Z- and E-selective Horner–Wadsworth–Emmons reactions

Article abstract of DOI:10.1080/00397911.2017.1319487

In the present work, we determined and evaluated the stereochemical outcome of the Horner–Wadsworth–Emmons (HWE) reaction of 2-oxoalkylphosphonates with different ester functions (bis(2,2,2-trifluoroethyl), 2,2,2-trifluoroethyl methyl, dimethyl) and side chains (aliphatic, aromatic) with three different aldehydes (benzaldehyde, THP- and PPB-protected Corey aldehydes) under two reaction conditions. The “trans” protocol is generally used in the E-selective HWE reactions, while “cis” protocol promotes the Z-selectivity.

Full text of DOI:10.1080/00397911.2017.1319487

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Z- and E-selective Horner-Wadsworth-Emmons
(HWE) Reactions
Katalin Molnár, László Takács, Mihály Kádár, Ferenc Faigl & Zsuzsanna
Kardos
To cite this article: Katalin Molnár, László Takács, Mihály Kádár, Ferenc Faigl & Zsuzsanna
Kardos (2017): Z- and E-selective Horner-Wadsworth-Emmons (HWE) Reactions, Synthetic
Communications, DOI: 10.1080/00397911.2017.1319487
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Date: 27 April 2017, At: 04:38

Z- and E-selective Horner-Wadsworth-Emmons (HWE) reactions
1
,
1
1
2
1
Katalin Molnár , László Takács , Mihály Kádár , Ferenc Faigl , Zsuzsanna Kardos
1
Prostaglandin Business Unit, Sanofi, Budapest, Hungary
2
MTA-BME Organic Chemical Technology Research Group, Hungarian Academy of
Sciences, Budapest University of Technology and Economics, Budapest, Hungary
Corresponding author Katalin Molnár. Email: katimolnar88@gmail.com
Abstract
In the present work, we determined and evaluated the stereochemical outcome of the
Horner-Wadsworth-Emmons (HWE) reaction of 2-oxoalkylphosphonates with different
ester functions (bis(2,2,2-trifluoroethyl), 2,2,2-trifluoroethyl methyl, dimethyl) and side-
chains (aliphatic, aromatic) with three different aldehydes (benzaldehyde, THP- and PPB-
protected Corey aldehydes) under two reaction conditions. The “trans” protocol is
generally used in the E-selective HWE reactions, while “cis” protocol promotes the Z-
selectivity.
Graphical Abstract
KEYWORDS: Horner-Wadsworth-Emmons reaction, stereoselectivity,
bis(trifluoroethyl) phosphonates, α,β-unsaturated ketones
1

INTRODUCTION
Prostaglandins are active ingredients for therapeutical applications. Quality control of the
active pharmaceutical ingredients requires the identification and quantification of trace
impurities arising during the large scale synthesis of prostaglandins. These impurities are
mainly the Z stereoisomers in the double bond of the lower side-chain. Both natural and
biologically active synthetic prostaglandins have an (E)-α,β-unsaturated secondary
[1]
alcohol subunit. This is routinely introduced using the Horner-Wadsworth-Emmons
HWE) reaction via the corresponding enone. In the frame of a comprehensive program,
we initiated the synthesis of Z-prostaglandin isomeric impurities. Our approach was the
(
[
1]
elaboration of a Z-selective version of the HWE reaction (Scheme 1) .
[1]
[2,3]
The Horner-Wadsworth-Emmons reaction is a modified Wittig
reaction where
stabilized phosphonate carbanions are reacted with carbonyl compounds to supply α,β-
unsaturated-oxo compounds with excellent E-selectivity. Because of the relatively mild
conditions, ease of work-up, high yields and selectivity, the HWE reaction is the
preferred method for creating double bonds with an E geometry. On the other hand, it
may be necessary to form double bonds selectively with either a Z or an E geometry in
the same position. In view of the advantages of HWE reactions, a plausible objective of
research was to extend its scope to the selective introduction of Z double bonds, as well.
Much effort has been expended to invert the E/Z selectivity resulting in two independent
and promising methods.
2

