Synthesis of (±)-bimatoprost

Article abstract of DOI:10.1080/00397911.2010.539754

A general synthetic approach has been developed for the synthesis of a key intermediate (6) that can be elaborated into several ophthalmic prostaglandins and their derivatives. Using these strategy, we have obtained (±)-bimatoprost (1) and its analog, (±)-homobimatoprost (5). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.539754

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Synthesis of (±)-Bimatoprost
M. Harikrishna a , H. Rama Mohan a , P. K. Dubey b , M. Shankar a
Gottumukkala V. Subbaraju a
&
a Aptuit Laurus Private Limited, ICICI Knowledge Park, Hyderabad,
India
b Department of Chemistry, College of Engineering, J N T University,
Hyderabad, India
Available online: 21 Oct 2011
To cite this article: M. Harikrishna, H. Rama Mohan, P. K. Dubey, M. Shankar & Gottumukkala V.
Subbaraju (2012): Synthesis of (±)-Bimatoprost, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 42:9, 1288-1305
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Synthetic Communications1, 42: 1288–1305, 2012
Copyright # Aptuit Laurus (P) Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.539754
SYNTHESIS OF (ꢀ)-BIMATOPROST
M. Harikrishna,1 H. Rama Mohan,1 P. K. Dubey,2
M. Shankar,1 and Gottumukkala V. Subbaraju1
1Aptuit Laurus Private Limited, ICICI Knowledge Park, Hyderabad, India
2Department of Chemistry, College of Engineering, J N T University,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A general synthetic approach has been developed for the synthesis of a key
intermediate (6) that can be elaborated into several ophthalmic prostaglandins and their
derivatives. Using these strategy, we have obtained (ꢀ)-bimatoprost (1) and its analog,
(ꢀ)-homobimatoprost (5).
Keywords (ꢀ)-Bimatoprost; (ꢀ)-homobimatoprost; ophthalmic; prostaglandins
INTRODUCTION
Glaucoma, a potentially blinding eye disorder, is characterized by increased
intraocular pressure (IOP), excavation of optic nerve head, and gradual loss of visual
field.[1] Initial treatment usually involves topical application of muscarinic agonists,
particularly pilocarpine, or adrenergic agonists or antagonists (e.g., epinephrine and
timolol, respectively).[2] If treatment with such topically applied drugs is not effec-
tive, systemic administration of carbonic anhydrase inhibitors or surgical inter-
vention may be employed.[3] In recent years, attention has been focused on
prostaglandins (PGs), primarily prostaglandin F2a esters, as IOP-lowering sub-
stances. They have the advantages of mechanism of action and their local and sys-
temic pharmacokinetic profiles.[4] There are currently four prostaglandin analogs
[latanoprost (2), bimatoprost (1), travoprost (3), and uniprostone (4)[5] (Fig. 1)
approved for glaucoma treatment by the U.S. Food and Drug Administration.
Received July 15, 2010.
Address correspondence to H. Rama Mohan, Aptuit Laurus Private Limited, ICICI Knowledge
Park, Turkapally, Shameerpet, Hyderabad 500 078, India. E-mail: mohan.hindupur@aptuitlaurus.com
1288

SYNTHESIS OF (ꢀ)-BIMATOPROST
1289
Figure 1. Ophthalmic prostaglandins.
Several studies have established that PGs of the F2a type reduce IOP by increasing
uveoscleral outflow of aqueous humor.[6]
The PG ocular hypotensives are PGF2 derivatives in which the a -side chain
has been converted to either ester or amide functionality. These esters are more lipo-
philic than the corresponding acid and penetrate ocular tissues more readily. In these
the x-side chain is modified with aromatic units. In this article, we report the devel-
opment of a versatile key intermediate (6) from racemic Corey lactone (purchased
from Hygeia Laboratories, India), which can be elaborated into a variety of ophthal-
mic prostaglandins and their derivatives. As a demonstration of this general
approach, we have converted key intermediate (6) into (ꢀ)-bimatoprost (1) and
(ꢀ)-homobimatoprost (5), and the details are reported.
RESULTS AND DISCUSSION
Synthesis of Key Intermediate 6 (Scheme 1)
Protection of primary alcohol of Corey lactone (7) with TBDMSCl in the pres-
ence of imidazole and a catalytic quantity of dimethylaminopyridine in dimethylfor-
mamide (DMF) solvent at room temperature gave 8, quantitatively. The secondary
hydroxyl group of 8 was benzoylated with benzoyl chloride using triethylamine base
in dichloromethane (DCM) solvent at reflux for 2 h followed by the usual workup to
obtain 9 in 55% yield after flash column purification. Formation of the desired lactol
(10) was achieved by reducing 9 with diisobutylaluminumhydride (DIBAL) in tetra-
hydrofuran (THF) at ꢁ78 ꢂC in 77% yield.[7] Wittig reaction of 10 with phosponate
reagent 11 in the presence of KOBut solution in THF (1 M) at ꢁ40 ꢂC gave 12
with 82% yield.[7,8] It was observed that during the preparation of 12, temperature
(ꢁ40 ꢂC) and content of KOH (<1.0%) in KOBut solution were very critical to avoid
debenzoylations. Esterification of 12 with isopropyl iodide using 1,8-diazabicyclo

1290
M. HARIKRISHNA ET AL.
Scheme 1. Reagents: (a) TBDMSCl, imidazole, DMAP, DMF, 4 h, 100%; (b) benzoyl chloride, TEA,
DMAP, DCM, 2 h, 55%; (c) DIBAL, THF, 1.5 h, ꢁ70 ꢂC, 77%; (d) KOBut (1 M soln. in THF), THF,
2 h, ꢁ40 ꢂC, 82%; (e) DBU, isopropyl iodide, acetone, 12 h, rt, 92%; (f) benzoyl chloride, TEA, DMAP,
DCM, 2 h reflux, 60%; (g) Dess–Martin periodinane, DCM, 1.5 h, 10 ꢂC, 100%.
[5.4.0]undec-7-ene (DBU) in acetone solvent in 12 h at room temperature gave 13
with 92% yield. Free secondary hydroxyl group of 13 was benzoylated with benzoyl
chloride using triethylamine followed by deprotection of the tert-butyldimethylsilyl
(TBDMS) group using tetrabutylammonium fluoride in THF for 2 h at room tem-
perature to give 14 with 60% yield. Oxidation of 14 with Dess–Martin periodinane
in DCM gave 6 in quantitative yield.[8,9]
Synthesis of 18[8] (Scheme 2)
Bromination of benzylacetone (15) with bromine in methanol solvent at
10–15 ꢂC for 2 h followed by selective recrystallization (dibromo compound remains
in the mother liquor) using hexane gave 16 in 50% yield. Iodination of 16 with
sodium iodide in acetone at room temperature for 6 h gave 17 in 80% yield. Reaction
of 17 with trimethylphosphite in acetonitrile at reflux temperature for 2 h followed by
column purification afforded 18 with 60% yield.

SYNTHESIS OF (ꢀ)-BIMATOPROST
1291
Scheme 2. Reagents: (a) Br, methanol, 2 h, 15–20 ꢂC, 50%; (b) NaI, acetone, 6 h, rt, 83%; (c) trimethylpho-
sphite, acetonitrile, 2 h reflux, 60%.
Synthesis of 24[8,10] (Scheme 3)
Reaction of phenylethyl bromide (19) with ethyl acetoacetate (20) in the pres-
ence of sodium metal in ethanol at reflux temperature followed by usual workup and
50% sulfuric acid treatment at 90 ꢂC for 5 h gave 21 in 40% yield. Bromination of 21
with bromine in methanol at 10–15 ꢂC for 2 h followed by workup and column chro-
matography gave 22 with 50% yield. Iodination of 22 with sodium iodide in acetone
at room temperature for 6 h yielded 23 in 70% and the reaction of 23 with trimethyl-
phosphite in acetonitrile at reflux temperature for 3 h followed by flash column chro-
matography gave 24 with 50% yield.
Scheme 3. Reagents: (a) Na, ethanol, 21 h, reflux, 5% NaOH, 5 h, reflux, 50% H2SO4, 5 h, 90 ꢂC, 40%; (b)
Br, methanol, 2 h, 10–15 ꢂC, 50%; (c) NaI, acetone, 6 h, rt, 70%; (d) trimethylphosphite, acetonitrile, 2 h
reflux, 50%.

