A novel convergent synthesis of the potent antiglaucoma agent tafluprost

Article abstract of DOI:10.3390/molecules22020217

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F_2α (PGF_2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde !-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF_2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

Full text of DOI:10.3390/molecules22020217

molecules
Article
A Novel Convergent Synthesis of the Potent
Antiglaucoma Agent Tafluprost
Małgorzata Krupa 1, Michał Chodyn´ski 1, Anna Ostaszewska 1, Piotr Cmoch 1,2 and
Iwona Dams 1,
*
1
R & D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland;
m.krupa@ifarm.eu (M.K.); m.chodynski@ifarm.eu (M.C.); a.ostaszewska@ifarm.eu (A.O.);
piotr.cmoch@icho.edu.pl (P.C.)
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland
Correspondence: dams@ifarm.eu; Tel.: +48-22-456-3929; Fax: +48-22-456-3838
2
*
Academic Editor: Derek J. McPhee
Received: 5 December 2016; Accepted: 25 January 2017; Published: 31 January 2017
Abstract: Tafluprost (AFP-168,
(PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and
ocular hypertension, as monotherapy, or as adjunctive therapy to -blockers. A novel convergent
synthesis of was developed employing Julia–Lythgoe olefination of the structurally advanced
prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical
grade latanoprost ( ), travoprost ( ) and bimatoprost ( ), with an aldehyde -chain synthon 17
The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all
commercially available antiglaucoma PGF2α analogs , significantly reduces manufacturing costs
5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α
β
5
2
3
4
ω
.
2–5
resulting from its synthesis on an industrial scale and development of technological documentation.
Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30
with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid
6
yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5)
and the application of comparatively cheap reagents. The preparation and identification of two
other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are
also described.
Keywords: tafluprost; prostaglandins; Corey lactone; Julia–Lythgoe olefination; fluorination
1. Introduction
The discovery of potent and efficacious intraocular pressure (IOP) lowering PGF2α analogs
(Figure 1) has revolutionized the treatment of ocular hypertension, a major risk factor for progression
of the irreversible blinding disease glaucoma [ ]. Until recently, free isopropyl ester prodrugs, i.e.,
unoprostone ( , Rescula), latanoprost ( , Xalatan) and travoprost ( , Travatan), and one amide prodrug
bimatoprost ( , Lumigan) of -chain modified PGF2α analogs have been used as first line therapy
for the treatment of open angle glaucoma and ocular hypertension due to their potent IOP-lowering
efficacy, low likelihood of systemic adverse effects, once-daily dosing and good patient adherence [ ].
However, all the available commercial preparations of contain preservatives to maintain the
sterility of the solutions, which may impair topical tolerance of these IOP-lowering agents during
long-term use [ ]. New preservative-free agents with greater IOP-lowering efficacy and milder local
side effects are therefore still needed.
Tafluprost ( ) is the newest 15-deoxy-15,15-difluorinated PGF2α receptor agonist possessing
effective IOP-reducing effects, and also the first hypotensive drug released in a preservative-free
formulation under trade names Taflotan or Saflutan in Europe and Zioptan in USA [ 12].
1–5
1,2
1
2
3
4
ω
3–6
1–4
7
5
8
–
Molecules 2017, 22, 217; doi:10.3390/molecules22020217
www.mdpi.com/journal/molecules

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A preservative-free tafluprost formulation is as potent as a preserved one (BAK-Tapros, Osaka, Japan),
but it has fewer and milder toxic effects on the eye. Therefore, it may be particularly beneficial
for patients who are sensitive to preservatives, such as patients with dry eyes, and patients who
discontinue medication early because of adverse events. Compared with other PGF2α analogs 2–4, the
major modification of tafluprost is the substitution of the C-15 hydrogen and hydroxyl group with two
fluorine atoms. Tafluprost is a prodrug containing an isopropyl ester moiety that is rapidly hydrolyzed
by corneal esterases to the pharmacologically active metabolite tafluprost free acid (AFP-172, 6) [13].
Tafluprost acid has 12 times the affinity for the prostaglandin F receptor as does latanoprost acid, while
having almost no affinity for related receptors, such as prostaglandin D or E [14].
Figure 1. Chemical structures of PGF2α analogs used in the therapy of glaucoma and ocular hypertension.
PGF2α analogs
method, in which lower and upper side chains are sequentially attached in a specific order
to a derivative of the commercially available ( )-Corey aldehyde/lactone [ 15 26]. In 2004,
Matsumura et al. [ ] published the first synthesis of tafluprost ( ) from Corey aldehyde derivative
comprising a sequence of the following reactions: (a) the installation of the lower side
1–5 are mostly synthesized by one of the known variants of the Corey
−
9, –
9
5
7
chain (
ω
-chain) via a Horner–Wadsworth–Emmons condensation of the Corey aldehyde
-chain 15-one
7
8
with
with
dimethyl (2-oxo-3-phenoxypropyl)phosphonate; (b) difluorination of the
morpholinosulfur trifluoride to a 15-deoxy-15,15-difluoro derivative
with potassium carbonate; (d) reduction of the lactone moiety to a lactol 11 with diisobutylaluminum
hydride; (e) addition of the -chain by Wittig olefination of 11 with an ylide prepared from
4-carboxybutyltriphenylphpsphonium bromide, leading to a cis-5,6-alkene; and (f) esterification of
the acid with isopropyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (Scheme 1).
Thus far, however, there was no convergent methodology that would allow effective and highly
ω
9; (c) removal of benzoyl group
α
6
diastereoselective preparation of a whole series of antiglaucoma PGF2α analogs
and structurally advanced prostaglandin intermediate.
2–5 from a common
Scheme 1. Corey strategy for synthesis of tafluprost (5).

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In 2007, Martynow et al. [27] reported preparation of the structurally advanced prostaglandin
phenylsulfone (5Z)-16 (Scheme 2) with the attached -chain possessing a carboxyl group
α
protected by 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (methyl-OBO). The choice of the methyl-OBO
carboxyl-masking group was predicted by its high stability under basic reaction conditions
commonly applied during prostaglandin synthesis. On the other side, the compounds of the
4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure are easily hydrolyzed under acidic conditions to
corresponding 2,2-bis(hydroxymethyl)-1-propyl esters, which can be in turn converted into other alkyl
esters, like for example alkyl esters, salts or carboxylic acids. Thus, the
phenylsulfone 16 by SN2 alkylation with enantiomerically pure alkyl halides allowed the synthesis
of 13,14-dihydro-15-ol PGF2α analogs, such as latanoprost ( ) [27]. The Julia–Lythgoe olefination
of the sulfone 16 with enantiomerically pure aldehyde -chain synthons allowed the synthesis of
trans-13,14-en-15-ol PGF2α analogs, such as travoprost ( ) and bimatoprost ( ) [28 29]. One of the
ω-chain elongation of the
2
ω
3
4
,
main reasons for choosing this method of phenylsulfone 16 ω-chain elongation was formation of
trans-13,14-ene as the only product of olefination. Compared to triphenylphosphonium or phosphonate
derivatives, used in competitive Wittig or Horner-Wadsworth-Emmons olefinations, phenylsulfones
are mostly stable and crystal compounds that could be easily purified to pharmaceutical grade at early
stage of prostaglandin synthesis. Recently, we envisaged that the prostaglandin key intermediate 16
could also find the application in the convergent synthesis of tafluprost (5), depending on the structure
of the aldehyde -chain synthon and the sequence of chemical reactions needed for the
ω
ω-chain
elongation and functionalization (Scheme 2). The use of the same structurally advanced prostaglandin
phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma
PGF2α analogs 2–5, would significantly reduce manufacturing costs resulting from its synthesis on an
industrial scale and development of technological documentation. Since the orthoester 16 is stable at
about 0 ◦C in the presence of a trace of pyridine, large amounts of 16 can be manufactured and stored
in a pure form for a long time allowing the synthesis of the desired PGF2α analog 2–5 at any time.
Scheme 2. Novel strategy for convergent synthesis of tafluprost (5) from prostaglandin phenylsulfone
16 and aldehyde -chain synthon 17, based on the reverse order of side chain attachment to the
ω
derivative of Corey lactone (12).
Glaucoma is one of the most common causes of irreversible visual impairment and blindness.
It is estimated that over 60 million individuals were afflicted with open-angle and angle-closure
glaucoma as of 2010, which will increase to almost 80 million by 2020 [30]. The disease affects all
ethnicities, and 6.7 million people are bilaterally blind consequently. As a result of a growing demand
for prostaglandin antiglaucoma drugs in the pharmaceutical market, we have developed a novel
synthesis of tafluprost (5) from the advanced prostaglandin phenylsulfone 16 and α-hydroxy protected
aldehyde 17 (Scheme 2) based on the reversed order of side chain attachment to the Corey lactone via
Wittig and Julia–Lythgoe olefinations. Since the fourth commercially available PGF2α drug tafluprost
(
5
) contains the trans-13,14-en-15-deoxy-15,15-difluoro moiety in the
latanoprost ( ) travoprost ( ) and bimatoprost ( ), some modifications in an earlier developed approach
-chain allylic moiety to incorporate the desired
ω-chain, when compared to
2
3
4
for the highly diastereoselective construction of the
C-15 difluorinated center needed to be developed.
ω