[
4]
According to the procedure published by Still and Gennari , bis(2,2,2-
trifluoroethyl)phosphonoesters were applied under strongly dissociated conditions i.e. in
the presence of potassium bis(trimethylsilyl)amide and 18-crown-6 base system in THF
at -78 °C. Under such conditions α,β-unsaturated esters could be prepared with excellent
or good Z-selectivity (>95%) from aromatic aldehydes. With aliphatic aldehydes,
however, selectivity was modest (>75%).
In the other method Ando used the less expensive ethyl (diarylphosphono)acetates for the
preparation of (Z)-α,β-unsaturated esters in the presence of different bases. Z-selectivity
[
5–7]
was optimized by varying the aryl-moiety, reaction temperature and the base system.
(Z)-α,β-unsaturated nitriles were also prepared with excellent selectivity from
8
diarylphosphononitriles with different aromatic and aliphatic aldehydes.
While a large number of methods cover the preparation of α,β-unsaturated carboxylic
acid derivatives and reaction conditions have been significantly modified to improve
[
9,10]
scalability,
only a few references deal with the formation of (Z)-α,β-unsaturated
[
11–16]
ketones.
Thus, Jin extended the scope of Still-Gennari’s modification by reacting
bis(2,2,2-trifluoroethyl) 2-oxopropylphosphonates with different aldehydes. Aryl
aldehydes gave methyl α,β-unsaturated ketones with exclusive Z-selectivity but with
[
11]
alkyl aldehydes the reaction was again less selective (75-91%).
Application of Z-selective HWE reaction for the preparation of enones with a Z double
bond is rather limited owing to the laborious synthesis of the reagents i.e. bis(2,2,2-
trifluoroethyl) 2-oxophosphonates all which were prepared using Jin’s method with
3

moderate yields. However, in our hands this method gave erratic results. To overcome
these problems, two practical methods for the preparation of the necessary reagents have
[
17,18]
been worked out in our labs.
RESULTS AND DISCUSSION
In the present publication we report about model experiments aimed at the exploration of
the scope and limitations of Z- and E-selective HWE reactions. For our study, three
aldehyde components were selected i.e. benzaldehyde (1), tetrahydropyranyl- and p-
phenylbenzoyl-protected Corey aldehydes (2 and 3), the latters being important, generally
used intermediates in prostaglandin chemistry.
Aldehydes 1-3 were reacted with three bis(2,2,2-trifluoroethyl) 2-oxoalkylphosphonates,
3
containing different alkyl groups (namely R = H, propyl, 3-methyl-phenyl), marked as
phosphonates F6 (4), dimethyl 2-oxoalkylphosphonates (phosphonates F0, 6) and mixed,
2
,2,2-trifluoroethyl methyl 2-oxoalkylphosphonates (phosphonates F3, 5). Remarkably,
the effect of mixed phosphonates F3 in HWE reactions has not been investigated yet. To
reveal the directing effect of the mixed 2-oxoalkylphosphonates F3 is of interest both
from a scientific and practical point of view because of the easier preparation of F3
[
19]
compared to that of F6 derivatives.
All reactions were performed under two conditions. The so-termed “cis” protocol means
the conditions applied by Still and Gennari to obtain the best Z-selectivity, while as
[
20]
“trans” protocol we applied our in-house method (solid KOH, toluene, 0 °C).
4

[
2]
Reactions and results are summarized in Scheme 2 and Table 1.
[21–
The HWE reaction is a complex multi-step process involving several transition states.
2
3]
The geometry of the double bond formed is the resultant of multiple effects. Since the
selectivity of the process highly depends on the conditions used, all reactions were
performed under one of the two identical conditions namely the “cis” and “trans”
1
2
3
protocols to enable to compare the directing effects of the groups R , R , R and Q.
Both protocols start with the deprotonation of the phosphonate, followed by the
reversible addition of the resulting phosphonate anion to the aldehyde forming an
alkoxide anion. The next step is the closure of this structure to a four-membered
oxaphosphetane ring which, after pseudorotation and successive cleavage of the apical P–
C, then C–O bonds supplies the E- or Z-enones. Stereostructure of the arising alkoxides
and especially of the oxaphosphetanes determines the geometry of the newly formed
[
3]
double bond (Scheme 3) .
Under the strongly dissociated condition ensured by “cis” protocol, potassium cation
from the base (KHMDS) is captured by the crown ether. The naked phosphonate anion
reacts fast with the aldehyde giving the more stable erithro alkoxide, where steric
1
2
hindrance between the aldehyde (Q group) and the alkyl groups (R , R ) of phosphonate
is less. The alkoxide is a powerful nucleophile generating immediately that
oxaphosphetane isomer, which leads to the Z-double bond (route “Z”, Scheme 3).
5

