A novel convergent synthesis of the potent antiglaucoma agent travoprost

Article abstract of DOI:10.1016/j.tet.2012.11.087

The 16-(3-trifluoromethyl)phenoxy PGF_2α analogue travoprost (8a) has potent topical ocular activity. A novel convergent synthesis of 13,14-en-15-ol PGF_2α analogues was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 with a new enantiomerically pure aldehyde ω-chain synthon (S)-(-)-16a. Subsequent hydrolysis of protecting groups and final esterification of fluprostenol (7a) yielded travoprost (8a). The main advantages are the preparation of high purity travoprost (8a) and the application of comparatively cheap reagents. The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol PGF_2α analogues from a common and structurally advanced prostaglandin intermediate 15. The preparation and identification of two synthetic impurities, 15-epi isomer (8b) of travoprost and a new prostaglandin related ester (5Z)-(+)-18, are also described.

Full text of DOI:10.1016/j.tet.2012.11.087

Tetrahedron 69 (2013) 1634e1648
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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A novel convergent synthesis of the potent antiglaucoma agent
travoprost
,
a
a
a
a
Iwona Dams a , Micha1 Chodynski , Ma1gorzata Krupa , Anita Pietraszek , Marta Zezula ,
*
ꢀ
,
b
a
a
Piotr Cmoch a , Monika Kosinska , Andrzej Kutner
ꢀ
a R&D Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2012
Received in revised form 11 November 2012
Accepted 26 November 2012
Available online 1 December 2012
The 16-(3-trifluoromethyl)phenoxy PGF2 analogue travoprost (8a) has potent topical ocular activity. A
a
novel convergent synthesis of 13,14-en-15-ol PGF2 analogues was developed employing JuliaeLythgoe
a
olefination of the structurally advanced prostaglandin phenylsulfone (5Z)-(þ)-15 with a new enantio-
merically pure aldehyde
u
-chain synthon (S)-(ꢀ)-16a. Subsequent hydrolysis of protecting groups and
final esterification of fluprostenol (7a) yielded travoprost (8a). The main advantages are the preparation
of high purity travoprost (8a) and the application of comparatively cheap reagents. The novel convergent
Keywords:
Travoprost
Prostaglandins
Corey lactone
Nucleophilic addition
strategy allows the synthesis of a whole series of 13,14-en-15-ol PGF2 analogues from a common and
a
structurally advanced prostaglandin intermediate 15. The preparation and identification of two synthetic
impurities, 15-epi isomer (8b) of travoprost and a new prostaglandin related ester (5Z)-(þ)-18, are also
described.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Fort Worth, TX), bimatoprost (10, LumiganÒ, Allergan, Irvine, CA)
and tafluprost (12, TaflotanÒ, Santen Oy, Finland) are the active
Glaucoma is a slowly progressive disease leading to optic nerve
damage and irreversible loss of vision. It is the second most com-
mon cause of world blindness with estimated cases reaching 79.6
million by the year 2020.1 Although the aetiology of glaucoma is
multi-factorial, elevated intraocular pressure (IOP) is the only
modifiable factor proven to alter the natural course of the disease.
Numerous studies have shown that pharmacological IOP reduction
prevents glaucoma or delays progression of glaucomatous dam-
age.2 Among various topical IOP-lowering medications currently
available, prostaglandin analogues (Fig. 1) are the newest and the
most potent class of first-line hypotensive drugs with a proven
safety and efficacy.3
ingredients of topical hypotensive medications approved by US FDA
and EMEA for use as first-line agents for reducing IOP in patients
with glaucoma or ocular hypertension.
The individual response to hypotensive pharmacotherapy in
glaucomatous patients is different, which creates a continuous
demand for a whole range of active PGF2a analogues. Synthesis of
diverse prostaglandin analogues over the past decades has
attracted attention of many organic chemists as attested by the
number of papers dealing with this subject. So far, however, there
is no convergent methodology that would allow effective and
highly diastereoselective preparation of a whole series of PGF2
a
analogues from a common and structurally advanced prosta-
glandin intermediate. Most synthetic procedures used to attain
Endogenous prostaglandin F2 (1) and its synthetic pro-drugs,
a
such as PGF2 isopropyl ester 2, reduce IOP in animals and
PGF2 (1) and its analogues 2e12 employ one of the known
a
a
humans, but also cause conjunctival hyperaemia and foreign-body
variants of the Corey 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.5e14
The Corey strategy involves first the installation of the lower
sensation.4 Intense drug discovery efforts over decades, designed to
improve the therapeutic index of the naturally occurring PGF2
,
a
have yielded five FP-class prostaglandin drugs with extraordinary
efficacy and relatively acceptable side effects. Unoprostone iso-
propyl ester (4, ResculaÒ, Ciba Vision, Duluth, GA), latanoprost
(6, XalatanÒ, Pfizer, New York, NY), travoprost (8a, TravatanÒ, Alcon,
side chain (
condensation of the Corey aldehyde with
u
-chain) via a HornereWadswortheEmmons (HWE)
suitable keto-
a
phosphonate. The HWE reaction is generally affected by some
drawbacks, such as easy epimerization of labile stereogenic
centres15 and, depending on the base used for deprotonation,
formation of additional side products.16 Subsequent reduction of
* Corresponding author. Tel.: þ48 22 456 39 29; fax: þ48 22 456 38 38; e-mail
the
u-chain 13,14-en-15-one to a 13,14-en-16-ol (prostaglandin
address: i.dams@ifarm.eu (I. Dams).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.087

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1635
Fig. 1. Chemical structure of PGF2 (1) and synthetic prostanoids 2e12 used in the therapy of glaucoma.
a
numbering, Fig. 1), addition of the
a
-chain by Wittig olefination
physicochemical properties of 15R/15S PGF2 diastereoisomers
a
leading to a cis-5,6-alkene and some further simple trans-
formations comprise a sequence of reactions needed for the
are usually very similar, so it is not a straightforward task to
discern between them by NMR spectroscopy, optical rotation or
even by analytical reverse-phase HPLC. Furthermore, the appli-
cation of preparative scale HPLC to remove even small amounts
of undesired 15-epi isomer is usually very costly and far from
trivial, while 5,6-trans diastereoisomer is much easier to
separate.
A growing demand for hypotensive PGF2a analogues stimulates
the need for the development of a novel convergent strategy for
prostaglandin synthesis that would also overcome disadvantages of
existing synthetic methods. The Corey lactone still provides the
Corey synthesis of trans-13,14-en-15-ol PGF2 analogues, such as
a
travoprost (8a) and bimatoprost (10). Other methods for the
preparation of PGF2 analogues from the (ꢀ)-Corey lactone were
a
reported, in which the introduction of the
u-chain already in the
correct stereochemical arrangement preceded the attachment of
the
a
-chain.8,18e20 The problematic reduction of a 13-en-15-one
to the corresponding 13-en-15-ol was avoided; however, the ef-
ficiency of these approaches was poor.
The tedious nature of prostaglandin purification and separa-
tion of diastereoisomers necessitates a highly diastereoselective
most facile and practical access to PGF2 analogues, yet the diffi-
a
industrial preparation of PGF2 analogues used as active phar-
culties with 15-epi isomers need to be overcome. In 2007, we re-
a
maceutical ingredients. The multiple chiral centres present in
prostaglandin molecules continue to create practical challenges
ported the preparation of the structurally advanced prostaglandin
phenylsulfone (5Z)-(þ)-15 (Scheme 1) with the attached
possessing carboxyl group protected by 4-methyl-2,6,7-
trioxabicyclo[2.2.2]octane (methyl-OBO).21
The -chain elongation of the phenylsulfone 15 by SN2 alkyl-
a-chain
and existing synthetic routes to PGF2 analogues by the Corey
a
a
strategy, in spite of considerable progress made in this field, are
not completely free of contaminating diastereoisomers. Besides
u
the
Wittig reaction, particular difficulty has been associated with
maintaining the purity at the -chain C-15 carbinol asymmetric
centre, which typically is formed by a diastereoselective re-
duction. The known methods for such reduction require expen-
sive reagents, often low-temperature conditions and, in practice,
do not lead to a completely stereoselective formation of the de-
sired prostaglandin diastereoisomer.5e13,17 The 15-epi isomers of
a
-chain 5,6-trans diastereoisomer typically formed from the
ation with enantiomerically pure alkyl halides allowed the syn-
thesis of 13,14-dihydro-15-ol PGF2 analogues with the desired C-
a
u
15 asymmetric centre configuration, such as latanoprost (6). Im-
portantly, we envisaged that the new prostaglandin key in-
termediate 15 could find applications in the convergent syntheses
of diverse active prostaglandins and related compounds, depending
on the structure of the
actions needed for the
u
-chain and the sequence of chemical re-
-chain elongation. Since three other
u
diverse PGF2 analogues, including (15S)-latanoprost, (15S)-
commercially available 13,14-en-15-ol PGF2 drugs, precisely trav-
a
a
travoprost (8b) and (15R)-bimatoprost, have been reported to
oprost (8), bimatoprost (10) and tafluprost (12), contain the trans-
form even in diastereoselective reduction of the
u
-chain 15-keto
13,14-double bond in the
diastereoselective construction of the
u
-chain, a new approach for the highly
-chain allylic alcohol
function in amounts exceeding at least several percent.5e13,17 The
u
Scheme 1. Strategy for convergent synthesis of PGF2a analogues via prostaglandin phenylsulfone 15, based on the reverse order of side chain attachment to the derivative of Corey
lactone (13).

1636
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
moiety with the desired C-15 asymmetric centre configuration
needed to be developed.
aldehyde, the aldehyde synthon should possess the stereochemical
arrangement corresponding to the ‘15R’ stereochemistry in the final
prostaglandin analogue. Critical to this disconnection, the enantio-
Travoprost (8a) is a commonly prescribed synthetic prosta-
glandin analogue that continues to hold a key position in the
antiglaucoma drug market with a global sale of over US $940 mil-
lion in 2011. Travoprost has been shown to lower intraocular
pressure more efficiently than latanoprost over a 24-h period.22 As
a result of growing demand for prostaglandins antiglaucoma drugs
in the pharmaceutical market, we have developed a novel conver-
gent synthesis of travoprost (8a) from the structurally advanced
prostaglandin phenylsulfone 15 and a new, enantiomerically pure
meric purity of the aldehyde
high, thus a priori establishing avery high diastereoisomeric excess of
the final product 8a. Importantly, the aldehyde -chain synthon 16a
u-chain synthon 16a should be very
u
with a well-chosen protecting group should not be capable of epi-
merization under basic reaction conditions.
Our synthetic approaches to travoprost (8a) and its epimeric
impurity 8b are convergent. The structurally advanced prosta-
glandin phenylsulfone 15 and the appropriately functionalized
a
-hydroxy protected aldehyde (S)-(ꢀ)-16a (Scheme 2). The paper
novel u-chain synthons 16a and 16b were prepared separately with
well-defined stereochemistry and then united by an efficient
JuliaeLythgoe olefination.
describes the first application of the potent prostaglandin in-
termediate 15 to the highly diastereoselective synthesis of trans-
13,14-en-15-ol PGF2 analogues with the desired C-15 asymmetric
a
centre configuration, based on the reverse order of side chain at-
tachment to the Corey lactone via Wittig and JuliaeLythgoe olefi-
nations. The preparation and identification of two synthetic
impurities, 15-epi isomer ((15S)-(þ)-8b) of travoprost and a new
prostaglandin related ester (5Z)-(þ)-18 (Fig. 2), are also described.
2.1. Synthesis of the aldehyde
and its enantiomeric impurity (R)-(D)-16b
u-chain synthon (S)-(L)-16a
To the best of our knowledge, the enantiomerically pure alde-
hydes (S)-(ꢀ)-16a and (R)-(þ)-16b (Scheme 3) are new chemical
Scheme 2. A novel strategy for convergent synthesis of travoprost (8a) from phenylsulfone 15 and aldehyde 16a.
Fig. 2. Structures of the key impurities 8b, 8c and 18 of travoprost.
2. Results and discussion
compounds that have never been obtained in optically active form.
The novel aldehyde synthon 16a used for the construction of the
u
-
The accessibility of the stable prostaglandin phenylsulfone 15
(Scheme 1) drew our attention to JuliaeLythgoe olefination,23 which
via reductive elimination of b-hydroxy sulfones could enable con-
struction of the allylic alcohol moiety of various prostaglandins. The
unique stereochemical features of the JuliaeLythgoe olefination
should allow to preserve the relative cis/trans stereochemistry of side
chains in the phenylsulfone 15 and give rise to the stereodefined
trans-13,14-double bond (prostaglandin numbering, Fig. 1) required
chain of travoprost (8a) contains a stereogenic centre at the carbon
C-2 corresponding to C-15 in the target molecule, with chirality
corresponding to the ‘15R’ configuration in the final product 8a. In
all areas of pharmaceutical research it is most essential to in-
vestigate pure and well-characterized compounds. Thus, the alde-
hyde 16a should possess
a very high enantiomeric excess,
preferably above 99.8% ee, as individual impurity content below
0.1% facilitates the registration process of active pharmaceutical
ingredients.
in the
of aliphatic
configuration of the
u
-chain. It is well documented that sodium amalgam reduction
-hydroxy sulfones furnishes olefins having the trans
-chain 13,14-double bond.23b Additionally, the
a
We envisaged, that the aldehyde u-chain synthon 16a could be
u
prepared in a seven-step synthesis from optically active solketal
(S)-(þ)-19a (Scheme 3). The desired enantiomeric purity of the
aldehyde 16a was achieved by employing the known acetonide (S)-
(þ)-21a as a source of chirality. The acetonide 21a was synthesized
in high enantiomeric purity from solketal 19a, which is commer-
cially available or can be easily prepared from an important chiral
appropriately functionalized aldehydes with steric encumbrance
shouldaffordtransalkenesastheonlyproductsof theJuliareaction.24
In the chemical structure of travoprost (8a) carbon 17 position in
the
constituent. We envisaged that combining of the sulfone 15 (Scheme
2) with the -hydroxy protected aldehyde 16a should give a mixture
u-chain is substituted by a phenoxy group with a trifluoromethyl
a
template 1,2:5,6-di-O-isopropylidene-D
-mannitol.25,26 The solketal
of hydroxy sulfones 17a, which in a few simple steps could be
transformed to travoprost 8a. Since the first step of the JuliaeLythgoe
protocol is the nucleophilic addition of an a-sulfonyl carbanion to an
19a was first converted into the known tosylate (R)-(ꢀ)-20a with p-
toluenesulfonyl chloride in pyridine according to the standard
procedures. O-Alkylation of 3-trifluoromethylphenol with tosylate