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Most common PGF2α analogs, latanoprost (2), travoprost (3), bimatoprost (4) and tafluprost (5),
are licensed for the reduction of elevated intraocular pressure in patients with open angle glaucoma
and ocular hypertension, but their non approved use as eyelash enhancers is becoming popular,
especially in patients with eyelashes hypotrichosis [31]. There are other prostaglandin derivatives,
such as tafluprost methyl ester (32) [32,33] and tafluprost ethyl amide (33) [34], that could be used in
antiglaucoma ophthalmic compositions or cosmetics because they appear capable of IOP reduction and
influencing eyelash growth; however, their efficacy and safety has not been fully studied and evaluated
yet. Therefore, there is also a strong demand for a convenient process that is suitable for preparation of
high purity tafluprost methyl ester (32) and tafluprost ethyl amide (33) on a commercial scale.
2. Results and Discussion
Based on our previous work on
with the aldehyde -chain synthons of travoprost and bimatoprost [28
Julia–Lythgoe olefination [35 37] of the sulfone 16 with the -hydroxy protected aldehyde 17 should
give a mixture of -hydroxysulfones 18 (Scheme 2), which via reductive dehydroxy-desulfonylation
and deprotection/protection of methyl-OBO and hydroxyl groups followed by oxidation of
the 15-ol and deoxydifluorination of 13,14-en-15-one could enable construction of the -chain
trans-13,14-en-15-deoxy-15,15-difluoro moiety. Irrespective of stereochemical configuration of the
C-2 carbon atom in the aldehyde 17, corresponding to the C-15 carbon atom in tafluprost ( ), the
ω-chain elongation of the prostaglandin phenylsulfone 16
ω
,29], we envisaged that the
–
α
β
ω
5
deprotection of tert-butyldimethylsilyl protected hydroxyl group and its oxidation to a 15-one followed
by its deoxydifluorination should lead to the non-chiral C-15 gem-difluorinated carbon atom in the
final prostaglandin analog 5. Therefore, for economic reasons, the 2-(tert-butyl-dimethylsilyloxy)-
3-phenoxypropanal (17) used for the construction of the
ω-chain of tafluprost (5) should be prepared
as a racemate.
2.1. Synthesis of the Aldehyde ω-Chain Synthon 17
To the best of our knowledge, the aldehyde
ω-chain synthon 17 has never been obtained in a
racemic form. In 2010, Lin et al. reported the preparation of optically active (R)-17 based on epoxide
ring-opening of (R)-benzyl glicydyl ether with phenol in the presence of organic base [38]. The
protection of the resulting secondary alcohol with tert-butyldimethylsilyl trifluoromethanesulfonate
followed by removing of benzyl group and Dess-Martin oxidation of the (S)-25 gave the optically
active aldehyde (R)-17. Although the route described above could be applied to supply of the racemic
aldehyde 17, the cost of benzyl glicydyl ether and the use of heavy metal catalyzed hydrogenation
process limit its large-scale application in the pharmaceutical industry. Therefore, a more industrially
applicable procedure for synthesis of racemic 2-(tert-butyldimethylsilyloxy)-3-phenoxypropanal (17
)
(Scheme 3) was developed based on a synthetic route applied earlier for the preparation of the aldehyde
ω-chain synthon of travoprost [28].
Scheme 3. Synthesis of the racemic aldehyde
ω
-chain synthon 17. Conditions: (1) TsCl, Py, 0 ◦C for
10 min, then r.t. overnight, 99% yield; (2) Method A: phenol, NaOH, EtOH-H2O, reflux for 30 h, 90%
◦
yield. Method B: phenol, PPh3, DIAD, toluene, 99–100 C for 18 h, 96% yield; (3) 1.0 M HCl, acetone,
◦
◦
70 C for 1 h, 98% yield; (4) PivCl, Py-CH2Cl2, 0 C for 1 h, then 1.5 h at r.t., 93% yield; (5) TBDMSCl,
◦
◦
ImH, DMF, 0 C for 15 min, then 18 h at r.t., 94% yield; (6) DIBAL-H, CH2Cl2,
2 h at r.t., 95% yield; (7) DMP, NaHCO3, CH2Cl2, 0 C for 15 min, then 1 h at r.t., 94% yield.
−
78 C for 20 min, then
◦

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2.2. Synthesis of Tafluprost (5), Tafluprost Methyl Ester (32) and Tafluprost Ethyl Amide (33)
The efficient
ω-chain elongation of phenylsulfone 16 with sterically hindered aldehyde 17 to
the mixture of diastereoisomeric
β-hydroxysulfones 18 was achieved by using freshly prepared
LDA (Scheme 4). Since significant losses of 18 were observed during column chromatography
due to limited stability of the methyl-OBO protecting group on silica gel, the crude mixture of
β
-hydroxysulfones 18 was subjected to reductive elimination with a fresh 20% sodium amalgam to
afford the methyl-OBO protected prostaglandin precursor 26. It is well documented that sodium
amalgam reduction of aliphatic -hydroxysulfones furnishes olefins having the trans configuration
of the -chain 13,14-double bond [36]. The phosphate-buffered conditions of Trost [39] were used
to ensure the optimal pH conditions and prevent deprotection of the cyclopentane hydroxyl groups.
Similarly to the methyl-OBO protected -hydroxysulfones 18, the methyl-OBO protected prostaglandin
α
ω
β
intermediate 26 was not purified by means of silica gel column chromatography. Significantly,
there was no need for purification of the prostaglandin intermediates 18 and 26, which was a
major advantage for any future scale-up. The triethylsilyl and methyl-OBO masking groups in
prostaglandin precursor 26 were all removed under the action of pyridinium p-toluenesulfonate
(PPTS) in a mixture of CH2Cl2–MeOH, immediately followed by esterification of free hydroxyl
groups with acetic anhydride to the diastereoisomeric 2,2-bis(acetoxymethyl)propyl ester 28a
/b.
The compound 28a was purified by silica gel flash chromatography; however, only a sample of one of
/
b
the diastereoisomers was isolated and identified by spectroscopic methods. The unique stereochemical
features of the Julia–Lythgoe olefination allowed preserving the relative cis/trans stereochemistry of
side chains in the isolated prostaglandin intermediate. Additionally, the appropriately functionalized
aldehyde
literature data for olefination with aldehydes with steric encumbrance [40], afforded trans-13,14-alkenes
28a as the only products of Julia–Lythgoe olefination. The tert-butyldimethylsilyl protecting group
was removed with camphor-10-sulfonic acid (CSA) to afford a mixture of diastereoisomeric 15-OH
prostaglandin derivatives 29a . Similarly to the ester 28a , silica gel flash chromatography allowed
isolation and identification by spectroscopic methods of only one C-15 epi-isomer from the mixture
of diastereoisomeric alcohols 29a . Most importantly, since the chirality of C-15 carbon atom
disappears during tafluprost ( ) final synthesis, there was no need for purification and separation
of the diastereoisomeric prostaglandin intermediates 27a 28a and 29a , which additionally
was a major advantage for any future scale-up. A mixture of diastereiosmeric alcohols 29a
ω-chain synthon 17 with bulky tert-butyldimethylsilyl group at C-2, in agreement with
/b
/b
/b
/b
5
/b
,
/b
/b
/b
was then oxidized with Dess-Martin periodinane [41] to a 15-keto intermediate 30. The use of
Dess-Martin periodinane avoided some difficulties encountered with other methods, e.g., oxidation
of 13,14-en-15-ols with toxic and unstable DDQ [19], such as adverse products, long reaction times,
difficult workup procedures or the need to apply a large excess of the oxidizing agent. Additionally,
the product of the oxidation route could be easily purified with short column chromatography.
The structure of 30 was confirmed by spectroscopic methods.
Although a gem-difluoride unit has been drawn more attention recently in medicinal chemistry,
there is no general method to prepare allyl difluorides from the corresponding 13,14-en-15-ones
efficiently [42,43]. Therefore, we studied the reaction using some commercially available
fluorinating agents, such as (diethylamino)sulfur trifluoride (DAST), (diethylamino)-difluorosulfonium
tetrafluoroborate (XtalFluor-E), difluoro(morpholino)sulfonium tetrafluoro-borate (XtalFluor-M),
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) and 4-tert-butyl-2,6-dimethylphenylsulfur
trifluoride (Fluolead). After exploring various possibilities, Deoxo-Fluor was found to be the best
reagent of choice. Thus, the fluorination reaction of 13,14-en-15-one 30 with Deoxo-Fluor in boiling
CH2Cl2 for 24 h afforded geminal difluoride 31 with 78% yield.

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Scheme 4. Synthesis of tafluprost (5), tafluprost methyl ester (32) and tafluprost ethylamide (33) from
phenylsulfone 16 an◦d aldehyde 17. Reagents and conditions: (1) LDA, THF,
−
78 ◦C, 1 h; (2) Na/Hg,
Na2HPO4, MeOH, 0 C for 60 min, then 16 h at r.t.; (3) PPTS, CH2Cl2, MeOH, 3 h at r.t., 79% yield from
16; (4) TEA, DMAP, Ac2O, CH2Cl2, 97% yield; (5) CAS, MeOH, CH2Cl2, 7 h at r.t., 82% yield; (6) DMP,
◦
NaHCO3, CH2Cl2, 99% yield; (7) Deoxo-Fluor, CH2Cl2; 0 C for 15 min, then reflux for 24 h, 78% yield;
(8) K2CO3, MeOH, 24 h at r.t., 76% yield; (9) LiOH H2O, MeOH, overnight, 98% yield; (10) i-PrI, DBU,
acetone, 21 h at r.t., 83% yield; (11) EtNH2, H2O, 60 h at r.t.; 85% yield.
The deprotection of acetyl and 2,2-bis(acetoxymethyl)propyl groups in 31 by means of potassium
carbonate in MeOH yielded tafluprost methyl ester (33) in 76% yield. The ester 31 was hydrolyzed
with lithium hydroxide monohydrate and, after acidification with citric acid, tafluprost acid (
was isolated in almost quantitative yield. In the final step of the synthesis, acid was successfully
esterified with i-Pr/DBU in acetone to afford tafluprost ( ). The crude was purified by silica gel flash
chromatography and identified by spectroscopic methods. The -chain allylic carbons C-4 and C-7
6)
6
5
5
α
of tafluprost are seen in the 13C-NMR spectrum as two singlets located at 25.7 and 26.6 ppm, which
is characteristic for 5,6-cis diastereoisomers of PGF2α analogs [27]. The fluorination of C-15 carbonyl
group in 30 with Deoxo-Fluor leads to several significant effects in NMR spectra, which are important
from the point of view of structure conformation/determination. The biggest change related to the
replacement of oxygen with two fluorine atoms leads to strong shielding increase of C-15 nucleus by
ca. 80 ppm and appearance of this signal in 13C-NMR spectrum as a triplet with relative large 1J(C-F)
coupling of ca. 240 Hz. Similar but rather smaller effects are observed for neighboring protons and
carbons. In the case of 1H-NMR spectrum, transition from 30 to
protons in
-chain by ca. 0.3–0.5 ppm. The same is true for 13C nuclei but the shielding effects are
5 leads to shielding increase of all
ω
stronger and vary in the range from 3 to 9 ppm. The biggest one (ca. 9 ppm) is observed for C-13
carbon. Two- and three- bonds C-F couplings visible in 13C-NMR spectrum as triplets are of typical
values for such difluorine compounds containing double bond [44] and are as follows: 8.8 Hz, 25.0 Hz
and 34.9 Hz for C-13, C-14 and C-16 nuclei, respectively. Complete 1H/13C and 19F-NMR chemical
shifts assignment for tafluprost (5) is presented in the Experimental Section 3.6.10.