1292
M. HARIKRISHNA ET AL.
Synthesis of (ꢀ)-Bimatoprost (1) (Scheme 4)
Wittig reaction of 6 with phosphonate reagent 18 in the presence of sodium
hydride in dimethoxyethane (DME) solvent for 2 h at 0–5 ꢂC followed by flash
chromatography afforded 25.[7,9] We have studied the synthesis of compound 25
in different solvents such as THF, 2-methyl THF, and DME and found that the best
results were obtained using DME as a solvent. Reduction of the keto group on 25
with sodium borohydride in methanol at 25 ꢂC for 30 min yielded compound 26 in
90% yield. Deprotection of both benzoyl groups of 26 with K2CO3 in methanol
for 6 h at room temperature gave 27 in 30% yield and its diastereo isomer was
separated by column chromatography. Trans-esterification was observed from
isopropyl ester to methyl ester during deprotection of 26 to 27 in methanol=
K2CO3. Reaction of 27 with 70% ethylamine solution in water for 12 h at room
temperature followed by flash column purification gave 1 with 70% yield. Spectral
data for (ꢀ)-1 compare well with those reported for bimatoprost.[11]
Synthesis of (ꢀ)-Homobimatoprost (5) (Scheme 5)
The Wittig reaction of 6 with phosphonate reagent 24[10] in the presence of
sodium hydride in DME solvent for 30 min at ꢁ30 ꢂC followed by flash chromato-
graphy gave 28[7,9] in 45% yield, and we have observed more impurities when we
Scheme 4. Reagents: (a) NaH, DME, 3 h, rt, 65%; (b) NaBH4, methanol, 0.5 h, rt, 90%; (c) K2CO3,
methanol, 5 h, rt, diastereo isomer separation, 30%; (d) 40% ethylamine, 12 h, rt, 70%.

SYNTHESIS OF (ꢀ)-BIMATOPROST
1293
Scheme 5. Reagents: (a) NaH, DME, 3 h, rt, 58%; (b) NaBH4, methanol, 0.5 h, rt, 80%; (c) K2CO3,
methanol, 5 h, rt, diastereo isomer separation, 25%; (d) 40% ethyl amine, 12 h, rt, 70%.
carried out the reaction at 0–5 ꢂC. Reduction of the keto group on 28 with sodium
borohydride in methanol at 25 ꢂC for 30 min gave 29 with 80% yield followed by
removal of benzoyl groups of 29 with K2CO3 in methanol for 6 h at room tempera-
ture, which yielded a mixture of diastereomers. The desired diastereo isomer, 30, was
separated by column chromatography. Reaction of 30 with 70% ethylamine solution
in water for 12 h at room temperature followed by flash column purification gave 5
with 60% yield.
CONCLUSION
A versatile intermediate 6 was obtained from (ꢀ)-Corey lactone, which can be
elaborated into all clinical ophthalmic prostaglandins. (ꢀ)-Bimatoprost was synthe-
sized using 6. Using the same strategy, the optically pure ophthalmic prostaglandins
can be obtained by starting from chiral pure Corey lactone.
EXPERIMENTAL
All reactions were performed either under an argon or nitrogen atmosphere,
unless otherwise mentioned. The progress of the reactions was monitored by
thin-layer chromatography (TLC) over silica gel 60 F (E. Merck, 0.25 mm). The
chromatograms were visualized by irradiation with ultraviolet light or by heat stain-
ing with polyphosphoric acid and p-anisaldehyde in ethanol=sulfuric acid. Column
chromatography was performed on silica gel 60 (Merck, 70–230 mesh), and flash
chromatography was performed on silica gel 60 (Merck, 230–400 mesh) using the

1294
M. HARIKRISHNA ET AL.
1
indicated solvent. Melting points are uncorrected. H and 13C NMR spectra were
recorded on a 300-MHz Bruker Avance-II NMR Spectrometer using CDCl3 as
solvent. Infrared (IR) spectra were recorded on a Perkin-Elmer FTIR 1605 spec-
trometer. Mass spectra were measured on Waters Quatro Micro mass spectrometer.
4-((tert-Butyldimethylsilyloxy)methyl)-5-hydroxyhexahydro-2H-
cyclopenta[b]furan-2-one (8)
A solution of 7 (50 g, 290.69 mmol) in DMF (180 mL) was added to a mixture
of dimethylaminopyridine (DMAP) (0.035 g, 0.29 mmol) and imidazole (29.68 g,
436.03 mmol) at 25 ꢂC. The reaction mixture was cooled to 0 ꢂC and stirred for
10 min at 0 ꢂC. TBDMSCl (52.5 g, 348.3 mmol) in DMF (70 mL) was added slowly
to the reaction mass at 0 ꢂC and stirred for 10 min at 0 ꢂC. The reaction mass tem-
perature was allowed to raise to 25 ꢂC and stirred for 4 h at 25 ꢂC, at which point
TLC indicated complete conversion of 7 to 8. The resulting reaction mixture was
added to water (2 L) and EtOAc (1 L) at 25 ꢂC and stirred for 45 min. Both layers
were separated, and the aqueous layer was extracted with EtOAc (2 ꢃ 100 mL).
The organic layer was washed with water (500 mL) followed by brine solution
(500 mL), dried over Na2SO4, and concentrated at 40 ꢂC under vacuum to get
83.19 g of 8 (100%) as a viscous syrup.
1
IR (KBr cells): 3379, 2896, 2926, 1758, 1468, 1359, 1208, 1108, 1089 cmꢁ1; H
NMR (300 MHz, CDCl3): d 0.05 (s, 6H, Si(CH3)2), 0.88 [s, 9H, (CH3)3], 1.93–2.02
(m, 3H, CH2, CH), 2.46–2.49 (m, 2H, CH2), 2.78 (dd, J ¼ 17.7, 9.9 Hz, 1H, CH),
3.58 (dd, J ¼ 9.9, 6.6 Hz, 1Ha), 3.71 (dd, J ¼ 10.2, 5.1 Hz, 1Hb), 4.12 (q, J ¼ 6.3 Hz,
1H, CH), 4.90 (td, J ¼ 6.9, 2.7, 1H, CH); MS (ES): m=z 287 (M þ H)þ.
4-((tert-Butyldimethylsilyloxy)methyl)-2-oxohexahydro-2H-
cyclopenta[b]furan-5-yl Benzoate (9)
A solution of 8 (83.19 g, 290.67 mmol) in DCM (832 mL), TEA (117.43 g,
1162.34 mmol), and DMAP (0.0354 g, 0.29 mmol) were added and stirred at 25 ꢂC
under a nitrogen atmosphere. The reaction mass was cooled to 0 ꢂC, and benzoyl
chloride (81.67 g, 581.34 mmol) was added slowly into the reaction mass at 0 ꢂC.
The reaction mixture temperature was raised to reflux and stirred for 2 h, at which
point TLC indicated complete conversion. The reaction mass temperature was
cooled to 25 ꢂC, MeOH (100 mL) was added, and the mixture was heated to reflux
for 20 min. The resulting reaction mixture was cooled to 25 ꢂC and concentrated
under vacuum at 40 ꢂC to get the residue. The residue was dissolved in water
(500 mL), and the aqueous layer was extracted with CH2Cl2 (3 ꢃ 200 mL). The
organic layer was washed with brine (500 mL), dried over Na2SO4, and concentrated
at 40 ꢂC under vacuum to get crude 9. The crude product was purified by flash col-
umn chromatography on silica gel (230–400 mesh) with an ethyl acetate–hexane (1:1)
as eluent to give 62.72 g of 9 (160.73 mmol, 55.3%) as a colorless viscous liquid.
1
IR (KBr cells): 2930, 2857, 1717, 1584, 1452, 1277, 1109, 837 cmꢁ1; H NMR
(300 MHz, CDCl3): d 0.05 [s, 6H, Si(CH3)2], 0.88 [s, 9H, (CH3)3], 2.28–2.34 (m, 1H,
CH), 2.41–2.59 (m, 3H, CH2, CH), 2.87–2.95 (m, 2H, CH2), 3.69 (qd, J ¼ 9.9, 5.1 Hz,
2H, CH2), 5.08 (t, J ¼ 5.7 Hz, 1H, O-CH), 5.34 (m, 1H, O-CH), 7.43 (t, J ¼ 7.5 Hz,

