Linear and Convergent Syntheses of Bifunctional Hydroxy-Bisphosphonic Compounds as Potential Bone-Targeting Prodrugs

Article abstract of DOI:10.1055/s-0037-1611540

The synthesis of two bifunctional compounds bearing a terminal hydroxy-bisphosphonic function (HBP) was achieved following a linear and a convergent strategy. In the linear approach, the free hydroxy-bisphosphonic function was introduced in the last step of the synthesis, under neutral conditions using an Arbuzov reaction with tris(trimethylsilyl) phosphite and a carboxylic acid precursor activated in situ with catecholborane. In the convergent approach, Huisgen type cycloaddition was studied starting from an HBP-functionalized alkyne partner to obtain the targeted bifunctional molecule. These complementary approaches allow for the preparation of complex bone-targeting molecules as potential prodrug candidates.

Full text of DOI:10.1055/s-0037-1611540

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
A
en
S. Aoun et al.
Paper
Synthesis
Linear and Convergent Syntheses of Bifunctional Hydroxy-Bis-
phosphonic Compounds as Potential Bone-Targeting Prodrugs
O
Sameh Aoun
OH
HO
HO
P
O
Me
N
O
P
Me
O
Pierre Sierocki
O
3
Me
HO
O
N
2
O
3
Me
Linear
synthesis
HO
O
2
O
5 steps
Jacques Lebreton*
Monique Mathé-Allainmat*
OH
HBcat
P(OSiMe3)3
HO
OH
Me
Me
Université de Nantes, CNRS, Laboratoire
CEISAM–UMR CNRS 6230, Faculté des Sciences
et des Techniques, 2 rue de la
Houssinière, BP 92208, 44322 Nantes Cedex 3,
France
Bifunctional HBP compounds
Me
3 steps
Me
O
O
N3
O
Me
R2O3P
HO
OH
Convergent
synthesis
O
3
O
O
P
+
O
3
Me
HO
2
N
monique.mathe@univ-nantes.fr
jacques.lebreton@univ-nantes.fr
R2O3P
HO
HO
P
N
N
OH
"Click"
R = H or Me
O
Me
This article is dedicated to the memory of our
colleague and friend Dr. Marc Padrines.
Me
Me
Me
Received: 09.01.2019
Accepted after revision: 17.04.2019
Published online: 14.05.2019
sis. These tetraalkylphosphonate precursors were prepared
by coupling a carboxylic or an aminophosphonate9 frag-
ment with the drug (Figure 1, compounds A to C), or involv-
ing the tetraethyl ethylidene-1,1′-bisphosphonate, which is
a good Michael acceptor10 (Figure 1, compound D). Similar
strategies were also extensively developed for protein deliv-
ery to bone.11
DOI: 10.1055/s-0037-1611540; Art ID: ss-2019-z0012-op
Abstract The synthesis of two bifunctional compounds bearing a ter-
minal hydroxy-bisphosphonic function (HBP) was achieved following a
linear and a convergent strategy. In the linear approach, the free hy-
droxy-bisphosphonic function was introduced in the last step of the
synthesis, under neutral conditions using an Arbuzov reaction with
tris(trimethylsilyl) phosphite and a carboxylic acid precursor activated
in situ with catecholborane. In the convergent approach, Huisgen type
cycloaddition was studied starting from an HBP-functionalized alkyne
partner to obtain the targeted bifunctional molecule. These comple-
mentary approaches allow for the preparation of complex bone-target-
ing molecules as potential prodrug candidates.
Taking into account the better bone-seeking ability of
the hydroxy-bisphosphonic function (HBP) compared to
the bisphosphonic (BP) one, and the wide use of HBP com-
pounds for the treatment of diseases such as osteoporosis,12
hydroxy-bisphosphonic conjugates have also been pro-
posed as drug or model drug delivery systems to bone.13
Some non-cleavable HBP conjugates such as HBP-analogue
of melphalan E,14 or HBP-derived 5-fluorouracil F,15 were
prepared but did not show obvious activity (Figure 2). The
HBP compounds could be prepared starting from a carbox-
ylic acid precursor in harsh acidic conditions (PCl3/H3-
PO3/MeSO3H at 65 °C)16a or from an acyl chloride precursor,
to give the expected hydroxy-bisphosphonic tetraester in a
two-step procedure. A first Michaelis–Arbuzov reaction
with trialkyl phosphite afforded the -ketophosphonate,
which reacted in a second step with the dialkyl phosphite,
to give the expected hydroxy-bisphosphonate tetraester.
However, this hydroxy-bisphosphonate compound showed
some tendency to rearrange to the corresponding phos-
phate-phosphonate, depending on the reaction condi-
tions.16c,d Moreover, the acidic hydrolysis or the dealkyla-
tion by halogeno trimethylsilane of the phosphonate func-
tions may be incompatible with sensitive functional groups
in the molecule. In the last years, several laboratories have
elaborated complex bioconjugated HBPs with the 4-amino-
1-hydroxybutylidene-1,1-bisphosphonic acid (alendro-
nate), a well-known anti-osteoporotic agent, introduced as
the HBP fragment.17 The terminal-free amino function of
alendronate appeared suitable to introduce the HBP frag-
Key words bisphosphonate, Arbuzov reaction, click reaction, bifunc-
tional derivatives, prodrug
The bone tissue differs from other tissues in that it
mainly contains a mineral phase, the hydroxyapatite, an in-
organic calcium phosphate compound.1 Because a limited
number of molecules exhibits a strong affinity to bone, os-
teotropic drug delivery systems (ODDS),2 based upon the
development of bioconjugates bearing bone-seeking func-
tions such as the bisphosphonic acid (BP) or the hydroxy-
bisphosphonic acid (HBP) function, have been proposed.3
Since the 1990s various approaches to combine anticancer,
antibacterial, anti-osteoporotic, and anti-inflammatory
agents with BP moieties have been reported in the litera-
ture.4 This is illustrated with the gem-bisphosphonic conju-
gate of methotrexate A5 and diclofenac B6 or with more
complex delivery systems of antibacterial or anticancer
agents such as the BP prodrug of gatifloxacin C7 or the BP
prodrug of doxorubicin D,8 respectively (Figure 1). These
gem-bisphosphonic acid bioconjugates or prodrugs were
generally obtained by deprotection of the corresponding
tetraalkylphosphonate esters in the last step of the synthe-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

B
S. Aoun et al.
Paper
Synthesis
ment by simple nucleophilic substitution under mild condi-
tions, and gave a chemically and biologically stable amide
or carbamate linkage. This amino HBP fragment could be
linked to a spacer bearing the drug, and which was also ef-
fective as a chemical-gate, as for example the biologically
sensitive 4-alkoxyphenylacetate-linker in compound G,18 or
the acid sensitive hydrazone-linker present in compound
H
19 (Figure 2). This strategy was also extended to HBP-bio-
polymers20 and HBP nanoscale particles.21
O
COONa
H
O
PO3HNa
PO3HNa
N
PO3HNa
PO3HNa
NH2
N
N
O
H
N
N
N
O
H
N
N
O
NH
H2N
Cl
Cl
amino-BP fragment
amino-BP fragment
methotrexate bioconjugate
diclofenac bioconjugate
A
B
PO3H2
O
N
F
CO2H
carboxylic-BP fragment
PO3H2
O
N
O
O
N
O
O
gatifloxacin bioconjugate C
O
OH
OH
O
OH
OH
PO3Na2
S
O
O
S
Na2O3P
OMe
O
O
O
3
N
HN
4
NH
O
HN
O
O
BP fragment
O
O
HN
OH
Me
doxorubicine bioconjugate D
Figure 1 BP bioconjugates of known drugs (BP fragment involved in the synthesis)
O
F
HN
PO3H2
OH
O
N
H2O3P
Cl
PO3HNa
OH
n
N
NaHO3P
HBP analogue of melphalan
HBP fluorouracil
Cl
E
F
COOEt
O
6
N
F
F
O
H
Ph
H2O3P
HO
N
N
H
N
O
O
PO3H2
NO2
O
alendronate fragment
H2O3P
HO
N
O
H
H
PO3H2
G
alendronate fragment
Figure 2 Some examples of HBP bioconjugates (HBP fragment involved in the synthesis)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

C
S. Aoun et al.
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Synthesis
In this study, we propose novel linear and convergent
strategies to prepare nitrogen containing hydroxyl-bisphos-
phonate prodrugs with potential dual biological effects that
include an antiresorptive activity. The synthetic challenge
was to avoid the preparation of the hydroxy-bisphospho-
nate ester intermediates and to access the expected hy-
droxy-bisphosphonic compounds under mild conditions.