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Most synthetic procedures used to attain prostamides F2α proceed via prostaglandin acid and
its esterification to the corresponding isopropyl ester, subsequently followed by amidation with
ethylamine [24,25]. Thus, tafluprost (5) was successfully amidated to tafluprost ethyl amide (33) with
ethylamine aqueous solution. The crude 33 was purified by silica gel flash chromatography and
identified by spectroscopic methods.
3. Experimental Section
3.1. General Information
D,L-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane (98%), phenol (99%), Dess-Martin periodinane
(97%), trimethyl acetyl chloride (99%), tert-butyldimethylsilyl chloride (97%), imidazole (99%),
diisobutylaluminum hydride solution (1.0 M in toluene), diisopropylamine (99.5%), butyllithium
solution (1.6 M in hexanes), sodium mercury amalgam (99.9% trace metal basis, Na 20% beads),
p-toluenesulfonyl chloride (98%), diisopropyl azodicarboxylate (97%), triphenylphosphine (99%),
pyridinium p-toluenesulfonate (98%), acetic anhydride (99%), triethylamine (99%), 4-(dimethyl-
amino)pyridine (99%), camphor-10-sulfonic acid (98%), bis(2-methoxyethyl)aminosulfur trifluoride
solution (Deoxo-Fluor solution, 50% in THF), 1,8-diazabicyclo[5.4.0]undec-7-ene (99%), 2-iodopropane
(99%), ethylamine (70% in H2O), pyridine (anhydrous, 99.8%), N,N-dimethylformamide (anhydrous,
99.5%), were purchased from Sigma Aldrich and Iris Biotech Gmbh chemical companies. 1-[(Z)-6-
{(1R,2R,3R,5S)-2-[(Phenyl-sulfonyl)methyl]- 3,5-bis(triethylsilyloxy)cyclopentyl}hex-4-enyl-4-methyl-
2,6,7-trioxabicyclo[2.2.2]-octane [27] was manufactured by Pharmaceutical Research Institute (Warsaw,
Poland). Reactions requiring anhydrous conditions were carried out using flame-dried glassware,
which was cooled to 20 ◦C in a desiccators under an argon atmosphere. All moisture- or air-sensitive
reactions were run under an argon atmosphere. Air-sensitive reagents were transferred via syringe
or cannula and were introduced to the apparatus through rubber septa. Solids were introduced
under a positive pressure of argon. Reactions were cooled via external cooling baths: ice water
(0 ◦C) or dry-acetone ( 78 ◦C). Heating was accomplished by either a heating mantle or silicone oil
−
bath. Deionized water was used for all aqueous extractions and for obtaining all aqueous solutions.
Solvents were removed under reduced pressure using standard rotary evaporators. The course of all
reactions and the purity of products were checked by thin-layer chromatography (TLC). Analytical
TLC was performed on silica gel DC-Alufolien Kieselgel 60 F254 (Merck, Darmstadt, Germany) with
mixtures of hexanes, ethyl acetate, dichloromethane, methanol, acetonitrile and toluene in various
ratios as developing systems. Compounds were detected by spraying the plates with 1% Ce(SO4)2/2%
H3[P(Mo3O10)4] in 10% H2SO4 followed by heating to 120 ◦C. Preparative column chromatography
was carried out on silica gel (Kieselgel 60, 40–63 µm, 230–400 mesh, Merck) with mixtures of ethyl
acetate, hexanes, dichloromethane, methanol, tert-butyl-methyl ether in varying ratios as eluents.
Flash chromatography was run with a positive air pressure generated by handheld, pear-shaped
rubber pumps.
3.2. Optical Rotation
Optical rotations were measured with a Perkin Elmer 341 automatic polarimeter in Me2CO or
CH2Cl2 solutions as the solvents with percent concentrations.
3.3. FT-IR Spectroscopy
IR spectra were taken for liquid films or KBr pellets on a Nicolet Impact 410 FT-IR spectrophotometer
.
3.4. NMR Spectroscopy
The NMR spectra of all the compounds were measured in CDCl3 solutions with a Varian VNMRS-600
1
(600 MHz) or Varian VNMRS-500 (500 MHz) at temperature 298 K using TMS (for H/13C-NMR
measurements) or CCl3F (for 19F-NMR measurements) as internal standards. Concentration of all
solutions used for measurements was about 20–30 mg of compounds in 0.6 mL of solvent.

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3.5. Mass Spectrometry
HRMS spectra were recorded on an AMD 604 Inectra Gmbh spectrometer or a Mariner PE
Biosystem ESI-TOF spectrometer.
3.6. Syntheses
The synthesis of the aldehyde
D,L-1,2-isopropylidene glycerol (19) is shown in Scheme 3. The detailed descriptions of the preparation
of compounds 20 25 and 17 as well as their physical and spectroscopic data are provided in the
ω-chain synthon 17 from the commercially available
–
Supplementary Materials.
3.6.1. 1-{(Z)-6-[(1R,2R,3R,5S)-2-[(1R/1S,2R/2S,3R/3S)-3-(tert-Butyldimethylsilyloxy)-4-phenoxy-1-
(phenylsulfonyl)butyl]-3,5-bis(triethylsilyloxy)cyklopentyl]hex-4-enyl}-4-methyl-2,6,7-
trioxabicyclo-[2.2.2]octane (18)
n-BuLi (28.6 mL, 45.8 mmol, 1.6 M in hexanes) was added dropwise to a solution of
◦
diisopropylamine (7.96 mL, 45.8 mmol) in anhydrous THF (12 mL) at
−
78 C under an argon
◦
atmosphere. After 15 min at
−
78 C, the phenylsulfone 16 (21.0 g, 30.2 mmol) in anhydrous THF
(40 mL) was added dropwise with vigorous stirring. The reaction mixture was stirred at
30 min and the aldehyde 17 (14.0 g, 50.0 mmol) in anhydrous THF (10 mL) was added dropwise. After
60 C for another 30 min, TLC analysis (6% MeCN/toluene) indicated disappearance
of the starting phenylsulfone 16. The cold reaction was quenched with saturated aqueous NaCl
−
60 ◦C for
◦
being stirred at
−
solution (30 mL). The resulting layers were separated and the aqueous phase was extracted with THF
(
3 × 25 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was carefully dried in vacuo to yield a mixture
of diastereoisomeric hydroxysulfones 18 (38.2 g), as a yellow oil. The hydroxysulfones 18 were directly
used for the next step without further purification.
3.6.2. 1-{(4Z)-6-[(1R,2R,3R,5S)-2-[(1E,3R/3S)-3-(tert-Butyldimethylsilyloxy)-4-(phenoxy)but-
1-enyl]-3,5-bis(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2] octane (26
)
The crude mixture of diastereoisomeric hydroxysulfones 18 (38.2 g) was dissolved in THF (25 mL)
◦
and saturated methanolic solution of Na2HPO4 (120 mL) was added in one portion. On cooling to 0 C
under an argon atmosphere, sodium amalgam (20%, 25.0 g, 217.4 mmol Na) was added portionwise
over 60 min with vigorous stirring. The cooling bath was removed and the resulting suspension
was stirred at room temperature for 16 h to disappearance of the starting hydroxysulfones 18 (TLC,
MeCN/toluene 1:1). The solution was decanted from the remaining amalgam and concentrated under
reduced pressure. The residue was diluted with H2O (60 mL) and AcOEt (60 mL). The resulting
layers were separated and the aqueous phase was extracted with AcOEt (3
×
50 mL). The combined
organic extracts were washed with brine (150 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product 26 (38.1 g) as a light yellow oil. The crude olefin 26
was directly used for the next step without further purification.
3.6.3. 2,2-Bis(hydroxymethyl)propyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E,3R/3S)-3-(tert-
butyldimethylsilylo-xy)-4-(phenoxy)but-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoate (27a/b)
PPTS (28.0 g, 111.42 mmol) was added to a solution of the crude silyl protected prostaglandin
derivatives 26 (38.1 g) in a mixture of CH2Cl2–MeOH (1:1, 300 mL). The resulting brown solution
was stirred for 3 h, whereupon brine (150 mL) and saturated aqueous solution NaHCO3 (150 mL)
were added. After being stirred for 15 min, the organic solvents were evaporated under reduced
pressure. The residue was extracted with AcOEt (3
×
100 mL). The combined organic extracts were
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude tetraol (24.8 g).
Purification by silica gel flash chromatography with gradient elution 1%–6% MeOH–CH2Cl2 afforded
a sample of prostaglandin analog (+)-27a (84 mg) and an inseparable mixture of diastereoisomeric

