (90 g, 1 mmol) in
acetonitrile (450 mL), tri methyl phosphate (77.5 mL, 2
mmol) was added at room temperature and stirred for 3
h at 65◦C. After completion of the reaction as indicated
in TLC, excess of tri methyl phosphate was removed
under high vacuum and obtained crude product puri-
fied by silica gel chromatography using ethyl acetate
and hexane mixture (50:50) to afford compound 6 as a
brown liquid (73 g, 86.73%).
HO
OH
Latanoprost (3)
Figure 1. Structure of some of Prostaglandins.
synthesis of the target molecule from Corey lactone
diol.
2. Experimental
2.1 Materials and Methods
All the reagents were purchased from Aldrich (Sigma–
Aldrich, USA). Progress of the reactions was monitored
by TLC, performed on silica gel glass plates containing
60 F-254. Column chromatography was performed with
Merck 60-120 mesh silica gel. IR spectra were recorded
on a Perkin-Elmer RX-1 FT-IR system. 1H NMR spec-
tra were recorded on a Bruker UXNMR/XWI-NMR-
300 MHz spectrometer. 13C NMR (75 MHz) spectra
were recorded on Bruker Avance-300 MHz spectrome-
ter. Chemical shifts (δ) are reported in parts per million
(ppm) downfield from internal TMS standard. Peaks
are labeled as singlet (s), doublet (d), triplet (t), quar-
tet (q), and multiplet (m). ESI spectra were recorded
on Micro mass, Quattro LC using ESI+ software with
a capillary voltage of 3.98 kV and ESI mode positive
ion trap detector. Optical rotations were measured with
a Horiba-SEPA-300 digital polar meter.
1H NMR (300 MHz, CDCl3): δ2.9 (q, 4H), 3.0
(s, 1H), 3.1 (s, 1H), 3.75 (s, 6H), 7.2 (m, 3H), 7.3
(m, 2H). 13C NMR (100 MHz, CDCl3): δ29.35, 40.81,
42.08, 45.45, 52.92, 52.98, 126.11, 128.32, 128.41,
140.47, 200.80, 200.86.
2.2c Synthesis of (3aR,4S,5R,6aS)-hexahydro-4,5-di-
triethylsilane-4-(methyl)cyclopenta[b]furan-2-one (8):
To a solution of compound 7 (50 g, 1 mmol) in pyri-
dine (500 mL), triethyl silylchloride (146 mL, 3 mmol)
was added at room temperature and the mixture was
stirred at 65◦C for 4 h. The solvent was removed under
reduced pressure after completion of reaction, residue
was dissolved in water (400 mL) and extracted with
2.2 Synthesis
2.2a Synthesis of 1-bromo-4-phenylbutan-2-one (5): dichloro methane (2 x 500 mL). The collected organic
To a stirred solution of 4-phenylbutan-2-one (4) (50 g, phases were washed with water followed by brine solu-
1 mmol) in methanol (350 mL), bromine (19 mL, 1.1 tion, dried over anhydrous Na2SO4 and concentrated
mmol) was added at 0◦C and the mixture was stirred under reduced pressure. The crude product was puri-
at 15◦C for 4 h. After completion of reaction, the reac- fied by silica gel chromatography using ethyl acetate
tion mixture was diluted with water (500 mL) and and hexane (10:90) to furnish desired compound 8 as a
1
extracted with dichloromethane (2 x 500 mL). The col- colorless liquid (110 g, 94.55%). H NMR (300 MHz,
lected organic layer was washed with brine solution and CDCl3): δ0.6 (m, 12H), 0.95 (J=15.9 Hz, t, 18H), 2

Efficient Synthesis of (15R)-Latanoprost
2025
(m, 2H), 2.25 (m, 1H), 2.55 (dd, 1H), 2.75 (m,2H), for 3 h at the same temperature. After completion of
3.55 (m,2H), 4.98 (m, 1H), 4.15 (m, 1H). 13C NMR the reaction, the reaction mixture was quenched with
(100 MHz, CDCl3): δ4.22 (3C), 4.63 (3C), 5.73 (2C), ammonium chloride solution at 0◦C. Organic solvent
6.50 (2C), 6.65 (2C), 35.57, 39.26, 41.07, 56.99, 62.41, was removed under reduced pressure, aqueous layer
74.30, 84.07, 177.28.
was extracted with dichloromethane (2 x 250 mL) and
organic layer washed with brine solution, dried over
anhydrous Na2SO4 and concentrated under reduced
pressure to afford compound 10 as a colorless liquid
(25 g, 99.04%).