On the contrary, applying the conditions provided by the “trans” protocol, the potassium
cation (from KOH) is present in the reaction mixture uncomplexed and can stabilize both
the phosphonate and the alkoxide anions as six-membered chelates. This promotes the
formation of a threo alkoxide and the thermodynamically more stable oxaphosphetane
isomer leading to the formation of an E double bond (route “E”, Scheme 3).
In general, the more powerful nucleophile is the alkoxid anion, the more Z-selective is the
HWE reaction.
Z/E stereoselectivity is largely determined by the reaction conditions but it is also
influenced by the structures of the reacting phosphonates and aldehydes.
1
2
As expected, the most significant effect was exerted by the alkyl groups (R , R )
connected to the P-O-bond.
In the phosphonates F6 the strong electron withdrawing effect of bis(trifluoroethyl)
groups increases the electrophilicity of the phosphorus atom rendering the phosphonate
anion less reactive: it reacts slower with the aldehyde and forms a sterically favoured
erithro alkoxide, which cyclizes fast to the thermodynamically less favoured
oxaphosphetane. The unstable oxaphosphetane gives readily the kinetically more
favoured Z double bond. Z-selectivity decreases with decreasing electrophilicity of the
phosphorous atom, in the order of phosphonates F6>F3>F0 explaining the directing
1
2
effects of groups R and R .
6

The effect was clearly demonstrated when benzaldehyde was reacted with different
phosphonates. Applying the “cis” protocol, benzaldehyde reacted with phosphonates F6
with excellent Z-selectivity, while the mixed phosphonates F3 gave an approx. 1:1
mixture of stereoisomers. Phosphonates F0 gave E-products in spite of the “cis” protocol
because the electronic effects of the phosphonate have a more significant impact on the
stereochemistry than reaction conditions used. Under the conditions of the “trans”
protocol, where the stabilizing effect of the base (KOH) decreases the reactivity of both
the phosphonate and the alkoxide, only phosphonates F6 gave 30-40 % of Z products,
whereas phosphonates F0 gave only the expected E products. This was the case with the
mixed phosphonates F3, as well (Figure 1).
3
The effect of the alkyl substituent R in the phosphonates is less explicit. However, it
1
2
could be demonstrated with the mixed phosphonates F3 where R and R groups have
strong but opposite directing effects compensating each other. Reacting phosphonates F3
with aldehydes 1-3 under the “cis” protocol, Z-selectivity is increased with the increasing
3
electron donating effect of the R groups in the order of propyl > H > 3-methylphenyl
(Figure 2).
Under the condition ensured by the “trans” protocol, the mixed phosphonates F3 gave
with aldehydes 1-3 the thermodynamically less stable threo alkoxide in a chelated form
following route “E” as was the case with benzaldehyde. However, steric demand of the
aldehydes also affects the stereochemical outcome. Thus, threo alkoxide arising from the
7

bulky PPB-Corey aldehyde transformed into the erithro alkoxide via the equilibria shown
in Scheme 3 giving a mixture of E/Z-products (Figure 3).
As it was presented in the previous paragraph, space demand as well as electronic
properties of the aldehydes have impact on the Z/E ratio of the forming α,β-unsaturated
ketones.
Using the “cis” protocol, phosphonates F6 gave excellent Z-selectivity with
benzaldehyde because of the relatively small size and electron withdrawing property of
the aromatic ring. Reaction with bulkier aldehydes i.e. THP- and PPB-protected Corey
aldehydes, Z-selectivity decreased because of the steric hindrance in both erithro and
threo alkoxides which can interconvert (Figure 4).
The most pronounced steric effect was experienced with the bulkiest PPB-Corey
aldehyde. Owing to severe steric hindrance of both alkoxides there was insignificant
difference in Z-selectivities when this aldehyde was reacted with phosphonates F6 under
the conditions of both “cis” or “trans” protocols (Figure 5).
CONCLUSION
Bis(2,2,2-trifluoroethyl), dimethyl and mixed trifluoroethyl methyl 2-
oxoalkylphosphonates were reacted with benzaldehyde, THP-Corey aldehyde and PPB-
Corey aldehyde. Reactions were performed under identical conditions, following either
8