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1637
Scheme 3. Synthesis of the aldehyde
u
-chain synthon (S)-(ꢀ)-16a and its enantiomer (R)-(þ)-16b. Reagents and conditions: (1) TsCl, Py, 0 ꢁC for 30 min, then rt overnight, 99% yield
of (R)-(ꢀ)-20a (99.9% ee); (2) method A: 3-trifluoromethylphenol, NaOH, EtOH, H2O, reflux, 20 h, 89% yield of (S)-(þ)-21a (99.9% ee). Method B: 3-trifluoromethylphenol, PPh3,
DIAD, toluene, 90e100 ꢁC, 1 h, 97% yield of 21a (89.5% ee); (3) 1.0 M aq HCl, acetone, 70 ꢁC, 1 h, 98% yield of (R)-(ꢀ)-22a (99.9% ee); (4) PivCl, Py, CH2Cl2, 0 ꢁC for 1 h, then 1 h at rt,
95% yield of (S)-(þ)-23a (99.9% ee); (5) TBDMSCl, ImH, DMF, 0 ꢁC for 15 min, then rt for 18 h, 93% yield of (S)-(ꢀ)-24a (99.9% ee); (6) DIBAL-H, CH2Cl2, ꢀ78 ꢁC for 20 min, rt for 2 h,
92% yield of (R)-(ꢀ)-25a (99.9% ee); (7) DMP, NaHCO3, CH2Cl2, 0 ꢁC, then 1 h at rt, 97% yield of (S)-(ꢀ)-16a.
20a gave the acetonide 21a in 89% yield and with high enantio-
meric purity (99.9% ee). The enantiomeric acetonide (R)-(ꢀ)-21b
(99.2% ee) was synthesized by the same synthetic route as illus-
trated in Scheme 3, but using the solketal (R)-(ꢀ)-19b as the
starting material. The course of all reactions and the enantiomeric
purity of products were controlled by thin-layer (TLC) and high-
performance liquid chromatography (HPLC). The stereochemical
assignment of the acetonides 21a and 21b was confirmed by the
values of optical rotation.26 Their structures were also proved by
NMR and IR spectra.
Selective esterification of the primary hydroxyl group of 22a with
pivaloyl chloride afforded the pivaloate
as the main product of this reaction (95% yield, 99.9% ee). A silicon-
based protecting group strategy at C-2 was envisaged to be suffi-
ciently stable to the reaction sequence yet easily removed under
mild basic conditions in the final steps of the synthesis. Our later
attempts to olefinate the phenylsulfone 15 with various a-silyloxy
protected aldehydes 16a using the JuliaeLythgoe protocol showed
that a tert-butyldimethylsilyl protecting group provided better 15R/
a
-hydroxy ester (S)-(þ)-23a
15S stereoselectivity for
u-chain elongation than triethylsilyl pro-
Although the route described above is expedient and amenable
to a large supply of the acetonide 21a, we envisaged that an alter-
native one-step approach could be etherification of solketal 19a
with 3-trifluoromethylphenol under Mitsunobu reaction condi-
tions.27 Encouraged by this perspective, we determined experi-
mentally the optimal conditions for convenient etherification of
solketal 19a with 3-trifluoromethylphenol. However, the Mitsu-
nobu reaction of solketal 19a with acidic 3-trifluoromethylphenol
resulted in partial racemization of the starting alcohol 19a (5.3%
of the opposite enantiomer), presumably due to the acetonide ring
opening and closing by phenol/phenolate. A reasonable mechanism
by which acidic reagents could cause the racemization of solketals
was proposed earlier by Baldwin.28
The acetonide group in aryl ether 21a was then removed using
aqueous hydrochloric acid in acetone to afford the diol (R)-(ꢀ)-22a
in 98% yield (99.9% ee). Selecting a protecting group strategy for
hydroxyl groups in the diol 22a, that would minimize side re-
actions, was critical in the design of the synthetic approach to the
new aldehyde 16a. Initially, we thought that selective mono-
tosylation29 of the primary hydroxyl group of 22a followed by
silylation of the secondary hydroxyl group and Kornblum oxida-
tion30 of tosylate would be the best way to synthesize the aldehyde
16a. However, monotosylation of the diol 22a was not selective
enough, yielding 15% of the unwanted secondary monotosylate.
tection. Thus, the secondary hydroxyl group of 23a was protected
by silylation with tert-butyldimethylsilyl chloride to give the silyl
ether (S)-(ꢀ)-24a in 93% yield (99.9% ee). Subsequent deprotection
of the C-1 pivaloate ester with DIBAL-H provided the desired al-
cohol (R)-(ꢀ)-25a in 70% yield over six steps from the solketal 19a.
The optical purity of the alcohol 25a was determined as 99.9% ee on
the basis of HPLC using a chiral stationary phase. The enantiomeric
impurity (S)-(þ)-25b (99.2% ee) was synthesized by the same
strategy as illustrated in Scheme 3, but starting from the chiral
acetonide (R)-(ꢀ)-21b.
The main problem accompanying the synthesis of the new al-
dehyde 16a was facile, probably mild base-catalyzed, elimination of
3-trifluoromethylphenol leading to the corresponding
a,b-un-
saturated aldehyde. The ParikheDoering oxidation31 (SO3$Py,
DMSO, Et3N) of the alcohol 25a resulted in the formation of alde-
hyde 16a immediately followed by 3-trifluoromethylphenol elim-
ination to the more stable 2-(tert-butyldimethylsilyloxy)propenal
(26) (Scheme 4). Importantly, the
u-chain synthon 16a should not
be contaminated with the aldehyde 26 as it easily reacts with
phenylsulfone 15. The attempts to synthesize the aldehyde 16a by
pyridinium chlorochromate oxidation also failed, mainly due to the
low reactivity of the alcohol 25a, accompanied by decomposition of
the product 16a under long-term oxidation conditions. After ex-
ploring various possibilities, we have found that oxidation of the
alcohol 25a with DesseMartin periodinane32 affords the crude al-
dehyde 16a in good yield and chemical purity (ca. 90%). The use of
DesseMartin periodinane avoided some difficulties encountered
with other methods, such as adverse products, long reaction times,
The Kornblum oxidation of the a-silyloxy protected monotosylate
also failed, probably due to the fast decomposition of the final
product 16a. After exploring various possibilities, trimethyl acetyl
chloride was found to be the best protecting reagent of choice.
Scheme 4. The ParikheDoering oxidation of the alcohol (R)-(ꢀ)-25a to the conjugated aldehyde 26.

1638
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
difficult workup procedures or the need to apply a large excess of
the oxidizing agent. Most importantly, DesseMartin periodinane is
well-known not to racemize chiral centres of optically active
reducing the ability of phenylsulfone 15 addition to the aldehyde
16a. The influence of steric encumbrance caused by the -silyloxy
substituent was clearly seen in our later attempts to olefinate the
sulfone 15 with a bulky, -tert-butyldiphenylsilyl protected alde-
a
compounds. Thus, the enantiomeric purity of the aldehyde
u
-chain
a
synthon 16a should be the same as the starting alcohol 25a.
a
-
hyde 16a (ca. 45% conversion). Thus, the main problem accompa-
nying the synthesis of the prostaglandin precursor 17a was the
choice of an optimal base capable of efficient and highly diaster-
Hydroxy protected aldehydes are usually readily available and
stable compounds. However, their stability is often insufficient for
purification and identification purposes. It was not surprising then,
that we observed a slight decomposition of the aldehyde 16a dur-
ing column chromatography and, in addition, we were unable to
evaluate its enantiomeric and chemical purity by HPLC on various
stationary phases. These problems were surmounted by applying
eoselective
u-chain elongation of phenylsulfone 15 with sterically
hindered aldehyde 16a. Based on the known behaviour of alkyl and
aryl sulfones,23,33 we studied the effects of various bases (LHMDS,
KHMDS, n-BuLi, t-BuOK, LDA) to determine the optimal conditions
for high-yield and highly diastereoselective synthesis of pentahy-
droxy ester 28a. Of all the bases screened, freshly prepared LDA
provided almost complete conversion (ca. 95%) of phenylsulfone 15
to the mixture of diastereoisomeric hydroxy sulfones 17a. The
the crude u-chain synthon 16a and experimental determination of
the best conditions for the JuliaeLythgoe olefination of phenyl-
sulfone 15. The enantiomeric aldehyde (R)-(þ)-16b was synthe-
sized by the same strategy as illustrated in Scheme 3, but using the
chiral alcohol (S)-(þ)-25b as the starting material. The presence of
the aldehyde and 3-(3-trifluoromethyl)phenoxy groups in com-
pounds 16a and 16b was confirmed by NMR and IR spectra.
choice of
a 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (methyl-
OBO) carboxyl masking group in phenylsulfone 15 was predicted by
its high stability under basic JuliaeLythgoe reaction conditions.
However, the limited stability of the methyl-OBO protecting group
on silica gel accompanied by the effect of lithium salts present in
the crude reaction product resulted in significant losses of 17a
2.2. Synthesis of travoprost (15R)-(D)-8a and its (15S)-(D)-
8b-epi isomeric impurity
during column chromatography. Thus, the crude mixture of b-hy-
droxy sulfones 17a was subjected to reductive elimination with
a fresh 20% sodium amalgam to afford the methyl-OBO protected
prostaglandin precursor 27a. The phosphate-buffered conditions of
Trost34 were used to ensure the optimal pH conditions and prevent
deprotection of the cyclopentane hydroxyl groups. Similarly to the
With the novel aldehyde
u
-chain synthon (S)-(ꢀ)-16a and the
prostaglandin phenylsulfone (5Z)-(þ)-1521 (a mixture of 5Z/5E
isomers in the ratio of 91.6%:8.4%, 83.2% de) in hand, we continued
the synthesis of the target compound (15R)-(þ)-8a according to the
convergent strategy illustrated in Scheme 5. The main problems
methyl-OBO protected b-hydroxy sulfones 17a, the prostaglandin
accompanying the
u
-chain elongation of phenylsulfone 15 to the
intermediate 27a was not purified by means of silica gel column
chromatography. Significantly, there was no need for purification of
the prostaglandin intermediates 17a and 27a, which was a major
advantage for any future scale-up. The triethylsilyl and tert-butyl-
dimethylsilyl protecting groups in prostaglandin precursor 27a
were all removed under the action of tetrabutylammonium fluoride
(TBAF) solution, immediately followed by hydrolytic opening of the
methyl-OBO masking group with citric acid solution to the stable
2,2-bis(hydroxymethyl)propyl ester 28a. The epimeric ester 28b
prostaglandin pentahydroxy ester (15R)-(þ)-28a were moderate
reactivity of the aldehyde 16a and the lability of triethylsilyl pro-
tecting groups in phenylsulfone 15. Considering the chemical
structure of the
u-chain synthon 16a, 3-trifluoromethylphenoxy-
and tert-butyldimethylsilyloxy substituents with electron-
withdrawing properties should activate the aldehyde 16a in nu-
cleophilic addition reactions. On the other hand, the bulky
a-situ-
ated tert-butyldimethylsilyl group creates steric hindrance
Scheme 5. Synthesis of travoprost (8a) and its (15S)-(þ)-epi isomer 8b from phenylsulfone 15 and aldehyde 16a or 16b. Reagents and conditions used: (1) LDA, THF, ꢀ78 ꢁC, 1 h; (2)
Na/Hg, Na2HPO4, MeOH, 0 ꢁC for 30 min, then 5 h at rt; (3) n-Bu4NF, 65e70 ꢁC, 1 h; (4) HOOCC(OH)(CH2COOH)2, H2O, 15 min, 89% yield of 28a from 15; (5) LiOH$H2O, MeOH,
overnight, 98% of 7a; (6) i-PrI, DBU, acetone, 20 h, 95% yield of 8a.

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1639
was synthesized by the same synthetic strategy as illustrated in
effectively deshielded by the trans-double bond of the
u
-chain.
Scheme 5, but using the chiral aldehyde 16b and phenylsulfone 15
Fortunately, this kind of contamination is easily detectable by
reverse-phase analytical HPLC and can be easily removed by pre-
parative HPLC on silica gel stationary phases. More importantly, the
amount of the far more difficult to remove epimeric impurity (15S)-
8b in the final product 8a was scarcely more than a trace (0.2%). The
physicochemical properties of 8a and 8b are very similar, so it is not
a straightforward task to discern between these two compounds by
NMR spectroscopy, optical rotation or even by analytical reverse-
phase HPLC. The 1H and 13C NMR spectroscopic chemical shifts
determined for epimers 8a and 8b are almost identical; however,
slight differences can be noticed in peak multiplicity given by some
as the starting materials. The 15R/15S stereoselectivity of
u-chain
elongation was first evaluated at this step. Thus, both compounds
28a and 28b were purified by silica gel flash chromatography and
identified by spectroscopic and chromatographic methods. The
HPLC and LCeMS recorded for the ester 28a confirmed the pres-
ence of the (5E,15R)-isomer at the level of 8.5%, which was com-
parable with the content of (5E)-isomer in the starting
phenylsulfone (5Z)-15. Fortunately, this kind of contamination
leads to the (5E,15R)-8c diastereoisomer of travoprost in the final
steps of the synthesis, which is easily removable from the final
product 8a by preparative HPLC. More importantly, the content of
the epimeric impurity (15S)-28b in the prostaglandin precursor 28a
was scarcely more than a trace (0.2%). Considering the high enan-
tiomeric purity of the alcohol 25a (25a/25b 99.95%:0.05%), the
chromatographic data for the ester 28a (28a/28b 99.81%:0.19%)
confirmed that the bulky tert-butyldimethylsilyl group made a very
u
-chain protons. The two protons of the u-chain CH2-4 group in
travoprost (8a) are seen as two doublets of doublets at 3.80 and
3.84 ppm, whereas in the 15-epi isomer they give a doublet at
3.79 ppm. The H-1 and H-2 protons of the trans-double bond in
travoprost (8a) are also seen as two doublets of doublets at 5.66 and
5.80 ppm, whereas in 15-epi isomer 8b they give one broad mul-
tiplet. The 1H and 13C NMR spectroscopic chemical shifts and peak
good protecting group for the aldehyde a-proton preventing the u-
chain synthon 16a from racemization. Following the final steps of
the synthesis illustrated in Scheme 5, the ester contaminant 28b
leads to the (15S)-8b epimer of travoprost, only a small amount of
which is present in the final product 8a and is readily separable by
preparative HPLC. Since the olefinic diastereoisomers 28 proved to
be hardly separable at this juncture, we found the better results
could be obtained when separation was performed on the final and
less polar product 8a.
multiplicity determined for the u-chain H-3 proton and C-3 carbon
in travoprost 8a (4.5 and 71.5 ppm) are highly comparable with
those of the 15-epi isomer 8b (4.5 and 70.6 ppm). Considering very
similar physicochemical properties of epimers 8a and 8b, pre-
parative HPLC can only be applied to remove trace amounts of
(15S)-8b diastereoisomer.
The pentahydroxy ester 28a was subsequently cleaved with
lithium hydroxide monohydrate and, after acidification with citric
acid, fluprostenol (15R)-(þ)-7a was isolated in almost quantitative
yield (98%). In the final step of the synthesis, acid 7a was success-
fully converted into travoprost (8a), with i-Pr/DBU/acetone, con-
ditions commonly used in the prostaglandin field.6,7,10,11,19 The
diastereoisomeric impurity (15S)-(þ)-8b of travoprost was syn-
thesized by the same synthetic strategy as illustrated on Scheme 5,
but using the 2,2-bis(hydroxymethyl)propyl ester 28b as the
starting material. The crude travoprost (8a) and its (15S)-epi isomer
(8b) were purified by silica gel flash chromatography and identified
by spectroscopic and chromatographic methods. The HPLC and
LCeMS recorded for the travoprost (8a) confirmed the presence of
the (5E,15R)-isomer (8c) (7.9%) formed from the (5E)-isomer pres-
ent in the starting phenylsulfone (5Z)-15. The NMR spectra of
travoprost 8a and its 5,6-trans diastereoisomer 8c are hardly dis-
2.3. Synthesis of the novel prostaglandin related ester (5Z)-
(D)-18, the new synthetic impurity of travoprost (15R)-(D)-8a
The JuliaeLythgoe olefination entails one main drawback in the
step of formation of the carbonecarbon bond with an a-sulfonyl
carbanion and carbonyl compounds. Since the hydrogen on the
carbon bearing the sulfonyl group is highly acidic, in some cases the
addition reaction of an
a-sulfonyl carbanion to carbonyl com-
pounds is reversible.35 The JuliaeLythgoe olefination of the phe-
nylsulfone 15 with the aldehyde 16a occurred under mild
conditions and gave good yields of stereodefined trans-13,14 alkene
28a (Scheme 5). The reaction stopped at ca. 95% conversion of
phenylsulfone 15 to b-hydroxy sulfones 17a despite using the al-
dehyde 16a in excess under highly anhydrous and air-free condi-
tions. The equilibrium was strongly shifted towards the products
17a; however, up to 5% of phenylsulfone 15 was left unreacted and
subsequently underwent reduction with Na/Hg to provide the
novel prostaglandin related ester (5Z)-(þ)-18 (Scheme 6). Finally,
the crude travoprost (8a) was contaminated with the new impurity
18, which was readily separable by silica gel flash chromatography.
cerned; however, the a-chain allylic carbons C-4 and C-7 of 8c are
seen in the 13C NMR spectrum as two singlets at a lower field (32.2
and 31.4 ppm) compared with the same carbons of 8a (26.9 and
25.7 ppm), therefore the C-4 and C-7 carbons of 8c are more
Scheme 6. Synthesis of the new impurity 18 of travoprost. Reagents and conditions used: (1) Na/Hg, Na2HPO4, MeOH, 0 ꢁC, 30 min, then 5 h at rt; (2) n-Bu4NF, 1 h; (3) HOOC-
C(OH)(CH2COOH)2, H2O, 15 min, 91% yield of 30 from phenylsulfone 15; (4) LiOH$H2O, MeOH, overnight, 97% yield of 31; (5) i-PrI, DBU, acetone, 22 h, 93% yield of 18.