2.2d Synthesis of (3aR,4S,5R,6aS)-hexahydro-4,5-di-
triethylsilane-4-(methyl)cyclopenta[b]furan-2-one (9):
Oxalyl chloride (27 mL, 2.5 mmol) was discharged
drop wise to a solution of dichloromethane (500 mL)
and dimethyl sulphoxide (28.5 mL, 3.5 mmol) at −72◦C
for 40 min and stirred for 10 min, then slowly added
compound 8 (50 g, 1 mmol) to the reaction mixture
and stirring continued for 4 h at the same temperature.
The reaction mixture was quenched with triethyl amine
(100 mL) at −72◦C and diluted with water (300 mL).
Organic layer was extracted with dichloromethane (500
mL), washed with brine solution and dried over anhy-
drous Na2SO4. After removal of solvent under reduced
pressure the resulted crude aldehyde was used for the
next step without further purification.
2.2f Synthesis of (3aR,4R,5R,6aS)-hexahydro-5-triethyl-
silane-4-((S,E)-3-triethylsilane-5-phenylpent-cyclopen-
ta[b]furan-2-one (11): To a solution of compound 3
(20 g, 1 mmol) in dichloromethane (200 mL) triethy-
lamine (40 mL, 6 mmol), triethylsilylchloride (24.17
mL, 3 mmol) was added drop wise at 5◦C and the
reaction mixture was stirred for 5 h at 10◦C. After com-
pletion of reaction, the reaction mixture was quenched
with water (140 mL), then aqueous layer was extracted
with dichloromethane (250 mL). The combined organic
layer washed with brine solution, dried over anhydrous
Na2SO4. The solvent was removed under reduced pres-
sure and the obtained crude compound was purified by
silica gel chromatography with mixture of ethyl acetate
and hexane (10:90) to furnish the desired compound
To a solution of compound 6 (32 g, 1 mmol) in
methyl tertiary butyl ether (500 mL) LiOH.H2O (4.9 g,
0.95 mmol) was added at room temperature and reac-
tion mixture was stirred for 1 h (solid precipitated).
Then aldehyde compound was added to the reaction
mixture at 5◦C and stirred for another 10 min. After
that water (18 mL) was added and stirring continued
for 45 min. After completion of reaction, the reac-
tion mixture was quenched with water (500 mL) and
aqueous layers were extracted with ethyl acetate (500
mL). The organic layer washed with brine solution
and dried over anhydrous Na2SO4, evaporated under
reduced pressure. The residue was purified by silica gel
chromatography with ethyl acetate and hexane (30:70)
solution to afford compound 9 as a yellow solid (27.5
1
11 as a colorless liquid (25 g, 98.23%). H NMR
(300 MHz, CDCl3): δ 0.6 (q, 12H), 0.95 (m, 18H),
1.35−1.55 (m, 4H), 1.75 (m, 3H), 2.0 (dd, 1H), 2.1
(m, 1H), 2.48−2.83 (m, 5H), 3.7 (m, 1H), 3.94 (m,
1H), 4.95 (m, 1H), 7.2 (m, 3H), 7.3 (m, 2H).
2.2g Synthesis of (3aR,4R,5R,6aS)-hexahydro-5-trie-
thylsilane-4-((S,E)-3-triethylsilane-5-phenylpent-cyclo-
penta[b]furan-2-ol (12): To a solution of compound
4 (27 g, 1 mmol) in THF (50 mL), DIBAL-H (176.89
mL, 3.5 mmol) was added dropwise at −70◦C and
stirring was continued for 1 h. After completion of
reaction as indicated by TLC, the reaction mixture was
quenched with methanol (67.5 mL) at below −70◦C,
then reaction temperature was raised to 5◦C and water
(67.5 mL), ethyl acetate (270 mL) were added and stir-
ring continued for 30 min at room temperature (solid
formed). The reaction mixture was filtered through a
celite pad and washed thoroughly with ethyl acetate
(2 × 150 mL). Later, organic layer was washed with
brine solution, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure to give compound 12
as a colorless liquid (27 g, 99.6%).