SYNTHESIS OF (ꢀ)-BIMATOPROST
1295
2H, HAr), 7.55 (m, 1H, HAr), 7.99 (d, J ¼ 7.5 Hz, 2H, HAr); MS (ES): m=z 391
(M þH)þ.
4-((tert-Butyldimethylsilyloxy)methyl)-2-hydroxyhexahydro-2H-
cyclopenta[b]furan-5-yl Benzoate (10)
A solution of 9 (60 g, 153.76 mmol) in THF (1.2 L) was cooled to ꢁ70 ꢂC, and
1 M DIBAL solution in THF (600 mL) was added slowly to the reaction mixture at
ꢁ70 ꢂC and stirred for 1.5 h at ꢁ70 ꢂC. Sodium bisulfate (15%,500 mL) was slowly
added to reaction mass at ꢁ70 ꢂC, and the reaction mass temperature was raised
to ꢁ30 ꢂC. The mixture was stirred for 20 min at ꢁ30 ꢂC. The resulting mixture tem-
perature further raised to 25–30 ꢂC, both layers were separated, and the aqueous
layer was extracted with EtOAc (2 ꢃ 250 mL). The combined organic layers were
dried over Na2SO4 and concentrated under vacuum at 40 ꢂC to give 54.2 g of 10
(138.45 mmol, 90%) as a pale yellow viscous liquid. IR (KBr cells): 3093, 2955,
2928, 1776, 1719, 1450, 1272, 1100, 1070, 838, 714 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 0.04 [s, 6H, Si(CH3)2], 0.89 [s, 9H, (CH3)3],
1.98–2.27 (m, 4H, CH2), 2.43–2.49 (m, 1H, CH), 2.68–2.74 (m, 1H, CH),
3.64–3.73 (m, 2H, CH2), 4.79 (td, J ¼ 6.6, 2.1 Hz, 1H, CH), 5.22–5.27 (m, 1H,
CH), 5.67–5.71(m, 1H, CH), 7.43 (t, J ¼ 7.2 Hz, 2H, HAr), 7.53–7.57 (m, 1H, HAr),
8.00 (d, J ¼ 7.2 Hz, 2H, HAr); MS (ES): m=z 415 (M þ Na)þ.
(Z)-7-(3-(Benzoyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-
5-hydroxycyclopentyl)hept-enoic Acid (12)
A solution of 11 (208.3 g, 469.14 mmol) in THF (230 mL) was cooled to
ꢁ40 ꢂC under a nitrogen atmosphere. Potassium tert-butoxide 1 M solution
(937.5 mL, 938.2 mmol) in THF was added at ꢁ40 ꢂC and stirred for 30 min at
ꢁ40 ꢂC. Compound 10 (46 g, 117.28 mmol) in THF (230 mL) was added slowly
to the reaction mass at ꢁ40 ꢂC. The reaction mass temperature was maintained
at ꢁ40 ꢂC for 2 h, at which point TLC indicated complete conversion. Reaction
mass temperature was raised to ꢁ20 ꢂC, and pH was adjusted to 6–7 with 10%
citric acid solution. The resulting mass was concentrated to remove THF, and
further pH of constants was adjusted to 4 using 10% citric acid solution. The
aqueous layer was extracted with EtOAc (3 ꢃ 200 mL), and combined organic
layers were washed with brine (200 mL), dried over Na2SO4, and concentrated
at 40 ꢂC under vacuum to get the crude material. The crude product was purified
by flash column chromatography on silica gel (230–400 mesh) with an ethyl acet-
ate–hexane (4:6) as eluent to give 46.0 g of 12 (96.49 mmol, 82.3%) as a yellow
viscous liquid.
IR (KBr cells): 3006, 2952, 2929, 1714, 1596, 1451, 1316, 1277, 1100, 837,
;
776 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.06 [s, 6H, Si(CH3)2], 0.86 [s, 9H,
(CH3)3], 1.71 (t, J ¼ 7.5 Hz, 2H, CH2), 1.74–1.89 (m, 3H, CH2, CH), 1.99–2.45 (m,
7H, 3CH2, CH), 3.66–3.69 (m, 1Ha), 3.89–3.94 (m, 1Hb), 4.22–4.27 (m, 1H, CH),
5.30–5.43 (m, 3H, CH), 7.42–7.48 (m, 2H, HAr), 7.56–7.60 (m, 1H, HAr),
8.02–8.06 (m, 2H, HAr); MS (ES): m=z 499 (M þ Na)þ.

1296
M. HARIKRISHNA ET AL.
(Z)-2-((tert-Butyldimethylsilyloxy)methyl)-4-hydroxy-3-
(7-isopropoxy-7-oxohept-2-enyl)cyclopentyl Benzoate (13)
A solution of 12 (46.0 g, 96.49 mmol) in acetone (1.0 L) was cooled to ꢁ5 ꢂC,
and DBU (88.12 g, 578.98 mmol) was added slowly to reaction mass at ꢁ5 ꢂC. The
reaction mass temperature raised to 25 ꢂC and stirred for 30 min at 25 ꢂC. Isopropyl
iodide (81.97 g, 482.48 mmol) was slowly added to the reaction mass at 25 ꢂC and
stirred for 12 h at 25 ꢂC, at which point TLC indicated complete conversion of 12
to 13. The reaction mass was concentrated under vacuum at 40 ꢂC to get the residue.
The residue was dissolved in EtOAc (1000 mL), 10% citric acid (500 mL) solution
was added and stirred for 10 min at 25 ꢂC (clear solution was observed). The organic
layer was separated and washed with 10% citric acid (500 mL), 5% sodium bicarbon-
ate solution (500 mL), and brine solution (500 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum at 40 ꢂC to get 46 g of 13 (88.68 mmol, 92%)
as a yellow viscous liquid.
1
IR (KBr cells): 3413, 2952, 2929, 1719, 1451, 1361, 1277, 1108, 777 cmꢁ1; H
NMR (300 MHz, CDCl3): d 0.05 [s, 6H, Si(CH3)2], 0.87 [s, 9H, (CH3)3], 1.21 (d,
J ¼ 6.3 Hz, 6H, 3CH2), 1.69 (t, J ¼ 7.5 Hz, 2H, CH2), 1.73–1.95 (m, 3H, CH2,
CH), 2.03–2.52 (m, 7H, 3CH2, CH), 3.67 (dd, J ¼ 10.2, 3.6 Hz, 1Ha,), 3.93 (dd,
J ¼ 10.2, 3.6 Hz, 1Hb), 4.22–4.26 (m, 1H, CH), 4.95–5.01 (m, 1H, CH), 5.32–5.47
(m, 3H, 3CH), 7.40–7.45 (m, 2H, HAr), 7.54–7.57 (m, 1H, HAr), 8.00–8.03 (m, 2H,
H
Ar); MS (ES): m=z 519 (M þ H)þ.
(Z)-4-(Hydroxymethyl)-5-(7-isopropoxy-7-oxohept-
2-enyl)cyclopentane-1,3-diyl Dibenzoate (14)
A solution of 13 (46.0 g, 88.68 mmol) in CH2Cl2 (460 mL) was cooled to
10 ꢂC, and TEA (71.75 g, 710.39 mmol) and DMAP (0.014 g, 0.116 mmol) were
added at 25 ꢂC under a nitrogen atmosphere. The reaction mass was cooled to
0 ꢂC, and benzoyl chloride (49.72 g, 355.14 mmol) was added slowly into the
reaction mass at 0 ꢂC. The reaction mixture was refluxed for 2 h, at which point
TLC indicated complete conversion. The reaction mass temperature was cooled
to 25 ꢂC, and MeOH (50 mL) was added and heated to reflux for 20 min. The
resulting reaction mixture was cooled to 25 ꢂC and evaporated under vacuum at
40 ꢂC to get the residue. The residue was dissolved in CH2Cl2 (600 mL) and
washed with water (2 ꢃ 200 mL). The organic layer was washed with brine
(200 mL), dried over Na2SO4, and concentrated at 40 ꢂC under vacuum to get
the crude material. The crude in THF (400 mL) was cooled to 0–5 ꢂC; TBAF
(102.9 mL, 103.0 mmol) was added at 0–5 ꢂC and stirred for 60 min at room
temperature, at which point TLC indicated complete conversion. Water
(300 mL) was added to the reaction mass at room temperature and extracted
with ethyl acetate (200 mL). The ethyl acetate layer was washed with 5%
sodium bicarbonate solution (100 mL) and the organic layer was dried over
anhydrous Na2SO4. The organic layer was concentrated to get the crude, which
was purified by flash column chromatography on silica gel (230–400 mesh) with
ethyl acetate–hexane (2:8) as eluent to give 27.0 g of 14 (53.28 mmol, 60%) as a
pale yellow viscous liquid.