Molecules 2017, 22, 217
9 of 16
tetraols 27a
/
b
(14.5 g, 79% yield from phenylsulfone 16) as a light yellow viscous oil. (+)-27a: Rf = 0.42
(cm−1): 3393, 2946, 2929,
(50% CH3CN/toluene). [α]2D0 = +17.72 (c 1.0, CH2Cl2). FT-IR (thin film)
ν
2899, 2857, 1731, 1717, 1600, 1587, 1497, 1471, 1388, 1301, 1248, 1172, 1143, 1044, 974, 837, 810, 779,
1
754, 733, 692, 596, 509. H-NMR (CDCl3, 600 MHz)
δ
(ppm): 0.10 (two s, 6H, (CH3)2Si), 0.84 (s, 3H,
-chain
-chain CH2-4, one of
-chain CH2-7 group, one of the cyclopentane CH2-4 group), 2.32 (m, 1H, one of the -chain CH2-7
group), 2.33–2.40 (m, 3H, -chain CH2-2 and cyclopentane CH-2), 3.52 (d, J = 11.5 Hz, 2H, -CH2OH),
3.57 (d, J = 11.5 Hz, 2H, -CH2OH), 3.86 (d, J = 6.0 Hz, 2H, -chain CH2-4), 3.99 (m, 1H, cyclopentane
CH-3), 4.15–4.20 (m, 3H, -OC 2C(CH3)(CH2OH)2 and cyclopentane CH-5), 4.51 (m, 1H, -chain CH-3),
5.36 (m, 1H, -chain CH-5), 5.42 (m, 1H, -chain CH-6), 5.62–5.68 (m, 2H, -chain CH-1 and CH-2),
6.88 (m, 2H, aromatic CH-2 and CH-6), 6.93 (m, 1H, aromatic CH-4), 7.27 (m, 2H, aromatic CH-3 and
CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 4.7 (CH3-Si), 4.6 (CH3-Si), 16.9 (-C( H3)(CH2OH)2),
18.4 ((CH3)3C-Si), 24.8 ( -chain C-3), 25.8 (3C, ( H3)3C-Si), 26.1 ( -chain C-7), 26.6 ( -chain C-4),
33.6 ( -chain C-2), 40.6 (- (CH3)(CH2OH)2), 42.8 (cyclopentane C-4), 50.6 (cyclopentane C-1), 56.0
(cyclopentane C-2), 66.5 (-O H2C(CH3)(CH2OH)2), 67.5 (2C, -OCH2C(CH3)( H2OH)2), 71.6 ( -chain
C-3), 72.2 ( -chain C-4), 73.6 (cyclopentane C-5), 78.4 (cyclopentane C-3), 114.4 (2C, aromatic C-2 and
C-6), 120.7 (aromatic C-4), 129.3 ( -chain CH-6), 129.4 (2C, aromatic C-3 and C-5), 129.5 ( -chain CH-5),
(-C(C
CH2-3), 1.81 (m, 1H, one of the cyclopentane CH2-4 group), 2.05–2.20 (m, 4H,
the
H3)(CH2OH)2), 0.91 (s, 9H, (CH3)3C-Si), 1.57 (m, 1H, cyclopentane CH-1), 1.71 (m, 2H, α
α
α
α
α
ω
H
ω
α
α
ω
δ
−
−
C
α
C
α
α
α
C
C
C
ω
ω
α
α
131.0 (ω-chain C-2), 133.0 (ω-chain C-1), 158.8 (aromatic C-1), 174.7 (C=O). HRMS (ESI): calcd. for
C33H54O8NaSi [M + Na]+ 629.3486; found 629.3474.
3.6.4. 2,2-Bis(acetoxymethyl)propyl (5Z)-7-{(1R,2R,3R,5S)-3,5-diacetoxy-2-[(1E,3R/3S)-3-
(tert-butyldi-methylsilyloxy)-4-(phenoxy)but-1-enyl]cyclopentyl}hept-5-enoate (28a/b)
TEA (23.7 mL, 173.3 mmol), DMAP (0.2 g) and Ac2O (8.2 mL, 86.5 mol) were added to a solution
of the diastereoisomeric prostaglandin derivatives 27a/b (10.5 g, 17.3 mmol) in CH2Cl2 (100 mL).
The mixture was stirred for 1 h at room temperature prior the addition of saturated aqueous solution
NH4Cl (100 mL). The resulting layers were separated and the aqueous phase was extracted with
CH2Cl2 (3
×
50 mL). The combined organic extracts were washed with saturated aqueous solution
NaHCO3 (50 mL) and dried over anhydrous MgSO4. Filtration and evaporation in vacuo furnished
the crude product, which was purified by silica gel flash chromatography with gradient elution
5%–10% AcOEt-hexanes to give a sample of ester (+)-28a (70 mg) and an inseparable mixture of
diastereoisomeric esters 28a
/b (12.97 g, yield 97% yield). (+)-28a: Rf = 0.35 (25% AcOEt/hexanes).
[α]2D0 = +23.72 (c 1.0, CH2Cl2). FT-IR (thin film)
ν
(cm−1): 2954, 2932, 2896, 2857, 1740, 1717, 1600, 1587,
1
1497, 1472, 1375, 1240, 1173, 1150, 1043, 974, 917, 838, 811, 779, 756, 692, 605, 510. H-NMR (CDCl3,
600 MHz)
1.64 (m, 3H, one of the cyclopentane CH2-4 group and
CH-1), 1.95–2.16 (three s and two m, 16H, four -COOCH3 groups,
2.28 (t, J = 7.7 Hz, 2H, -chain CH2-2), 2.55–2.65 (m, 2H, one proton of the cyclopentane CH2-4 group
and cyclopentane CH-2), 3.83 (dd, J = 9.4 and 5.2 Hz, 1H, one of the -chain CH2-4 group), 3.89 (dd,
J = 9.4 and 6.9 Hz, 1H, one of the -chain CH2-4 group), 3.99 (s, 6H, -OC 2C(CH3)(C 2OH)2), 4.50 (m,
-chain CH-3), 4.90 (m, 1H, cyclopentane CH-3), 5.09 (m, 1H, cyclopentane CH-5), 5.30–5.38 (m,
-chain CH-5 and -chain CH-6), 5.62 (dd, J = 8.3 and 15.3 Hz, 1H, -chain CH-1), 5.67 (dd, J = 5.6
-chain CH-2), 6.87 (m, 2H, aromatic CH-2 and CH-6), 6.93 (m, 1H, aromatic CH-4),
7.27 (m, 2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 4.7 (CH3-Si), 4.6
(CH3-Si), 17.0 (-C( H3)(CH2OH)2), 18.3 ((CH3)3 -Si), 20.7, 21.0 and 21.2 (4C, four -COO H3 groups),
24.7 ( -chain C-3), 24.9 ( -chain C-7), 25.8 (3C, ( H3)3C-Si), 26.6 ( -chain C-4), 33.5 ( -chain C-2), 38.2
(– (CH3)(CH2OH)2), 39.0 (cyclopentane C-4), 47.3 (cyclopentane C-1), 51.8 (cyclopentane C-2), 65.6
(-O H2C(CH3)(CH2OH)2), 65.7 (2C, -OCH2C(CH3)( H2OH)2), 71.7 ( -chain C-3), 72.1 ( -chain C-4),
74.3 (cyclopentane C-5), 77.8 (cyclopentane C-3), 114.4 (2C, aromatic C-2 and C-6), 120.9 (aromatic
C-4), 128.0 ( -chain CH-6), 129.4 (2C, aromatic C-3 and C-5), 129.7 ( -chain CH-5), 131.4 ( -chain C-1),
δ
(ppm): 0.08 (two s, 6H, (CH3)2Si), 0.89 (s, 9H, (CH3)3C-Si), 1.00 (s, 3H, (-C(C
-chain CH2-3), 1.68 (m, 1H, cyclopentane
-chain CH2-4 and -chain CH2-7),
H3)(CH2OH)2),
α
α
α
α
ω
ω
H
H
1H,
2H,
ω
α
α
ω
and 15.3 Hz, 1H,
ω
δ
−
−
C
C
C
α
α
C
α
α
C
C
C
ω
ω
α
α
ω