Owing to the fact that promising biological results were
obtained with an anti-inflammatory prodrug such as BP
conjugated diclofenac B (Figure 1),6a we first selected a non-
steroidal anti-inflammatory agent such as ibuprofen, which
could therefore be linked to our HBP-spacers with ester for-
mation (Figure 3, compounds 1 to 3). The HBP-linker was
based on interesting structures reported earlier by Novartis
as potent antiresorptive compounds.22 Particularly the 1-
hydroxy-(3-phenoxypropylamino)propylidene-1,1-bis-
phosphonate (Figure 3, compound I) revealed potency-en-
hancing effect compared to the dimethylamino analogue ol-
padronate J, probably due to the addition of a terminal phe-
nyl group associated with the presence of the tertiary
amine function. By combining ibuprofen with such (phe-
noxypropylamino)propylidene HBP fragment, as depicted
in prodrug 2 (Figure 3), a dual anti-inflammatory–antire-
sorptive effect could therefore be expected. It is also to be
noted that similar hydrosoluble prodrugs were recently
claimed as effective bone-seekers with in vivo activity.23
To validate our linear strategy, we first prepared the
ibuprofen HBP prodrug without nitrogen containing linker
(Scheme 1). The commercially available 3-hydroxybenzal-
dehyde was first reduced with NaBH4 to give quantitatively
the corresponding benzylic alcohol 4. All attempts to couple
the ibuprofen with the benzylic alcohol 4 in the presence of
coupling reagents such as dicyclohexylcarbodiimide (DCC)
in the presence of N,N-dimethylaminopyridine (DMAP) sys-
tematically afforded a mixture of esters as the result of the
acylation of the primary alcohol and the phenol functions.
The phenol function was then blocked first by simple al-
kylation with the 5-bromo-1-pentene, under Williamson’s
conditions (K2CO3, DMF). A moderate yield (55%) of the ex-
pected ether 5 was obtained in DMF, but the yield could be
increased up to 78% in a mixture of acetonitrile/water (5:1),
at 75 °C. The terminal alkene in 5 appeared for us as a suit-
able masked function, to later introduce the carboxylic acid
function required for the HBP formation. In this way, this O-
protected compound 5 was esterified with ibuprofen using
DCC and a catalytic amount of DMAP to afford compound 6
in good yield. The next steps consisted in an oxidative cleav-
age of the terminal alkene function with ozone to generate
the aldehyde 7, followed by an oxidation of the aldehyde
under mild Pinnick conditions,24 to give the carboxylic acid
8 in 66% yield over the two steps.
To access to the targeted molecule 1, we tried Lecou-
vey’s method,25 which involved the activation of the car-
boxylic acid as the corresponding acyl chloride, followed by
Arbuzov reaction with 2.5 equivalents of the nucleophilic
tris(trimethylsilyl) phosphite [P(OSiMe3)3]. This sequence
applied to compound 8 delivered after methanolysis, the
expected hydroxy-bisphosphonic acid 1, with some
amount of the methyl ester of 8, together with phosphorous
acid by-products. Purification of 1 could then be achieved
by precipitation in a mixture of Et2O/petroleum ether, to
give the expected HBP prodrug 1, in 62% yield. Alternatively,
the one-pot procedure developed in our laboratory26 al-
lowed us to obtain HBP compound 1, in one-pot and 64%
yield after reversed-phase chromatography purification,
from the carboxylic acid 8 via the acyloxydioxaborolane in-
termediate.
O
Me
N
O
P
HO
O
P
Me
N
OH
P
OH
HO
OH
HO
HO
N
P
HO
N
O
Me
HO
OH
P
O
OH
P
O
OH
HO
HO
O
HO
I
Olpadronate J
K
O
P
O
P
O
OH
P
HO
HO
OH
HO
X
n
O
O
O
n
n
HO
OH
HO
P
N
O
O
O
O
OH
N
N
HO
1: n = 0, X = CH2
2: n = 1, X = NMe
3
Figure 3 Potent antiresorptive compounds I–K [I : ED50 = 0.5 g/kg; J (olpadronate) ED50 = 12 g/kg, K : ED50 = 45 g/kg]22 and the three targeted
ibuprofen HBP prodrugs 1–3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

D
S. Aoun et al.
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Synthesis
O
K2CO3 (1.1 equiv)
NaBH4 (0.5 equiv)
5-bromo-1-pentene (3 equiv)
HO
HO
O
H
OH
OH
EtOH, 0 °C, 1 h
quant.
MeCN/H2O (9:1), 75 °C, 24 h
78%
4
5
O3 (10 min)
DCM/MeOH (15:1)
–78 °C to RT
ibuprofen (1 equiv)
DCC (1.2 equiv)
DMAP (0.05 equiv)
O
O
O
O
O
H
O
O
DCM, RT, overnight
81%
68%
6
7
O
O
1) SOCl2 (1.2 equiv)
DCM, reflux, 5 h
NaClO2, NaH2PO4
2-methyl-2-butene
PO3H2
O
HO
H2O3P
O
O
HO
O
O
t-BuOH/H2O (2.5:1)
RT, overnight
2) P(OSiMe3)3 (2.5 equiv), RT, 22 h
then MeOH, RT, 2 h
1
8
98%
62% (2 steps)
1) catecholborane (3.5 equiv), RT, 1 h
then P(OSiMe3)3 (4.5 equiv), RT, 17 h
then MeOH, RT, 2 h
64%
Scheme 1 Synthetic linear pathway to prepare the free HBP compound 1
We then turned to the preparation of the ibuprofen HBP
prodrug 2, with a tertiary amine containing linker, accord-
ing to a close linear strategy (Scheme 2).
tion, the excess of catecholborane probably blocked the ba-
sic amine by complexation, as observed previously with
simpler amino acid compounds,26 thus avoiding side reac-
tions (Scheme 2).
Benzylic alcohol 4 was mono-alkylated with an excess
of 1,3-dibromopropane to avoid dimer formation. Com-
pound 9 thus obtained was engaged in the esterification re-
action with ibuprofen to give 10, followed by a nucleophilic
substitution with methylamine to furnish the amino ester
11 in 45% yield over the two steps. We first tried to access
the carboxylic acid 13 directly by simple Michael addition
of the secondary amine 11 onto acrylic acid (2 equiv) in
MeOH and in the presence of the Hünig base (2 equiv). We
observed more than 80% conversion, however excess of
acrylic acid always poisoned the expected compound 13 af-
ter purification. To circumvent this problem tert-butyl ac-
rylate was chosen as the Michael acceptor. Diester 12 was
then gently deprotected in anhydrous acidic conditions to
give the carboxylic acid 13 in 68% yield (2 steps). As we did
for the preparation of the HBP-ibuprofen prodrug 1, we
tried to prepare the HBP 2 from the corresponding amino
acid 13, using Lecouvey’s method without success. Gratify-
ingly, with our one-pot procedure, HBP-prodrug 2 could be
obtained with some residual phosphorous acid after simple
purification by successive precipitations with selected sol-
vents (37% yield), or in a pure form after reversed-phase
chromatography purification (45% yield). During the reac-
To open the route to a more straightforward approach to
prepare similar HBP prodrugs, we explored a convergent
strategy, based upon Huisgen 1,3-dipolar cycloaddition and
access so to the compound 3 (Figure 3). Indeed, it was
shown by Novartis group that the replacement of the basic
tertiary nitrogen of the olpadronate J by the nitrogen of a
heteroaromatic ring system such as in compound K, gave
analogues with quite similar activity (Figure 3).22 We there-
fore supposed that a 1,4-disubstituted-1,2,3-triazole ana-
logue of compound 2, such as compound 3 could also be de-
signed as a promising antiresorptive and anti-inflammatory
prodrug.