SYNTHESIS OF (ꢀ)-BIMATOPROST
1297
IR (KBr cells): 3490, 3063, 2979, 2933, 1717, 1585, 1451, 1374, 1272, 1111,
1
1071, 712 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.18 [d, J ¼ 6.3 Hz, 6H, (CH3)2],
1.51–1.57 (m, 2H, CH2), 1.91–1.97 (m, 3H, CH2, CH), 2.08 (t, J ¼ 7.5 Hz, 2H,
CH2), 2.32–2.37 (m, 5H, 2CH2, CH), 3.73 (dd, J ¼ 11.1, 6.9 Hz, 1Ha), 3.91 (dd,
J ¼ 11.1, 3.6 Hz, 1Hb), 4.92–4.96 (m, 1H, CH), 5.37–5.48 (m, 4H, 4CH), 7.23 (t,
J ¼ 7.5 Hz, 2H, HAr), 7.40 (t, J ¼ 7.5 Hz, 2H, HAr), 7.43–7.47 (m, 1H, HAr),
7.55–7.58 (m, 1H, HAr), 7.84 (dd, J ¼ 8.1, 1.2 Hz, 2H, HAr), 8.08 (dd, J ¼ 8.1,
1.2 Hz, 2H, HAr); MS (ES): m=z 509 (M þ H)þ.
(Z)-4-Formyl-5-(7-isopropoxy-7-oxohept-
2-enyl)cyclopentane-1,3-diyl Dibenzoate (6)
A suspension of Dess–Martin periodinane (44.8 g, 106.7 mmol) in CH2Cl2
(675 mL) was cooled to 0 ꢂC under a nitrogen atmosphere and stirred for 10 min.
Compound 14 (45 g, 88.9 mmol) in CH2Cl2 (125 mL) was added slowly to the reac-
tion mass at 0 ꢂC. The reaction mass temperature was raised to 10 ꢂC and stirred for
1.5 h at 15 ꢂC, at which point TLC indicated complete conversion. The reaction mix-
ture was added to a mixture of sodium thiosulfate (900 mL) and aqueous sodium
bicarbonate solution (180 mL) at 15 ꢂC and stirred for 10 min. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (2 ꢃ 200 mL). Com-
bined organic layers were washed with saturated sodium bicarbonate solution
(3 ꢃ 200 mL) followed by brine (2 ꢃ 100 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum at 40 ꢂC to get 6 with quantitative yield
as a colorless viscous liquid.
IR (KBr cells): 2948, 2939, 2843, 1728, 1712, 1472, 1357, 1268, 1109, 773 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.17 [d, J ¼ 6.3 Hz, 6H, (CH3)2], 1.56–1.60 (m, 2H,
CH2), 1.93–1.97 (m, 2H, CH2), 2.09 (t, J ¼ 7.5 Hz, 2H, CH2), 2.17–2.62 (m, 5H,
2CH2, CH), 3.10–3.16 (m, 1H, CH), 4.89–4.96 (m, 1H, CH), 5.36–5.41 (m, 2H,
2CH), 5.48–5.54 (m, 2H, 2CH), 7.29 (t, J ¼ 8.1 Hz, 2H, HAr), 7.41 (t, J ¼ 8.1 Hz,
2H, HAr), 7.48–7.52 (m, 1H, HAr), 7.55–7.58 (m, 1H, HAr), 7.89 (dd, J ¼ 8.1,
1.2 Hz, 2H, HAr), 8.06 (dd, J ¼ 8.1, 1.2 Hz, 2H, HAr), 10.07 (d, J ¼ 2.1 Hz, aldehyde
-CH); 13C NMR (75 MHz, CDCl3) d: 21.70 (CH3)2, 24.60 (CH2), 26.29 (CH2), 26.52
(CH2), 33.82 (CH2), 38.67 (CH2), 45.62 (CH), 63.17 (CH), 67.27 (CH), 75.78 (CH),
126.99, 128.22, 128.37, 129.43, 129.52 (HC¼CH), 129.53, 130.09 (HC¼CH), 131.05,
=
=
133.09, 133.12, 165.62 (Bz C O), 166.18 (Bz Cþ O), 172.80 [COOCH(CH3)2], 200.54
=
(aldehyde C O); MS (ES): m=z 529 (M þ Na) ; HRMS (ESI): calcd. for C30H34O7
NH4[M þ NH4]þ 524.2643; found 524.2629.
1-Bromo-4-phenylbutan-2-one (16)
A solution of 15 (100.0 g, 675 mmol) in methanol (400 mL) was cooled to ꢁ5 to
0 ꢂC, and bromine (40.3 mL, 783 mmol) dissolved in precooled methanol (200 mL)
was added at ꢁ5 to 0 ꢂC over a period of 50 min. Reaction mass temperature was
raised to 15–20 ꢂC and stirred for 2 h, at which point TLC indicated, complete con-
version of the product. The reaction mass was added to water at 5–10 ꢂC and stirred
for 10 min, and both layers were separated. The organic layer was added to hexane
(200 mL) and stirred for 0–5 ꢂC for 30 min. The resulting mass was filtered, and the

1298
M. HARIKRISHNA ET AL.
product obtained was washed with 2 ꢃ 100 mL hexane to get 76.0 g of 16[8b]
(337 mmol, 50%) as a white crystalline solid. Mp 39–40 ꢂC; IR (KBr): 3085, 3029,
2933, 2866, 1719, 1497, 1388, 756, 701 cmꢁ1 1H NMR (300 MHz, CDCl3): d
;
2.92–3.05 (m, 4H, 2CH2), 3.84 (s, 2H), 7.18–7.24 (m, 5H, HAr).
1-Iodo-4-phenylbutan-2-one (17)
Compound 16 (50 g, 220 mmol) in acetone (200 mL) was added to a suspension of
sodium iodide (33.3 g, 220 mmol) in acetone (300 mL) at room temperature, and the
reaction mass was stirred for 6 h at room temperature, at which point TLC indicated,
complete conversion of 17. The resulting mass was filtered, and the cake was washed
with acetone (100 mL). The filtrate was concentrated to get the residue. The residue
was dissolved in DCM (300 mL) and washed with water (100 mL) followed by 10%
sodium thiosulfate solution (100 mL). The organic layer was evaporated under vacuum
at 40 ꢂC to get 50 g of 17[8] (182 mmol, 83%) as a yellow crystalline solid.
Mp 44–45 ꢂC; IR (KBr): 3084, 3027, 2988, 2928, 1711, 1601, 1495, 1378, 753,
1
551 cmꢁ1; H NMR (300 MHz, CDCl3): d 2.92–3.06 (m, 4H, 2CH2), 3.76 (s, 2H,
CH2), 7.18–7.29 (m, 5H, HAr); MS (ES): m=z 297 (M þ Na)þ.
Dimethyl 2-Oxo-4-phenylbutylphosphonate (18)
Trimethyl phosphite (57.0 g 460 mmol) was added to a solution of 17 (70.0 g,
255 mmol) in acetonitrile (300 mL) at room temperature over a period of 30 min.
The reaction mass temperature was raised to reflux, and the mixture was stirred
for 2 h at reflux temperature, at which point TLC indicated complete conversion
of 18. The reaction mass was cooled to 0–5 ꢂC, and 5% sodium hydroxide solution
(300 mL) was added at below 15 ꢂC. The resulting mass was extracted with DCM
(3 ꢃ 250 mL) and concentrated to get the residue, which was purified by column
chromatography to get 39.2 g of 18[8c] (153 mmol, 60%) as a pale green liquid.
IR (KBr cells): 3062, 3028, 2958, 2927, 1716, 1604, 1497, 1455, 1258, 1185,
751 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.88–2.93 (m, 4H, 2CH2), 3.05 (d,
;
J ¼ 24.0 Hz, 2H, P-CH2), 3.72 [d, J ¼ 11.2 Hz, 6H, P-OCH3)2], 7.15–7.25 (m, 5H,
H
Ar); MS (ES): m=z 257 (M þ H)þ.
5-Phenylpentan-2-one (21)
Sodium metal (2.33 g, 101.6 mmol) was added to a solution of ethanol (60 mL),
at room temperature under a nitrogen atmosphere and stirred until the sodium dis-
solved at room temperature. Compound 20 (13.16 g, 102.7 mmol) was added to the
reaction mass at room temperature, and stirred for 1 h at reflux. The reaction mass
was cooled to room temperature, and 19 (20 g, 108.1 mmol) was added at rt, heated
to reflux, and maintained at reflux for 21 h. TLC indicated complete conversion of
product, and the resulting mixture was cooled to rt and filtered. The filtrate was
concentrated under reduced pressure to get the residue. To the residue, 5% NaOH sol-
ution (106 mL) was added at rt and heated at 90 ꢂC for 5 h. The reaction mass was
cooled to rt, and 50% sulfuric acid (46 mL) was added at rt. The reaction mass was
heated to 90 ꢂC and stirred for 5 h at 90 ꢂC. The resulting mass was cooled to room