the “cis” or the “trans” protocol, promoting the formation of Z- and E-products,
respectively.
Our results indicated that it was the alkoxy groups attached to the phosphorous atom
which exerted the most significant effect on the stereochemistry of double bond
formation. However, to achieve high Z-selectivity, it is essential to use both the
appropriate bis(2,2,2-trifluoroethyl) phosphonate (4) and the reaction conditions of „cis”
protocol (-78°C, KHMDS, 18-crown-6). Bulkiness and electronic properties of the
aldehyde partner also influences the geometry of the new double bond. Alkyl side-chains
of the phosphonates have less directing potency.
Molecular mechanistic computations are in progress to support the experimental results
and provide more insight into the mechanism of HWE reactions.
EXPERIMENTAL
General
During the preparation of all our products (7-15) we performed at least one purification
by column chromatography to isolate the Z and E isomers. The structure of them was
confirmed with NMR and HRMS measurements, and they were used as standards for the
determination of Z/E ratio in the products of HWE-reactions. Isomer ratio was
determined by GC-FID measurement.
9

1
13
31
H, C and P NMR spectra were recorded on Bruker AvanceIII instrument at 500.15
MHz, 125.8 MHz and 202.5 MHz, respectively, in the solvents indicated; chemical shifts
(δ) are given in parts per million (ppm) relative to TMS, coupling constants (J) in hertz
(Hz). GC analyses were carried out on a Shimadzu GC-2010 Plus by using an Agilent
DB-5MS capillary column (30 m x 0.25 mm x 0.25 m) with the time program: 5 min at
0°C, 10°C/min to 260°C, 6 min at 260°C. HRMS was obtained using a Micromass, Q-
6
TOF Premier spectrometer equipped with an Acquity UPLC.
2
4
All the reagents were commercially available (Sigma-Aldrich). THP-Corey aldehyde,
2
5
17-19
PPB-Corey aldehyde and the phosphonates used
were prepared according to
literature. Solvents were purified by distillation prior to use.
General Procedures For The HWE Reaction
“
Cis” Protocol
The solution of phosphonate (4-6, 1.1 mmol) and 18-crown-6 (0.35 g, 1.32 mmol) in abs.
THF (6 mL) was cooled to -78 °C under nitrogen atmosphere followed by addition of
KHMDS (2.01 mL, 0.52 M, 1.045 mmol) over 20 min at -78 °C, then stirred for 20 min.
Aldehydes 1-3 (1.02 mmol) were added and the reaction mixture was stirred for another
1
-3 h, quenched with sat. NH Cl solution (7 mL). The aqueous phase was extracted with
4
THF (2 x 10 mL) and the combined organic layers were washed with brine (1 x 7 mL,
5% w/w; 2 x 10 mL, 30% w/w), respectively, dried (Na SO ) and evaporated under
1
2
4
reduced pressure. The residue was purified by column chromatography.
“
Trans” Protocol
1
0