1640
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
The ester 18 was synthesized and identified to establish the full
2,6,7-trioxabicyclo[2.2.2]-octane21 ((5Z)-(þ)-15, a mixture of 5Z/5E
isomers in the ratio of 91.6%:8.4%, 83.2% de) was manufactured
by Pharmaceutical Research Institute (Warsaw, Poland). The HPLC
standards, travoprost (8a) and its diastereoisomers 8be8c, were
purchased from Cayman Chemicals.
profile of impurities accompanying our novel synthesis of the active
pharmaceutical ingredient 8a. Thus, phenylsulfone 15 (83.2% de)
was subjected to the reductive desulfonylation followed by
deprotection of the triethylsilyl groups with TBAF solution and
subsequent hydrolytic opening of the methyl-OBO protecting group
with citric acid solution to afford the stable 2,2-bis(hydroxymethyl)
propyl ester (5Z)-(þ)-30 (91% yield from 15). Hydrolysis of the ester
30 with lithium hydroxide monohydrate followed by esterification
of the acid 31 with i-Pr/DBU gave the new prostaglandin related
ester 18. The LCeMS confirmed the presence of (5E)-18 isomer in
the amount comparable with that of (5E)-15 isomer in the starting
4.2. General procedures
Reactions requiring anhydrous conditions were carried out us-
ing flame-dried glassware, which was cooled to 20 ꢁC in a desicca-
tor under an argon atmosphere. All moisture- or air-sensitive
reactions were run under an argon atmosphere. Air-sensitive re-
agents 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 ex-
ternal 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 re-
duced 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) with mixtures of hexanes,
ethyl acetate, dichloromethane, methanol, 2-propanol in various
ratios as developing systems. Compounds were detected by
phenylsulfone 15. Similarly to travoprost (8a) and its a-chain 5,6-
trans diastereoisomer 8c, the allylic carbons C-4 and C-7 of (5E)-18
isomer are seen in the 13C NMR spectrum as two singlets at a lower
field (31.8 and 31.9 ppm) compared with the same carbons of (5Z)-
18 isomer (26.4 and 26.6 ppm), therefore the C-4 and C-7 carbons of
(5E)-18 are more effectively deshielded by the trans-double bond.
The (5Z)-18 diastereoisomer can be easily separated from its (5E)-
18 isomer by preparative HPLC.
3. Conclusions
The 16-(3-trifluoromethyl)phenoxy PGF2 analogue travoprost
a
(8a) has potent topical ocular activity. A novel convergent synthesis
of 13,14-en-15-ol PGF2a analogues with the desired C-15 asymmetric
centre configuration was developed employing JuliaeLythgoe ole-
fination of the structurallyadvanced phenylsulfone(5Z)-(þ)-15 with
spraying the plates with 1% Ce(SO4)2/2%H3[P(Mo3O10)4] in 10%
ꢁ
H2SO4 followed by heating to 120 C. Preparative column chroma-
tography was carried out on silica gel (Kieselgel 60, 40e63
mm,
a new enantiomerically pure aldehyde
u
-chain synthon (S)-(ꢀ)-16a.
230e400 mesh, Merck) with mixtures of ethyl acetate, dichloro-
methane, methanol, 2-propanol in varying ratios as eluents. Flash
chromatography was run with a positive air pressure generated by
handheld, pear-shaped rubber pumps. The NMR spectra of all the
compounds were measured in CDCl3 or C6D6 solutions with a Var-
ian-NMR-vnmrs600 (at temperature 298 K) equipped with
a 600 MHz PFG Auto XID (1H/15Ne31P 5 mm) indirect probehead.
Standard experimental conditions and standard Varian programs
were used. To assign the structures under consideration, the fol-
lowing 1D and 2D experiments were employed: the 1D selective
NOESY and 2D gradient selected COSY, 1He13C HSQC and 1He13C
HMBC. The 1H and 13C NMR chemical shifts were given relative to
the TMS signal at 0.0 ppm. Concentration of all solutions used for
measurements was about 20e30 mg of compounds in 0.6 mL of
solvent. IR spectra were taken for liquid films or KBr pellets on
a Nicolet Imapct 410 FT-IR spectrophotometer. HRMS spectra were
recorded on an AMD 604 Inectra Gmbh spectrometer or a Mariner
PE Biosystem ESI-TOF spectrometer. Melting points were de-
termined from DSC termograms performed on a Mettler Toledo
DSC822E differential scanning calorimeter. Optical rotations were
measured with a Perkin Elmer 341 automatic polarimeter in EtOH,
CH2Cl2 or CHCl3 solutions as the solvents with percent concentra-
tions. Analytical HPLC was performed on a Waters Alliance 2695
system equipped with 2998 PDA detector, using the following
Subsequent hydrolysis of protecting groups and final esterification
of fluprostenol (7a) yielded travoprost (8a). The new strategy is
based on the reverse order of side chain attachment to the Corey
lactone by Wittig and JuliaeLythgoe olefinations. The occurrence of
the (15S)-(þ)-8b diastereoisomer has been an ‘Achilles heel’ of most
existing syntheses of travoprost. Therefore, the new method for the
synthesis of travoprost targeted a very high enantiomeric purity at
the C-15 carbionol centre of the product. The novel aldehyde
u-
chain synthon (S)-(ꢀ)-16a used for the construction of the -chain
u
of travoprost (8a) was envisaged to contain a stereogenic centre at
the carbon C-2 corresponding to C-15 in the target molecule, with
chiralitycorresponding tothe ‘15R’ configuration in the final product
8a. This ensured the absence of an appreciable quantity of the un-
desired (15S)-(þ)-8b diastereoisomer in the final prostaglandin
analogue 8a. The main advantages of the new method are the
preparation of high purity travoprost (8a) and the application of
comparativelycheap reagents. The novel convergent strategyallows
the synthesis of a whole series of trans-13,14-en-15-ol PGF2 ana-
logues from a common and structurally advanced prostaglandin
intermediate (5Z)-(þ)-15.
4. Experimental section
4.1. Reagents
columns: Chiralpak IA (5
250ꢂ4.6 mm), Chiracel OD OD00CE-EL068 (10
Chiracel OD-H (5
m, 250ꢂ4.6 mm), Gemini C18 (3
250ꢂ4.6 mm) and AS-3R (3
m
m, 250ꢂ4.6 mm), Chiracel OJ (10
m, 250ꢂ4.6 mm),
m,
m, 150ꢂ4.6 mm). The LCeMS was
mm,
m
(S)-(þ)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-diox-olane (99.9%,
99.7% ee), (R)-(ꢀ)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane
(98.6%, 99.4% ee), 3-trifluoromethylphenol (99%), DesseMartin
periodinane (97%), trimethyl acetyl chloride (99%), tert-butyldime-
thylsilyl chloride (97%), imidazole (99%), diisobutylaluminum
hydride solution (1.0 M in toluene), diisopropylamine (99.5%),
butyllithium solution (1.6 M in hexanes), sodium mercury amal-
gam (99.9% trace metal basis, Na 20% beads) and tetrabutylammo-
nium fluoride solution (1.0 M in THF) were purchased from
SigmaeAldrich, Tokyo Chemical Industries and Iris Biotech Gmbh
chemical companies. 1-h(Z)-6-{(1R,2R,3R,5S)-2-[(Phenylsulfonyl)-
methyl]-3,5-bis(triethylsilyloxy)cyclopentyl}hex-4-en-yli-4-methyl-
m
m
m
recorded on a Shimadzu LC-2010A HT high-performance liquid
chromatograph coupled with an Applied Biosystems Qtrap 3200
mass spectrometer equipped with a Gemini C18, AS-3R or Poroshell
120 EC-C8 column.
4.3. (R)-(L)-2,2-Dimethyl-4-(toluenesulfonyloxymethyl)-1,3-
dioxolane (20a)
p-Toluenesulfonyl chloride (6.18 g, 31.7 mmol) was added por-
tionwise over a period of 10 min to a solution of (S)-(þ)-2,2-

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1641
dimethyl-4-(hydroxymethyl)-1,3-dioxolane
(19a)
(4.0
g,
(CH3-2), 66.6 (C-5), 69.0 (C-10), 73.8 (C-4), 109.9 (C-2), 111.4 (d,
J¼3.7 Hz, aromatic C-2), 117.8 (d, J¼3.4 Hz, aromatic C-4), 118.0 (d,
J¼1.2Hz, aromaticC-6),123.9 (q, J¼272.1 Hz, eCF3),130.0(aromatic C-
5),131.9 (q, J¼32.4 Hz, aromatic C-3),158.7 (aromatic C-1) ppm. HRMS
(EI): calcd for C13H15F3O3 276.09733; found 276.09712. Chiral HPLC:
30.2 mmol) in anhydrous pyridine (50 mL) in an ice bath. The
resulting solution was slowly brought to room temperature and
stirred overnight. During that time, a white precipitate formed. The
pyridine was removed under reduced pressure and the residue was
diluted with ethyl acetate (50 mL), washed subsequently with cold
aqueous 1 M HCl (2ꢂ150 mL), saturated NaHCO3 (100 mL) and brine
(200 mL). The organic layer was dried over Na2SO4, filtered and
concentrated to give a light yellow oil. The crude product was pu-
rified by column chromatography over silica gel with gradient
elution 10e30% AcOEt/hexanes to afford (R)-(ꢀ)-3-tosyloxy-1,2-
Chiracel OJ,10
m
m, 250ꢂ4.6 mm column, hexanes/ethanol 100:0.5 (v/
v),1.0 mL/min, tR¼8.27 min(0.06% yieldof21b), tR¼14.24 min(99.94%
yield of 21a), 99.88% ee.
Method B.
A
solution of (S)-(þ)-2,2-dimethyl-4-(hydrox-
ymethyl)-1,3-dioxolane (19a) (3.56 g, 27.0 mmol) and DIAD
(6.98 mL, 33.7 mmol) in toluene (10 mL) was slowly added to
a mixture of 3-trifluoromethylphenol (2.75 mL, 2ꢁ2.5 mmol) and
PPh3 (8.93 g, 33.7 mmol) in toluene (50 mL) at 90 C over 30 min.
After heating at 100 ꢁC for another 1 h, TLC analysis (CH2Cl2/MeOH,
20:1) indicated disappearance of the starting solketal 19a. The
excess of toluene (30 mL) was evaporated and the residue was put
into refrigerator for several hours. Triphenylphosphine oxide was
propanediol acetonide 20a (8.54 g, 99% yield, 99.9% ee) as a col-
20
ourless viscous oil. Rf¼0.37 (20% AcOEt/hexanes). [
a]
ꢀ4.8 (c 1.0,
D
EtOH) (lit. [
a
]
24 ꢀ4.6 (c 13.0, EtOH)).25 FTIR (thin film)
n
3073, 2987,
D
2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096,
1055, 979, 829, 788, 665, 555 cmꢀ1. 1H NMR (600 MHz, CDCl3)
d 1.31
(s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J¼5.1
and 8.8 Hz,1H, one of the CH2-5 group), 3.98 (dd, J¼6.0 and 10.2 Hz,
1H, one of the CH2-10 group), 3.99e4.05 (m, 2H, one of the CH2-10
group and one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H,
aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6) ppm. 13C
€
removed by filtration on a Buchner funnel and washed with cold
toluene (3ꢂ15 mL). The filtrate and washings were combined and
concentrated under reduced pressure to give the crude product 21a
(9.6 g) as an orange-yellow oil. The crude product was distilled to
afford the acetonide (S)-(þ)-21a (5.98 g, 97% yield, 89.5% ee) as
a colourless oil. Bp 80e94 ꢁC (0.2 mmHg). The characterization data
from IR and NMR spectra were identical in all aspects with those of
(S)-(þ)-21a obtained according to the Method A.
NMR (150 MHz, CDCl3) d 21.5 (AreCH3), 25.1 (CH3-2), 26.5 (CH3-2),
66.1 (C-5), 69.4 (C-10), 72.8 (C-4), 109.9 (C-2), 127.9 (2C, aromatic
C-2 and C-6), 129.8 (2C, aromatic C-3 and C-5), 132.6 (aromatic C-1),
145.0 (aromatic C-4) ppm. HRMS (ESI): calcd for C13H18NaO5S
[MþNa]þ 309.07672; found 309.0762. Chiral HPLC: Chiralpak IA,
5
m
m, 250ꢂ4.6 mm column, hexanes/2-propanol/methanol 97:2:1
4.4.1. (R)-(ꢀ)-2,2-Dimethyl-4-(3-trifluoromethylphenoxy)methyl-
1,3-dioxolane (21b). In the same manner as described for the
preparation of (S)-(þ)-21a (Method A), the tosylate (S)-(þ)-20b
(v/v/v), 1.0 mL/min, tR¼21.71 min (0.06% yield of 20b),
tR¼24.20 min (99.94% yield of 20a), 99.88% ee. All physical and
spectroscopic data match those reported in the literature.
(5.0 g, 17.5 mmol) afforded the acetonide (R)-(ꢀ)-21b (4.13 g, 86%
20
yield, 99.2% ee). [
a
]
ꢀ7.4 (c 0.5, EtOH). The characterization data
D
4.3.1. (S)-(þ)-2,2-Dimethyl-4-(toluenesulfonyloxymethyl)-1,3-
dioxolane (20b). According to the procedure described for the
preparation of (R)-(ꢀ)-20a, (R)-(ꢀ)-2,2-dimethyl-4-(hydrox-
ymethyl)-1,3-dioxolane (19b) (2.50 g, 18.7 mmol) afforded the right-
hand (S)-(þ)-3-tosyloxy-1,2-propanediol acetonide 20b (5.23 g, 98%
from IR, NMR and HRMS spectra were identical in all aspects with
those of (S)-(þ)-21a enantiomer.
4.5. (R)-(L)-3-(3-Trifluoromethylphenoxy)propane-1,2-diol
(22a)
20
25
yield, 99.2% ee). [
a
]
þ4.5 (c 1.0, EtOH) (lit. [
a]
þ4.7 (c 1.0,
D
D
EtOH)).26 The characterization data from IR, NMR and HRMS spectra
1.0 M aq HCl (40.0 mL) was added in one portion to a solution of
acetonide (S)-(þ)-21a (6.90 g, 25.0 mmol) in acetone (50 mL). After
heating at 70 ꢁC for 1 h, TLC analysis (CH2Cl2/MeOH, 20:1) indicated
the reactionwas complete. The solutionwas cooled, acetonewas then
evaporated and the aqueous acidic residue was slowly neutralized
with slightly more than the equivalent amount of solid NaHCO3. The
resulting solution was extracted with CH2Cl2 (3ꢂ25 mL). The com-
bined extracts were washed with water (3ꢂ150 mL), dried over
Na2SO4, filtered and concentrated to give a light yellow oil (5.88 g).
Purification by silica gel flash chromatography with CH2Cl2/MeOH
(20:1) elution afforded the diol (R)-(ꢀ)-22a (5.79 g, 98% yield, 99.9%
ee) as a white solid. Rf¼0.30 (20% MeOH/CH2Cl2), mp 71e78 ꢁC, peak
were identical in all aspects with those of (R)-(ꢀ)-20a enantiomer.
4.4. (S)-(D)-2,2-Dimethyl-4-(3-trifluoromethylphenoxy)
methyl-1,3-dioxolane (21a)
Method A. Sodium hydroxide (1.73 g, 43.2 mmol) was added por-
tionwise to a stirred solution of 3-trifluoromethylphenol (7.08 g,
43.2 mmol) in a mixture of EtOH and H2O (4:1, 125 mL). After being
stirred for 10 min, a solution of tosylate (R)-(ꢀ)-20a (8.25 g,
28.8 mmol) in EtOH (25 mL) was added dropwise and the reaction
mixture was heated at reflux for 20 h with disappearance of the
starting tosylate (R)-(ꢀ)-20a (TLC, AcOEt/hexanes 1:4). The EtOH was
then evaporated, the residue was treated with 10% aq NaOH (25 mL)
and extracted with CH2Cl2 (3ꢂ25 mL). The combined organic layers
were washed with H2O (3ꢂ100 mL), dried over Na2SO4, filtered and
evaporated to give a light yellow oil (7.80 g, 98% yield). The crude
product was distilled to afford the acetonide (S)-(þ)-21a (7.06 g, 89%
74 ꢁC, heating rate 10.0 ꢁC/min (lit. mp 68e69 ꢁC).26
[a]
20 ꢀ12.6 (c 1.0,
D
EtOH). FTIR (KBr)
n 3318, 3224, 2954, 2927, 1607, 1495, 1451, 1341,
1244, 1178, 1123, 1054, 996, 902, 862, 793, 698, 659 cmꢀ1. 1H NMR
(600 MHz, CDCl3)
d
2.90 (br s, 2H, two eOH groups), 3.74 (dd, J¼5.9
and 11.4 Hz, 1H, one of the CH2-1 group), 3.84 (dd, J¼3.6 and 11.4 Hz,
1H, one of the CH2-1 group), 4.04 (m, 2H, CH2-3), 4.13 (m, 1H, CH-2),
7.07 (dd, J¼2.4 and 8.2 Hz,1H, aromatic H-6), 7.14 (m,1H, aromatic H-
2), 7.22 (dm, J¼7.6 Hz, 1H, aromatic H-4), 7.36 (m, 1H, aromatic H-
yield, 99.9% ee)as a colourless oil. Bp80e94 ꢁC (0.2 mmHg). [
a
]
20 þ7.5
D
25
(c 0.5, EtOH) (lit. [
a
]
þ11 (c 0.5, EtOH)).26 FTIR (thin film)
n 3074,
D
2988, 2938, 2883,1608,1593,1493,1450,1372,1330,1233,1168,1127,
5) ppm. 13C NMR (150 MHz, CDCl3)
d 63.5 (C-1), 69.3 (C-3), 70.4 (C-2),
1096,1066, 976, 904, 843, 793, 698, 657, 520 cmꢀ1.1H NMR (600 MHz,
111.4 (d, J¼3.9 Hz,aromaticC-2),117.9(d, J¼1.0Hz,aromatic C-6),118.0
(d, J¼3.8 Hz, aromatic C-4), 123.8 (q, J¼272.1 Hz, eCF3), 130.1 (aro-
matic C-5), 131.9 (q, J¼32.0 Hz, aromatic C-3), 158.5 (aromatic
C-1) ppm. HRMS (EI): calcd for C10H11F3O3 236.06603; found
CDCl3)
d
1.41 (s, 3H, CH3-2), 1.46 (s, 3H, CH3-2), 3.91 (dd, J¼5.8 and
8.5 Hz,1H, one of the CH2-5 group), 3.98 (dd, J¼5.8 and 9.5 Hz,1H, one
of the CH2-10 group), 4.08 (dd, J¼5.5 and 9.5, 1H, one of the CH2-10
group), 4.18(dd,J¼6.4and8.5Hz,1H,oneof theCH2-5group), 4.49(m,
1H, CH-4), 7.09 (dd, J¼2.4 and 8.2 Hz, 1H, aromatic H-6), 7.15 (m, 1H,
aromatic H-2), 7.22 (dm, J¼7.6 Hz, 1H, aromatic H-4), 7.38 (m, 1H,
236.06637. Chiral HPLC: Chiracel OD OD00CE-EL068, 10
mm,
250ꢂ4.6 mm column, hexanes/2-propanol 96:4 (v/v), 1.0 mL/min,
tR¼25.21 min (99.97% yield of 22a), tR¼31.14 min (0.03% yield of 22b),
99.94% ee.
aromatic H-5) ppm. 13C NMR (150 MHz, CDCl3)
d 25.3 (CH3-2), 26.7