SYNTHESIS OF (ꢀ)-BIMATOPROST
1299
temperature, extracted with diethyl ether (2 ꢃ 100 mL), dried over Na2SO4, and con-
centrated under vacuum to get the crude product. The crude product was purified by
flash column chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane
(9:1) as eluent to give 7 g of 21[10a] (43.2 mmol, 40%) as a colorless liquid.
1
IR (KBr cells): 3058, 3025, 2983, 2953, 1718, 1652, 1495, 1427, 758 cmꢁ1; H
NMR (300 MHz, CDCl3): d 1.90 (p, J ¼ 7.5 Hz, 2H, CH2CH2CH2), 2.11 (s, 3H,
=
O C-CH3), 2.43 (t, J ¼ 7.5 Hz, 2H, CH2), 2.62 (t, J ¼ 7.5 Hz, 2H, CH2), 7.18–7.28
(m, 5H, HAr).
1-Bromo-5-phenylpentan-2-one (22)
A solution of 21 (10 g, 61.65 mmol) in methanol (60 mL) was cooled to ꢁ5 to
0 ꢂC. Precooled bromine (3.6 mL, 71.51 mmol) in methanol (40 mL) was added
slowly to the reaction mass at ꢁ5 to 0 ꢂC. After completion of the addition, the reac-
tion mass was maintained at 10–15 ꢂC for 2 h, at which point TLC indicated com-
plete conversion of the product. Water (100 mL) was added to the reaction mass
at room temperature and stirred for 1 h. The aqueous layer was extracted with
EtOAc (2 ꢃ 100 mL), dried over Na2SO4, and concentrated under vacuum to get
the residue. The residue obtained was purified by flash column chromatography
on silica gel (230–400 mesh) with ethyl acetate–hexane (9:1) as eluent to give 7.4 g
of 22[10c] (30.7 mmol, 50%) as a pale brown liquid.
1
IR (KBr cells): 3062, 3026, 2926, 1715, 1603, 1496, 1393, 750 cmꢁ1; H NMR
(300 MHz, CDCl3): d 1.93–1.98 (p, J ¼ 7.2 Hz, 2H, CH2CH2CH2), 2.62–2.68 (m, 4H,
=
2CH2), 3.85 (s, 2H, O CH2-Br), 7.17–7.29 (m, 5H, HAr); MS (ES): m=z 241
(M þ H)þ and 263 (M þ Na)þ (bromine isotopic abundance was observed).
1-Iodo-5-phenylpentan-2-one (23)
A suspension of NaI (3.1 g, 21.07 mmol) in acetone (30 mL) was stirred at room
temperature. Compound 22 (5 g, 20.73 mmol) in acetone (20 mL) was slowly added to
the reaction mass and stirred for 4 h at room temperature, at which point TLC indi-
cated complete conversion of the starting material. The reaction mass was filtered,
and the cake was washed with acetone (10 mL). The filtrate was concentrated under
vacuum at 40 ꢂC to get the residue and was dissolved in DCM (100 mL) and water
(50 mL). Both layers were separated, and the organic layer was washed with water
(50 mL) followed by 10% sodium thiosulfate (50 mL), dried over Na2SO4, and distilled
under vacuum at 40 ꢂC to obtain 4.2 g of 23 (14.53 mmol, 70%) as a pale brown liquid.
1
IR (KBr cells): 3083, 3026, 2934, 2858, 1706, 1602, 1496, 1367, 749 cmꢁ1; H
NMR (300 MHz, CDCl3): d 1.92–1.98 (p, J ¼ 7.2 Hz, 2H, CH2CH2CH2), 2.64 (t,
=
J ¼ 7.2 Hz, 2H, CH2), 2.72 (t, J ¼ 7.2 Hz, 2H, CH2), 3.77 (s, 2H, O CH2-I),
7.18–7.29 (m, 5H, HAr); MS (ES): m=z 289 (M þ H)þ; HRMS (ESI): calcd. for
C11H13IO NH4[M þ NH4]þ 306.0349; found 306.0336.
Dimethyl 2-Oxo-5-phenylpentylphosphonate (24)
A solution of 23 (4.5 g, 15.6 mmol) in acetonitrile (45 mL) was cooled to 20 ꢂC.
Trimethyl phosphite (3.3 mL, 28.1 mmol) was added to the reaction mass at room

1300
M. HARIKRISHNA ET AL.
temperature. The resulting mass was stirred at reflux for 2 h, at which point TLC
indicated complete conversion of the starting material. The reaction mass was cooled
to ꢁ5 to 0 ꢂC, and 5% NaOH solution (225 mL) was added and stirred for 15 min.
Both layers were separated, and the aqueous layer was extracted with EtOAc
(2 ꢃ 50 mL), dried over Na2SO4, and distilled under vacuum at 40 ꢂC to get the crude
product. The crude product was purified by flash column chromatography on silica
gel (230–400 mesh) with ethyl acetate–hexane (9:1) as eluent to give 2.1 g of 24[10d]
(7.8 mmol, 50%) as a light green liquid.
IR (KBr cells): 3062, 3026, 2956, 2856, 1714, 1648, 1497, 1371, 1254, 1184,
;
1031, 751 cmꢁ1
1H NMR (300 MHz, CDCl3): d 1.89–1.94 (p, J ¼ 7.2 Hz, 2H,
CH2CH2CH2), 2.62 (t, J ¼ 7.2 Hz, 4H, 2CH2), 3.05 (d, J ¼ 22.8, 2H, P-CH2), 3.76
[d, J ¼ 11.2 Hz, 6H, P-(OCH3)2], 7.15–7.27 (m, 5H, HAr); MS (ES): m=z 271
(M þ H)þ and 293 (M þ Na)þ.
(ꢀ)-(1R,3S,4R,5R)-4-((Z)-6-(Isobutyryloxy)hex-2-enyl)-5-((E)-3-oxo-5-
phenylpent-1-nyl)cyclopentane-1,3-diyl Dibenzoate (25)
A suspension of 55% sodium hydride (6.9 g, 158.1 mmol) in DME (200 mL) was
cooled to ꢁ5 ꢂC under a nitrogen atmosphere. Compound 18 (37.9 g, 148.22 mmol)
was dissolved in DME (100 mL), added slowly to the reaction mass at ꢁ5 to 0 ꢂC,
and stirred for 15 min at 0 ꢂC. The reaction mass temperature was raised to 25 ꢂC
and stirred for 1 h at 25 ꢂC, then cooled to ꢁ5 ꢂC. Compound 6 (25 g, 49.34 mmol) dis-
solved in DME (100 mL) was added slowly to the reaction mass for 30 min at ꢁ5 ꢂC.
The temperature of the reaction mass was raised to 25 ꢂC and stirred for 1.5 h, at
which TLC indicated completion of the reaction. The reaction mixture was cooled
to 10 ꢂC, and saturated ammonium chloride solution (250 mL) was added. Then
the reaction mass temperature was raised to 25 ꢂC, stirred for 10 min, and concen-
trated under vacuum at 40 ꢂC. The residue was dissolved in EtOAc (100 mL) and both
layers were separated. The aqueous layer was extracted with EtOAc (3 ꢃ 200 mL).
The combined organic layers were washed with brine, dried over Na2SO4, and con-
centrated under vacuum at 40 ꢂC. The obtained crude was purified by flash column
chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane (1:9) as elu-
ent to give 20.4 g of 25 (32.11 mmol, 65%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.17 [d, J ¼ 6.3 Hz, 6H, HC-(CH3)2], 1.35–1.76
(m, 4H, 2CH2), 1.78–2.45 (m, 6H, 3CH2), 2.55–3.15 (m, 6H, 2CH2, 2CH), 4.91–4.97
[m, 1H, CH(CH3)2], 5.30 (m, 1H, OBz-CH), 5.35 (m, 1H, OBz-CH), 5.44–5.48 [m,
=
=
2H, HC CH(cis)], 6.25 [d, J ¼ 15.9 Hz, 1H, O C-CH (trans)], 6.84 [dd, J ¼ 15.9,
8.7 Hz, 1H, HC-CH (trans)], 7.10–7.38 (m, 7H, HAr), 7.44 (d, J ¼ 7.2 Hz, 2H,
H
Ar), 7.50 (t, J ¼ 7.5 Hz, 1H, HAr), 7.59 (t, J ¼ 7.5 Hz, 1H, HAr), 7.88–7.91 (m,
2H, HAr), 8.05–8.08 (m, 2H, HAr); MS (ES): m=z 659 (M þ Na)þ; HRMS (ESI):
calcd. for C40H44O7[M þ H]þ 637.316; found 637.3178.
(ꢀ)-(1S, 3R, 4R, 5R)-4-((E)-3-Hydroxy-5-phenylpent-1-enyl)-5-((Z)-6-
(isobutyryloxy)hex-2-enyl)cyclopentane-1,3-diyl Dibenzoate (26)
A solution of 25 (10.0 g, 15.70 mmol) in methanol (100.0 mL) was cooled to
0 ꢂC, and sodium borohydride (1.16 g, 31.40 mmol) was added at 0 ꢂC and stirred