Molecules 2017, 22, 217
10 of 16
133.2 (
ω
-chain C-2), 158.8 (aromatic C-1), 170.4, 170.6 and 170.7 (4C, four –
C
OOCH3 groups). 173.1
(-CH2COOCH2-). HRMS (ESI): calcd. for C41H62O12NaSi [M + Na]+ 797.3908; found 797.3898.
3.6.5. 2,2-Bis(acetoxymethyl)propyl (5Z)-7-{(1R,2R,3R,5S)-3,5-Diacetoxy-2-[(1E,3R/3S)-4-phenoxy-
3-hydroxybut-1-enyl]cyclopentyl}hept-5-enoate (29a/b)
Camphorosulfonic acid (1.12 g, 4.81 mmol) was added to a solution of diastereoisomeric esters
28a/b (11.3 g, 14.58 mmol) in a mixture of MeOH-CH2Cl2 (1:1, 100 mL). The resulting solution was
stirred for 7 h, whereupon NaHCO3 (0.47 g) was added. After being stirred for 30 min, the mixture was
filtered through a Büchner funnel and the filtrate was concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography with gradient elution 5%–40% AcOEt-hexanes
to give a sample of alcohol (+)-29a (59 mg) and an inseparable mixture of diastereoisomeric alcohols
29a/b
(6.94 g, 82% yield). (+)-29a: Rf = 0.37 (50% AcOEt/hexanes). [α]2D0 = +32.46 (c 1.0, MeOH). FT-IR
(thin film)
606, 512. H-NMR (CDCl3, 600 MHz)
ν
(cm−1): 3501, 2940, 1740, 1600, 1497, 1378, 1243, 1173, 1152, 1042, 975, 915, 814, 757, 693,
(ppm): 1.00 (s, 3H, (-C(CH3)(CH2OH)2), 1.60–1.74 (m, 4H, one
-chain CH2-3), 1.95–2.10 (three s and two m,
-chain CH2-4), 2.14 (m, 2H, -chain CH2-7), 2.30 (t, J = 7.7 Hz, 2H,
-chain CH2-2), 2.55 (m, 1H, one of the cyclopentane CH2-4 group), 2.62 (m, 1H, cyclopentane CH-2),
3.91 (dd, J = 7.2 and 9.0 Hz, 1H, one of the -chain CH2-4), 3.99 (m, 7H, -OCH2C(CH3)(CH2OH)2 and
one of the -chain CH2-4 group), 4.54 (m, 1H, -chain CH-3), 4.94 (m, 1H, cyclopentane CH-3), 5.11 (m,
1H, cyclopentane CH-5), 5.30–5.38 (m, 2H, -chain CH-5 and -chain CH-6), 5.71 (dd, J = 5.4 and 15.6
Hz, 1H, -chain CH-1), 5.74 (dd, J = 7.2 and 15.6 Hz, 1H, -chain CH-2), 6.92 (m, 2H, aromatic CH-2
and CH-6), 6.98 (m, 1H, aromatic CH-4), 7.29 (m, 2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz,
CDCl3) (ppm): 17.0 (-C( H3)(CH2OH)2), 20.7, 21.1 and 21.2 (4C, four -COO H3 groups), 24.6
-chain C-3), 24.8 ( -chain C-7), 26.6 (
(cyclopentane C-4), 47.3 (cyclopentane C-1), 52.0 (cyclopentane C-2), 65.6 (-O
65.7 (2C, -OCH2C(CH3)( H2OH)2), 70.5 ( -chain C-3), 71.7 (
77.8 (cyclopentane C-3), 114.6 (2C, aromatic C-2 and C-6), 121.2 (aromatic C-4), 128.1 (
129.5 (2C, aromatic C-3 and C-5), 129.8 ( -chain CH-5), 131.1 ( -chain C-2), 132.6 ( -chain C-1), 158.5
(aromatic C-1), 170.4, 170.6 and 170.7 (4C, four - OOCH3 groups). 173.2 (-CH2 OOCH2-). HRMS
(ESI): calcd. for C35H48O12Na [M + Na]+ 683.3043; found 683.3040.
1
δ
of the cyclopentane CH2-4 group, cyclopentane CH-1,
14H, four -COOCH3 groups and
α
α
α
α
α
ω
ω
α
α
ω
ω
δ
C
C
(α
α
α
-chain C-4), 33.5 (
α
-chain C-2), 38.2 (–
C
C
(CH3)(CH2OH)2), 39.0
H2C(CH3)(CH2OH)2),
C
ω
ω-chain C-4), 74.3 (cyclopentane C-5),
α
-chain CH-6),
α
ω
ω
C
C
3.6.6. 2,2-Bis(acetoxymethyl)propyl (5Z)-7-{(1R,2R,3R,5S)-3,5-Diacetoxy-2-[(1E)-4-(phenoxy)-3-oxo-
but-1-enyl]cyclopentyl}hept-5-enoate (30)
Dess-Martin periodinane (4.48 g, 10.56 mmol) was added portionwise to a suspension of
diastereoisomeric alcohols 29a
CH2Cl2 (50 mL). After being stirred for 1 h at room temperature, TLC analysis (AcOEt/hexanes, 1:1)
indicated disappearance of the starting alcohols 29a . Saturated aqueous NaHCO3 (100 mL) and
/b (5.8 g, 8.8 mmol) and dry NaHCO3 (2.22 g, 26.4 mmol) in anhydrous
/b
Na2SO3 (8.87 g, 70.4 mmol) were then added simultaneously and the mixture was stirred at room
temperature for 30 min The resulting layers were separated and the aqueous phase was extracted
with CH2Cl2 (3
×
50 mL). The combined extracts were washed with water brine (100 mL) and dried
over Na2SO4. Filtration and evaporation in vacuo furnished the crude product as a light yellow oil,
which was purified by flash column chromatography (silica gel, 2%–20% AcOEt/hexanes) to give
the ketone 30 (5.76 g, 99% yield) as a colorless oil. Rf = 0.54 (50% AcOEt/hexanes). [α]2D0 = +40.67
(c 1.0, CH2Cl2). FT-IR (thin film)
1239, 1174, 1043, 984, 917, 785, 757, 693, 645, 606, 509. H-NMR (CDCl3, 600 MHz)
ν
(cm−1): 2944, 1740, 1697, 1626, 1600, 1589, 1496, 1474, 1435, 1376,
1
δ (ppm): 1.01 (s,
3H, -C(CH3)(CH2OH)2), 1.64 (m, 2H,
of the cyclopentane CH2-4 group), 1.84 (m, 1H, cyclopentane CH-1), 1.92–2.10 (three s and two m,
15H, four -COOCH3 groups, -chain CH2-4 and one of the -chain CH2-7 group), 2.15 (m, 1H, one
of the -chain CH2-7 group), 2.29 (t, J = 7.6 Hz, 2H, -chain CH2-2 group), 2.58 (ddd, J = 5.6, 9.1 and
15.8 Hz, 1H, one of the cyclopentane CH2-4 group), 2.76 (m, 1H, cyclopentane CH-2 group), 3.99 (m,
α-chain CH2-3), 1.73 (ddd, J = 1.3, 4.2 and 15.8 Hz, 1H, one
α
α
α
α

Molecules 2017, 22, 217
11 of 16
6H, -OCH2C(CH3)(CH2OH)2), 4.72 (two d, J = 16.4 Hz,
ω-chain CH2-4), 4.98 (ddd, J = 4.2, 7.4 and
11.7 Hz, 1H, cyclopentane CH-3), 5.12 (m, 1H, cyclopentane CH-5), 5.29 (m, 1H,
(m, 1H, -chain CH-5), 6.51 (dd, J = 0.8 and 15.7 Hz, 1H, -chain CH-2), 6.90 (m, 2H, aromatic CH-2
and CH-6), 6.92 (dd, J = 9.1 and 15.7 Hz, 1H, -chain CH-1), 6.99 (m, 1H, aromatic CH-4), 7.29 (m,
2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 17.0 (-C( H3)(CH2OH)2), 20.7,
21.1 and 21.2 (4C, four -COO H3 groups), 24.6 ( -chain C-3), 25.0 ( -chain C-7), 26.6 ( -chain C-4),
33.5 ( -chain C-2), 38.2 (- (CH3)(CH2OH)2), 39.1 (cyclopentane C-4), 47.7 (cyclopentane C-1), 52.4
(cyclopentane C-2), 65.6 (-O H2C(CH3)(CH2OH)2), 65.7 (2C, -OCH2C(CH3)( H2OH)2), 72.0 ( -chain
C-4), 74.3 (cylopentane C-5), 77.2 (cyclopentane C-3), 114.6 (2C, aromatic C-2 and C-6), 121.7 (aromatic
C-4), 127.2 ( -chain CH-2), 127.4 ( -chain CH-6), 129.6 (2C, aromatic C-3 and C-5), 130.3 ( -chain
CH-5), 147.7 ( -chain C-1), 157.8 (aromatic C-1), 170.2, 170.4 and 170.7 (4C, four - OOCH3 groups),
173.1 (-CH2 OOCH2), 195.5 (
-chain C-3). HRMS (ESI): calcd. for C35H46O12Na [M + Na]+ 681.2887;
found 681.2877.
α-chain CH-6), 5.34
α
ω
ω
δ
C
C
α
α
α
α
C
C
C
ω
ω
α
α
ω
C
C
ω
3.6.7. 2,2-Bis(acetoxymethyl)propyl (5Z)-7-{(1R,2R,3R,5S)-3,5-diacetoxy-2-[(1E)-3,3-difluoro-4-(phe-
noxy)-but-1-enyl]cyclopentyl}hept-5-enoate (31)
Deoxo-Fluor (39.1 mL, 91.2 mmol, 50% in THF) was added dropwise to a stirred solution of ketone
30 (5.0 g, 7.6 mmol) in CH2Cl2 (60 mL) at 0 ◦C under an argon atmosphere. The resulting mixture
was refluxed for 24 h, cooled to 0–5 ◦C, whereupon saturated aqueous solution of NaHCO3 (200 mL)
was added dropwise. After being stirred for 30 min at room temperature, the layers were separated
and the aqueous phase was extracted with CH2Cl2 (3
×
50 mL). The combined extracts were washed
with brine (100 mL) and dried over Na2SO4. Filtration and evaporation in vacuo furnished the crude
product as a light yellow oil, which was purified by flash column chromatography (silica gel, 5%–20%
AcOEt/hexanes) to give the difluoro derivative 31 (4.03 g, 78% yield) as a colorless oil. Rf = 0.64 (50%
AcOEt/hexanes). [α]2D0 = +27.75 (c 1.0, MeOH). FT-IR (thin film)
ν
(cm−1): 2945, 1739, 1599, 1496,
(ppm): 1.00 (s, 3H,
1
1378, 1239, 1159, 1046, 977, 849, 757, 693, 606, 509. H-NMR (CDCl3, 600 MHz)
δ
-C(CH3)(CH2OH)2), 1.64 (m, 2H,
of the cyclopentane CH2-4 group), 1.77 (m, 1H, cyclopentane CH-1), 1.95–2.10 (three s and two m,
14H, four -COOCH3 groups and -chain CH2-4), 2.14 (m, 2H, -chain CH2-7), 2.28 (t, J = 7.6 Hz, 2H,
-chain CH2-2), 2.58 (ddd, J = 5.8, 9.0 and 15.8 Hz, 1H, one proton of the cyclopentane CH2-4), 2.68 (m,
1H, cyclopentane CH-2), 4.00 (m, 6H, -OCH2C(CH3)(CH2OH)2), 4.19 (m, 2H, -chain CH2-4), 4.95
(ddd, J = 4.5, 7.7 and 11.9 Hz, 1H, cyclopentane CH-3), 5.12 (m, 1H, cyclopentane CH-5), 5.32–5.40
(m, 2H, -chain CH-5 and -chain CH-6), 5.84 (m, 1H, -chain CH-2), 6.11 (m, 1H, -chain CH-1),
6.91 (m, 2H, aromatic CH-2 and CH-6), 7.00 (m, 1H, aromatic CH-4), 7.30 (m, 2H, aromatic CH-3 and
CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 17.0 (-C( H3)(CH2OH)2), 20.8, 21.1 and 21.2 (4C, four
-COO H3 groups), 24.6 ( -chain C-3), 24.8 ( -chain C-7), 26.6 ( -chain C-4), 33.5 ( -chain C-2), 38.2
(- (CH3)(CH2OH)2), 39.0 (cyclopentane C-4), 47.4 (cyclopentane C-1), 51.8 (cyclopentane C-2), 65.6
(-O H2C(CH3)(CH2OH)2), 65.8 (2C, -OCH2C(CH3)( -chain C-4), 74.2
H2OH)2), 69.5 (2JC-F = 35.0 Hz,
(cyclopentane C-5), 77.2 (cyclopentane C-3), 114.7 (2C, aromatic C-2 and C-6), 118.0 (1JC-F = 240.5 Hz,
-chain C-3), 121.8 (aromatic C-4), 125.2 (2JC-F = 25.0 Hz,
-chain C-2), 127.6 ( -chain CH-6), 129.6
(2C, aromatic C-3 and C-5), 130.1 ( -chain C-1), 157.9 (aromatic
-chain CH-5), 136.8 (3JC-F = 8.8 Hz,
C-1), 170.3, 170.6 and 170.8 (4C, four - OOCH3 groups), 173.1 (-CH2 OOCH2). HRMS (ESI): calcd. for
C35H46O11NaF2 [M + Na]+ 703.2906; found 703.2900.
α-chain CH2-3), 1.70 (ddd, J = 1.3, 4.5 and 15.8 Hz, 1H, one proton
α
α
α
ω
α
α
ω
ω
δ
C
C
α
α
α
α
C
C
C
ω
ω
ω
α
α
ω
C
C
3.6.8. Methyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-(phenoxy)but-1-enyl]-3,5-dihydroxycyclo-
pentyl}hept-5-enoate (32)
K2CO3 (0.46 g, 3.3 mmol) was added to a solution of ester 31 (0.75 g, 1.1 mmol) in MeOH (25 mL).
The resulting suspension was stirred for 24 h at room temperature and then concentrated under
reduced pressure. The residue was diluted with H2O (50 mL) and the product was extracted with
AcOEt (3
×
25 mL). The combined extracts were washed with brine (100 mL) and dried over Na2SO4.