According to the literature data there are still only very
few examples of Huisgen 1,3-dipolar cycloaddition involv-
ing an alkyne as well as an azide bearing functions such as
hydroxy-bisphosphonic esters27 or hydroxy-bisphosphonic
acids.28 So we first explored the click reaction between
azide 16 and free HBP alkyne substrate 15. Because no reac-
tion occurred between 16 and 15 in simple thermal condi-
tions using acetonitrile as the solvent, and observing a deg-
radation of the alkyne 15 in solution, the corresponding so-
dium salt was prepared.28a We then moved to reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

E
S. Aoun et al.
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Synthesis
conditions inspired from those reported by Guénin and col-
laborators,28a and carried out the cycloaddition with CuSO4
in a mixture of DMF/water, instead of t-BuOH/water, due to
poor solubility of compound 16.29 After 48 hours at room
temperature, some conversion occurred, but the expected
compound 3 seemed to be copper complexed30 and no clear
resolved 1H NMR analysis could be obtained. However, the
formation of some HBP derivative 3 was confirmed by mass
spectrometry analysis. The copper(I) thiophene-2-carbox-
ylate (CuTC) was then tested, which was previously identi-
fied as a good Cu(I) catalyst in difficult CuAAC reactions.31
To the best of our knowledge, this copper salt has never
been tested with HBP substrates. In similar reaction condi-
tions, the compound 3 was obtained in low yield, after suc-
cessive precipitations in a mixture of methanol/diethyl
ether (Scheme 3, Route A), and recovering also a large part
of the azide starting material 16. We suspected that this
specific pentynyl-HBP substrate 15 underwent side reac-
tion such as intramolecular P–OH addition into alkyne in
the presence of Cu(I).32 Undesirable side reactions were also
observed by Mindt and collaborators with the 4-pentynoic
acid, which mainly gave enol lactone in similar aqueous
click reaction conditions.33 So we turned to the preparation
of the targeted compound 3 from the alkynyl tetramethyl-
phosphonate 18 and azide 16 (Scheme 3, Route B).
phosphonate 17 in 51% yield. As recently published by Tur-
hanen,27a reaction of 17 with dimethyl phosphite under
neat conditions always afforded a mixture of the expected
compound 18 in ca. 30% yield due to the partial formation
of the corresponding phosphate-phosphonate. We did the
reaction in toluene at 0 °C, and in the presence of a catalytic
amount of n-Bu2NH.16c The expected compound 18 precipi-
tated out during the reaction and it could be obtained pure
by simple filtration in 77% yield. Then, 1,3-dipolar cycload-
dition between 16 and 18 in classical conditions of click
chemistry gave triazole derivative 19 in 97% yield. The pro-
drug 3 was finally obtained by simple dealkylation with
TMSBr, followed by methanolysis and isolated pure in a
quantitative yield after removal of the volatiles.
In summary, we have proposed two complementary
(linear and convergent) strategies towards the synthesis of
bifunctional compounds bearing a bone-targeting hydroxy-
bisphosphonic function. In the linear approach, we have
shown that the hydroxy-bisphosphonic function could be
introduced in the last step of the synthesis in mild condi-
tions, from the carboxylic acid precursor, using catecholbo-
rane as a neutral activating agent. In the convergent ap-
proach, the CuAAC step starting with free hydroxy-bisphos-
phonic alkyne as the substrate was not satisfying compared
to the same approach conducted on the corresponding hy-
droxybisphosphonate tetraester. Both strategies could be
applied to selected drugs bearing a carboxylic acid function
for the anchorage to the HBP-linker. Moreover, the cleavable
ester bond and the specific structure of the HBP linker for
The compound 18 was prepared in three steps starting
from commercially available 4-pentynoic acid (14). The lat-
ter was activated as its acyl chloride form before being en-
gaged in an Arbuzov reaction with P(OMe)3 to furnish acyl-
O
ibuprofen (1 equiv)
DCC (1.2 equiv)
DMAP (0.05 equiv)
O
K2CO3 (1.1 equiv)
O
1,3-dibromopropane (3 equiv)
HO
O
Br
OH
OH
Br
MeCN/H2O (9:1), 75 °C, 24 h
62%
DCM, RT, overnight
68%
10
4
9
O
MeNH2 (1 M in THF, 3.3 equiv)
K2CO3 (1.2 equiv)
CO2tBu
O
O
O
NaI (0.3 equiv)
t-BuO
N
O
(5 equiv)
O
HN
DMF, RT, 24 h
71%
O
DMF, RT, overnight
67%
11
12
O
O
O
catecholborane (1 M in THF, 3.5 equiv)
then P(OSiMe3)3 (4.5 equiv), 17 h
then MeOH
OH
P
HO
N
O
HO
O
P
N
O
HCl (2 N in Et2O)
O
O
HO
OH
RT, 7 h
96%
O
45%
HO
2
13
Scheme 2 Synthetic linear pathway to prepare the free HBP compound 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

F
S. Aoun et al.
Paper
Synthesis
OH
P
O
HO
O
Route A :
ref 26
OH
P
OH
OH
HO
O
14
15
MeOH,
Na2CO3
15, sodium salt
O
HO
HO
P
OH
O
P
O
N3
O
O
15, sodium salt
HO
N
O
NaN3 (2.2 equiv)
O
O
10
OH
N
N
DMF, RT, 5 h
94%
CuTC (0.2 equiv), DMF/H2O, pH 7.0
16
3
Cu
25%
O
O
S
OMe
P
O
MeO
O
Route B :
O
1) SOCl2 (2.5 equiv)
reflux, 90 min
HP(O)(OMe)2 (1.1 equiv)
n-Bu2NH (3 mol%)
OH
OMe
OMe
OH
P
P
OMe
MeO
toluene, 0 °C, 4 h
77%
2) P(OMe)3 (1 equiv)
0 °C to RT, 2 h
O
O
14
17
18
51% (2 steps)
OMe
O
O
MeO
HO
OMe
O
O
MeO
P
P
OH
P
O
N3
O
CuSO4 (5 mol%)
sodium ascorbate (30 mol%)
+
OMe
MeO P
N
O
MeO
O
O
O
OMe
N
N
t-BuOH/H2O (4:1), RT, 24 h
18
16
19
97%
TMSBr (6 equiv)
DCM, RT, 5 h
O
P
HO
OH
HO
P
O
O
then MeOH, RT, 2 h
quant.