SYNTHESIS OF (ꢀ)-BIMATOPROST
1301
for 10 min. The reaction mass temperature was raised to 25 ꢂC and stirred for 30 min,
at which point TLC indicated complete conversion of the reaction. The solvent was
distilled out under vacuum at 40 ꢂC. Ammonium chloride solution (100 mL) was
added to the residue at 25 ꢂC and stirred for 10 min. Both the layers were separated,
and the aqueous layer was extracted with EtOAc (3 ꢃ 100 mL). The organic layer
was dried over Na2SO4 and concentrated under vacuum at 40 ꢂC to obtain the crude.
The crude product was purified by flash column chromatography on silica gel (230–
400 mesh) with an ethyl acetate–hexane (2:8) as eluent. The pure fractions were com-
bined, and the solvent was removed in vacuo at 40 ꢂC to give 9.0 g of 26 (14.15 mmol,
90%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.20 (d, J ¼ 6.3 Hz, 6H, HC-(CH3)2), 1.63–1.67
(m, 2H, CH2), 1.70–2.35 (m, 12H), 2.66–2.71 (m, 2H, CH2), 4.07–4.11 [m, 2H,
OH-CH, HC-(CH3)2], 4.95–4.99 (m, 1H, OBz-CH), 5.31–5.34 (m, 1H, OBz-CH),
=
5.45–5.49 [m, 2H, HC CH(cis)], 5.56–5.61 [m, 2H, HC-CH (trans)], 7.08–7.68 (m,
11H, HAr), 8.00–8.04 (m, 2H, HAr), 8.04–8.07 (m, 2H, HAr); MS (ES): m=z 661
(M þ Na)þ; HRMS (ESI): calcd. for C40H46O7 NH4[M þ NH4]þ 656.3582; found
656.3589.
(ꢀ)-(Z)-Methyl7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-3-hydroxy-5-
phenylpent-1-nyl)cyclopentyl)hept-5-enoate (27)
Potassium carbonate (8.65 g, 62.61 mmol) was added to a mixture of 26 (10.0 g,
15.65 mmol) in MeOH (100 mL) at 25 ꢂC and stirred for 5 h, at which point TLC indi-
cated complete conversion of the reaction. Demineralized (DM) water (100 mL) was
added to the reaction mixture at 25 ꢂC and stirred for 10 min. The pH of the reaction
mixture was adjusted to 2 with 10% citric acid (100 mL), and the aqueous layer was
extracted with EtOAc (3 ꢃ 100 mL). The organic layers were dried over Na2SO4 and
concentrated under vacuum at 40 ꢂC to obtain the crude product. The crude product
contained two diastereo isomers, and the desired isomer was purified by flash column
chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane (6:4) as elu-
ent. The pure fractions were combined, and the solvent was removed in vacuum at
40 ꢂC to give 1.88 g of 27 (4.70 mmol, 30%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.44–1.49 (m, 1H, CH), 1.62–1.67 (m, 2H,
CH2-CH2-CH2), 1.74–2.28 (m, 10H, 5CH2), 2.31–2.35, [m, 1H, HC-CH (trans)-CH],
2.66–2.73 (m, 2H, Ph-CH2), 3.67 (s, 3H, O-CH3), 3.91–3.96 (m, 1H, HO-CH),
4.05–4.10 (m, 1H, HO-CH), 4.10–4.13 (m, 1H, HO-CH), 5.35–5.40 (m, 2H,
=
=
HC CH(cis)), 5.50–5.61 (m, 2H, HC CH(trans)), 7.16–7.21 (m, 3H, HAr),
7.23–7.27 (m, 2H, HAr); 13C NMR (75 MHz, CDCl3): d 24.66, 25.29, 26.49, 31.72,
33.30, 38.59, 42.69, 50.40, 51.47, 55.33, 71.44, 72.30, 77.79, 125.68, 128.25, 128.30,
129.46, 131.92, 133.22, 135.13, 141.82, 174.32; MS (ES): m=z 410 (M þ Na)þ; HRMS
(ESI): calcd. for C24H34O5 Na [M þ Na]þ 425.2298; found 425.2318.
(ꢀ)N-((Z)-6-((1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-3-hydroxy-5-
phenylpent-1-enyl)cyclopentyl)hex-4-enyl)propionamide (1)
A solution of 27 (500.0 mg, 1.2 mmol) in ethylamine (70%) in water solution
(15.0 mL) was stirred for 12 h at 25 ꢂC, at which point TLC indicated complete