Molecules 2017, 22, 217
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Filtration and evaporation in vacuo furnished the crude product as a light yellow oil, which was
purified by flash column chromatography (silica gel, 10%–40% AcOEt/hexanes) to give the methyl
ester 32 (0.35 g, 76% yield) as a colorless oil. Rf = 0.48 (75% AcOEt/hexanes). [α]2D0 = +23.97 (c 1.0,
MeOH). FT-IR (thin film)
1155, 1055, 975, 935, 848, 756, 692, 509. H-NMR (CDCl3, 600 MHz)
ν
(cm−1): 3412, 3009, 2935, 1733, 1676, 1599, 1497, 1456, 1438, 1303, 1250,
1
δ (ppm): 1.62 (m, 1H, cyclopentane
CH-1), 1.68 (m, 2H,
(m, 1H, one of the
the -chain CH2-7 group and one of the cyclopentane CH2-4 group), 2.18–2.26 (br s, 2H, two -OH),
2.27–2.36 (m, 3H, one of the -chain CH2-7 group and -chain CH2-2), 2.47 (m, 1H, cyclopentane
CH-2), 3.66 (s, 3H, -COOC 3), 4.03 (m, 1H, cyclopentane CH-3), 4.17–4.23 (m, 2H, cyclopentane CH-5
and -chain CH2-4), 5.33–5.42 (m, 2H, -chain CH-5 and -chain CH-6), 5.80 (m, 1H, -chain CH-2),
6.11 (m, 1H, -chain CH-1), 6.91 (m, 2H, aromatic CH-2 and CH-6), 7.00 (m, 1H, aromatic CH-4), 7.30
(m, 2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 24.7 ( -chain C-3), 25.7
-chain C-7), 26.6 ( -chain C-4), 33.3 ( -chain C-2), 43.0 (cyclopentane C-4), 50.5 (cyclopentane C-1),
51.6 (-COOC -chain C-4), 73.3 (cyclopentane C-5),
3), 55.8 (cyclopentane C-2), 69.5 (2JC-F = 35.0 Hz,
78.0 (cyclopentane C-3), 114.7 (2C, aromatic C-2 and C-6), 118.1 (1JC-F = 241.0 Hz,
-chain C-3), 121.8
(aromatic C-4), 123.6 (2JC-F = 24.9 Hz,
-chain C-2), 128.6 ( -chain CH-6), 129.6 (2C, aromatic C-3
-chain C-1), 157.9 (aromatic C-1), 174.3 (C=O).
α
-chain CH2-3), 1.85 (m, 1H, one proton of the cyclopentane CH2-4 group), 2.07
α
-chain CH2-4 group), 2.10–2.18 (m, 3H, one of the -chain CH2-4 group, one of
α
α
α
α
H
α
α
α
ω
ω
δ
α
(α
α
α
H
ω
ω
ω
α
and C-5), 130.0 (α ω
-chain CH-5), 138.6 (3JC-F = 9.1 Hz,
HRMS (ESI): calcd. for C23H30O5NaF2 [M + Na]+ 447.1959; found 447.1960.
3.6.9. (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-(phenoxy)but-1-enyl]-3,5-dihydroxycyclopentyl}-
hept-5-enoic acid (6)
LiOH H2O (1.4 g, 33.36 mmol) was added in one portion to a solution of ester 31 (2.84 g, 4.17 mmol)
·
in MeOH (50 mL). The resulting suspension was stirred overnight resulting in disappearance of
the starting material 31 (TLC, MeOH/AcOEt 1:6). After cooling and evaporating the solvent, the
residual solid was dissolved in water (150 mL) and washed with Et2O (25 mL) to remove organic
impurities. The water layer was acidified with citric acid to pH 4–5 and the product was extracted
with AcOEt (3 × 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered
and evaporated in vacuo to afford the crude acid. Purification by silica gel flash chromatography with
gradient elution 10%–50% MeOH/AcOEt afforded the pure tafluprost acid (
thick pale yellow oil. Rf = 0.49 (15% MeOH/AcOEt). [α]2D0 = +17.98 (c 1.0, MeOH). FT-IR (thin film)
(cm−1): 3370, 2933, 1709, 1599, 1497, 1457, 1406, 1302, 1249, 1155, 1055, 974, 934, 849, 755, 692, 509.
1H-NMR (CDCl3, 600 MHz)
(ppm): 1.59 (m, 1H, cyclopentane CH-1), 1.66 (m, 2H, -chain CH2-3),
1.84 (m, 1H, one of the cyclopentane CH2-4), 2.00–2.20 (m, 3H, one of the -chain CH2-4, one of the
-chain CH2-7 and one of the cyclopentane CH2-4 group), 2.28–2.36 (m, 3H, one of the -chain CH2-7
-chain CH2-2), 2.47 (m, 1H, cyclopentane CH-2), 4.03 (m, 1H, cyclopentane CH-3), 4.17–4.22 (m,
-chain CH2-4), 5.33–5.42 (m, 2H, -chain CH-5 and -chain CH-6), 5.80
-chain CH-2), 6.10 (m, 1H, -chain CH-1), 6.91 (m, 2H, aromatic CH-2 and CH-6), 6.99 (m,
1H, aromatic CH-4), 7.29 (m, 2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 24.5
-chain C-3), 25.7 ( -chain C-7), 26.4 ( -chain C-4), 33.2 ( -chain C-2), 42.8 (cyclopentane C-4), 50.4
(cyclopentane C-1), 55.5 (cyclopentane C-2), 69.5 (2JC-F = 34.7 Hz,
-chain C-4), 73.4 (cyclopentane
C-5), 77.8 (cyclopentane C-3), 114.8 (2C, aromatic C-2 and C-6), 118.2 (1JC-F = 240.0 Hz,
-chain C-3),
121.8 (aromatic C-4), 123.7 (2JC-F = 25.0 Hz,
-chain C-2), 128.8 ( -chain CH-6), 129.6 (2C, aromatic C-3
-chain C-1), 158.0 (aromatic C-1), 178.8 (C=O).
6) (1.69 g, 98% yield) as a
ν
δ
α
α
α
α
and
α
3H, cyclopentane CH-5 and
(m, 1H,
ω
α
α
ω
ω
δ
(α
α
α
α
ω
ω
ω
α
and C-5), 129.9 (α ω
-chain CH-5), 138.6 (3JC-F = 8.7 Hz,
HRMS (ESI): calcd. for C22H28O5NaF2 [M + Na]+ 433.1803; found 433.1801.
3.6.10. Isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-(phenoxy)but-1-enyl]-3,5-dihydroxycy-
clopentyl}hept-5-enoate (5)
DBU (3.4 mL, 22.82 mmol) w◦as added dropwise to a stirred solution of acid
6 (1.34 g, 3.26 mmol)
in anhydrous Me2CO (20 mL) at 0 C under an argon atmosphere. The mixture was allowed to warm to