1642
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
4.5.1. (S)-(þ)-3-(3-Trifluoromethylphenoxy)propane-1,2-diol
(22b). Treatment of the acetonide (R)-(ꢀ)-21b (4.0 g, 14.5 mmol)
similar to the hydrolysis of (S)-(þ)-21a afforded the diol (S)-
6e10% AcOEt/hexanes) to give TBDMS ether (S)-(ꢀ)-24a (8.66 g,
93% yield, 99.9% ee) as a colourless oil. Rf¼0.49 (5% AcOEt/hexanes),
20
[a
]
ꢀ6.7 (c 1.0, EtOH). FTIR (thin film)
n 3077, 2957, 2932, 2885,
D
(þ)-22b (3.32 g, 97% yield, 99.2% ee). [
a
]
D
20 þ12.5 (c 1.0, EtOH). The
2858, 1732, 1609, 1593, 1449, 1399, 1330, 1283, 1252, 1167, 1131,
1066, 1051, 1003, 880, 837, 780, 698 cmꢀ1 1H NMR (600 MHz,
CDCl3) 0.12 (s, 3H, CH3eSi), 0.14 (s, 3H, CH3eSi), 0.89 (s, 9H,
characterization data from IR, NMR and HRMS spectra were iden-
tical in all aspects with those of (R)-(ꢀ)-22a enantiomer.
.
d
(CH3)3CeSi), 1.21 (s, 9H, (CH3)3CeC), 3.96 (dd, J¼5.9 and 9.5 Hz, 1H,
one of the CH2-3 group), 4.02 (dd, J¼4.6 and 9.5 Hz, 1H, one of the
CH2-3 group), 4.12 (dd, J¼6.7 and 13.0 Hz, 1H, one of the CH2-1
group), 4.21e4.25 (m, 2H, one of the CH2-1 group and CH-2), 7.07
(dd, J¼2.4 and 8.3 Hz, 1H, aromatic H-6), 7.12 (m, 1H, aromatic H-2),
7.22 (dm, J¼7.7 Hz, 1H, aromatic H-4), 7.39 (m, 1H, aromatic H-
4.6. (S)-(D)-2-Hydroxy-3-(3-trifluoromethylphenoxy)propyl
pivalate (23a)
Trimethylacetyl chloride (3.04 mL, 24.5 mmol) was added to
a stirred solution of diol (R)-(ꢀ)-22a (5.50 g, 23.3 mmol) in a mix-
ture of CH2Cl2 and pyridine (1:1, 50 mL) at 0 ꢁC under an argon
atmosphere. After stirring at 0 ꢁC for 1 h and at room temperature
for 1 h, the reaction was quenched with crushed ice (25 g) and the
solution was partitioned between AcOEt (50 mL) and 10% aqueous
HCl (50 mL). The resulting layers were separated and the aqueous
phase was extracted with AcOEt (3ꢂ25 mL). The combined organic
extracts were washed successively with H2O (150 mL), saturated
aqueous NaHCO3 (150 mL), brine (200 mL) and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished the
crude ester (8.45 g), which was purified by flash column chroma-
tography over silica gel (AcOEt/hexanes 1:4) to afford the pivalate
5) ppm. 13C NMR (150 MHz, CDCl3)
d
ꢀ4.9 (CH3eSi), e4.7 (CH3eSi),
18.0 ((CH3)3CeSi), 25.7 (3C, (CH3)3CeSi), 27.2 (3C, (CH3)3CeC), 38.8
((CH3)3CeC), 65.4 (C-1), 69.1 (C-2), 69.8 (C-3), 111.2 (d, J¼4.1 Hz,
aromatic C-2), 117.7 (d, J¼4.1 Hz, aromatic C-4), 118.0 (d, J¼1.2 Hz,
aromatic C-6), 123.9 (q, J¼272.2 Hz, eCF3), 130.0 (aromatic C-5),
131.9 (q, J¼32.4 Hz, aromatic C-3), 158.8 (aromatic C-1), 178.3 (C]
O) ppm. HRMS (ESI): calcd for C21H33F3NaO4Si [MþNa]þ 457.19924;
found 457.1973. Chiral HPLC: Chiracel OD-H, 5
column, hexanes/2-propanol 100:1 (v/v), 1.0 mL/min, tR¼7.08 min
(0.06% yield of 24b), tR¼7.49 min (99.94% yield of 24a), 99.88% ee.
m
m, 250ꢂ4.6 mm
(S)-(þ)-23a (7.09 g, 95% yield, 99.9% ee) as a colourless oil. Rf¼0.32
4.7.1. (R)-(þ)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluorometh-
ylphenoxy)propyl pivalate (24b). In the same manner as described for
the preparation of (S)-(ꢀ)-24a, the alcohol (R)-(ꢀ)-23b (3.60 g,
11.2 mmol) afforded the ether (R)-(þ)-24b (4.46 g, 91% yield, 99.2%
20
(20% AcOEt/hexanes), [
a
]
þ1.90 (c 1.0, EtOH). FTIR (thin film)
n
D
3467, 3075, 2975, 2938, 2876, 1731, 1593, 1493, 1481, 1451, 1330,
1285, 1240, 1167, 1128, 1066, 1047, 999, 940, 884, 793, 698,
659 cmꢀ1. 1H NMR (600 MHz, CDCl3)
d
1.22 (s, 9H, eC(CH3)3), 4.05
ee). [
a
]
20 þ6.4 (c 1.0, EtOH). The characterization data from IR, NMR
D
(dd, J¼5.5 and 9.4 Hz, 1H, one of the CH2-3 group), 4.08 (dd, J¼4.6
and 9.4 Hz,1H, one of the CH2-3 group), 4.26 (m,1H, CH-2), 4.30 (m,
2H, CH2-1), 7.07 (dd, J¼2.4 and 8.2 Hz, 1H, aromatic H-6), 7.15 (m,
1H, aromatic H-2), 7.24 (dm, J¼7.9 Hz, 1H, aromatic H-4), 7.36 (m,
and HRMS spectra were identical in all aspects with those of (S)-
(ꢀ)-24a enantiomer.
4.8. (R)-(L)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluoromet-
hylphenoxy)propan-1-ol (25a)
1H, aromatic H-5) ppm. 13C NMR (150 MHz, CDCl3)
d
27.1 (3C,
(CH3)3Ce), 38.9 ((CH3)3Ce), 65.2 (C-1), 68.6 (C-2), 69.0 (C-3), 111.4
(d, J¼3.8 Hz, aromatic C-2), 118.0 (d, J¼1.0 Hz, aromatic C-6), 118.0
(d, J¼3.8 Hz, aromatic C-4), 123.8 (q, J¼271.6 Hz, eCF3), 130.1 (ar-
omatic C-5), 132.0 (q, J¼32.3 Hz, aromatic C-3), 158.4 (aromatic
C-1), 178.8 (C]O) ppm. HRMS (ESI): calcd for C15H19F3NaO4
[MþNa]þ 343.11277; found 343.1134. Chiral HPLC: Chiracel OD-H,
Diisobutylaluminum hydride (1.0
49.0 mmol) was added dropwise over 20 min to a stirred solution of
M in toluene, 49.0 mL,
pivalate (S)-(ꢀ)-24a (8.45 g, 19.4 mmol) in anhydrous CH2Cl2
(100 mL) at ꢀ78 ꢁC under an argon atmosphere. The resulting
ꢁ
mixture was allowed to warm to ꢀ20 C for a 30 min period and
5
mm, 250ꢂ4.6 mm column, hexanes/ethanol/methanol 98:1.5:1
stirred at this temperature for another 2 h. TLC analysis (hexanes/
AcOEt, 8:1) indicated disappearance of the starting pivalate (S)-
(ꢀ)-24a. The clear colourless solution was re-cooled to ꢀ78 ꢁC and
the excess of DIBAL was quenched by addition of MeOH (25 mL)
dropwise. On warming to 0 ꢁC, 10% aqueous potassium sodium
tartrate (150 mL) was added and the mixture was stirred vigorously
at room temperature for 2 h. The resulting layers were separated
and the aqueous phase was extracted with CH2Cl2 (3ꢂ75 mL). The
combined extracts were washed with water (150 mL), brine
(200 mL) and dried over anhydrous Na2SO4. Filtration and evapo-
ration in vacuo furnished the crude product (7.29 g), which was
purified by flash column chromatography (silica gel, 3e11% AcOEt/
hexanes) to afford the primary alcohol (R)-(ꢀ)-25a (6.28 g, 92%
yield, 99.9% ee) as a colourless oil. Rf¼0.41 (20% AcOEt/hexanes).
(v/v/v), 1.0 mL/min, tR¼11.09 min (99.93% yield of 23a),
tR¼12.60 min (0.07% yield of 23b), 99.86% ee.
4.6.1. (R)-(ꢀ)-2-Hydroxy-3-(3-trifluoromethylphenoxy)propyl piv-
alate (23b). According to the procedure described for the prepa-
ration of (S)-(þ)-23a, the diol (S)-(þ)-22b (3.0 g,12.7 mmol) yielded
20
the pivalate (R)-(ꢀ)-23b (3.83 g, 94% yield, 99.2% ee). [
a
]
ꢀ1.5 (c
D
1.0, EtOH). The characterization data from IR, NMR and HRMS
spectra were identical in all aspects with those of (S)-(þ)-23a
enantiomer.
4.7. (S)-(L)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluorometh-
ylphenoxy)propyl pivalate (24a)
[
a
]
20 ꢀ29.4 (c 1.0, EtOH). FTIR (thin film)
n 3434, 3074, 2954, 2931,
D
tert-Butyldimethylsilyl chloride (4.02 g, 25.9 mmol) was added
in one portion to a stirred solution of alcohol (S)-(þ)-23a (6.90 g,
21.5 mmol) and imidazole (3.70 g, 53.9 mmol) in anhydrous DMF
(50 mL) at 0 ꢁC under an argon atmosphere. The reaction was
allowed to proceed for 18 h at room temperature and then
quenched with crushed ice (25 g). The resulting mixture was par-
titioned between hexanes (50 mL) and H2O (100 mL). The aqueous
layer was extracted with hexanes (3ꢂ25 mL). The combined or-
ganic extracts were washed successively with H2O (100 mL), brine
(150 mL) and dried over Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (9.61 g) as a light yellow oil,
which was purified by flash column chromatography (silica gel,
2886, 2858, 1608, 1592, 1493, 1449, 1330, 1254, 1169, 1130, 1066,
1048, 999, 881, 837, 781, 697, 659 cmꢀ1. 1H NMR (600 MHz, CDCl3)
d
0.13 (s, 3H, CH3eSi), 0.15 (s, 3H, CH3eSi), 0.92 (s, 9H, (CH3)3CeSi),
2.02 (br s,1H, eOH), 3.69 (dd, J¼4.2 and 11.3 Hz, 1H, one of the CH2-
1 group), 3.74 (dd, J¼4.2 and 11.3 Hz, 1H, one of the CH2-1 group),
3.96 (dd, J¼6.3 and 9.3, 1H, one of the CH2-3 group), 4.04 (dd, J¼5.4
and 9.3 Hz,1H, one of the CH2-3 group), 4.13 (m,1H, CH-2), 7.07 (dd,
J¼2.4 and 8.3 Hz, 1H, aromatic H-6), 7.12 (m, 1H, aromatic H-2), 7.21
(dm, J¼7.7 Hz, 1H, aromatic H-4), 7.38 (m, 1H, aromatic H-5) ppm.
13C NMR (150 MHz, CDCl3)
((CH3)3CeSi), 25.8 (3C, (CH3)3CeSi), 64.1 (C-1), 69.3 (C-3), 71.1 (C-
2), 111.1 (d, J¼3.7 Hz, aromatic C-2), 117.6 (d, J¼4.0 Hz, aromatic C-
d
ꢀ4.9 (CH3eSi), e4.6 (CH3eSi), 18.1