1
g, 53.6%). H NMR (300 MHz, CDCl3): δ0.55 (q,
6H), 0.9 (J=10.8 Hz, t, 9H), 2.0 (m, 1H), 2.3 (m,
1H), 2.45 (J=15 Hz, d, 1H), 2.55 (m, 1H), 2.7−3.0
(m, 6H), 4.0 (m, 1H), 4.95 (td, 1H), 6.15 (dd,1H), 6.1
(q,1H), 7.2 (J=12.6 Hz, t, 3H), 7.3 (J=12.9 Hz, d, 2H).
13C NMR (100 MHz, CDCl3): δ4.59 (2C), 4.68, 6.61
(3C), 29.90, 31.70, 34.58, 41.72, 42.36, 56.78, 82.62,
83.02, 125.81, 127.89, 128.16, 128.29, 128.45, 131.06,
145.35, 140.91, 176.17, 198.55.
2.2e Synthesis of (3aR,4R,5R,6aS)-hexahydro-5-hydro-
xy-4-((S,E)-3-triethylsilane-5-phenylpent-cyclopenta[b]
furan-2-one (10): To a stirred solution of compound 9
(25 g, 1 mmol) in methanol (250 mL) NaBH4 (4.56 g,
2 mmol) and nickel chloride hexa hydrate (1.43 g, 0.1 2.2h Synthesis of (Z)-isopropyl7-((1R,2R,3R,5S)-3,5-
mmol) was added at 0◦C and the mixture was stirred di-triethylsilane-2-((S,E)-3-triethylsilane-5-phenylpent-

2026
K Vijendhar et al.
(150 mL) and water (150 mL) at room temperature
1-enyl)cyclopentyl)hept(3aR,4R,5R,6aS)-hexahydro-5-
triethylsilane-4-((S,E)-3-triethylsilane-5-phenylpent-cy- and the reaction mixture was stirred for 8 h. After
clopenta[b]furan-2-one-5-enoate (13): To a solution completion of the reaction, the reaction mixture was
of 4-carboxy butyl triphenyl phosphonium bromide diluted with water (150 mL). Aqueous solution was
(112 g, 5 mmol), potassium ter-butoxide (45.31 g, 8 extracted with ethyl acetate (2 × 200 mL), the organic
mmol) in THF (270 mL), compound 12 was added phase was washed with saturated solution of NaHCO3,
(27 g, 1 mmol) in THF (54 mL) at 5◦C and the reac- brine solution and dried over anhydrous Na2SO4, evap-
tion mixture was stirred for 6 h. After completion of orated under vacuum. The residue was purified by silica
reaction, reaction mixture was poured into cold water gel column chromatography using dichloromethane and
(270 mL) and pH of the solution was adjusted to 2 acetone (70:30) to afford compound 14 as a colorless
using sodium bisulphate solution. Aqueous layer was liquid (15 g, 89.65%).
extracted with ethyl acetate (2 × 270 mL), the collected
organic phase washed with brine solution, dried over
anhydrous Na2SO4, concentrated under reduced pres-
sure. The obtained crude acid compound 13 (40 g) was
used for the next step without further purification.
To a solution of crude acid compound (40 g) in ace-
chromatography with acetonitrile and water mixture to
tone (1080 mL), 2-iodopropane (128.7 g, 15 mmol) and
DBU (130.63 g, 17 mmol) was added at room tem-
perature and the reaction mixture was stirred for 16 h.
2.2j Synthesis of (Z)-isopropyl7-((1R,2R,3R,5S)-3,5-di-
hydroxy-2-((R)-3-hydroxy-5- phenylpentyl)cyclopentyl)
hept-5-enoate(3): The compound 14 (20 g) was puri-
fied by flash purification method using silica (40 mm)
afford pure compound 3 as a colorless liquid (12g).