HO
N
O
O
OH
N
N
3
Scheme 3 Convergent routes to prepare HBP prodrug 3 with triazole ring containing linker starting with hydroxybisphosphate 15 (Route A) or te-
tramethyl hydroxybisphosphonate 18 (Route B)
the compounds designed in this study, could be in favor of a
putative dual antiresorptive and anti-inflammatory activi-
ty.
recorded on a Bruker Vector 22 spectrometer. NMR spectra were re-
corded on a Bruker AC 300 (300 MHz for 1H) or on a Bruker 400 (400
MHz for 1H) at RT, on samples dissolved in an appropriate deuterated
solvent. Used references were TMS for 1H NMR, deuterated solvent
signal for 13C NMR and 85% aq H3PO4 for 31P NMR. Chemical displace-
ment values () are expressed in parts per million (ppm), and cou-
pling constants (J) in hertz (Hz). Low-resolution mass spectra (MS)
were recorded in the CEISAM laboratory on a Thermo-Finnigan DSQII
quadripolar at 70 eV (CI with NH3 gas). High-resolution mass spec-
trometry (HRMS in Da unit) analyses were recorded on an LC-Q-TOF
(Synapt-G2 HDMS, Waters) in the IRS-UN center (Mass Spectrometry
platform, Nantes) or on a MALDI-TOF-TOF apparatus (Autoflex III from
Bruker) in the INRA center (BIBS platform, Nantes).
All solvents used were reagent grade and TLC was performed on sili-
ca-covered aluminum sheets (Kieselgel 60F254, MERCK). Eluted TLC
was revealed using UV radiation ( = 254 nm), or molybdate solution.
Flash chromatography was performed on silica gel (60 ACC 40–63 m,
SDS-CarloErba) and low pressure chromatography column on C18 re-
versed-phase (FlashPure cartridge 40 M Büchi). Melting points were
determined on a Stuart Scientific apparatus 7SMP3. IR spectra were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

G
S. Aoun et al.
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Synthesis
3-Hydroxybenzyl Alcohol (4)34
MS (CI): m/z = 398 [M + NH4]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + Na]+ calcd for C25H32O3Na:
403.2244; found: 403.2247.
To a solution of the commercial 3-hydroxybenzaldehyde (5 g, 40.94
mmol) in EtOH (25 mL) was cautiously added NaBH4 (774 mg, 20.47
mmol) in small portions at 0 °C under argon. The mixture was stirred
at 0 °C for 1 h. Aq 2 N HCl was then added stepwise until pH 3. After
stirring for 10 min, sat. aq NaHCO3 was added to obtain a neutral solu-
tion (pH 7). The organic phase was dried (anhyd Na2SO4), filtered, and
concentrated under reduced pressure to afford pure 4 (5.06 g, quant.)
as a viscous brown oil, which crystallized at 0 °C.
1H NMR (300 MHz, MeOD):  = 7.14 (t, J = 7.8 Hz, 1 Harom), 6.82–6.80
(m, 2 Harom), 6.70 (dd, J = 7.3, 1.9 Hz, 1 Harom), 4.53 (s, 2 H, CH2).
13C NMR (75 MHz, MeOD):  = 158.3, 144.1, 130.3, 119.1, 115.1, 114.7,
3-(4-Oxobutoxy)benzyl 2-(4-Isobutylphenyl)propanoate (7)
A solution of 6 (369 mg, 0.97 mmol) in DCM/MeOH (50 mL, 15:1) at –
78 °C, was stirred through an argon flow during 15 min. Then O3 was
bubbled into the solution until a blue color persisted. Me2S (2.15 mL,
29.1 mmol) was added and the mixture was allowed to warm to RT
overnight. After concentration in vacuo, the oil was dissolved in DCM
and the organic layer was washed with brine (3 ×), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel (DCM to DCM/MeOH 95:5) to af-
ford 7 (251 mg, 68%) as a colorless oil.
65.1.
MS (CI): m/z = 142 [M + NH4]+.
IR (film): 2954, 2931, 2724, 1732, 1603, 1586, 1453, 1267, 1160 cm–1
.
[3-(Pent-4-enyloxy)phenyl]methanol (5)
1H NMR (300 MHz, CDCl3):  = 9.81 (t, J = 1.1 Hz, 1 H, CHO), 7.24–7.16
(m, 3 Harom), 7.10–7.07 (m, 2 Harom), 6.80–6.75 (m, 3 Harom), 5.06 [AB
system, JAB = 12.7 Hz, ΔAB = 15.4 Hz, 2 H, CH2OC(O)], 3.92 (t, J = 6.0
Hz, 2 H, CH2O), 3.75 [q, J = 7.2 Hz, 1 H, CH3CHC(O)], 2.63 (td, J = 7.0, 1.1
Hz, 2 H, CH2CHO ), 2.44 [d, J = 7.2 Hz, 2 H, CH2CH(CH3)2], 2.08 (qt, J =
6.5 Hz, 2 H, CH2CH2O), 1.84 [nonet, J = 6.8 Hz, 1 H, CH(CH3)2], 1.51 [d,
J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d, J = 6.6 Hz, 6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 201.7, 174.5, 158.8, 140.6, 137.7 (2 C),
129.6, 129.4 (2 C), 127.3 (2 C), 120.1, 114.2, 113.6, 66.6, 66.1, 45.2,
45.1, 40.7, 30.2, 22.4 (2 C), 22.0, 18.5.
To a solution of 4 (250 mg, 2.01 mmol) in a mixture of MeCN/H2O (1.5
mL, 9:1) at room temperature was added K2CO3 (305 mg, 2.21 mmol).
After 10 min, 5-bromo-1-pentene (715 L, 6.03 mmol) was added
and the reaction mixture was heated at 75 °C during 24 h. After cool-
ing to RT, Et2O was added and the organic layer washed with brine (3
×), dried (anhyd Na2SO4), filtered,and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel (DCM) to give pure 5 (300 mg, 78%) as a colorless oil.
IR (film): 3345, 2936, 1641, 1602, 1585, 1449, 1264 cm–1
.
MS (CI): m/z = 400 [M + NH4]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + Na]+ C24H30O4Na: 405.2036;
1H NMR (300 MHz, CDCl3):  = 7.25 (t, J = 8.1 Hz, 1 Harom), 6.91–6.89
(m, 2 Harom), 6.81 (dd, J = 8.2, 2.3 Hz, 1 Harom), 5.85 (ddt, J = 17.0, 10.3,
6.7 Hz, 1 H, CH2=CH), 5.10–4.98 (m, 2 H, CH2=CH), 4.63 (s, 2 H,
CH2OH), 3.96 (t, J = 6.4 Hz, 2 H, CH2OPh), 2.27–2.20 (m, 2 H,
CH2CH=CH2), 1.97 (br s, 1 H, OH), 1.92–1.83 (m, 2 H, CH2CH2O).
found: 405.2039.
4-(3-{[2-(4-Isobutylphenyl)propanoyloxy]methyl}phenoxy)buta-
noic Acid (8)
13C NMR (75 MHz, CDCl3):  = 159.4, 142.6, 137.9, 129.7, 119.1, 115.3,
113.9, 113.0, 67.2, 65.3, 30.2, 28.5.
MS (ESI): m/z = 175 [M + H – H2O]+; 215 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16O2Na: 215.1042; found:
215.1046.
To a solution of the aldehyde 7 (731 mg, 1.91 mmol) in t-BuOH (40
mL) was added 2-methyl-2-butene (9.5 mL, 89.77 mmol) at RT under
an argon atmosphere. NaH2PO4 (1.6 g, 13.37 mmol) and NaClO2 (1.94
g, 17.2 mmol) were dissolved in H2O and introduced into the reaction
mixture. After stirring overnight, sat. aq NaHCO3 was added and the
resulting mixture was extracted with Et2O (3 ×). The combined organ-
ic layers were washed with brine, dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The crude product was purified by
flash chromatography on silica gel (DCM to DCM/MeOH 95:5) to give
pure 8 (745 mg, 98%) as a white solid; mp 49–52 °C.