Molecules 2017, 22, 217
13 of 16
room temperature, whereupon 2-iodopropane (2.3 mL, 22.82 mmol) was added dropwise. The resulting
solution was stirred for 21 h resulting in disappearance of the starting acid (TLC, MeOH/AcOEt
1:6). The reaction was quenched with AcOEt (100 mL). The resulting white solid was filtered off and
washed with AcOEt (3 15 mL). The filtrate and washings were combined and acidified with 3% citric
acid solution to pH 5–6. The resulting layers were separated and the aqueous phase was extracted
with AcOEt (3 15 mL). The combined extracts were washed with saturated NaHCO3 (100 mL),
6
×
×
brine (100 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the
crude product, which was purified by silica gel flash chromatography with gradient elution 10%–45%
AcOEt/hexanes to afford the title compound
5 (1.23 g, 83% yield) as a pale yellow oil. This sample
was further purified by preparative HPLC on silica gel to give pharmaceutical grade tafluprost (
5
)
as a thick colorless oil. [α]2D0 = +22.46 (c 1.0, MeOH). Lit. [α]2D3 = +21.6 (c 1.0, CHCl3) [45]. Rf = 0.48
(75% AcOEt/hexanes). FT-IR (thin film)
ν
(cm−1): 3408, 2980, 2935, 1727, 1599, 1497, 1456, 1375, 1303,
1
1250, 1154, 1108, 1055, 973, 936, 848, 821, 755, 691, 509. H-NMR (CDCl3, 600 MHz)
δ
(ppm): 1.22 (d,
-chain CH2-3), 1.85 (m, 1H, one of
the cyclopentane CH2-4 group), 2.06 (m, 1H, one of the cyclopentane CH2-4 group), 2.09–2.16 (m, 3H,
one of the -chain CH2-4, one of the -chain CH2-7 group and one of the cyclopentane CH2-4 group),
2.24–2.36 (m, 3H, -chain CH2-2 and one of the -chain CH2-7), 2.47 (m, 1H, cyclopentane CH-2), 4.02
(m, 1H, cyclopentane CH-3), 4.17–4.22 (m, 2H, cyclopentane CH-5 and -chain CH2-4), 5.00 (sept,
J = 6.30 Hz, 1H, -C (CH3)2), 5.33–5.42 (m, 2H, -chain CH-5 and -chain CH-6), 5.80 (m, 1H, -chain
CH-2), 6.10 (m, 1H, -chain CH-1), 6.92 (m, 2H, aromatic CH-2 and CH-6), 7.00 (m, 1H, aromatic CH-4),
7.30 (m, 2H, aromatic CH-3 and CH-5). 13C-NMR (150 MHz, CDCl3)
(ppm): 21.8 (2s, 2C, -CH( H3)2),
24.8 ( -chain C-3), 25.7 ( -chain C-7), 26.6 ( -chain C-4), 34.0 ( -chain C-2), 42.9 (cyclopentane C-4), 50.5
(cyclopentane C-1), 55.7 (cyclopentane C-2), 67.7 (- -chain C-4), 73.3
H(CH3)2), 69.5 (2JC-F = 34.9 Hz
(cyclopentane C-5), 77.9 (cyclopentane C-3), 114.8 (2C, aromatic C-2 and C-6), 118.2 (1JC-F = 240.0 Hz
-chain C-3), 121.8 (aromatic C-4), 123.6 (2JC-F = 25.0 Hz
-chain C-2), 128.6 ( -chain CH-6), 129.6
(2C, aromatic C-3 and C-5), 130.1 ( -chain C-1), 157.9 (aromatic
-chain CH-5), 138.6 (3JC-F = 8.8 Hz
C-1), 173.5 (C=O). 19F-NMR (470 MHz, CDCl3) 102.6 (2JF-F = 255.8 Hz), 103.1 (2JF-F
(ppm):
255.8 Hz). HRMS (ESI): calcd. for C25H34O5NaF2 [M + Na]+ 475.2272; found 475.2272.
6H, -CH(CH3)2), 1.61 (m, 1H, cyclopentane CH-1), 1.67 (m, 2H,
α
α
α
α
α
ω
H
α
α
ω
ω
δ
C
α
α
α
α
C
, ω
,
ω
,
ω
α
α
, ω
δ
−
−
=
3.6.11. (5Z)-N-Ethyl-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-(phnoxy)but-1-enyl]-3,5-dihydroxycy-
clopentyl}hept-5-enamide (33)
EtNH2 (50 mL, 629.0 mmol, 70% in water) was added in one portion to the tafluprost
5 (0.8 g,
1.77 mmol). The resulting solution was stirred for 60 h to disappearance of the starting material
5
(TLC, 7% MeOH/CH2Cl2). The excess of EtNH2 was then removed by evaporation under reduced
pressure and the aqueous residue was diluted with brine (50 mL) and AcOEt (50 mL). The resulting
layers were separated and the aqueous phase was extracted with AcOEt (3
×
25 mL). The combined
extracts were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product, which was purified by silica gel flash chromatography with gradient elution from 1%–5%
MeOH/CH2Cl2 to afford the title compound 33 (0.66 g, 85% yield) as colorless oil. Rf = 0.34 (7%
MeOH/CH2Cl2). [α]2D0 = +27.55 (c 1.0, MeOH). FT-IR (thin film)
1553, 1497, 1456, 1294, 1249, 1155, 1055, 974, 933, 848, 755, 691, 509. H-NMR (CDCl3, 600 MHz)
ν
(cm−1): 3308, 3095, 2934, 1645, 1599,
1
δ
(ppm): 1.12 (t, 3H, -CH2CH3), 1.58 (m, 1H, cyclopentane CH-1), 1.67 (m, 2H, α-chain CH2-3), 1.87 (m,
1H, one of the cyclopentane CH2-4 group), 2.00 (m, 1H, one of the -chain CH2-4 group), 2.05–2.22 (m,
5H, one of the -chain CH2-4 group, one of the -chain CH2-7 group, one of the cyclopentane CH2-4
group and -chain CH2-2), 2.38 (m, 1H, one of the -chain CH2-7 group), 2.49 (m, 1H, cyclopentane
CH-2), 2.94 (br s, 2H, two -OH), 3.26 (m, 2H, -CH2CH3), 4.04 (m, 1H, cyclopentane CH-3), 4.16–4.22
(m, 2H, cyclopentane CH-5 and -chain CH2-4), 5.33–5.42 (m, 2H, -chain CH-5 and -chain CH-6),
5.69 (br s, 1H, -N -), 5.79 (m, 1H, -chain CH-2), 6.11 (m, 1H, -chain CH-1), 6.91 (m, 2H, aromatic
CH-2 and CH-6), 7.00 (m, 1H, aromatic CH-4), 7.30 (m, 2H, aromatic CH-3 and CH-5). 13C-NMR
(150 MHz, CDCl3) (ppm): 14.8 (-CH2 H3), 25.6 ( -chain C-3), 25.7 ( -chain C-7), 26.6 ( -chain C-4),
α
α
α
α
α
ω
α
α
H
ω
ω
δ
C
α
α
α

Molecules 2017, 22, 217
14 of 16
34.4 (-
C
H2CH3), 35.8 (
α
-chain C-2), 43.1 (cyclopentane C-4), 50.7 (cyclopentane C-1), 55.7 (cyclopentane
C-2), 69.5 (2JC-F = 34.7 Hz,
ω
-chain C-4), 73.1 (cyclopentane C-5), 78.0 (cyclopentane C-3), 114.8 (2C,
aromatic C-2 and C-6), 118.2 (1JC-F = 240.0 Hz, -chain C-3), 121.8 (aromatic C-4), 123.3 (2JC-F = 24.8 Hz
-chain C-2), 128.9 ( -chain CH-6), 129.6 (2C, aromatic C-3 and C-5), 130.0 ( -chain CH-5), 138.9
(3JC-F = 8.8 Hz, -chain C-1), 158.0 (aromatic C-1), 173.2 (C=O). 19F-NMR (470 MHz, CDCl3)
(ppm):
102.4 (2JF-F = 255.8 Hz), 103.1 (2JF-F = 255.8 Hz). HRMS (ESI): calcd. for C24H33NO4NaF2 [M + Na]+
ω
,
ω
α
α
ω
δ
−
−
460.2275; found 460.2274.
4. Conclusions
Tafluprost (5) is the newest 15-deoxy-15,15-difluorinated PGF2α receptor agonist used as an
efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, and
also the first hypotensive drug released in a preservative-free formulation with fewer and milder
toxic effects on the eye. A novel convergent synthesis of tafluprost (
Julia–Lythgoe olefination of the structurally advanced phenylsulfone (5Z)-16, also successfully applied
for manufacturing of pharmaceutical grade latanoprost ( ), travoprost ( ) and bimatoprost ( ), with an
aldehyde -chain synthon 17. The use of the same prostaglandin sulfone 16, as a starting material
in parallel syntheses of all commercially available antiglaucoma PGF2α analogs , significantly
reduces manufacturing costs resulting from its synthesis on an industrial scale and development
5) was developed employing
2
3
4
ω
2–5
of technological documentation. The preparation and identification of two other tafluprost acid (6)
derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/22/
2/217/s1.
Acknowledgments: Polish Ministry of Science and Higher Education (MNiSW) provided financial support
under 3741/E-223/S/2015-2016 program. The authors would like to kindly acknowledge Anna Witkowska
and Krzysztof Kuziak from the R & D Analytical Chemistry Department, Pharmaceutical Research Institute, for
recording of IR spectra and measuring optical rotations.
Author Contributions: Iwona Dams designed and carried out the synthetic experiments, analyzed the data and
wrote the paper. Małgorzata Krupa, Michał Chodyn´ski and Anna Ostaszewska participated in carrying out
synthetic experiments. Piotr Cmoch carried out NMR experiments and interpreted the spectra.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
Piplani, P.; Aggarwal, D.; Abbhi, V.; Saini, L. Prostaglandin analogues: Current treatment opinion for
glaucoma. Med. Chem. Res. 2016, 25, 1031–1048. [CrossRef]
Dams, I.; Wasyluk, J.; Prost, M.; Kutner, A. Therapeutic uses of prostaglandin F2α analogues in ocular disease
and novel synthetic strategies. Prostaglandins. Other Lipid Med. 2013, 104–105, 109–121. [CrossRef] [PubMed]
Fung, D.S.; Whitson, J.T. An evidence-based review of unoprostone isopropyl ophthalmic solution 0.15% for
glaucoma: Place in therapy. Clin. Ophthalmol. 2014, 8, 543–554. [PubMed]
Perry, C.M.; McGavin, J.K.; Culy, C.R.; Ibbotson, T. Latanoprost: An update of its use in glaucoma and ocular
hypertension. Drugs Aging 2003, 20, 597–630. [CrossRef] [PubMed]
5.
6.
Waugh, J.; Jarvis, B. Travoprost. Drugs Aging 2002, 19, 465–471. [CrossRef] [PubMed]
Easthope, S.E.; Perry, C.M. Topical bimatoprost: A review of its use in open-angle glaucoma and ocular
hypertension. Drugs Aging 2002, 19, 231–248. [CrossRef] [PubMed]
7.
Hommer, A. A review of preserved and preservative-free prostaglandin analogues for the treatment of
open-angle glaucoma and ocular hypertension. Drugs Today 2010, 46, 409–416. [CrossRef] [PubMed]
Wang, Y.; Bolós, J.; Serradell, N. Tafluprost. Drugs Future 2006, 31, 788–792. [CrossRef]
Matsumura, Y.; Mori, N.; Nakano, T.; Sasakura, H.; Matsugi, T.; Hara, H.; Morizawa, Y. Synthesis of the
highly potent prostanoid FP receptor agonist, AFP-168: A novel 15-deoxy-15,15-difluoroprostaglandin F2α
derivative. Tetrahedron Lett. 2004, 45, 1527–1529. [CrossRef]
8.
9.
10. Pozarowska, D. Safety and tolerability of tafluprost in treatment of elevated intraocular pressure in
open-angle glaucoma and ocular hypertension. Clin. Ophthalmol. 2010, 4, 1229–1236. [CrossRef] [PubMed]