1H NMR (300 MHz, CDCl3): δ 1.25 (J=6.3 Hz, d,
6H), 1.45 (m,2H), 1.5 (q, 2H), 1.65−1.8 (m, 6H), 1.9
After completion of reaction, the reaction mixture was
filtered and washed with acetone. The organic solvent
(J=6 Hz, t, 2H), 2.1−2.4 (m, 8H), 2.75 (m, 3H), 3.65
was removed completely under vacuum below 40◦C,
the obtained residue dissolved in dichloromethane (400
mL) and washed with citric acid solution (400 mL),
sodium bicarbonate solution and brine solution and
dried over anhydrous Na2SO4. The solvent removed
under reduced pressure and obtained crude ester com-
pound 13 (55 g) was subjected for the next step without
further purification.
(m, 1H), 3.95 (J=2.4 Hz, d, 1H), 4.18 (q, 1H), 5.0
(m, 1H), 5.45 (m,2H) 7.2 (J=16.2 Hz, t, 3H), 7.3 (J=7.8
Hz, d, 2H). 13C NMR (125 MHz, CDCl3): δ 21.76 (2C),
24.88, 26.56, 29.53, 32.06, 34.01, 35.72, 38.97, 42.46,
51.75, 52.67, 67.60, 71.23, 74.48, 78.62, 125.73, 128.33
(4C), 129.34, 129.44, 142.09, 173.46. IR (Neat, cm−1):
γmax 1108, 1728, 2860, 2932, 2978, 3394. Mass (ESI)
m/z: 433.2 (M+1); m/z calcd for C26H40O5 [M+1]
433.2; found: 433.17.
The solution of crude ester compound (55 g) in
dichloromethane (800 mL), triethylamine (70.8 mL,
10 mmol) was added and triethylsilylchloride (51 mL,
6 mmol) was added drop wise at 5◦C and the reac-
tion mixture was stirred at 10◦C for 6 h. After comple-
tion of the reaction, water was added; aqueous layers
were extracted with dichloromethane (2 × 400 mL).
The combined organic layer washed with brine solu-
tion, dried over anhydrous Na2SO4, evaporated under
vacuum. The residue was purified by silicagel column
chromatography with ethyl acetate and hexane (10:90)
mixture to afford compound 13 as a colorless liquid
3. Results and Discussion
The retro synthetic approach for the synthesis of
latanoprost (3) is outlined in scheme 1. The latanoprost
can be prepared from intermediate 12. Intermediate 12
OH
HO
O
COOiPr
1
(33 g, 84.33%). H NMR (300 MHz, CDCl3): δ 0.6
OH
OH
OTES
OTES
(m, 18H), 0.9 (m, 27H), 1.25 (J=6.3 Hz, d, 6H), 1.4
(m, 2H), 1.5 (q, 2H), 1.65−1.8 (m, 6H), 2.0−2.3
(m, 8H), 2.65 (m, 2H), 3.7 (m, 2H), 4.1 (q, 1H), 5.0
(m, 1H), 5.4 (m, 2H) 7.2 (m, 3H), 7.3 (m, 2H).
12
Latanoprost(3)
O
O
O
O
OH
O
OTES
2.2i Synthesis of (Z)-isopropyl7-((1R,2R,3R,5S)-3,5-
dihydroxy-2-((R)-3-hydroxy-5- phenylpentyl)cyclopentyl)
hept-5-enoate(14): To a solution of compound 13 (30
g, 1 mmol) in THF (300 mL) was added, acetic acid
OH
9
Corey lactone diol (7)
Scheme 1. Retro synthetic approach for Latanoprost (3).

Efficient Synthesis of (15R)-Latanoprost
2027
can be synthesized from 9 which can be prepared from
Corey lactone diol (7).
The Corey lactone diol (7) utilized for the synthe-
sis of latanoprost (3) was purchased from Hwasun
In accordance with the synthetic plan, our synthesis biotechnology, China (CAS NO-32233-40-2). The diol
began with the bromination reaction of 4-phenylbutan2- 7 was protected by triethylsilylchloride in presence of
one 4 to obtain 1-bromo-4-phenylbutan-2-one 5. The pyridine at 65◦C for 4 h, resulted compound 8. Then
compound 5 was transformed to iodo intermediate by it was subjected to Swern’s oxidation to afford the
treating with NaI in acetone at 30oC for 12 h. This inter- mono protected aldehyde, which afforded compound 9
mediate (without isolation) was further treated with tri in good yield on treatment with compound 6 under Wit-
methyl phosphate to support the compound 6 in good tig reaction conditions. The allylic double bond of com-
yield as shown in scheme 2.
pound 9 was reduced by stirring with nickel chloride
O
O
P
O
O
OMe
OMe
O
c
Br
I
a
b
6
5
4
Scheme 2. Reagents and Conditions: (a) Br2, methanol, 0◦C, 4 h; (b) NaI, acetone, 27◦C, 12h; (c)
(CH3)3PO4, acetonitrile, 65◦C, 3 h.