3-(Pent-4-enyloxy)benzyl 2-(4-Isobutylphenyl)propanoate (6)
To a solution of DCC (300 mg, 1.45 mmol) in anhyd DCM (10 mL) at RT
was added the commercial ibuprofen (250 mg, 1.21 mmol), followed
by compound 5 (279 mg, 1.45 mmol) and DMAP (0.3 mL of a freshly
prepared 0.2 M solution of DMAP in anhyd DCM, 0.06 mmol). After
completion of the reaction as monitored by TLC, the organic layer was
washed with H2O (3 ×), dried (MgSO4), filtered, and concentrated un-
der reduced pressure. The crude product was purified by flash chro-
matography on silica gel (PE/Et2O, 98:2 to 90:10) to afford pure 6 (376
mg, 81%) as a colorless oil.
IR (film): 3200, 2953, 2869, 1719, 1585, 1452, 1274, 1159, 1059 cm–1
1H NMR (300 MHz, CDCl3):  = 7.24–7.16 (m, 3 Harom), 7.10–7.07 (m, 2
arom), 6.81–6.76 (m, 3 Harom), 5.06 [AB system, JAB = 12.7 Hz, ΔAB
.
H
=
15.5 Hz, 2 H, CH2OC(O)], 3.95 (t, J = 6.0 Hz, 2 H, CH2O), 3.75 [q, J = 7.2
Hz, 1 H, CH3CHC(O)], 2.57 (t, J = 7.2 Hz, 2 H, CH2CO2H), 2.44 [d, J = 7.2
Hz, 2 H, CH2CH(CH3)2], 2.09 (qt, J = 6.7 Hz, 2 H, CH2CH2O), 1.84 [nonet,
J = 6.7 Hz, 1 H, CH(CH3)2], 1.51 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d,
J = 6.6 Hz, 6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 179.4, 174.7, 158.9, 140.7, 137.7 (2 C),
129.6, 129.4 (2 C), 127.3 (2C), 120.2, 114.3, 113.7, 66.5, 66.3, 45.2,
45.1, 30.6, 30.3, 24.4, 22.5 (2 C), 18.6.
IR (film): 2953, 2932, 2868, 1736, 1603, 1586, 1452, 1267, 1160 cm–1
1H NMR (300 MHz, CDCl3):  = 7.22–7.17 (m, 3 Harom), 7.10–7.07 (m, 2
arom), 6.82–6.78 (m, 3 Harom), 5.85 (ddt, J = 17.1, 10.3, 6.6 Hz, 1 H,
.
H
CH2=CH), 5.11–4.98 [m, 4 H, CH2=CH and CH2OC(O)], 3.90 (t, J = 6.4
Hz, 2 H, CH2O), 3.75 [q, J = 7.2 Hz, 1 H, CH3CHC(O)], 2.44 [d, J = 7.2 Hz,
2 H, CH2CH(CH3)2], 2.26–2.19 (m, 2 H, CH2CH=CH2), 1.90–1.77 [m, 3 H,
CH2CH2O and CH(CH3)2], 1.51 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d,
J = 6.6 Hz, 6 H, CH(CH3)2].
MS (CI): m/z = 416 [M + NH4]+.
HRMS (MALDI, DHB, PEG 200): m/z [M + Na]+ C24H30O5Na: 421.1985;
13C NMR (75 MHz, CDCl3):  = 174.6, 159.3, 140.7, 137.9, 137.7 (2 C),
129.6, 129.4 (2 C), 127.3 (2 C), 119.9, 115.3, 114.3, 113.8, 67.2, 66.3,
45.3, 45.2, 30.3, 30.2, 28.5, 22.5 (2 C), 18.6.
found: 421.1981.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

H
S. Aoun et al.
Paper
Synthesis
1-Hydroxy-4-(3-{[2-(4-isobutylphenyl)propanoyloxy]methyl}phe-
noxy)butane-1,1-bis(phosphonic acid) (1)
1H NMR (300 MHz, CDCl3):  = 7.22–7.17 (m, 3 Harom), 7.10–7.07 (m, 2
H
arom), 6.81–6.77 (m, 3 Harom), 5.06 (AB system, JAB = 12.9 Hz, ΔAB =
14.0 Hz, 2 H, CH2O), 4.01 (t, J = 5.8 Hz, 2 H, CH2CH2O), 3.75 [q, J = 7.2
Hz, 1 H, CH3CHC(O)], 3.57 (t, J = 6.4 Hz, 2 H, CH2Br), 2.44 [d, J = 7.2 Hz,
2 H, CH2CH(CH3)2], 2.27 (qt, J = 6.1 Hz, 2 H, CH2CH2Br), 1.84 [nonet, J =
6.8 Hz, 1 H, CH(CH3)2], 1.50 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d, J =
6.6 Hz, 6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 174.5, 158.8, 140.6, 137.8, 137.7, 129.6,
129.4 (2 C), 127.3 (2 C), 120.2, 114.2, 113.7, 66.1, 65.2, 45.2, 45.1, 32.4,
30.3, 30.0, 22.5 (2 C), 18.5.
A catecholborane solution (1 M solution in THF, 1.36 mL, 1.36 mmol)
was added to neat carboxylic acid 8 (155 mg, 0.39 mmol) under an
argon atmosphere at RT. The mixture was stirred for 1 h at RT until no
more gas evolution. Then P(OSiMe3)3 (585 L, 1.75 mmol) was added
without solvent, and stirred for 16 h. MeOH (1.3 mL) was added, and
after stirring for 1 h, the solvents were evaporated under reduced
pressure. The crude product was taken up in DCM and a large amount
of Et2O was added to give an oil, which separated. It was purified by
low pressure C18 reversed-phase chromatography (MeCN/MeOH,
100:0 to 70:30) to afford the pure compound 1 (170 mg, 64%) as an
amorphous white solid. Following Lecouvey’s method,25 purification
could be done by successive precipitations of the residue in a mixture
of Et2O/PE to give 1 (62%) with an inseparable amount of H3PO3 (see
SI).
1H NMR (500 MHz, DMSO-d6):  = 7.20–7.17 (m, 3 Harom), 7.11–7.09
(m, 2 Harom), 6.85–6.81 (m, 2 Harom), 6.75–6.73 (m, 1 Harom), 5.04 (AB
system, JAB = 13.2 Hz, ΔAB = 13.3 Hz, 2 H, PhCH2O), 3.88 (t, J = 5.6 Hz, 2
H, CH2OPh), 3.82 [q, J = 7.1 Hz, 1 H, CH3CHC(O)], 2.41 [d, J = 7.1 Hz, 2 H,
CH2CH(CH3)2], 2.01 [m, 4 H, CH2C(OH)(PO3H2)2 and CH2CH2O], 1.80
[nonet, J = 6.8 Hz, 1 H, CH(CH3)2], 1.40 [d, J = 7.1 Hz, 3 H, CH3CHC(O)],
0.85 [d, J = 6.6 Hz, 6 H, CH(CH3)2].
MS (CI): m/z = 450 [M + NH4]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + Na]+ calcd for C23H2979BrO3-
Na: 455.1192; found: 455.1195.
3-[3-(Methylamino)propoxy]benzyl 2-(4-Isobutylphenyl)propa-
noate (11)
K2CO3 (1.55 g, 11.2 mmol) followed by NaI (460 mg, 3.1 mmol) were
successively added to a solution of 10 (4.43 g, 9.29 mmol, 1 equiv) in
DMF (90 mL) at RT. After 20 min, MeNH2 (15.3 mL of a 2 M solution in
THF, 30.66 mmol) was added. The reaction mixture was stirred at RT
overnight and diluted with Et2O. The organic phase was washed with
brine, dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography on
neutral alumina (DCM/MeOH, 100:0 then 95:5) to give pure 11 (2.63
g, 67%) as a yellow amorphous compound.