The aldehyde (1-3, 1.00 mmol) and the phosphonate (4-6, 1.09 mmol) were dissolved in
dist. toluene (15 mL) under nitrogen atmosphere. The reaction mixture was cooled to 0
°
C, KOH (0.115 g, 85%, 1.75 mmol) was added, stirred for 30-90 min and quenched with
M NaHSO solution (5 mL). The aqueous phase was extracted with toluene (2 x 10
1
4
mL) and the combined organic phases were washed with 1 M NaHCO (10 mL), water
3
(
10 mL) and brine (1 x 10 mL, 15% w/w; 10 mL, 30% w/w), respectively, dried
Na SO ) and evaporated under reduced pressure. The residue was purified by column
(
2
4
chromatography.
Sample Experiments
Preparation Of [(3ar,4R,5R,6as)-4-[(1Z/E)-4-(3-Methylphenyl)-3-Oxo-But-1-En-1-
Yl]-2-Oxo-Hexahydro-2H-Cyclopenta[B]Furan-5-Yl Biphenyl-4-Carboxylate (15)
By HWE Reaction
Purification by column chromatography: hexane: ethyl acetate = 3:2 HRMS (EI): m/z [M
+
1
+
H] calcd for C H O : 481.2015; found: 481.2034. Z-product (Figure 6): H NMR
31 29 5
(
500.15 MHz, CDCl ): δ = 2.31 (s, 3 H, CH ), 2.375 (m (ddd), J = 15.4 Hz, J = 4.5 Hz
3 3 gem
and ~1.5 Hz, CHOCH H CHO), 2.53 (m (dt), J = 15.4 Hz and J = 6.3 Hz,
a
b
gem
CHOCH H CHO), 2.73 (m (dtd), J = 9.6 Hz, 6.5 Hz and 3.0 Hz, CHOCH(CH )CH), 2.82
a
b
2
(
m (dd), Jgem = 18.6 Hz and J = 3.0 Hz, COOCH H CH), 2.89 (m (dd), J = 18.6 Hz
a b gem
and J = 9.8 Hz, COOCH H CH), 3.70 (s, 2 H, COCH C ), 4.01 (m (dt/ddd), J = 9.4 Hz
a
b
2
ar
and 5.4 Hz, CHCH(CH)CHO), 5.04 (td, J = 6.8 Hz and 2.0 Hz, CHCHOCH ), 5.275 (m
2
(
dt), J = 5.9 Hz and 4.8 Hz, CH CHOPPBCH), 5.875 (dd, J = 11.3 Hz and 9.1 Hz,
2
CHCHCH), 6.29 (m (dd), J = 11.4 Hz and 1.0, CHCO), 7.015-6.93 (m, 2 H: 6.96 (m (d),
1
1

CH C CH (o)CH (m)), 6.985 (m (s), CH C CH (o)C )), 7.055 (d, J = 7.9 Hz,
2
ar
ar
ar
2
ar
ar
ar
CH (p)C (m)CH ), 7.18 (m (t), J = 7.5 Hz, CH C CH (o)CH (m)), 7.395 (m (t/tt), J =
ar
ar
3
2
ar
ar
ar
7
2
.3 Hz and 1.5 Hz, CH (p)), 7.47 (m (t), 2 H, J = 7.5 Hz, CH (m)CH (p)), 7.62 (m (d),
ar ar ar
H, CH (o)CH (m)CH (p)), 7.66 (m (d), 2 H, J = 8.5 Hz, C CH (o)CH (m)C ), 8.04
ar
ar
ar
ar
ar
ar
ar
(
m (d), 2 H, J = 8.5 Hz, COOC CH (o)).
ar ar
1
3
C NMR (125.8 MHz, CDCl ): δ = 21.5 (CH ), 35.3 (COOCH CH), 38.4
3
3
2
(
CHOCH CHO), 45.1 (CHOCH(CH )CH), 51.0 (CHCH(CH)CHO), 51.3 (COCH C ),
2 2 2 ar
7
9.4 (CH CHOPPBCH), 83.1 (CHCHOCH ), 126.6 (CH C CH (o)CH (m)), 127.26 (2
2 2 2 ar ar ar
C, C CH (o)CH (m)C ), 127.41 (2 C, CH (o)CH (m)CH (p)), 128.1 (2 C, CHCO and
ar
ar
ar
ar
ar
ar
ar
CH (p)C (m)CH ), 128.31 (CH (p)), 128.32 (COOC ), 128.8 (CH C CH (o)CH (m)),
ar
ar
3
ar
ar
2
ar
ar
ar
1
1
1
29.1 (2 C, CH (m)CH (p)), 130.35 (CH C CH (o)C ), 130.40 (2 C, COOC CH (o)),
ar ar 2 ar ar ar ar ar
33.7 (CH C ), 138.7 (C CH ), 140.1 (C CH (o)CH (m)CH (p)), 145.4 (CHCHCH),
2
ar
ar
3
ar
ar
ar
ar
46.1 (CH (o)CH (m)C C ), 165.9 (C COO), 176.7 (CH COO), 198.1 (COCH ).
ar
ar
ar ar
ar
2
2
1
E-product (Figure 7): H NMR (500.15 MHz, CDCl ): δ = 2.34-2.26 (m, 4 H: 2.30 (m
3
(
ddd), Jgem = 15.4 Hz, J = 4.8 Hz and 1.5 Hz, CHOCH H CHO), 2.31 (s, 3 H, CH )), 2.48
a b 3
(
m (dd), Jgem = 22.6 Hz and J = 6.6 Hz, COOCH H CH), 2.595 ( dt, J = 15.6 Hz and J
a b gem
=
6.6 Hz, CHOCH H CHO), 2.95-2.82 (m, 3 H: 2.865 (m, CHOCH(CH )CH), 2.87 (m
a b 2
(
dd), Jgem = 22.5 Hz and J = 10.0 Hz, COOCH H CH), 2.905 (m (ddd), J = 8.0 Hz and
a b
6
.3 Hz, CHCH(CH)CHO)), 3.78 (s, 2 H, COCH C ), 5.08 (td, J = 6.3 Hz and 1.5 Hz,
2 ar
CHCHOCH ), 5.35 (m (dt), J = 6.2 Hz and 5.1 Hz, CH CHOPPBCH), 6.29 (m (dd), J =
2
2
1
5.6 Hz and 0.8 Hz, CHCO), 6.70 (dd, J = 15.8 Hz and 7.6 Hz, CHCHCH), 7.05-6.94 (m,
1
2