1302
M. HARIKRISHNA ET AL.
conversion of the reaction. The reaction mass was concentrated under vacuum to
distill off ethylamine from the reaction mass. Water (10 mL) was added to the reac-
tion mixture at 25 ꢂC and stirred for 10 min, and then the aqueous layer was
extracted with EtOAc (3 ꢃ 20 mL). The organic layers were dried over Na2SO4
and concentrated under vacuum at 40 ꢂC to give the crude product. The crude pro-
duct was purified by flash column chromatography on silica gel (230–400 mesh) with
ethyl acetate–hexane (9:1) followed by EtOAc–methanol (9.5:0.05) as eluent to give
360 mg of 1[11] (0.87 mmol, 70%) as a pale yellow viscous liquid.
IR (KBr cells): 3323, 3025, 2931, 2862, 1758, 1645, 1634, 1558, 1454, 1295,
1
1031, 749 cmꢁ1; H NMR (300 MHz, CDCl3): d 1.11 (t, 3H, J ¼ 7.2 Hz, N-CH2-
CH3), 1.46–1.52 (m, 1H, CH), 1.66–2.26 (m, 12H, 6CH2), 2.33–2.37 (m, 1H, CH),
2.70–2.75 (m, 2H, HC-Ph), 3.23–3.28 (m, 2H, N-CH2-CH3), 3.93–3.98 (m, 1H,
HC-OH), 4.08–4.13 (m, 1H, HC-OH), 4.15–4.20 (m, 1H, HC-OH), 5.38–5.43 [m,
=
2H, HC CH(cis)], 5.55 (br, NH), 5.52–5.61 (m, 2H, HC-CH(trans)), 7.16–7.21 (m,
3H, HAr), 7.23–7.27 (m, 2H, HAr); 13C NMR (75 MHz, CDCl3): d 14.72, 25.45,
26.51, 27.22, 34.31, 35.66, 35.73, 36.70, 42.85, 50.55, 51.00, 55.63, 72.36, 72.93,
78.05, 125.60, 128.18, 128.30, 129.59, 132.55, 134.72, 142.28, 173.08; MS (ES):
m=z 438 (M þ Na)þ.
(ꢀ)-(1R,3S,4R,5R)-4-((Z)-6-(Isobutyryloxy)hex-2-enyl)-5-((E)-3-oxo-6-
phenylhex-1-enyl)cyclopentane-1,3-diyl Dibenzoate (28)
A suspension of 55% sodium hydride (0.68 g, 15.8 mmol) in DME (12.5 mL)
was cooled to ꢁ5 ꢂC under a nitrogen atmosphere.Compound 24 (4.2 g, 14.8 mmol)
was dissolved in DME (12.5 mL), added slowly to the reaction mass at ꢁ5 to 0 ꢂC
and stirred for 15 min at 0 ꢂC. The reaction mass was raised to 25 ꢂC and stirred
for 1 h at 25 ꢂC, then cooled to ꢁ5 ꢂC. Compound 6 (2.5 g, 4.9 mmol) dissolved
in DME (12.5 mL) was added slowly to the reaction mass for 30 min at ꢁ5 ꢂC.
The temperature of the reaction mass was raised to 25 ꢂC and stirred for 1.5 h,
at which point TLC indicated completion of the reaction. The reaction mixture
was cooled to 10 ꢂC, and saturated ammonium chloride solution (25 mL) was
added. The reaction mass was raised to 25 ꢂC, stirred for 10 min, and concentrated
under vacuum at 40 ꢂC to get the residue. The residue was dissolved in EtOAc
(50 mL), and the aqueous layer was separated and extracted with EtOAc
(3 ꢃ 10 mL). The combined organic layers were washed with brine solution, dried
over Na2SO4, and concentrated under vacuum at 40 ꢂC to get the crude product.
The crude product was purified by flash column chromatography on silica gel
(230–400 mesh) with ethyl acetate–hexane (3:7) as eluent to give 1.86 g 28
(2.86 mmol, 58%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.18 [d, J ¼ 6.3 Hz, 6H, HC-(CH3)2], 1.47–1.52
(m, 2H), 1.73–2.49 (m, 12H), 2.57–2.65 (m, 5H, 2CH2, CH), 2.97–2.99 (m, 1H, CH),
=
4.89–4.98 [m, 1H, CH(CH3)2], 5.33–5.47 [m, 4H, HC CH(cis), benzoyl (CH)2], 6.24
=
[dd, J ¼ 15.9, 0.6 Hz, 1H, O C-CH (trans)], 6.80 [dd, J ¼ 15.9, 9.0 Hz, 1H, HC-CH
(trans)], 7.16–7.20 (m, 3H, HAr), 7.24–7.35 (m, 4H, HAr), 7.42–7.65 (m, 4H, HAr),
7.88–7.91 (m, 2H, HAr), 8.05–8.08 (m, 2H, HAr); MS (ES): m=z 651 (M þ H)þ and
673 (M þ Na)þ; HRMS (ESI): calcd. for C41H46O7 NH4[M þ NH4]þ 668.3582;
found 668.3589.

SYNTHESIS OF (ꢀ)-BIMATOPROST
1303
(ꢀ)-(1S,3R,4R,5R)-4-((E)-3-Hydroxy-6-phenylhex-1-enyl)-5-((Z)-6-
(Isobutyryloxy)hex-2-enyl)cyclopentane-1,3-diyl Dibenzoate (29)
A solution of 28 (2.0 g, 3.0 mmol) in methanol (20.0 mL) was cooled to 0 ꢂC and
sodium borohydride (0.22 g, 5.94 mmol) was added at 0 ꢂC, and stirred for 10 min. The
reaction mass temperature was raised to 25 ꢂC and stirred for 30 min, at which point
TLC indicated complete conversion of the reaction. Methanol was distilled out under vac-
uum at 40 ꢂC to get the residue. Ammonium chloride solution (20 mL) was added to the
residue at 25 ꢂC and stirred for 10 min. Both layers were separated, and the aqueous layer
was extracted with EtOAc (3ꢃ 20 mL). The organic layer was dried over Na2SO4 and
concentrated under vacuum at 40ꢂC to obtain the crude. The crude product was purified
by flash column chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane
(2:8) as eluent to give 1.6 g of 29 (2.45 mmol, 80%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.22 [d, J ¼ 6.3 Hz, 6H, HC-(CH3)2], 1.48–1.82
(m, 11H), 2.04–2.29 (m, 5H, 2CH2, CH), 2.63 (t, J ¼ 7.5 Hz, 2H, CH2), 3.91–3.96 (m,
1H, HO-CH), 4.08–4.12 (m, 1H, BzO-CH), 4.20 (t, J ¼ 3.6 Hz, 1H, BzO-CH),
=
4.98–5.03 [m, 1H, HC(CH3)2], 5.37–5.42 [m, 2H, HC CH(cis)], 5.48–5.58 [m, 2H,
HC-CH (trans)], 7.13–7.30 (m, 5H, HAr), 7.40–7.62 (m, 6H, HAr), 7.98–8.10 (m,
4H, HAr); MS (ES): m=z 675 (M þ Na)þ.
(ꢀ)-(Z)-Methyl-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-3-hydroxy-6-
phenylhex-1-enyl)cyclopentyl)hept-5-enoate (30)
Potassium carbonate (1.27 g, 9.2 mmol) was added at 25 ꢂC to a mixture of 29
(1.5 g, 2.3 mmol) in MeOH (15 mL), and stirred for 5 h, at which point TLC indi-
cated complete conversion of the reaction. DM water (15 mL) was added to the reac-
tion mixture at 25 ꢂC and stirred for 10 min. The pH of the reaction mixture was
adjusted to 2 with 10% citric acid (15 mL), and the aqueous layer was extracted with
EtOAc (3 ꢃ 20 mL). The organic layer was dried over Na2SO4 and concentrated
under vacuum at 40 ꢂC to get the crude product. The crude product contained
two diastereo isomers, and the desired stereo isomer was purified by flash column
chromatography on silica gel (230–400 mesh) with ethyl acetate–hexane (1:1) as elu-
ent to give 0.23 g of 30 (0.57 mmol, 25%) as a colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d 1.40–1.88 (m, 4H), 2.00–2.48 (m, 11H, 5CH2,
CH), 2.52–2.68 (m, 3H, CH2, CH), 3.66 (s, 3H, COOCH3), 3.90–3.96 (m, 1H, HO-C-
=
H), 4.07–4.15 (m, 2H, (HO-CH)2), 5.35–5.41 [m, 2H, HC CH(cis)], 5.50–5.58 [m,
2H, HC-CH (trans)], 7.14–7.18 (m, 3H, HAr), 7.23–7.29 (m, 2H, HAr); 13C NMR
(75 MHz, CDCl3): d 24.6, 25.44, 26.43, 27.19, 33.23, 35.67, 36.65, 42.81, 50.55,
51.53, 55.43, 72.11, 72.79, 77.95, 125.60, 128.18, 128.29, 129.14, 129.39, 131.83,
134.63, 142.25, 174.40; MS (ES): m=z 439 (M þ Na)þ; HRMS (ESI): calcd. for
C25H36O5 Na [M þ Na]þ 439.2455; found 439.2475.
(ꢀ)-(Z)-7-((1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-3-hydroxy-6-
phenylhex-1-enyl)cyclopentyl)-N-ethylhept-5-enamide (5)
A solution of 30 (0.2 g, 0.48 mmol) in ethylamine (70% in water) solution
(6.0 mL) was stirred for 12 h at 25 ꢂC, at which point TLC indicated complete