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1643
4), 118.0 (d, J¼1.2 Hz, aromatic C-6), 123.9 (q, J¼272.1 Hz, eCF3),
130.0 (aromatic C-5), 131.9 (q, J¼32.3 Hz, aromatic C-3), 158.8 (ar-
omatic C-1) ppm. HRMS (ESI): calcd for C16H25F3NaO3Si [MþNa]þ
de) in anhydrous THF (5.0 mL) was added dropwise with vigorous
stirring. The reaction mixture was allowed to warm to ꢀ40 ꢁC and
the crude aldehyde (S)-(ꢀ)-16a (4.60 g, 13.2 mmol) in anhydrous
ꢁ
373.14173; found 373.1420. Chiral HPLC: Chiracel OD-H, 5
mm,
THF (5 mL) was added dropwise. After being stirred at ꢀ40 C for
another 1 h, TLC analysis (toluene/AcOEt 12:1) indicated disap-
pearance of the starting phenylsulfone 15. The cold reaction was
quenched with saturated aqueous NaCl solution (50 mL). The
resulting layers were separated and the aqueous phase was
extracted with AcOEt (3ꢂ25 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 epimeric hydroxy sulfones 17a (7.82 g)
as a light yellow oil. The hydroxy sulfones 17a were directly used for
the next step without further purification.
250ꢂ4.6 mm column, hexanes/2-propanol 100:0.5 (v/v), 1.0 mL/
min, tR¼15.96 min (0.05% yield of 25b), tR¼21.88 min (99.95% yield
of 25a), 99.90% ee.
4.8.1. (S)-(þ)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluoromet-
hylphenoxy)propan-1-ol (25b). Treatment of the pivalate (R)-(þ)-24b
(4.2 g, 9.67 mmol) similar to the reduction of (S)-(ꢀ)-24a afforded the
primary alcohol (S)-(þ)-25b (3.07 g, 91% yield, 99.2% ee). [
a
]
20 þ28.5
D
(c 1.0, EtOH). The characterization data from IR, NMR and HRMS
spectra were identical in all aspects with those of (R)-(ꢀ)-25a
enantiomer.
4.10.1. 1-{(Z)-6-[(1R,2R,3R,5S)-2-[(1R/1S,2R/2S,3S)-3-(tert-But-yldime-
thylsilyloxy)-4-(3-trifluoromethylphenoxy)-1-(phenylsulfonyl)butyl]-
3,5-bis(triethylsilyloxy)cyclopentyl]-hex-4-enyl}-4-methyl-2,6,7-
trioxabicyclo[2.2.2] octane (17b). In the same manner as described for
the preparation of hydroxy sulfones 17a, the phenylsulfone 15 (2.16 g,
3.11 mmol, 83.2% de) and aldehyde (R)-(þ)-16b (2.71 g, 7.77 mmol)
afforded the crude mixture of hydroxy sulfones 17b (4.78 g).
4.9. (S)-(L)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluorometh-
ylphenoxy)propanal (16a)
DesseMartin periodinane (9.06 g, 20.7 mmol) was added por-
ꢁ
tionwise to a cold (0 C) suspension of alcohol (R)-(ꢀ)-25a (6.05 g,
17.3 mmol) and dry NaHCO3 (4.35 g, 51.8 mmol) in anhydrous CH2Cl2
(100 mL). After being stirred for 1 h at room temperature, TLC analysis
(hexanes/AcOEt, 9:1) indicated disappearance of the starting alcohol
(R)-(ꢀ)-25a. Saturated aqueous NaHCO3 (100 mL) and Na2SO3 (15.2 g,
121 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
(3ꢂ50 mL). The combined extracts were washed with water
(3ꢂ150 mL), dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was co-evaporated with anhydrous tetrahydrofu-
ran (3ꢂ50 mL) and carefully dried under reduced pressure to afford
the crude aldehyde (S)-(ꢀ)-16a (5.82 g, 97%) as a light yellow oil. The
aldehyde (S)-(ꢀ)-16a was directly used for the next step without
4.11. 1-{(Z)-6-[(1R,2R,3R,5S)-2-[(R)-3-(tert-Butyldimethylsi-
lyloxy)-4-(3-trifluoromethylphenoxy)but-1-enyl]-3,5-
bis(triethylsilyloxy)-cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-
trioxabicyclo[2.2.2] octane (27a)
The crude mixture of diastereoisomeric hydroxy sulfones 17a
(7.82 g) was dissolved in anhydrous MeOH (100 mL) and Na2HPO4
ꢁ
(6.0 g, 42.2 mmol) was added in one portion. On cooling to 0 C
under an argon atmosphere, sodium amalgam (20%, 7.28 g,
63.4 mmol Na) was added portionwise over 30 min with vigorous
stirring. The cooling bath was removed and the resulting suspen-
sion was stirred at room temperature for 5 h to disappearance of
the starting hydroxy sulfones 17a (TLC, toluene/AcOEt 12:1). The
solution was decanted from the remaining amalgam and concen-
trated under reduced pressure. The residue was diluted with water
(100 mL) and AcOEt (50 mL). The resulting layers were separated
and the aqueous phase was extracted with AcOEt (3ꢂ25 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 27a (6.14 g) as a light yellow oil. The
crude olefin 27a was directly used for the next step without further
purification.
further purification. [
a
]
20 ꢀ26.4 (c 1.0, CHCl3). FTIR (thin film)
n 3077,
D
2954, 2932, 2886, 2859,1740,1593,1493,1450,1330,1254,1169,1130,
976, 881, 838, 782, 697, 658 cmꢀ1. 1H NMR (CDCl3, 600 MHz)
d 0.13 (s,
3H, CH3eSi), 0.17 (s, 3H, CH3eSi), 0.94 (s, 9H, (CH3)3CeSi), 4.13 (dd,
J¼6.6 and 9.9 Hz, 1H, one of the CH2-3 group), 4.26 (dd, J¼3.6 and
9.9 Hz, 1H, one of the CH2-3 group), 4.40 (ddd, J¼0.8, 3.6 and 6.6 Hz,
1H, CH-2), 7.07 (dd, J¼2.4 and 8.3 Hz, 1H, aromatic H-6), 7.12 (m, 1H,
aromatic H-2), 7.23 (dm, J¼7.7 Hz, 1H, aromatic H-4), 7.39 (m, 1H,
aromatic H-5), 9.75 (d, J¼0.8 Hz, 1H, eCHO) ppm. 13C NMR (150 MHz,
CDCl3)
d
ꢀ4.9 (CH3eSi), ꢀ4.7 (CH3eSi), 18.2 ((CH3)3CeSi), 25.7 (3C,
(CH3)3CeSi), 69.2 (C-3), 76.7 (C-2), 111.3 (d, J¼3.5 Hz, aromatic C-2),
117.7 (d, J¼4.0 Hz, aromatic C-4), 118.0 (d, J¼1.2 Hz, aromatic C-6),
123.9 (q, J¼272.1 Hz, eCF3), 130.1 (aromatic C-5), 132.0 (q, J¼32.2 Hz,
aromatic C-3), 158.5 (aromatic C-1), 202.0 (eCHO) ppm.
4.11.1. 1-{(Z)-6-[(1R,2R,3R,5S)-2-[(S)-3-(tert-Butyldimethylsilyloxy)-4-
(3-trifluoromethylphenoxy)but-1-enyl]-3,5-bis(triethylsilyloxy)cyclo-
pentyl]hex-4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2] octane (27b).
Treatment of the mixture of epimeric hydroxy sulfones 17b (4.78 g)
similar to the reductive desulfonylation of 17a afforded the crude
olefine 27b (4.19 g).
4.9.1. (R)-(þ)-2-(tert-Butyldimethylsilyloxy)-3-(3-trifluorom-
ethylphenoxy)propanal (16b). According to the procedure described
for the preparation of (S)-(ꢀ)-16a, the alcohol (S)-(þ)-25b (3.80 g,
10.8 mmol) yielded the crude aldehyde (R)-(þ)-16b (3.60 g, 95%
20
yield). [
a
]
þ26.2 (c 1.0, CHCl3). The characterization data from IR
4.12. 2,2-Bis(hydroxymethyl)propyl (Z)-7-{(1R,2R,3R,5S)-3,5-
dihydroxy-2-[(R,E)-3-hydroxy-4-(3-trifluoromethylphenoxy)
but-1-enyl]cyclopentyl}hept-5-enoate (28a)
D
and NMR spectra were identical in all aspects with those of (S)-
(ꢀ)-16a enantiomer.
4.10. 1-{(Z)-6-[(1R,2R,3R,5S)-2-[(1R/1S,2R/2S,3R)-3-(tert-Bu-
tyldimethylsilyloxy)-4-(3-trifluoromethylphenoxy)-1-(phe-
nylsulfonyl)-butyl]-3,5-bis(triethylsilyloxy)cyclopentyl]hex-
4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2] octane (17a)
TBAF (15.8 mL, 15.8 mmol, 1.0 M in THF) was added dropwise to
a solution of the crude silyl protected prostaglandin analogue 27a
(6.14 g) in anhydrous THF (15 mL). The resulting brown solution
was stirred at 65e70 ꢁC under an argon atmosphere for 1 h,
whereupon the THF was evaporated under reduced pressure. The
viscous residue was then diluted with 10% aqueous solution of citric
acid (25 mL) to hydrolyze the 4-methyl-OBO carboxyl masking
group. After being stirred for 15 min, the product was salted out
with sodium chloride, separated and dried in vacuo to give the
n-BuLi (8.25 mL, 13.2 mmol, 1.6 M in hexanes) was added
dropwise to a solution of diisopropylamine (2.03 mL, 14.3 mmol) in
anhydrous THF ꢁ(15 mL) at ꢀ78 ꢁC under an argon atmosphere. After
15 min at ꢀ78 C, the phenylsulfone 15 (3.67 g, 5.28 mmol, 83.2%