13C NMR (125 MHz, DMSO-d6):  = 173.7, 158.7, 139.8, 137.7, 137.6,
129.4, 129.1 (2 C), 127.1 (2 C), 119.2, 113.9, 113.4, 72.0 (t, 1JCP = 140.8
Hz), 68.2, 65.4, 44.1 (2 C), 29.7, 29.5, 23.3 (t, 3JCP = 6.5 Hz), 22.1 (2 C),
18.4.
31P NMR (121.5 MHz, DMSO-d6):  = 20.9 (s, 2 P).
MS (ESI): m/z = 545 [M + H]+.
IR (film): 3331, 2951, 2790, 1734, 1449, 1271, 1161, 1054 cm–1
1H NMR (300 MHz, CDCl3):  = 7.22–7.17 (m, 3 Harom), 7.10–7.07 (m, 2
arom), 6.83–6.79 (m, 3 Harom), 5.06 [AB system, JAB = 12.6 Hz, ΔAB
.
H
=
20.0 Hz, 2 H, CH2OC(O)], 4.57 (br s, 1 H, NH), 3.99 (t, J = 6.1 Hz, 2 H,
CH2CH2O), 3.75 [q, J = 7.2 Hz, 1 H, CH3CHC(O)], 2.88 (t, J = 7.1 Hz, 2 H,
HRMS (ESI): m/z [M + H]+ calcd for C24H35O10P2: 545.1711; found:
545.1702.
CH2NHCH3), 2.53 (s,
3 H, NHCH3), 2.44 [d, J = 7.2 Hz, 2 H,
CH2CH(CH3)2], 2.07 [qt, J = 6.8 Hz, 2 H, CH2CH2O], 1.84 [nonet, J = 6.7
Hz, 1 H, CH(CH3)2], 1.50 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d, J = 6.6
Hz, 6H, CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 174.6, 158.9, 140.6, 137.7 (2 C), 129.6,
129.4 (2 C), 127.3 (2 C), 120.1, 114.2, 113.8, 66.2, 65.8, 48.5, 45.2, 45.1,
35.6, 30.3, 28.6, 22.5 (2 C), 18.6.
[3-(3-Bromopropoxy)phenyl]methanol (9)
The compound 9 was prepared according to the method described for
the preparation of 5, starting with 4 (3 g, 24.17 mmol) and 1,3-dibro-
mopropane (7.4 mL, 72.5 mmol) as the alkylating agent. The crude
product was purified by flash chromatography on silica gel (DCM to
DCM/MeOH 97:3) to give a mixture of bromo compound 9 (3.97 g,
62%) as a brown viscous oil, which slowly crystallized to give beige or
brown crystals.
MS (CI): m/z = 384 [M + H]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + H]+ calcd for C24H34NO3:
384.2533; found: 384.2526.
IR (film): 3300, 2949, 2875, 1585, 1451, 1261, 1150, 1033 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.25 (m, 1 Harom), 6.92–6.90 (m, 2 Har-
om), 6.81 (m, 1 Harom), 4.61 (s, 2 H, CH2OH), 4.08 (t, J = 5.8 Hz, 2 H,
CH2O), 3.59 (t, J = 6.4 Hz, 2 H, CH2Br), 2.29 (qt, J = 6.1 Hz, 2 H,
CH2CH2Br), 2.24 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3):  = 159.0, 142.7, 129.7, 119.4, 113.8, 112.9,
65.3, 65.1, 32.4, 30.2.
tert-Butyl {3-[3-(3-{[2-(4-Isobutylphenyl)propanoyloxy]meth-
yl}phenoxy)propyl](methyl)amino}propanoate (12)
To a solution of amine 11 (3.35 g, 8.73 mmol) in DMF (14 mL) was
added tert-butyl acrylate (6.35 mL, 43.66 mmol). The reaction mix-
ture was stirred for 24 h at RT under an argon atmosphere. After dilu-
tion with Et2O, the organic phase was washed with brine, dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
(DCM/MeOH, 100:0 to 95:5) to afford pure 12 (3.16 g, 71%) as a
brownish oil.
MS (CI): m/z = 262 [M + NH4]+.
HRMS (ESI): m/z [M + Na]+ calcd for C10H1379BrO2Na: 266.9991; found:
266.9992.
IR (film): 2954, 2925, 2869, 2849, 1732, 1454, 1367, 1268, 1160 cm–1
1H NMR (300 MHz, CDCl3):  = 7.22–7.16 (m, 3 Harom), 7.09–7.07 (m, 2
arom), 6.82–6.77 (m, 3 Harom), 5.06 [AB system, JAB = 12.6 Hz, ΔAB
18.4 Hz, 2 H, CH2OC(O)], 3.94 (t, J = 6.3 Hz, 2 H, CH2CH2O), 3.75 [q, J =
7.2 Hz, 1 H, CH3CHC(O)], 2.68 (t, J = 7.2 Hz, 2 H, CH2CH2CO2tBu), 2.52
[t, J = 7.0 Hz, 2H, CH2(CH2)2O], 2.44 [d, J = 7.2 Hz, 2 H, CH2CH(CH3)2],
2.38 (t, J = 7.2 Hz, 2 H, CH2CO2tBu), 2.25 (s, 3 H, NCH3), 1.92 (qt, J = 6.7
.
3-(3-Bromopropoxy)benzyl 2-(4-Isobutylphenyl)propanoate (10)
The compound 10 was prepared according to the coupling method
described for the preparation of compound 6, starting from 9 (2.75 g,
11.3 mmol). The crude product was purified by flash chromatography
on silica gel (PE/Et2O, 98:2 to 90:10) to afford 10 (3.16 g, 68%) as a yel-
low oil.
H
=
IR (film): 2954, 2868, 1735, 1604, 1453, 1268, 1160 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

I
S. Aoun et al.
Paper
Synthesis
Hz, 2 H, CH2CH2O), 1.84 [nonet, J = 6.8 Hz, 1 H, CH(CH3)2], 1.50 [d, J =
7.2 Hz, 3 H, CH3CHC(O)], 1.43 [s, 9 H, C(CH3)3], 0.89 [d, J = 6.6 Hz, 6 H,
CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 174.5, 172.0, 159.2, 140.6, 137.7, 137.6,
129.5, 129.4 (2 C), 127.3 (2 C), 119.9, 114.2, 113.8, 80.3, 66.2, 66.0,
54.1, 53.1, 45.2, 45.1, 42.0, 33.8, 30.2, 28.2 (3 C), 27.3, 22.5 (2 C), 18.5.
13C NMR (100 MHz, DMSO-d6):  = 173.6, 158.2, 139.7, 137.6 (2 C),
129.4, 128.9 (2 C), 127.0 (2 C), 119.5, 113.8, 113.6, 65.3, 64.9, 52.4,
51.7, 44.1, 44.0, 39.4, 29.4, 27.6, 23.5, 22.0 (2 C), 18.5; one Cq signal
missing.
31P NMR (121.5 MHz, DMSO-d6):  = 20.4 (2 P).
MS (ESI): m/z = 600 [M – H]–.
MS (CI+): m/z = 512 [M + H]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + H]+ calcd for C31H46NO5:
HRMS (ESI): m/z [M – H]– calcd for C27H40NO10P2: 600.2127; found:
600.2132.
512.3370; found: 512.3364.
3-(3-Azidopropoxy)benzyl 2-(4-Isobutylphenyl)propanoate (16)
3-{[3-(3-{[2-(4-Isobutylphenyl)propanoyloxy]methyl}phe-
noxy)propyl](methyl)amino}propanoic Acid (13)
NaN3 (44 mg, 0.67 mmol) was added to bromide 10 (146 mg, 0.31
mmol) in DMF (3 mL), at RT. The resulting mixture was stirred for 4 h
and diluted with Et2O. The organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (PE/Et2O, 100:0 to 90:10)
gave pure azide 16 (116 mg, 94%) as a colorless oil.