2
H: 6.975 (m (d), CH C CH (o)CH (m)), 6.995 (m (s), CH C CH (o)C )), 7.05 (d, J
2 ar ar ar 2 ar ar ar
=
7.6 Hz, CH (p)C (m)CH ), 7.18 (m (t), J = 7.5 Hz, CH C CH (o)CH (m)), 7.40 (m
ar ar 3 2 ar ar ar
(
t/tt), J = 7.3 Hz and 1.5 Hz, CH (p)), 7.47 (m (t), 2 H, J = 7.5 Hz, CH (m)CH (p)),
ar ar ar
7
.62 (m (d), 2 H, CH (o)CH (m)CH (p)), 7.67 (m (d), 2 H, J = 8.5 Hz,
ar ar ar
C CH (o)CH (m)C ), 8.03 (m (d), 2 H, J = 8.5 Hz, COOC CH (o)).
ar
ar
ar
ar
ar
ar
1
3
C NMR (125.8 MHz, CDCl ): δ = 21.5 (CH ), 35.0 (COOCH CH), 38.0
3
3
2
(
CHOCH CHO), 42.7 (CHOCH(CH )CH), 48.7 (COCH C ), 54.2 (CHCH(CH)CHO),
2 2 2 ar
7
8.7 (CH CHOPPBCH), 83.3 (CHCHOCH ), 126.6 (CH C CH (o)CH (m)), 127.35 (2
2 2 2 ar ar ar
C, C CH (o)CH (m)C ), 127.41 (2 C, CH (o)CH (m)CH (p)), 128.0 (COOC ), 128.1
ar
ar
ar
ar
ar
ar
ar
ar
(
CH (p)C (m)CH ), 128.4 (CH (p)), 128.8 (CH C CH (o)CH (m)), 129.1 (2 C,
ar ar 3 ar 2 ar ar ar
CH (m)CH (p)), 130.29 (CH C CH (o)C ), 130.34 (2 C, COOC CH (o)), 130.39
ar
ar
2
ar
ar
ar
ar
ar
(
(
(
CHCO), 133.8 (CH C ), 138.6 (C CH ), 140.0 (C CH (o)CH (m)CH (p)), 143.7
2 ar ar 3 ar ar ar ar
CHCHCH), 146.4 (CH (o)CH (m)C C ), 165.8 (C COO), 175.9 (CH COO), 199.8
ar
ar
ar ar
ar
2
COCH2).
SUPPORTING INFORMATION
1
1
Characterization ( H and 3C NMR spectra and HRMS) and purification method of
products 7-15 can be found via the “Supplementary Content” section of this article’s
webpage.
ACKNOWLEDGEMENTS
1
3