1644
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
crude pentaol 28a (5.56 g). Purification by silica gel flash chroma-
tography with gradient elution 1e6% methanol/ethyl acetate
afforded the prostaglandin analogue (15R)-(þ)-28a (2.63 g, 89%
NMR (150 MHz, CDCl3) -chain C-3), 25.7 (
d
16.8 (eCH3), 24.6 (
a
a-
chain C-7), 26.4 -chain C-4), 33.4 (a-chain C-2), 40.6
(
a
(eC(CH3)(CH2OH)2), 42.9 (cyclopentane C-4), 50.3 (cyclopentane
C-1), 55.7 (cyclopentane C-2), 66.6 (2C, eC(CH3)(CH2OH)2), 66.7
yield
from
phenylsulfone
15,
28a/28b/(5E,15R)-iso-
mer¼91.36%:0.18%:8.46%) as a light yellow viscous oil. Rf¼0.45
(a-chain CH2-1), 70.5 (u-chain C-3), 72.1 (u-chain C-4), 72.9
20
(MeOH/CH2Cl2) [
2934, 1716, 1592, 1493, 1451, 1330, 1240, 1167, 1125, 1040, 972, 792,
698 cmꢀ1. 1H NMR (CDCl3, 600 MHz)
0.82 (s, 3H, eCH3), 1.50 (m,
1H, cyclopentane CH-1), 1.66e1.70 (m, 3H, -chain CH2-3 and one
of the cyclopentane CH2-4 group), 2.04 (m, 2H, one of the
CH2-4 group and one of the
of the -chain CH2-4 group), 2.24e2.34 (m, 5H, one of the
CH2-7 group,
and cyclopentane CH-2), 3.51 (s, 4H, two eCH2OH), 3.92 (m, 1H,
cyclopentane CH-3), 3.97 (m, 2H, -chain CH2-4), 4.07 (s, 2H,
chain CH2-1), 4.11 (m, 1H, cyclopentane CH-5), 4.49 (m, 1H, -chain
CH-3), 5.32 (m, 1H, -chain CH-5), 5.40 (m, 1H, -chain CH-6), 5.66
(m, 2H, -chain CH-1 and
a
]
þ18.7 (c 1.0, CHCl3). FTIR (thin film)
n
3369,
(cyclopentane C-5), 77.9 (cyclopentane C-3), 111.5 (q, J¼3.8 Hz,
D
aromatic C-2), 117.7 (q, J¼3.8 Hz, aromatic C-4), 118.1 (s, aromatic
d
C-6), 123.9 (q, J¼271.0 Hz, eCF3), 129.3 (
a-chain C-6), 129.4 (a-
-chain C-2), 130.0 (aromatic C-5), 131.8 (q,
-chain C-1), 158.7 (aromatic
a
chain C-5), 129.6 (
u
a
-chain
-chain
J¼32.2 Hz, aromatic C-3), 134.7 (
u
a
-chain CH2-7 group), 2.11 (m, 1H, one
C-1), 174.6 (C]O) ppm. HRMS (ESI): calcd for C28H39F3NaO8
a
a
[MþNa]þ 583.24892; found 583.2507. HPLC: Gemini C18, 3
mm,
a
-chain CH2-2, one of the cyclopentane CH2-4 group
250ꢂ4.6 mm column, KH2PO4 (4 g/L)/CH3CN/MeOH (90:5:5)
(phase A)/CH3CN (phase B) with gradient elution 67e10%, 1.0 mL/
min, tR¼35.43 min (8.37% yield of (5E,15S)-isomer), tR¼37.96 min
(91.1% yield of (15S)-(þ)-28b), tR¼39.62 min (0.53% yield of (15R)-
u
a-
u
a
a
(þ)-28a). LCeMS (ESI): Gemini C18, 3 m, 250ꢂ4.6 mm column,
m
u
u
-chain CH-2), 7.08 (dd, J¼2.4 and 8.3 Hz,
CH3COONH4 (1.44 g/L)/CH3CN/MeOH (90:5:5) (phase A)/CH3CN
(phase B) with gradient elution 67e10%, 1.0 mL/min, tR¼35.68 min
(m/z¼561.2 [MþH]þ for (5E,15S)-isomer), tR¼37.90 min (m/
z¼561.2 [MþH]þ for (15S)-(þ)-28b), tR¼40.50 min (m/z¼561.2
[MþH]þ for (15R)-(þ)-28a).
1H, aromatic CH-6), 7.14 (m, 1H, aromatic CH-2), 7.20 (dm, J¼7.7 Hz,
1H, aromatic CH-4), 7.37 (m, 1H, aromatic CH-5) ppm. 13C NMR
(150 MHz, CDCl3)
7), 26.4 ( -chain C-4), 33.3 (
42.8 (cyclopentane C-4), 49.7 (cyclopentane C-1), 55.4 (cyclo-
pentane C-2), 66.4 (2C, eC(CH3)(CH2OH)2), 66.5 ( -chain CH2-1),
71.0 ( -chain C-3), 71.9 ( -chain C-4), 72.4 (cyclopentane C-5), 77.4
d
16.7 (eCH3), 24.6 (a-chain C-3), 25.5 (a-chain C-
a
a-chain C-2), 40.5 (eC(CH3)(CH2OH)2),
a
4.13. (Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(R,E)-3-hydroxy-
4-(3-trifluoromethylphenoxy)but-1-enyl]cyclopentyl}hept-5-
enoic acid (7a)
u
u
(cyclopentane C-3), 111.4 (q, J¼4.0 Hz, aromatic C-2), 117.8 (q,
J¼4.0 Hz, aromatic C-4), 118.0 (aromatic C-6), 124.4 (q, J¼273.0 Hz,
eCF3), 129.2 (
a
-chain C-6), 129.4 (
a
-chain C-5), 130.0 (aromatic C-
LiOH$H2O (0.67 g, 16.1 mmol) was added in one portion to
a solution of ester (15R)-(þ)-28a (1.80 g, 3.21 mmol) in MeOH
(10 mL). The resulting suspension was stirred overnight resulting in
disappearance of the starting material 28a (TLC, CH3CN/toluene
6:1). After cooling and evaporating the solvent, the residual solid
was dissolved in water (100 mL) and washed with Et2O (25 mL) to
remove organic impurities. The water layer was acidified with citric
acid to pH 4e5 and the product was extracted with ethyl acetate
(3ꢂ25 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, filtered and evaporated in vacuo to afford the crude
acid 7a (1.67 g). Purification by silica gel flash chromatography
(AcOEt/MeOH 10:1) afforded the pure fluprostenol (15R)-(þ)-7a
5), 130.3 (
u
-chain C-2), 131.8 (q, J¼32.0 Hz, aromatic C-3), 135.5 (
u-
chain C-1), 158.7 (aromatic C-1), 174.6 (C]O) ppm. HRMS (ESI):
calcd for C28H39F3NaO8 [MþNa]þ 583.24892; found 583.2495.
HPLC: Gemini C18, 3
mm, 250ꢂ4.6 mm column, KH2PO4 (4 g/L)/
CH3CN/MeOH (90:5:5) (phase A)/CH3CN (phase B) with gradient
elution 67e10%, 1.0 mL/min, tR¼36.13 min (8.46% yield of (5E,15R)-
isomer) tR¼37.96 min (0.18% yield of (15S)-(þ)-28b), tR¼39.62 min
(91.36% yield of (15R)-(þ)-28a). LCeMS (ESI): Gemini C18, 3
mm,
250ꢂ4.6 mm column, CH3COONH4 (1.44 g/L)/CH3CN/MeOH
(90:5:5) (phase A)/CH3CN (phase B) with gradient elution 67e10%,
1.0 mL/min, tR¼37.33 min (m/z¼561.2 [MþH]þ for (5E,15R)-isomer),
tR¼37.90 min (m/z¼561.2 [MþH]þ for (15S)-(þ)-28b), tR¼40.56 min
(m/z¼561.2 [MþH]þ for (15R)-(þ)-28a).
(1.43 g, 98%, 7a/7b/(5E,15R)-isomer¼91.84%:0.18%:7.98%) as a thick
20
pale yellow oil. Rf¼0.27 (AcOEt/MeOH 5:1). [
a
]
þ21.1 (c 1.0,
D
CHCl3). FTIR (thin film)
1239, 1168, 1125, 1066, 1035, 972, 913, 882, 792, 698 cmꢀ1. 1H NMR
(CDCl3, 600 MHz) 1.49 (m, 1H, cyclopentane CH-1), 1.64 (m, 2H,
chain CH2-3), 1.70 (m, 1H, one of the cyclopentane CH2-4 group),
2.08e2.14 (m, 3H, -chain CH2-4 and one of the -chain CH2-7
group), 2.18e2.40 (m, 5H, -chain CH2-2, one of the -chain CH2-7
group, one of the cyclopentane CH2-4 group and cyclopentane CH-
2), 3.93 (m, 1H, cyclopentane CH-3), 3.98 (m, 2H, -chain CH2-4),
4.14 (m, 1H, cyclopentane CH-5), 4.52 (m, 1H, -chain CH-3), 5.35
(m, 1H, -chain CH-5), 5.44 (m, 1H, -chain CH-6), 5.64e5.72 (m,
2H, -chain CH-1 and
n 3363, 3009, 1710, 1593, 1493, 1451, 1330,
4.12.1. 2,2-Bis(hydroxymethyl)propyl (Z)-7-{(1R,2R,3R,5S)-3,5-
dihydroxy-2-[(S,E)-3-hydroxy-4-(3-trifluoromethylphenoxy)but-1-
enyl]cyclopentyl}hept-5-enoate (28b). According to the procedure
described for the preparation of the pentaol (15R)-(þ)-28a, the
crude silyl protected derivative 27b (4.19 g) yielded the pure
prostaglandin analogue (15S)-(þ)-28b (1.49 g, 86% yield from
phenylsulfone 15, 28a/28b/(5E,15S)-isomer¼0.53%:91.1%:8.37%).
d
a-
a
a
a
a
u
[
a
]
20 þ23.8 (c 1.0, CHCl3). FTIR (thin film)
n
3368, 2962, 2935, 2879,
u
D
1726, 1592, 1493, 1450, 1330, 1241, 1167, 1125, 1039, 972, 916, 882,
a
a
792, 699 cmꢀ1. 1H NMR (CDCl3, 600 MHz)
(m, 1H, cyclopentane CH-1), 1.60e1.73 (m, 2H,
(m, 1H, one of the cyclopentane CH2-4 group), 2.12e2.24 (m, 4H,
-chain CH2-4, one of the -chain CH2-7 group, one of the cyclo-
pentane CH2-4), 2.24e2.38 (m, 3H, -chain CH2-2 and one of the
-chain CH2-7 group), 2.42 (m, 1H, cyclopentane CH-2), 3.53 (s,
4H, two eCH2OH), 3.95 (dd, J¼7.7 and 9.4 Hz, 1H, one of the
chain CH2-4 group), 3.97 (m, 1H, cyclopentane CH-3), 4.02 (dd,
-chain CH2-4 group), 4.10 (m, 2H,
-chain CH2-1 group), 4.15 (m, 1H, cyclopentane CH-5), 4.53 (m,
d
0.84 (s, 3H, eCH3), 1.55
-chain CH2-3), 1.80
u
u
-chain CH-2), 7.09 (dd, J¼2.4 and 8.3 Hz, 1H,
a
aromatic CH-6), 7.15 (m, 1H, aromatic CH-2), 7.21 (dm, J¼7.7 Hz, 1H,
aromatic CH-4), 7.38 (m, 1H, aromatic CH-5) ppm. 13C NMR
a
a
(150 MHz, CDCl3)
chain C-4), 33.0 (
(cyclopentane C-1), 55.3 (cyclopentane C-2), 70.7 (
71.8 ( -chain C-4), 72.1 (cyclopentane C-5), 77.2 (cyclopentane
C-3), 111.4 (q, J¼3.8 Hz, aromatic C-2), 117.7 (q, J¼4.0 Hz, aromatic
C-4), 118.0 (aromatic C-6), 123.9 (q, J¼271.2 Hz, eCF3), 128.9 (
chain C-6), 129.6 ( -chain C-5), 129.9 ( -chain C-2), 130.0 (aromatic
-chain C-1), 158.7
d
24.5 (
-chain C-2), 42.6 (cyclopentane C-4), 50.0
-chain C-3),
a-chain C-3), 25.1 (a-chain C-7), 26.3 (a-
a
a
a
u
u
-
u
J¼3.8 and 9.4 Hz, 1H, one of the
u
a-
a
a
u
1H,
u
-chain CH-3), 5.35 (m, 1H,
a
-chain CH-5), 5.44 (m, 1H,
a
-
C-5), 131.8 (q, J¼32.2 Hz, aromatic C-3), 135.2 (
u
chain CH-6), 5.70 (dd, J¼5.4 and 15.5 Hz, 1H,
u
-chain CH-2), 5.75
(aromatic C-1), 176.8 (C]O) ppm. HRMS (ESI): calcd for
(dd, J¼8.0 and 15.5 Hz, 1H,
u
-chain CH-1), 7.09 (dd, J¼2.4 and
C23H29F3NaO6 [MþNa]þ 481.18084; found 481.1802. HPLC: Gemini
8.3 Hz, 1H, aromatic CH-6), 7.15 (m, 1H, aromatic CH-2), 7.21 (dm,
C18, 3
m
m, 250ꢂ4.6 mm column, with gradient elution 67e10%
J¼7.7 Hz, 1H, aromatic CH-4), 7.38 (m, 1H, aromatic CH-5) ppm. 13C
KH2PO4 (4 g/L)/CH3CN/MeOH (90:5:5) (phase A)/CH3CN (phase B),