A solution of dry HCl (3.9 mL of a 2 N solution in Et2O, 7.8 mmol) was
added at 0 °C to the neat ester 12 (135 mg, 0.26 mmol) and the mix-
ture was stirred at RT for 7 h. The solvent was concentrated under re-
duced pressure to give a white precipitate, which was purified by
flash chromatography on silica gel (DCM/MeOH, 100:0 to 90:10) to
give 13 (116 mg, 96%) as an amorphous yellow compound.
IR (film): 2955, 2870, 2099, 1735, 1452, 1266, 1160 cm–1
1H NMR (300 MHz, CDCl3):  = 7.12–7.05 (m, 3 Harom), 6.99–6.96 (m, 2
arom), 6.71–6.67 (m, 3 Harom), 4.96 [AB system, JAB = 13.3 Hz, ΔAB
.
IR (film): 3400, 2955, 2869, 1734, 1587, 1454, 1268, 1162 cm–1
.
H
=
1H NMR (400 MHz, DMSO-d6):  = 7.21–7.17 (m, 3 Harom), 7.10–7.08
(m, 2 Harom), 6.83 (dd, J = 8.0, 2.1 Hz, 1 Harom), 6.79–6.75 (m, 2 Harom),
5.05 [AB system, JAB = 13.2 Hz, ΔAB = 13.3 Hz, 2 H, CH2OC(O)], 3.94 (t,
J = 6.3 Hz, 2 H, CH2CH2O), 3.81 [q, J = 7.1 Hz, 1 H, CH3CHC(O)], 2.86 (t,
J = 7.2 Hz, 2 H, CH2CH2CO2H), 2.75 [t, J = 7.3 Hz, 2 H, CH2(CH2)2O], 2.49
(t, J = 7.2 Hz, 2 H, CH2CO2H), 2.41–2.39 [m, 5 H, CH2CH(CH3)2 and
NCH3], 1.95 (qt, J = 7.0 Hz, 2 H, CH2CH2O), 1.80 [nonet, J = 6.7 Hz, 1 H,
CH(CH3)2], 1.39 [d, J = 7.1 Hz, 3 H, CH3CHC(O)], 0.84 [d, J = 6.6 Hz, 6 H,
CH(CH3)2].
13.3 Hz, 2 H, CH2OC(O)], 3.84 (t, J = 5.9 Hz, 2 H, CH2O), 3.64 [q, J = 7.1
Hz, 1 H, CH3CHC(O)], 3.36 (t, J = 6.6 Hz, 2 H, CH2N3), 2.34 [d, J = 7.2 Hz,
2 H, CH2CH(CH3)2], 1.88 (qt, J = 6.3 Hz, 2 H, CH2CH2O), 1.74 [nonet, J =
6.8 Hz, 1 H, CH(CH3)2], 1.40 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.79 [d, J =
6.6 Hz, 6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3):  = 174.4, 158.7, 140.5, 137.7, 137.6, 129.5,
129.3 (2 C), 127.2 (2 C), 120.1, 114.1, 113.5, 66.0, 64.3, 48.2, 45.1, 45.0,
30.2, 28.7, 22.4 (2 C), 18.5.
MS (CI): m/z = 413 [M + NH4]+.
HRMS (MALDI, DHB, PEG 400): m/z [M + Na]+ calcd for C23H29N3O3Na:
13C NMR (100 MHz, DMSO-d6):  = 173.7, 173.0, 158.4, 139.8, 137.7 (2
C), 129.4, 129.0 (2 C), 127.1 (2 C), 119.5, 113.9, 113.4, 65.3 (2 C), 52.8,
51.9, 44.2, 44.1, 40.4, 30.8, 29.5, 25.2, 22.1 (2 C), 18.3.
418.2101; found: 418.2101.
MS (ESI): m/z = 456 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H38NO5: 456.2750; found:
Dimethyl Pent-4-ynoylphosphonate (17)35
Freshly distilled SOCl2 (11.1 mL, 152.9 mmol) was added to the com-
mercial 4-pentynoic acid (14; 6 g, 61.16 mmol) and the resulting
mixture was heated to reflux for 90 min. Distillation under reduced
pressure afforded pure expected acyl chloride (3.6 g, 51%) as a color-
less oil; bp 51 °C/30 mbar.
1H NMR (300 MHz, CDCl3):  = 3.14 [t, J = 7.1 Hz, 2 H, CH2C(O)Cl], 2.57
[td, J = 7.1, 2.7 Hz, 2 H, CH2CH2C(O)Cl], 2.05 (t, J = 2.7 Hz, 1 H).
456.2741.
1-Hydroxy-3-{[3-(3-{[2-(4-isobutylphenyl)propanoyloxy]meth-
yl}phenoxy)propyl](methyl)amino}propane-1,1-bis(phosphonic
acid) (2)
The compound 2 was prepared according to the method described for
the preparation of the analogue 1, starting from 13 (270 mg, 0.6
mmol) in the presence of catecholborane (3.5 equiv) and P(OSiMe3)3
(4.5 equiv). The crude product was taken up in DCM and a large
amount of Et2O was added to give an oil which separated. It was puri-
fied by low pressure C18 reversed-phase chromatography
(MeCN/MeOH, 100:0 to 50:50) to give 2 (160 mg, 45%) as an amor-
phous white solid. The oil could also be taken up in a mixture of
MeOH/Et2O until a white precipitate appeared, which was filtered. Af-
ter evaporation of the filtrate, 2 (37%) could be obtained with an in-
separable amount of H3PO3 (see SI).
13C NMR (75 MHz, CDCl3):  = 172.3, 80.5, 70.4, 45.7, 14.8.
To the above neat acyl chloride (2.1 g, 17.88 mmol) cooled at 0 °C was
added dropwise trimethyl phosphite (2.11 mL, 17.88 mmol) with vig-
orous stirring. After complete addition, the reaction mixture was
stirred for 2 h at RT, while monitoring by 31P NMR spectroscopy. After
evaporation of the volatiles, acyl phosphonate 17 was obtained as a
yellow oil (3.43 g, ~100%) and used without further purification.
1H NMR (300 MHz, CDCl3):  = 3.89 (d, 3JHP = 10.7 Hz, 6 H, 2 × OCH3),
3.10 [td, J = 7.1, 1.6 Hz, 2 H, CH2C(O)], 2.50 [td, J = 7.1, 2.6 Hz, 2 H,
CH2CH2C(O)], 1.99 (t, J = 2.6 Hz, 1 H, CH).
1H NMR (300 MHz, DMSO-d6):  = 7.19 (d, J = 8 Hz, 2 Harom), 7.10 (d, J =
8 Hz, 2 Harom)–6.85 (m, 3 Harom), 5.04 [s, 2 H, CH2OC(O)], 4.00 (m, 2 H,
CH2CH2O), 3.81 [q, J = 7.1 Hz, 1 H, CH3CHC(O)], 3.29 [m, 2 H,
CH2N(CH3)], 3.13 [m, 2 H, N(CH3)CH2], 2.71 [s, 3 H, N(CH3)], 2.40 [d, J =
1
13C NMR (75 MHz, CDCl3):  = 208.4 (d, JCP = 171.3 Hz), 81.9, 69.4,
54.1 (d, 2JCP = 7.1 Hz, 2 C), 42.4 (d, 2JCP = 56.4 Hz), 11.8 (d, 3JCP = 4.5 Hz).
31P NMR (121.5 MHz, CDCl3):  = –1.2.