This work was supported by Sanofi-Chinoin, Pro Progressio and Varga József
Foundations. We thank Professor Mihály Nógrádi for helpful discussions.
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1
5

Table 1. Z-selectivities in the model HWE reactions.
a
Aldehyde
Phosphonate
Z-selectivity
“cis” “trans”
protocol protocol
Product
1
2
3
No. Type R
R
R
b
b
benzaldehyde 4a F6
1)
4b F6
CF CH2 CF CH2
H
98
98
96
30
35
40
7
8
9
3
3
(
CF CH2 CF CH2 propyl
3
3
4
c
F6
CF
3
CH
2
CF
3
CH
2
3-
methylphenyl
5
5
5
a
b
c
F3
F3
F3
CF
CF
CF
3
3
3
CH
CH
CH
2
2
2
CH
CH
CH
3
H
52
65
42
2
4
2
7
8
9
propyl
3
3
3-
methylphenyl
6
6
6
a
b
c
F0
F0
F0
CH
CH
CH
3
CH
CH
CH
3
3
3
H
2
1
2
0
0
0
7
8
9
propyl
3
3
3-
methylphenyl
H
THP-Corey
4a F6
CF CH2 CF CH2
70
71
75
56
56
69
10
11
12
3
3
aldehyde (2) 4b F6
CF CH2 CF CH2 propyl
3
3
4
c
F6
CF
3
CH
2
CF
3
CH
2
3-
methylphenyl
5
5
5
a
b
c
F3
F3
F3
CF
CF
CF
3
3
3
CH
CH
CH
2
2
2
CH
CH
CH
3
H
51
64
46
-
-
-
10
11
12
propyl
3-
3
3
1
6

methylphenyl
6
6
6
a
b
c
F0
F0
F0
CH
CH
CH
3
3
3
CH
CH
CH
3
3
3
H
-
-
-
2
1
1
10
11
12
propyl
3-
methylphenyl
H
PPB-Corey
4a F6
CF CH2 CF CH2
56
64
41
48
52
51
13
14
15
3
3
aldehyde (3) 4b F6
CF CH2 CF CH2 propyl
3
3
4
c
F6
CF
3
CH
2
CF
3
CH
2
3-
methylphenyl
5
5
5
a
b
c
F3
F3
F3
CF
CF
CF
3
3
3
CH
CH
CH
2
2
2
CH
CH
CH
3
H
38
39
22
30
35
28
13
14
15
propyl
3
3
3-
methylphenyl
6
6
6
a
b
c
F0
F0
F0
CH
CH
CH
3
CH
CH
CH
3
3
3
H
9
1
7
3
13
14
15
propyl
21
7
3
3
3-
methylphenyl
a
b
c
Z-selectivity = Z/(Z+E)*100%. Determination of isomer ratio by GC-FID.
“cis” protocol: KHMDS, 18-crown-6, -78 °C, THF.
“trans” protocol: KOH, 0 °C, toluene.
1
7

Scheme 1. Synthesis of the lower side-chain of PGF .
2
α
1
8

Scheme 2. Summary of HWE reactions.
1
9

Scheme 3. Proposed mechanism of HWE reactions.
2
0

Figure 1. Z-selectivities of the reactions of benzaldehyde (1) with 2-
oxoalkylphosphonates.
2
1

Figure 2. Reaction of phosphonates F3 with aldehydes by “cis” protocol.
2
2

Figure 3. Reaction of phosphonates F3 with aldehydes by “trans” protocol.
2
3

Figure 4. Reaction of phosphonates F6 with aldehydes.
2
4

Figure 5. Reaction of phosphonates F6 with PPB-Corey aldehyde (3).
2
5

Figure 6. Z-[(3aR,4R,5R,6aS)-4-[(1Z/E)-4-(3-Methylphenyl)-3-oxo-but-1-en-1-yl]-2-oxo-
hexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (Z-15).
2
6

Figure 7. E-[(3aR,4R,5R,6aS)-4-[(1Z/E)-4-(3-Methylphenyl)-3-oxo-but-1-en-1-yl]-2-
oxo-hexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (E-15).
2
7