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1645
1.0 mL/min, tR¼30.43 min (7.98% yield of (5E,15R)-isomer),
tR¼33.18 min (0.18% yield of (15S)-(þ)-7b), tR¼34.23 min (91.84%
the aqueous phase was extracted with AcOEt (3ꢂ25 mL). The
combined extracts were washed with saturated NaHCO3 (100 mL),
water (150 mL) and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude product 8a
(1.42 g), which was purified by silica gel flash chromatography
with gradient elution 5e10% 2-propanol/CH2Cl2 to afford the
title compound (15R)-(þ)-8a (1.19 g, 95% yield, 8a/8b/
8c¼91.95%:0.18%:7.87%) as a pale yellow oil. This sample was fur-
ther purified by preparative HPLC on silica gel to give travoprost
(8a, 0.79 g, 64% yield) as a thick colourless oil. Rf¼0.3 (2-propanol/
yield of (15R)-(þ)-7a). LCeMS (ESI): Gemini C18,
3 mm,
250ꢂ4.6 mm column, with gradient elution 67e10% CH3COONH4
(4 g/L)/CH3CN/MeOH (90:5:5) (phase A)/CH3CN (phase B), 1.0 mL/
min, tR¼36.06 min (m/z¼497.4 [MþH]þ for (5E,15R)-isomer),
tR¼37.87 min (m/z¼497.4 [MþH]þ for (15S)-(þ)-7b), tR¼38.62 min
(m/z¼497.4 [MþH]þ for (15R)-(þ)-7a).
4.13.1. (Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(S,E)-3-hydroxy-4-(3-
20
20
trifluoromethylphenoxy)but-1-enyl]cyclopentyl}hept-5-enoic
acid
CH2Cl2 8:1). [
CH2Cl2)).19 FTIR (thin film)
1450, 1375, 1241, 1168, 1127, 1066, 1035, 970, 951, 915, 882, 792,
698 cmꢀ1. 1H NMR (C6D6, 600 MHz)
1.05 (s, 3H, eCH3), 1.06 (s, 3H,
eCH3), 1.36 (m, cyclopentane CH-1), 1.63 (m, 2H, -chain CH2-3),
1.88 (dd, J¼4.2 and 15.0 Hz, one of the cyclopentane CH2-4 group),
2.00e2.08 (m, 1H, one of the -chain CH2-4 group), 2.10e2.17 (m,
3H, -chain CH2-2 and one of the -chain CH2-4 group), 2.20e2.26
(m, 2H, one of the -chain CH2-7 group and one of the cyclo-
pentane CH2-4 group), 2.47 (m, 1H, one of the -chain CH2-7
group), 2.62 (m, 1H, cyclopentane CH-2), 3.80 (dd, J¼4.2 and 9.6 Hz,
one of the
-chain CH2-4 group), 3.86 (dd, J¼6.9 and 9.6 Hz, one of
the -chain CH2-4 group), 3.96 (m, 1H, cyclopentane CH-3), 4.08
a
]
þ16.3 (c 1.0, CH2Cl2). (lit. [
a
]
þ14.6 (c 1.0,
D
D
(7b). In the same manner as described for the preparation of
fluprostenol (15R)-(þ)-7a, hydrolysis of the ester (15S)-(þ)-28b
n 3376, 2975, 2934, 1727, 1592, 1493,
(1.0 g, 1.78 mmol) afforded the pure acid (15S)-(þ)-7b (0.79 g, 96%
d
20
yield, 7a/7b/(5E,15S)-isomer¼0.53%:91.37%:8.10%). [
a
]
þ24.0 (c
a
D
1.0, CHCl3). FTIR (thin film)
1330, 1239, 1168, 1126, 1066ꢁ, 1036, 972, 913, 882, 792, 698 cmꢀ1. 1H
NMR (CDCl3, 600 MHz, 25 C) 1.48 (m, 1H, cyclopentane CH-1),
1.63 (m, 2H, -chain CH2-3), 1.77 (m, 1H, one of the cyclo-
pentane CH2-4 group), 2.10 (m, 2H, -chain CH2-4), 2.13e2.24 (m,
2H, -chain CH2-7), 2.25e2.32 (m, 3H, one of the cyclopentane
CH2-4 group and -chain CH2-2), 2.37 (m, 1H, cyclopentane CH-2),
3.95 (dd, J¼7.4 and 9.4 Hz, one of the -chain CH2-4 group), 3.98
(m, 1H, cyclopentane CH-3), 4.02 (dd, J¼3.5 and 9.4 Hz, one of
chain CH2-4 group), 4.18 (m, 1H, cyclopentane CH-5), 4.56 (m, 1H,
-chain CH-3), 5.35 (m, 1H, -chain CH-5), 5.47 (m, 1H, -chain
CH-6), 5.68 (dd, J¼5.6 and 15.4 Hz, 1H, -chain CH-2), 5.72 (dd,
n 3370, 3009, 2935, 1709, 1593, 1450,
a
d
a
a
a
a
a
a
a
a
u
u
u
u
-
(br s, 1H, cyclopentane CH-5), 4.30 (s, 1H, eOH), 4.53 (m, 1H,
chain CH-3), 4.98 (septet, J¼6.3 Hz, 1H, eCH(CH3)2), 5.37 (m, 1H,
u
a
-
-
u
a
a
chain CH-5), 5.54 (m, 1H,
a
-chain CH-6), 5.66 (dd, J¼9.2 and
u
15.4 Hz,
u
-chain CH-1), 5.81 (dd, J¼7.2 and 15.4 Hz,
u-chain CH-2),
J¼8.2 and 15.4 Hz, 1H,
u
-chain CH-1), 7.07 (dd, J¼2.4 and 8.3 Hz,
6.90 (dd, J¼2.2 and 8.5 Hz, 1H, aromatic CH-6), 6.98 (m, 1H, aro-
1H, aromatic CH-6), 7.13 (m, 1H, aromatic CH-2), 7.20 (dm,
matic CH-5), 7.05 (dm, J¼7.7 Hz, 1H, aromatic CH-4), 7.25 (m, 1H,
J¼7.7 Hz, 1H, aromatic CH-4), 7.36 (m, 1H, aromatic CH-5) ppm. 13C
aromatic CH-2) ppm. 13C NMR (150 MHz, C6D6)
d
21.7 (eCH3), 21.8
-chain C-4),
-chain C-2), 43.5 (cyclopentane C-4), 50.2 (cyclopentane C-
1), 55.8 (cyclopentane C-2), 67.6 (eCH(CH3)2), 71.5 ( -chain C-3),
72.2 (cyclopentane C-5), 72.3 ( -chain C-4), 77.6 (cyclopentane C-
3), 111.9 (q, J¼3.8 Hz, aromatic C-2), 117.7 (q, J¼3.8 Hz, aromatic C-
4), 118.4 (aromatic C-6), 124.8 (q, J¼274.2 Hz, eCF3), 129.6 ( -chain
C-6), 129.8 ( -chain C-5), 130.3 (aromatic C-5), 131.4 ( -chain C2),
132.0 (q, J¼32.2 Hz, aromatic C-3), 136.0 ( -chain C-1), 159.4 (ar-
NMR (150 MHz, CDCl3)
d
24.4 (
a
-chain C-3), 25.1 (
a
-chain C-7),
(eCH3), 25.2 (
a-chain C-3), 25.7 (a-chain C-7), 26.9 (a
26.2 (
50.6 (cyclopentane C-1), 55.6 (cyclopentane C-2), 70.8 (
3), 71.9 ( -chain C-4), 72.6 (cyclopentane C-5), 77.7 (cyclopentane
C-3), 111.6 (q, J¼4.1 Hz, aromatic C-2), 117.8 (q, J¼3.6 Hz, aromatic
C-4), 118.1 (aromatic C-6), 123.9 (q, J¼272.4 Hz, eCF3), 129.0 (
chain C-6), 129.5 ( -chain C-2), 129.7 ( -chain C-5), 130.1 (aro-
-chain C-1),
a
-chain C-4), 32.8 (
a
-chain C-2), 42.9 (cyclopentane C-4),
34.1 (
a
u
-chain C-
u
u
u
a
-
a
u
a
a
u
matic C-5), 131.9 (q, J¼32.3 Hz, aromatic C-3), 135.1 (
u
u
158.6 (aromatic C-1), 177.3 (C]O) ppm. HRMS (ESI): calcd for
omatic C-1), 173.3 (C]O) ppm. HRMS (ESI): calcd for C26H35F3NaO6
C23H29F3NaO6 [MþNa]þ 481.18084; found 481.1809. HPLC: Gemini
[MþNa]þ 523.2278; found 523.2272. Chiral HPLC: AS-3R, 3
mm,
C18, 3
m
m, 250ꢂ4.6 mm column, KH2PO4 (4 g/L)/CH3CN/MeOH
150ꢂ4.6 mm column, H2O/CH3CN with gradient elution from 80%
to 10%, 1.0 mL/min, tR¼32.67 min (91.95% yield of (15R)-(þ)-8a),
tR¼35.97 min (0.18% yield of (15S)-(þ)-8b), tR¼36.70 min (7.87%
(90:5:5) (phase A)/CH3CN (phase B) with gradient elution 67e10%,
1.0 mL/min, tR¼29.52 min (8.10% yield of (5E,15S)-isomer),
tR¼33.18 min (91.37% yield of (15S)-(þ)-7b), tR¼34.23 min (0.53%
yield of (5E,15R)-8c). LCeMS (ESI): AS-3R, 3
mm, 150ꢂ4.6 mm
yield of (15R)-(þ)-7a). LCeMS (ESI): Gemini C18,
3
m
m,
column, H2O/CH3CN with gradient elution from 80% to 10%, 1.0 mL/
min, tR¼34.60 min (m/z¼501.3 [MþH]þ for (15R)-(þ)-8a),
tR¼38.67 min (m/z¼501.3 [MþH]þ for (15S)-(þ)-8b), tR¼39.40 min
(m/z¼501.3 [MþH]þ for (5E,15R)-8c).
250ꢂ4.6 mm column, with gradient elution 67e10% CH3COONH4
(4 g/L)/CH3CN/MeOH (90:5:5) (phase A)/CH3CN (phase B), 1.0 mL/
min, tR¼33.82 min (m/z¼497.4 [MþH]þ for (5E,15S)-isomer),
tR¼37.87 min (m/z¼497.4 [MþH]þ for (15S)-(þ)-7b), tR¼38.62 min
(m/z¼497.4 [MþH]þ for (15R)-(þ)-7a).
4.14.1. Isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(S,E)-3-
hydroxy-4-(3-trifluoromethylphenoxy)but-1-enyl]cyclopentyl}hept-
5-enoate (8b). Treatment of the acid (15S)-(þ)-7b (0.65 g,
1.42 mmol) similar to the esterification of (15R)-(þ)-7a afforded
4.14. Isopropyl (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(R,E)-3-
hydroxy-4-(3-trifluoromethylphenoxy)but-1-enyl]cyclo-
pentyl}hept-5-enoate (8a)
the pure epimer (15S)-(þ)-8b of travoprost (0.66 g, 92% yield, 8a/
20
8b/(5E,15S)-isomer¼0.53%:91.84%:7.63%).
[
a
]
þ27.15 (c 1.0,
D
DBU (2.65 mL, 17.56 mmol) was added dropwise to a stirred
solution of fluprostenol (15R)-(þ)-7a (1.15 g, 2.51 mmol) in anhy-
drous acetone (10 mL) at 0 ꢁC under an argon atmosphere. The
mixture was allowed to warm to room temperature, whereupon 2-
iodopropane (1.77 mL, 17.56 mmol) was added dropwise. The
resulting solution was stirred for 20 h resulting in disappearance of
the starting acid 7a (TLC, CH3CN/toluene 1:1). The reaction was
quenched with ethyl acetate (100 mL). The resulting white solid
was filtered off and washed with ethyl acetate (3ꢂ25 mL). The
filtrate and washings were combined and acidified with 3% citric
acid solution to pH 5e6. The resulting layers were separated and
CH2Cl2). FTIR (thin film)
1330, 1241, 1168, 1127, 1109, 1066, 1036, 971, 917, 881, 792,
698 cmꢀ1. 1H NMR (C6D6, 600 MHz)
1.05 (s, 3H, eCH3), 1.05 (two
d, J¼6.6 Hz, 6H, two eCH3), 1.40 (m, 1H, cyclopentane CH-1), 1.63
(m, 2H, -chain CH2-3), 1.85 (m, 1H, one of the cyclopentane CH2-4
group), 2.05e2.13 (m, 2H, one of the cyclopentane CH2-4 group
and one of the -chain CH2-4 group), 2.13e2.20 (m, 3H, one of the
-chain CH2-4 group and -chain CH2-2), 2.30 (m, 1H, one of the
chain CH2-7 group), 2.45 (m, 1H, one of the -chain CH2-7 group),
2.59 (m, 1H, cyclopentane CH-2), 2.96 (br s, 1H, eOH), 3.37 (br s,
1H, eOH), 3.49 (br s, 1H, eOH), 3.79 (d, J¼5.5 Hz, 2H, -chain CH2-
n 3394, 2981, 2936, 1726, 1593, 1493, 1450,
d
a
a
a
a
a-
a
u

1646
I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
4), 3.97 (s, 1H, cyclopentane CH-3), 4.08 (m, 1H, cyclopentane CH-
5), 4.51 (m, 1H,
-chain CH-3), 4.99 (septet, J¼6.3 Hz, 1H,
eCH(CH3)2), 5.38 (m, 1H, -chain CH-5), 5.57 (m, 1H, -chain CH-
6), 5.73e5.80 (m, 2H, -chain CH-1 and -chain CH-2), 6.87 (dd,
NMR (CDCl3, 600 MHz)
J¼7.0 Hz, 3H, cyclopentane 2-CH3), 1.35 (m, 1H, cyclopentane CH-
1), 1.70e1.78 (m, 3H, -chain CH2-3 and cyclopentane CH-2), 1.80
d 0.85 (s, 3H, a-chain eCH3), 1.06 (d,
u
a
a
a
u
u
(dm, J¼14.5 Hz, 1H, one of the cyclopentane CH2-4 group), 2.02
J¼2.4 and 8.3 Hz, 1H, aromatic CH-6), 6.97 (m, 1H, aromatic CH-5),
(ddd, J¼4.4, 6.5 and 14.5 Hz, 1H, one of the cyclopentane CH2-4
7.04 (dm, J¼7.7 Hz, 1H, aromatic CH-4) and 7.23 (s, 1H, aromatic
group), 2.10e2.26 (m, 3H, a-chain CH2-4 and one of the a-chain
CH-2) ppm. 13C NMR (150 MHz, C6D6)
d
21.7 (eCH3), 21.8 (eCH3),
CH2-7 group), 2.31 (m, 1H, one of the
(m, 2H,
-chain CH2-2), 3.54 (d, J¼11.1 Hz, 2H, eCH2OH), 3.58 (d,
J¼11.1 Hz, 2H, eCH2OH), 3.82 (m, 1H, cyclopentane CH-3), 4.16 (m,
1H, cyclopentane CH-5), 4.19 (s, 2H, -chain CH2-1), 5.39 (m, 1H,
chain CH-5), 5.48 (m, 1H,
-chain CH-6) ppm. 13C NMR (150 MHz,
CDCl3) 16.9 ( -chain eCH3), 18.6 (cyclopentane 2-CH3), 24.8 (
chain C-3), 26.2 ( -chain C-4), 26.8 ( -chain C-7), 33.6 ( -chain C-
2), 40.7 (eC(CH3)(CH2OH)2), 42.3 (cyclopentane C-4), 47.4 (cyclo-
pentane C-2), 52.7 (cyclopentane C-1), 66.5
(eCH2C(CH3)(CH2OH)2), 67.6 (2C, eC(CH3)(CH2OH)2), 74.8 (cyclo-
pentane C-5), 80.7 (cyclopentane C-3), 129.4 ( -chain C-5), 129.7
a-chain CH2-7 group), 2.39
25.2 (
chain C-2), 43.6 (cyclopentane C-4), 50.9 (cyclopentane C-1), 55.8
(cyclopentane C-2), 67.7 (eCH(CH3)2), 70.6 ( -chain C-3), 72.5 (
a
-chain C-3), 25.8 (
a
-chain C-7), 26.9 (
a
-chain C-4), 34.0 (
a
-
a
u
u
-
a
a-
chain C-4), 72.6 (cyclopentane C-5), 78.1 (cyclopentane C-3), 111.9
(q, J¼4.0 Hz, aromatic C-2), 117.7 (q, J¼3.6 Hz, aromatic C-4), 118.5
a
d
a
a-
(aromatic C-6), 124.8 (q, J¼272.3 Hz, eCF3), 129.7 (
a
-chain C-6),
-chain C-2),
u-chain C-1), 159.4
a
a
a
129.8 (a-chain C-5), 130.3 (aromatic C-5), 130.6 (u
132.0 (q, J¼32.2 Hz, aromatic C-3), 134.5 (
(aromatic C-1), 173.4 (C]O) ppm. HRMS (ESI): calcd for
C26H35F3NaO6 [MþNa]þ 523.2278; found 523.2287. Chiral HPLC:
a
AS-3R, 3
m
m, 150ꢂ4.6 mm column, H2O/CH3CN with gradient
(a-chain C-6), 174.7 (C]O) ppm. HRMS (ESI): calcd for C18H32NaO6
elution 80e10%, 1.0 mL/min, tR¼32.67 min (0.53 yield of (15R)-
(þ)-8a), tR¼35.97 min (91.84% yield of (15S)-(þ)-8b), tR¼39.43 min
[MþNa]þ 367.20911; found 367.2107. HPLC: Poroshell 120 EC-C8,
2.7
m
m, 150ꢂ4.6 mm column, H2O/CH3CN (8:2, phase A)/H2O/
(7.63% yield of (5E,15S)-isomer). LCeMS (ESI): AS-3R, 3
mm,
CH3CN (1:1, phase B)/with gradient elution 100e10%, 1.0 mL/min,
tR¼7.529 min (8.37% yield of (5E)-30), tR¼7.822 min (91.63% yield
150ꢂ4.6 mm column, H2O/CH3CN with gradient elution 80e10%,
1.0 mL/min, tR¼34.60 min (m/z¼501.3 [MþH]þ for (15R)-(þ)-8a),
tR¼38.67 min (m/z¼501.3 [MþH]þ for (15S)-(þ)-8b), tR¼41.86 min
(m/z¼501.3 [MþH]þ for (5E,15S)-isomer).
of (5Z)-30). LCeMS (ESI): Poroshell 120 EC-C8, 2.7
mm,
150ꢂ4.6 mm column, 0.1% CH3COOH (phase A)/CH3CN (phase B)/
8:2, 1.0 mL/min, tR¼14.95 min (m/z¼345.4 [MþH]þ for (5E)-30),
tR¼15.50 min (m/z¼345.4 [MþH]þ for (5Z)-30).
4.15. 1-{(Z)-6-[(1R,2R,3R,5S)-2-methyl-3,5-
bis(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-
trioxabicyclo[2.2.2] octane (29)
4.17. (Z)-(D)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-methylcycl-
opentyl]hept-5-enoic acid (31)
LiOH$H2O (1.0 g, 24.0 mmol) was added in one portion to a so-
lution of ester 30 (1.65 g, 4.79 mmol) in MeOH (15 mL). The
resulting suspension was stirred overnight resulting in disappear-
ance of the starting material 30 (TLC, AcOEt/MeOH 10:1). After
cooling and evaporating the solvent, the residual solid was dis-
solved in water (100 mL) and washed with Et2O (25 mL) to remove
organic impurities. The water layer was acidified with citric acid to
pH 4e5 and the product was extracted with ethyl acetate
(3ꢂ25 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, filtered and evaporated in vacuo to afford the crude
product 31 (1.59 g). Purification by silica gel flash chromatography
(AcOEt/MeOH 10:1) afforded the pure acid 31 (1.12 g, 97% yield,
83.5% de) as a thick pale yellow oil. Rf¼0.35 (AcOEt/CH3OH 10:1).
Sulfone 15 (5.0 g, 7.14 mmol, 83.2% de) was dissolved in anhydrous
MeOH (70 mL) and Na2HPO4 (4.05 g, 28.56 mmol) was added in one
portion. On cooling to 0 ꢁC under an argon atmosphere, sodium
amalgam (20%, 3.21 g, 27.948 mmol Na) was added portionwise
with vigorous stirring. The cooling bath was removed and the
resulting suspension was stirred for 3 h at room temperature with
disappearance of the starting phenylsulfone 15 (TLC toluene/AcOEt
12:1). The solution was decanted from the remaining amalgam and
concentrated under reduced pressure. The residue was diluted with
water (100 mL) and AcOEt (50 mL). The resulting layers were
separated and the aqueous phase was extracted with AcOEt
(3ꢂ25 mL). The combined organic extracts were washed with brine
(150 mL) and dried over anhydrous Na2SO4. Filtration and evapo-
ration in vacuo furnished the crude product 29 (4.78 g) as a thick
pale yellow oil. The crude olefin 29 was directly used for the next
step without further purification.
[a
]
20 þ48.1 (c 1.0, EtOH). FTIR (thin film)
n 3368, 3006, 2953, 2930,
D
2870, 1708, 1457, 1411, 1377, 1243, 1097, 1039, 973, 912, 780, 735,
626 cmꢀ1. 1H NMR (CDCl3, 600 MHz)
1.31 (m, 1H, cyclopentane CH-1), 1.70 (m, 2H,
d
1.05 (d, J¼7.0 Hz, 3H, ꢀCH3),
a
-chain CH2-3), 1.77
(m, 1H, cyclopentane CH-2), 1.79 (dm, J¼15.0 Hz, 1H, one of the
4.16. 2,2-Bis(hydroxymethyl)propyl (Z)-7-[(1R,2R,3R,5S)-3,5-
cyclopentane CH2-4 group), 2.06 (m, 1H, one of the cyclopentane
dihydroxy-2-methylcyclopentyl]hept-5-enoate (30)
CH2-4 group), 2.09e2.23 (m, 3H,
chain CH2-7 group), 2.24e2.30 (m, 1H, one of the
group), 2.34 (m, 2H, -chain CH2-2), 3.81 (m, 1H, cyclopentane CH-
3), 4.15 (m, 1H, cyclopentane CH-5), 5.38 (m, 1H, -chain CH-5),
5.45 (m, 1H,
-chain CH-6), 5.69 (br s, 2H, two eOH) ppm. 13C
NMR (150 MHz, CDCl3) 18.1 (CH3), 24.5 ( -chain C-3), 26.3 (
chain C-7), 26.4 ( -chain C4), 33.2 ( -chain C-2), 42.1 (cyclopentane
C-4), 46.7 (cyclopentane C-2), 52.5 (cyclopentane C-1), 74.3
(cyclopentane C-5), 80.3 (cyclopentane C-3), 129.4 ( -chain C-5),
a
-chain CH2-4 and one of the
a-
a
-chain CH2-7
TBAF (14.9 mL, 14.9 mmol, 1.0 M in THF) was added dropwise to
a solution of the crude silyl protected alcohol 29 (4.78 g) in an-
hydrous THF (15 mL). The resulting solution was stirred at room
temperature under an argon atmosphere for 1 h, whereupon THF
was evaporated under reduced pressure. The viscous residue was
then diluted with 10% aqueous solution of citric acid (20 mL) to
hydrolyze 4-methyl-OBO carboxyl masking group. After being
stirred for 15 min, the product was salted out with sodium chlo-
ride, separated and dried in vacuo to give the crude tetraol 30
(4.23 g). Purification by silica gel flash chromatography with gra-
dient elution 6e10% methanol/ethyl acetate afforded the prosta-
glandin analogue 30 (2.25 g, 91% yield from phenylsulfone 15,
a
a
a
d
a
a-
a
a
a
129.5 (a-chain C6), 178.3 (C]O) ppm. HRMS (ESI): calcd for
C13H22NaO4 [MþNa]þ 265.14103; found 265.1420. Chiral HPLC: AS-
3R, 3
m
m, 150ꢂ4.6 mm column, H2O/CH3CN with gradient elution
90e10%, 1.0 mL/min, tR¼7.03 min (91.77% yield of (5Z)-31),
tR¼7.56 min (8.23% yield of (5E)-31). LCeMS (ESI): Kinetex XB-18,
83.3% de) as a thick pale yellow oil. Rf¼0.32 (AcOEt/CH3OH 10:1).
2.7
m
m, 150ꢂ4.6 mm column, H2O/CH3CN (8:2, phase A)/CH3CN
20
[
a
]
þ31.8 (c 1.0, EtOH). FTIR (thin film)
n
3370, 2954, 1715, 1459,
(phase B) 8:2, 1.0 mL/min, tR¼8.99 min (m/z¼243.3 [MþH]þ for
D
1378, 1315, 1247, 1174, 1089, 1046, 974, 912, 736, 702, 597 cmꢀ1. 1H
(5Z)-31), tR¼9.25 min (m/z¼243.3 [MþH]þ for (5E)-31).