O
O
O
O
O
O
O
O
a
b
c
OH
OTES
CHO
OTES
OH
O
OTES
OTES
O
9
7
8
d
O
OH
O
O
O
e
f
OTES
OTES12
g
OH
OTES
OTES
OTES
11
10
HO
SETO
HO
COOH
COOiPr
COOiPr
i
h
OTES
OTES
OTES
OTES
OTES
OTES
13
j
HO
HO
COOiPr
COOiPr
k
OH
OH
OH
OH
14
Latanoprost (3)
Scheme 3. Reagents and Conditions: (a) Triethyl silylchloride, pyridine, 65◦C, 4 h; (b) (COCl)2,
DMSO, Et3N, CH2Cl2, –72◦C, 4 h; (c) Compound 6, methyl tertiary butyl ether, LiOH.H2O, 5◦C,
45 min; (d) NiCl2.6H2O, methanol, NaBH4, 0◦C, 3 h; (e) Triethyl silylchloride, TEA, CH2Cl2, 5◦C,
5 h; (f) DIBAL-H,dry THF, −70◦C, 60 min; (g) 4-Carboxy butyl triphenyl phosphonium bromide,
t-BuOK, THF, 5◦C, 6 h; (h) 2-Iodopropane, DBU, dry acetone, 30◦C, 16 h; (i) Triethyl silylchloride,
TEA, CH2Cl2, 5◦C, 6 h; (j) aq AcOH, THF, 30◦C, 8 h; (k) flash purification.

2028
K Vijendhar et al.
spectra (figures S1-S7), 13C NMR spectra (figures S8-
S12), IR spectra (figures S13) HPLC chromatogram
(figure S14), Mass spectra (figure S15) and SOR spec-
trum data (table S1) are available at www.ias.ac.in/
chemsci.
hexahydrate, sodium borohydride in methanol for 3h at
0◦C which resulted in hydroxyl derivative compound
10. The hydroxyl group present in compound 10 was
protected by triethylsilylchloride with triethylamine in
dichloromethane at 5◦C for 5 h, to obtain compound 11
in good yield.
The lactone ring of compound 11 was reduced with
DIBAL-H in THF at −70◦C for 1 h to give compound
12. The lactone ring of compound 12 was cleaved by
reacting with 4-carboxy butyl triphenylphosphonium
bromide and potassium tert-butoxide in THF at 5◦C
for 6 h under Wittig conditions. The resulted Wittig
compound without further purification was subjected
for esterification reaction by treating with DBU and 2-
Iodopropane in dry acetone at 30◦C for 16 h to have
isopropyl ester compound. This crude compound was
treated with triethylsilylchloride and triethylamine in
dichloromethane at 5◦C for 6 h to afford TES protected
compound 13 with quantitative yield.
Finally, deprotection of compound 13 with aqueous
acetic acid and THF solvent at 30◦C for 8 h was done
to obtain target compound 14 with good yield and was
separated by flash purification to get target molecule
enantiopure latanoprost 3. The physical and spectro-
scopic data of 3 were in congruence with reported data
in the literature.8 The present methodology provides
an enhanced stereo selectivity and efficient synthetic
approach for the synthesis of compound 3 with good
yield as shown in scheme 3.
Acknowledgements
One of the authors KV is grateful to the Aspen Bio
Pharma Labs Pvt. Ltd for providing research opportu-
nity to carry out his research program.
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4. Conclusions
In the present study, an attempt has been made to
develop a simple, convenient and convergent approach
for the synthesis of latanoprost 3 using Corey lactone
diol under Swern oxidation, allylic reduction and Wit-
tig reaction conditions. This new synthetic protocol pro-
vides good stereo selectivity and an efficient alternative
synthetic route for the synthesis of compound 3 in good
yield.
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69
Supplementary Information
The supplementary information pertaining to character-
ization of the synthesized compounds using H NMR
1