Molecules 2017, 22, 217
15 of 16
11. Swymer, C.; Neville, M.W. Tafluprost: The first preservative-free prostaglandin to treat open-angle glaucoma
and ocular hypertension. Ann. Pharmacother. 2012, 46, 1506–1510. [CrossRef] [PubMed]
12. Konstas, A.G.P.; Quaranta, L.; Katsanos, A.; Riva, I.; Tsai, J.C.; Giannopoulos, T.; Voudouragkaki, I.C.;
Paschalinou, E.; Floriani, I.; Haidich, A.-B. Twenty-four hour efficacy with preservative free tafluprost
compared with latanoprost in patients with primary open angle glaucoma or ocular hypertension.
Br. J. Ophthalmol. 2013, 97, 1510–1515. [CrossRef] [PubMed]
13. Takagi, Y.; Nakajima, T.; Shimazaki, A.; Kageyama, M.; Matsugi, T.; Matsumura, Y.; Gabelt, B.-T.;
Kaufaman, P.L.; Hara, H. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP
receptor agonist, as an ocular hypotensive drug. Exp. Eye Res. 2004, 78, 767–776. [CrossRef] [PubMed]
14. Merck Sharpe & Dohme Ltd. SAFLUTAN 15 Micrograms/ml, Eye Drops, Solution, in Single-Dose Container:
UK Summary of Product Characteristics. 2014. Available online: http://www.mhra.gov.uk/spc-pil/
(accessed on 22 November 2016).
15. Corey, E.J.; Weinshenker, N.M.; Schaaf, T.K.; Huber, W.J. Stereo-controlled synthesis of prostaglandins F2α
and E2 (dl). J. Am. Chem. Soc. 1969, 91, 5675–5677. [CrossRef] [PubMed]
16. Corey, E.J.; Schaaf, T.K.; Huber, W.; Koelliker, U.; Weinshenker, N.M. Total synthesis of prostaglandins F2α
and E2 as the naturally occurring forms. J. Am. Chem. Soc. 1970, 92, 397–398. [CrossRef] [PubMed]
17. Corey, E.J.; Noyori, R.; Schaaf, T.K. Total synthesis of prostaglandins F1α, E1, and E2 (natural forms) from a
common synthetic intermediate. J. Am. Chem. Soc. 1970, 92, 2586–2587. [CrossRef] [PubMed]
18. Corey, E.J. The logic of chemical synthesis: Multistep synthesis of complex carbogenic molecules (Nobel
lecture). Angew. Chem. Int. Ed. Engl. 1991, 30, 455–465. [CrossRef]
19. Resul, B.; Stjernschantz, J.; No, K.; Liljebris, C.; Selén, G.; Astin, M.; Karlsson, M.; Bito, L.Z. Phenyl-substituted
prostaglandins: Potent and selective antiglaucoma agents. J. Med. Chem. 1993, 36, 243–248. [CrossRef]
[PubMed]
20. Selliah, R.; Dantanarayana, A.; Haggard, K.; Egan, J.; Do, E.U.; May, J.A. Synthesis of [phenyl-2-3H]-travoprost
:
Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J. Label. Compd. Radiopharm. 2001
44, 173–183. [CrossRef]
,
21. Collins, P.W.; Djuric, S.W. Synthesis of therapeutically useful prostaglandin and prostacyclin analogs.
Chem. Rev. 1993, 93, 1533–1564. [CrossRef]
22. Liljebris, C.; Selén, G.; Resul, B.; Stjernschantz, J.; Hacksell, U. Derivatives of 17-phenyl-18,19,20-
trinorprostaglandin F2α isopropyl ester: Potential antiglaucoma agents. J. Med. Chem. 1995, 38, 289–304.
[CrossRef] [PubMed]
23. Bowler, J.; Crossley, N.S. Cyclopentane Derivatives. GB Patent 1,350,971, 24 April 1974.
24. Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Yudovich, L.; Pertsikov, B.; Tishin, B. Process for the
Preparation of Prostaglandin Derivatives. U.S. Patent 2005/0209337 A1, 8 September 2005.
25. Woodward, D.F.; Andres, S.W.; Burk, R.M.; Garst, M.E. Non-Acidic Cyclopentane Heptanoic Acid,
2-Cycloalkyl or Arylalkyl Derivatives as Therapeutic Agents. WO 94/06433, 31 March 1994.
26. Henegar, K.E. Process and Intermediates to Prepare Latanoprost. US Patent 2003/0187071 A1, 2 February 2003.
27. Martynow, J.G.; Józ´wik, J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.; Wis´niewski, K.; Winiarski, J.;
Zegrocka-Stendel, O.; Gołe˛biewski, P. A new synthetic approach to high-purity (15R)-latanoprost. Eur. J.
Org. Chem. 2007, 4, 689–703. [CrossRef]
28. Dams, I.; Chodyn´ski, M.; Krupa, M.; Pietraszek, A.; Zezula, M.; Cmoch, P.; Kosin´ska, M.; Kutner, A. A novel
convergent synthesis of the potent antiglaucoma agent travoprost. Tetrahedron 2013, 69, 1634–1648. [CrossRef]
29. Dams, I.; Chodyn´ski, M.; Krupa, M.; Pietraszek, A.; Zezula, M.; Cmoch, P.; Kosin´ska, M.; Kutner, A.
A novel convergent synthesis of the antiglaucoma PGF2α analogue bimatoprost. Chirality 2013, 25, 170–179.
[CrossRef] [PubMed]
30. Quigley, H.A.; Broman, A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol.
2006, 90, 262–267. [CrossRef] [PubMed]
31. Marchei, E.; de Orsi, D.; Guarino, C.; Rotolo, M.C.; Graziano, S.; Pichini, S. High performance liquid
chromatography tandem mass spectrometry measurement of bimatoprost, latnaoprost and travoprost in
eyelash enhancing cosmetic serums. Cosmetics 2016, 3, 4. [CrossRef]
32. Nakajima, T.; Matsugi, T.; Goto, W.; Kageyama, M.; Mori, N.; Matsumura, Y.; Hara, H. New fluoroprostaglandin
F2α derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents.
Biol. Pharm. Bull. 2003, 26, 1691–1695. [CrossRef] [PubMed]

Molecules 2017, 22, 217
16 of 16
33. Shirasawa, E.; Kageyama, M.; Nakajima, T.; Nakano, T.; Mori, N.; Sasakura, H.; Matsumura, Y.; Morizawa, Y.
Difluoroprostaglandin Derivatives and Their Use. EP Patent 0850926 A2, 1 July 1998.
34. Brinkenhoff, M.C. Composition, Metod and Kit for Enhancing Hair. US Patent 2011/0293549 A1, 1 December 2011.
35. Julia, M.; Paris, J.-M. Syntheses a l’aide de sulfones V(+)—Methode de synthese generale de doubles liaisone.
Tetrahedron Lett. 1973, 14, 4833–4836. [CrossRef]
36. Kocien´ski, P.J.; Lythgoe, B.; Ruston, S. Scope and stereochemistry of an olefin synthesis from β-hydroxysulphones
J. Chem. Soc. Perkin Trans. 1978, 1, 829–834. [CrossRef]
.
37. Kocien´ski, P.J. Recent sulphone-based olefination reactions. Phosphorus Sulphur Relat. Elem. 1985, 24, 97–127.
[CrossRef]
38. For synthesis of (S)-26 and (R)-18 enantiomers see: Lin, P.; Chang, L.; Edmondson, S.D. Pyrrolidine-Derived
beta 3 Adrenergic Receptor Agonists. WO Patent 2010/129326 A1, 11 November 2010.
39. Trost, B.M.; Arndt, H.C.; Strege, P.E.; Verhoeven, T.R. Desulfonylation of aryl alkyl sulfones. Tetrahedron Lett.
1976, 17, 3477–3478. [CrossRef]
40. Blakemore, P.R.; Ho, D.K.H.; Nap, W.M. Ethyl (benzothiol-2-ylsulfonyl)acetate: A new reagent for the
stereoselective synthesis of
[CrossRef] [PubMed]
α,β-unsaturated esters from aldehydes. Org. Biomol. Chem. 2005, 3, 1365–1368.
41. Dess, D.B.; Martin, J.C. Readily accessible 12-I-51 oxidant for the conversion of primary and secondary
alcohols to aldehydes and ketones. J. Org. Chem. 1983, 48, 4155–4156. [CrossRef]
42. Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A. Aminodifluorosulfinium
tetrafluoroborate salts as stable and crystalline deoxofluorinating reagents. Org. Lett. 2009, 11, 5050–5053.
[CrossRef] [PubMed]
43. L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D.R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.;
Tovell, D.; Couturier, M. Aminodifluorosulfinium salts: Selective fluorination reagents with enhanced
thermal stability and ease of handling. J. Org. Chem. 2010, 75, 3401–3411. [CrossRef] [PubMed]
44. Tellier, F.; Sauvêtre, R. Introduction stéréosélective du groupment difluorométhylène en position allylique.
J. Fluorine Chem. 1995, 70, 265–270. [CrossRef]
45. Wu, P.; Wu, H.; Wen, W. Metal-Catalyzed Asymmetric 1,4-Conjugate Addition of Vinylboron Compounds to
2-Substituted-4-Oxy-Cyclopent-2-en-1-Ones Yielding Prostaglandins and Prostaglandin Analogs. WO Patent
2016/005943 A1, 14 January 2016.
Sample Availability: Samples of the compounds 5–6, 17, 20–25 and 27–33 and are available from the authors.
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