7.1 Hz,
2 H, CH2CH(CH3)2], 2.26–2.11 [m, 4 H, CH2CH2O and
CH2C(OH)(PO3H2)2], 1.80 [nonet, J = 6.8 Hz, 1 H, CH(CH3)2], 1.39 [d, J =
7.1 Hz, 3 H, CH3CHC(O)], 0.84 [d, J = 6.6 Hz, 6 H, CH(CH3)2].
Tetramethyl 1-Hydroxy-4-pentylidene-1,1-bis(phosphonate) (18)
To a solution of the acyl phosphonate 17 (1.91 g, 10.04 mmol) in
freshly distilled toluene (9 mL) was added dimethyl phosphite (1.06
mL, 11.55 mmol) and a catalytic amount of n-Bu2NH (55 L, 0.32
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

J
S. Aoun et al.
Paper
Synthesis
mmol) at 0 °C. A white solid began to form 20 min after the introduc-
tion of the base. Stirring was continued for 4 h. After completion of
the reaction (31P NMR monitoring), the precipitate was filtered to give
pure hydroxy-bisphosphonate 18 (2.3 g, 77%) as a white powder; mp
81–83 °C.
was then added (20 mg, 0.1 mmol) and the reaction mixture was
stirred for 18 h. After addition of MeOH followed by a large amount of
Et2O, a brownish precipitated appeared, which was collected. It was
dissolved in MeOH and acidified with HCl (1 mL of a 2 M HCl solution
in anhyd Et2O) to give a yellowish solution. After concentration, the
residue was dissolved in a minimum of MeOH and a large amount of
Et2O was added to give the compound 3 as a colored powder, which
was filtered (80 mg, 25%).
IR (film): 3224, 2961, 1247, 1217, 1037 cm–1
.
1H NMR (400 MHz, CDCl3):  = 4.08 (br s, 1 H, OH), 3.90–3.87 (m, 12 H,
4 × OCH3), 2.57 [td, J = 8.1, 2.6 Hz, 2 H, CH2CH2C(OH)], 2.37–2.26 [m, 2
H, CH2C(OH)], 1.98 (t, J = 2.6 Hz, 1 H, CH).
13C NMR (100 MHz, CDCl3):  = 84.0, 74.8 (t, 1JCP = 152.8 Hz), 69.0, 54.5
(m, 4 C), 33.0, 13.4 (t, 3JCP = 7.1 Hz).
31P NMR (121.5 MHz, CDCl3):  = 21.6 (2 P).
MS (ESI) : m/z = 323 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C9H18O7P2Na: 323.0425; found:
From 19: To a solution of phosphonate 19 (287 mg, 0.41 mmol) in
DCM (4 mL) was added TMSBr (377 mg, 2.46 mmol). After stirring for
5 h at RT, volatile fractions were eliminated by concentration in vac-
uo. MeOH (4 mL) was added to the isolated silylated intermediate and
the solution was stirred for 2 h at RT. Concentration under reduced
pressure afforded pure hydroxy-bisphosphonic compound 3 (260 mg,
~100%) as a beige hygroscopic powder.
1H NMR (400 MHz, DMSO-d6):  = 7.92 (s, 1 Htriazolyl), 7.22–7.08 (m, 5
323.0421.
H
arom), 6.83–6.76 (m, 3 Harom), 5.05 [AB system, JAB = 13.5 Hz, ΔAB =
13.5 Hz, 2 H, CH2OC(O)], 4.49 (t, J = 6.9 Hz, 2 H, CH2N), 3.91 (t, J = 6.0
Hz, 2 H, CH2O), 3.82 [q, J = 7.1 Hz, 1 H, CH3CHC(O)], 2.97–2.92 [m, 2 H,
CH2CH2C(OH)(PO3H2)2], 2.40 [d, J = 7.1 Hz, 2 H, CH2CH(CH3)2], 2.28–
2.17 [m, 4 H, CH2CH2O and CH2C(OH)(PO3H2)2], 1.79 [nonet, J = 6.7 Hz,
1 H, CH(CH3)2], 1.39 [d, J = 7.1 Hz, 3 H, CH3CHC(O)], 0.83 [d, J = 6.6 Hz,
6 H, CH(CH3)2].
13C NMR (100 MHz, DMSO-d6):  = 173.7, 158.3, 146.9, 139.8, 137.8,
138.7, 129.5, 129.1 (2 C), 127.1 (2 C), 122.1, 119.6, 113.9, 113.4, 72.0
(t, 1JCP = 143.2 Hz), 65.3, 64.4, 46.6, 44.2, 44.1, 32.8, 29.6, 29.4, 22.1 (2
C), 19.7 (t, 3JCP = 6.9 Hz), 18.4.
Tetramethyl 1-Hydroxy-3-{1-[3-(3-{[2-(4-isobutylphenyl)propa-
noyloxy]methyl}phenoxy)propyl]-1H-1,2,3-triazol-4-yl}-1,1-
bis(phosphonate) (19)
Alkyne phosphonate 18 (151 mg, 0.5 mmol) and azide 16 (218 mg,
0.55 mmol) were suspended in a 4:1 mixture of t-BuOH and H2O (2
mL). The solution was degassed for 15 min and CuSO4 (25 L of freshly
prepared 1 M solution in H2O, 0.025 mmol) was added, followed by
sodium L-ascorbate (75 L of freshly prepared 2 M solution in H2O,
0.15 mmol). The heterogeneous mixture was stirred vigorously for 24
h, until TLC analysis indicated complete consumption of the alkyne.
The reaction mixture was diluted with brine (8 mL) and the aqueous
layer was extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (DCM/MeOH, 100:0 to
96:4) gave pure compound 19 (338 mg, 97%) as a brownish gum.
31P NMR (121.5 MHz, DMSO-d6):  = 20.6 (2 P).
MS (ESI) : m/z = 638 [M – H]–.
HRMS (ESI): m/z [M – H]– calcd for C28H38N3O10P2: 638.2038; found:
638.2021.
IR (film): 3200, 2956, 1734, 1587, 1453, 1252, 1050 cm–1
1H NMR (400 MHz, CDCl3):  = 7.33 (s, 1 Htriazolyl), 7.23–7.19 (m, 3 Harom),
7.09–7.07 (m, 2 Harom), 6.83–6.76 (m, 3 Harom), 5.07 [AB system, JAB
.
Funding Information
=
12.7 Hz, ΔAB = 16.8 Hz, 2 H, CH2OC(O)], 4.52 (t, J = 6.9 Hz, 2 H, CH2N),
3.92–3.87 (m, 14 H, CH2O and 4 × OCH3), 3.75 [q, J = 7.2 Hz, 1 H,
CH3CHC(O)], 3.12 [t, J = 7.1 Hz, 2 H, CH2CH2C(OH)(PO3H2)2], 2.49 [tt,
JHP = 14.6 Hz, JHH = 7.2 Hz, 2 H, CH2C(OH)(PO3H2)2], 2.44 [d, J = 7.2 Hz, 2
H, CH2CH(CH3)2], 2.35 (qt, J = 6.0 Hz, 2 H, CH2CH2O), 1.84 [nonet, J =
6.8 Hz, 1 H, CH(CH3)2], 1.51 [d, J = 7.2 Hz, 3 H, CH3CHC(O)], 0.89 [d, J =
6.6 Hz, 6 H, CH(CH3)2].
We thank the Ministère de l’Enseignement Supérieur de la Recherche
et de l’Innovation for Ph.D. financial support.()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611540.
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13C NMR (100 MHz, CDCl3):  = 174.5, 158.6, 147.0, 140.6, 137.9,
137.7, 129.7, 129.4 (2 C), 127.3 (2 C), 121.5, 120.5, 114.1, 113.7, 75.3
1
(t, JCP = 155.4 Hz), 66.1, 64.0, 54.5 (4 C), 47.2, 45.2, 45.1, 32.5, 30.2,
References
30.0, 22.4 (2 C), 20.6 (t, 3JCP = 8.0 Hz), 18.6.
31P NMR (121.5 MHz, CDCl3):  = 22.1 (2 P).
MS (ESI) : m/z = 694 [M – H]–, 730 [M – Cl]–.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K