1304
M. HARIKRISHNA ET AL.
conversion of the reaction. The reaction mass was concentrated under vacuum at less
than 50 ꢂC to get the residue. Water (6 mL) was added to the residue at 25 ꢂC and
stirred for 10 min, and the aqueous layer was extracted with EtOAc (3 ꢃ 10 mL).
The organic layer was dried over Na2SO4 and concentrated under vacuum at
40 ꢂC to get the crude. The crude product was purified by flash column chromato-
graphy on silica gel (230–400 mesh) with ethyl acetate as eluent to give 0.14 g of 5
(0.336 mmol, 70%) as a pale yellow viscous liquid.
IR (KBr cells): 3306, 3089, 2934, 1645, 1634, 1557, 1454, 1375, 1078, 751 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.18 (t, J ¼ 7.2 Hz, 3H, CH3), 1.52–1.83 (m, 10H),
2.05–2.36 (m, 6H, 2CH2, 2CH), 2.63 (t, J ¼ 7.5 Hz, 2H), 3.22–3.31 (m, 2H, N-C-
H2CH3), 3.94–3.96 (m, 1H, HO-CH), 4.10 (t, 1H, J ¼ 7.2 Hz, HO-CH), 4.15–4.19
=
(m, 1H, HO-CH), 5.36–5.41 [m, 2H, HC CH(cis)], 5.51–5.54 [m, 2H, HC-CH
(trans)], 5.56–5.61 (m, NH), 7.14–7.30 (m, 5H, HAr); 13C NMR (75 MHz, CDCl3):
d 14.68, 25.52, 26.58, 27.28, 34.29, 34.39, 35.65, 35.76, 36.63, 42.81, 50.09, 55.35,
72.29, 72.70, 77.61, 125.59, 128.17, 128.28, 129.13, 129.55, 132.84, 135.06, 142.29,
173.31; MS (ES): m=z 452 (M þ Na)þ; HRMS (ESI): calcd. for C26H39 NO4 Na
[M þ Na]þ 452.2771; found 452.2767.
ACKNOWLEDGMENT
The authors thank C. Satyanarayana, CEO, Aptuit Laurus Private Ltd.,
for his encouragement.
REFERENCES
1. (a) Tielsch, J. M.; Sommer, A.; Katz, J.; Royall, R. M.; Quigley, H. A.; Javitt, J. Racial
variations in the prevalence of primary open-angle glaucoma. Baltimore Eye Survey 1991,
266, 369–374; (b) Quigley, H. A. Number of people with glaucoma worldwide. Br. J.
Ophthalmol. 1991, 80, 389–393; (c) Quigley, H. A.; Vitale, S. Models of open-angle glau-
coma prevalence and incidence in the United States. Invest. Ophthalmol. Vis. Sci. 1991, 38,
83–91; (d) Asrani, S.; Zeimer, R.; Wilensky, J.; Gieser, D.; Vitale, S.; Lindenmuth, K.
Large diurnal fluctuations in intraocular pressure is an independent risk factor in patients
with glaucoma. J. Glaucoma 2000, 9, 134–142.
2. (a) Jay, W. M.; Aziz, M. Z.; Green, K. Effect of topical epinephrine and timolol on ocular
and optic nerve blood flow in phakic and aphakic rabbit eyes. Curr. Eye Res. 1984, 3,
1199–1202; (b) Liljebris, C.; Selen, G.; Resul, B.; Stjernschantz, J.; Hacksell, U. Deriva-
tives of 17-phenyl-18,19,20-trinorprostaglandin F2a isopropyl ester: Potential antiglau-
coma agents. J. Med. Chem. 1995, 38, 289–304.
3. Hoyng, P. F.; van Beek, L. M. Pharmacological therapy for glaucoma: A review. Drugs
2000, 59, 411–434.
4. (a) Villumsen, J.; Alm, A.; Soderstrom, M. Prostaglandin F2 a-isopropyl ester eye drops:
Effect on intraocular pressure in open-angle glaucoma. Br. J. Ophthalmol. 1989, 73, 975–
979; (b) Bito, L. Z. Species differences in the responses of the eye to irritation and trauma.
Exp. Eye Res. 1984, 38, 181–194 (c) Bib, L. Z.; Camras, C.; Gum, G.; Resul, B. In The
Ocular Effects of Prostaglandins and Other Eicosanoids; L. Z. Bilto and J. Stjernschantz
(Eds.); New York: Alan, R. Liss, 1989, pp. 349–368.
5. (a) Stjernschantz, J. W. From PGF2 ffagg-isopropyl ester to latanoprost: A review of the
development of xalatan, the Proctor lecture, Investig. Ophthalmol. Visual Sci. 2001, 42,

SYNTHESIS OF (ꢀ)-BIMATOPROST
1305
1134–1145 (b) Rajeev, G.; Lata, H.; Narang, S.; Sood, S. Comparison of latanoprost,
bimatoprost, and travoprost. Asian J. Ophthalmol. 2003, 5, 13–14.
6. (a) Crawford, K.; Kaufman, P. L. Pilocarpine antagonizes prostaglandin F2a induced
ocular hypotension in monkeys. Arch. Ophthumol (Chicago) 1987, 106, 1112–1116; (b)
Nibeon, S. F. E.; Samueleson, M.; Bill, A.; Stjernechantz, J. Increased PGF2a i-Pr ester
in the cynomolgus monkeys. J. Exp. Eye Res. 1989, 48, 707–716.
7. (a) Resul, B.; Stjernschantz, J.; No, K.; Liljebris, C.; Selen, G.; Astin, M.; Karlsson, M.;
Laszlo, Z. Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. J.
Med. Chem. 1993, 36, 243–248; (b) Yankee, E. W.; Axen, U.; Bundy, G. L. Total synthsis
of 15-methylprostaglandins. J. Am. Chem. Soc. 1974, 96, 5865–5876; (c) Schaaf, T. K.;
Bindra, J. S.; Eggler, J. F.; Plattner, J. J.; Nelson, J.; Johnson, M. R.; Constantine,
J. W.; Hess, H. J. N-(Methanesulfonyl)-16-phenoxyprostaglandincarboxamides: Tissue-
selective uterine stimulants. J. Med. Chem. 1981, 24, 1353–1359 (d) Liljebris, C.; Nilsson,
B. M.; Resul, B.; Hacksell, U. Regio-and stereoselective reactions of 17-phenyl-18,19,20-
trinorprostaglandin F2a isopropyl ester. J. Org. Chem. 1996, 61, 4028–4036; (e) Boulton,
L. T.; Brick, D.; Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.; Parkin, N.;
Rhodes, D.; Ruecroft, G. Synthesis of the potent antiglaucoma agent, travoprost. Org.
Proc. Res. Devel. 2002, 6, 138–145; (f) Resul, B. A. Method for synthesis of prostaglandin
derivatives. WO Patent 92=02496 A1, 1992.
8. (a) Gutman, A. L.; Nisnevich, G. A new process for the preparation of 17-phenyl-18,
19,20-trinor-PGF2A and its derivatives. WO Patent 2002=096868 A2, 2002; (b) Roman,
G.; Riley, G. J.; Vlahakis, N. J.; Kinobe, T. R.; Brien, F. J.; Nakatsu, K.; Szarek, A.
W. Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbu-
tanes: Effect of halogen substitution in the phenyl ring. Bioorg. Med. Chem. 2007, 15,
3225–3234; (c) deLong, M. A.; Amburgey, J.; Taylor, C.; Wos, J. A.; Soper, D. L.; Wang,
Y.; Hicks, R. Synthesis and in vitro evaluation of human FP-receptor selective prostaglan-
din analogues. Bioorg. Med. Chem. Lett. 2000, 10, 1519–1522.
9. Gutman, A.; Nisnevich, G.; Zaltzman, I. Process for the preparation of latanoprost. U.S.
Patent 2003=0149294 A1, 2003.
10. (a) Montgomery, F. C.; Saunders, W. H. Migration aptitudes in the photolysis of some
tertiary alkyl azides. J. Org. Chem. 1976, 41, 2368–2372; (b) Hassan, J. G. Jomaa Phar-
maka GmbH, Organophosphorus compounds and the use thereof. U.S. Patnet No.
2003=6534489 B1, 2003; (c) Ochiai, M.; Nishitani, J.; Nishi, Y. A new route for generation
of a-k3-iodanyl ketones via ester exchange of (Z)-(b-acetoxyvinyl)-k3-iodanes: Their
nucleophilic substitutions with halides and sulfur and phosphorus nucleophiles. J. Org.
Chem. 2002, 67, 4407–4413 (d) Zurawinski, R.; Nakamura, K.; Drabowicz, J.;
Kielbasinski, P.; Mikolajczyk, M. Biocatalytic syntheses of chiral non-racemic 2-hydro-
xyalkanephosphonates. Tetrahedron: Asymmetry 2001, 12, 3139–3146.
11. Yao, C. H.; Yang, C. M.; Chao, H. H.; Lee, G. R. Method for preparing prostaglandin F
analogue. U.S. Patent No. 2009=0259066 A1, 2009.