I. Dams et al. / Tetrahedron 69 (2013) 1634e1648
1647
J. Am. J. Health Syst. Pharm. 2005, 62, 691e699; (h) Collaborative Normal-Tension
Glaucoma Study Group Am. J. Ophthalmol. 1998, 126, 487e497.
4.18. Isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-methyl-
cyclopentyl]hept-5-enoate (18)
3. (a) Ishida, N.; Odani-Kawabata, N.; Shimazaki, A.; Hara, H. Cardiovasc. Drug Rev.
2006, 24, 1e10; (b) Bean, G. W.; Camras, C. B. Surv. Ophthalmol. 2008, 53,
S69eS84; (c) Eisenberg, D. L.; Toris, C. B.; Camras, C. B. Surv. Ophthalmol. 2002, 47,
S105eS115; (d) Alm, A. Prog. Retin. Eye Res. 1998, 17, 291e312; (e) Toris, C. B.;
Gabelt, B. T.; Kaufman, P. L. Surv. Ophthalmol. 2008, 53, S107eS120; (f) Stjern-
schantz, J. W. Invest. Ophthalmol. Vis. Sci. 2001, 42, 1134e1145; (g) Brooks, T. C.;
Burlingame, M.; Burk, M.; Tortorice, K.; Dong, D.; Glassman, P. A.; Lynch, J. A.;
Good, C. B.; Rickman, H. S.; Claborn, M.; Appleman, D.; Jones, W.; Shaverd, L.
Formulary 2009, 44, 322e328; (h) Waugh, J.; Jarvis, B. Drugs Aging 2002, 19,
465e471; (i) Burk, R. M.; Woodward, D. F. Drug Dev. Res. 2007, 68, 147e155; (j)
Sharif, N. A.; Klimko, P. Expert Rev. Ophthalmol. 2009, 4, 477e489; (k) Easthope, S.
E.; Perry, C. M. Drugs Aging 2002, 19, 231e248; (l) Woodward, D. F.; Phelps, R. L.;
Krauss, A. H.-P.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A. Cardiovasc.
Drug Rev. 2004, 22, 103e120; (m) Sit, A. J.; Asrani, S. Surv. Ophthalmol. 2008, 53,
S45eS55; (n) Cantor, L. B. Exp. Opin. Invest. Drugs 2001, 10, 721e731; (o) Perry, C.
M.; McGavin, J. K.; Culy, C. R.; Ibbotson, T. Drugs Aging 2003, 20, 597e630.
4. (a) Bito, L. Z.; Draga, A.; Blanco, J.; Camras, C. B. Invest. Ophthalmol. Vis. Sci. 1983,
DBU (2.43 mL, 16.1 mmol) was added dropwise to a stirred so-
lution of acid 31 (0.78 g, 3.22 mmol) in anhydrous acetone (10 mL)
at 0 ꢁC under an argon atmosphere. The mixture was allowed to
warm to room temperature, whereupon 2-iodopropane (1.62 mL,
16.1 mmol) was added dropwise. The resulting solution was stirred
for 22 h resulting in disappearance of the starting acid 31 (TLC,
CH3CN/toluene 1:1). The reaction was quenched with ethyl acetate
(100 mL). The resulting white solid was filtered off and washed
with AcOEt (3ꢂ25 mL). The filtrate and washings were combined
and acidified with 3% citric acid solution to pH 5e6. The resulting
layers were separated and the aqueous phase was extracted with
AcOEt (3ꢂ25 mL). The combined extracts were washed with satu-
rated aqueous NaHCO3 (100 mL), water (150 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude product 18 (1.14 g), which was purified by silica gel flash
chromatography with gradient elution 5e10% 2-propanol/CH2Cl2 to
afford the ester 18 (0.85 g, 93% yield, 84.4% de) as a pale yellow oil.
This sample was further purified by preparative HPLC on silica gel
to give the isopropyl ester 18 (0.62 g, 68.1% yield) as a thick col-
ꢀ
24, 312e319; (b) Giufree, G. Graefe’s Arch. Clin. Exp. Ophthalmol. 1985, 222,
139e141; (c) Camras, C. B.; Bito, L. Z.; Eakins, K. E. Invest. Ophthalmol. Vis. Sci.
1977, 16, 1125e1134; (d) Bito, L. Z. Surv. Ophthalmol. 1997, 41, S1eS14.
5. For a review on Corey synthesis of PGF2 see: (a) Corey, E. J.; Weinshenker, N.
a
M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675e5677; (b) Corey, E.
J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M. J. Am. Chem. Soc.
1970, 92, 397e398; (c) Corey, E. J.; Noyori, R.; Schaaf, T. K. J. Am. Chem. Soc. 1970,
92, 2586e2587; (d) Corey, E. J. Angew. Chem., Int. Ed. Engl. 1991, 30, 455e465;
(e) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New York,
NY, 1989, pp 255e256.
ourless oil. Rf¼0.47 (CH2Cl2/i-PrOH 8:1). [
FTIR (thin film)
1312, 1247, 1180, 1109, 1040, 969, 822, 723 cmꢀ1
600 MHz)
1.06 (d, J¼7.0 Hz, 3H, ꢀCH3), 1.23 and 1.24 (two s, 6H,
eCH(CH3)), 1.31 (m, 1H, cyclopentane CH-1), 1.69 (m, 2H, -chain
a
]
20 þ31.4 (c 1.0, CH2Cl2).
ꢀ
6. Resul, B.; Stjernschantz, J.; No, K.; Liljebris, C.; Selen, G.; Astin, M.; Karlsson, M.;
D
Bito, L. Z. J. Med. Chem. 1993, 36, 243e248.
7. Selliah, R.; Dantanarayana, A.; Haggard, K.; Egan, J.; Do, E. U.; May, J. A. J. La-
belled Cpd. Radiopharm. 2001, 44, 173e183.
n
3395, 2979, 2953, 2933, 2870, 1731, 1456, 1375,
.
1H NMR (CDCl3,
d
8. Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533e1564.
ꢀ
9. Liljebris, C.; Selen, G.; Resul, B.; Stjernschantz, J.; Hacksell, U. J. Med. Chem. 1995,
a
38, 289e304.
CH2-3), 1.76 (m, 1H, cyclopentane CH-2), 1.80 (dm, J¼15.0 Hz, 1H,
one of the cyclopentane CH2-4 group), 2.02 (ddd, J¼4.4, 6.5 and
14.5 Hz, 1H, one of the cyclopentane CH2-4 group), 2.07e2.24 (m,
10. Klimko, P.; Hellberg, M.; McLaughlin, M.; Sharif, N.; Severns, B.; Williams, G.;
Haggard, K.; Liao, J. Bioorg. Med. Chem. 2004, 12, 3451e3469.
11. Matsumura, Y.; Mori, N.; Nakano, T.; Sasakura, H.; Matsugi, T.; Hara, H.; Mor-
izawa, Y. Tetrahedron Lett. 2004, 45, 1527e1529.
12. Bowler, J.; Crossley, N. S. GB Patent 1,350,971, 1974.
13. Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Yudovich, L.; Pertsikov, B.;
Tishin, B. U.S. Patent 7,166,730, 2007.
14. Henegar, K. E. US Patent Application 2003/0187071 A1, 2003.
15. Hwang, S.-W.; Adiyaman, M.; Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1996,
37, 779e782.
3H,
2H,
a
-chain CH2-4 and one of the
a-chain CH2-7 group), 2.29 (m,
a-chain CH2-2), 2.87 (br s, 2H, two eOH), 2.94 (m, 1H, one of the
a
-chain CH2-7), 3.80 (m, 1H, cyclopentane CH-3), 4.15 (m, 1H,
cyclopentane CH-5), 5.00 (septet, J¼6.3 Hz, 1H, eCH(CH3)2), 5.39
(m, 1H, -chain CH-5), 5.47 (m, 1H,
-chain CH-6) ppm. 13C NMR
(150 MHz, CDCl3) 18.3 (CH3), 21.8 (2C, eCH(CH3)2), 24.9 ( -chain
C-3), 26.4 ( -chain C-7), 26.6 ( -chain C-4), 34.1 ( -chain C-2), 42.3
a
a
16. Kim, S.; Bellone, S.; Maxey, K. M.; Powell, W. S.; Lee, G.-J.; Rokach, J. Bioorg. Med.
d
a
Chem. Lett. 2005, 15, 1873e1876.
a
a
a
17. (a) Corey, E. J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma, R. K. J. Am.
Chem. Soc. 1971, 93, 1491e1493; (b) Corey, E. J.; Becker, K. B.; Varma, R. K. J. Am.
Chem. Soc. 1972, 94, 8616e8618; (c) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen,
C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925e7926; (d) Aswathanar-
ayanappa, C.; Bheemappa, E.; Bodke, Y. D. Org. Process Res. Dev. 2011, 15,
1085e1087; (e) Zanoni, G.; D’Alfonso, A.; Porta, A.; Feliciani, L.; Nolan, S. P.;
Vidari, G. Tetrahedron 2010, 66, 7472e7478; (f) Corey, E. J. Pure Appl. Chem. 1990,
(cyclopentane C-4), 47.0 (cyclopentane C-2), 52.8 (cyclopentane C-
1), 67.6 (eCH(CH3)2), 74.3 (cyclopentane C-5), 80.4 (cyclopentane
C-3), 129.4 (a-chain C-6), 129.5 (a-chain C-5), 173.4 (C]O) ppm.
HRMS (ESI): calcd for C16H28NaO4 [MþNa]þ 307.18798; found
307.1890. Chiral HPLC: AS-3R, 3
m
m, 150ꢂ4.6 mm column, H2O/
ꢀ
ꢁ
ꢀ
ꢀ ꢁ
62, 1209e1216; (g) Obadalova, I.; Pilarcík, T.; Slavíkova, M.; Hajícek, J. Chirality
2005, 17, S109eS113; (h) Hutton, J.; Senior, M.; Wright, N. C. A. Synth. Commun.
1979, 9, 799e808; (i) Hutton, J. Synth. Commun. 1979, 6, 483e486; (j) Node, M.;
Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000, 122,
1927e1936; (k) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6717e6725.
CH3CN with gradient elution 80e10%, 1.0 mL/min, tR¼15.65 min
(91.88% yield of (5Z)-(þ)-18), tR¼17.09 min (8.12% yield of (5E)-18).
LCeMS (ESI): AS-3R, 3
m
m, 150ꢂ4.6 mm column, H2O/CH3CN with
gradient elution 80e10%, 1.0 mL/min, tR¼15.39 min (m/z¼285.2
[MþH]þ for (5Z)-(þ)-18), tR¼16.95 min (m/z¼285.2 [MþH]þ for
(5E)-18).
18. Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankowski, J.; Wicha, J.
Tetrahedron 1988, 44, 4989e4998.
19. Boulton, L. T.; Brick, D.; Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.;
Parkin, N.; Rhodes, D.; Ruecroft, G. Org. Process Res. Dev. 2002, 6, 138e145.
ꢀ
20. Das, S.; Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286e3337.
ꢀꢀ
21. (a) Martynow, J. G.; Jozwik, J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.;
Acknowledgements
ꢀ
Wisniewski, K.; Winiarski, J.; Zegrocka-Stendel, O.; Go1e˛biewski, P. Eur. J. Org.
Chem. 2007, 689e703; (b) Martynow, J. G.; Szyc, J.; Szelejewski, W.; Achmato-
wicz, O.; Kutner, A.; Wisniewski, K.; Winiarski, J.; Zegrocka-Stendel, O.;
Go1e˛biewski, P. U.S. Patent 7,897,793 B2, March 1, 2011.
Financial support was provided by the European Union from the
European Regional Development Fund (ERDF) under the Innovative
Economy Operational Programme (UDA-POIG.01.03.01-14-068/
08-00).
ꢀ
22. (a) Dubiner, H. B.; Sircy, M. D.; Landry, T.; Bergamini, M. V. W.; Silver, L. H.;
Turner, F. D.; Robertson, S.; Andrew, R. M.; Weiner, A.; Przydryga, J. Clin. Ther.
2004, 26, 84e91; (b) Van der Valk, R.; Webers, C. A. B.; Schouten, J. S. A. G.;
Zeegers, M. P.; Hendrikse, F.; Prins, M. H. Ophthalmology 2005, 112, 1177e1185.
ꢀ
23. (a) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833e4836; (b) Kocienski, P. J.;
ꢀ
Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin Trans. 1 1978, 829e834; (c) Kocienski,
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(d) Kocienski, P. J. Phosphorus Sulphur 1985, 24, 97e127; (e) Blakemore, P. R.;
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Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26e28.
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