Functional bisphosphonate synthesis for the development of new anti-resorption bone drug candidates

Article abstract of DOI:10.1039/c9nj02504a

Herein we present the synthesis of β-mono and β-bis-substituted vinylidenebisphosphonate esters bearing a carboxylic ester moiety to be used as building blocks for further functionalizations. Reactions of these new bisphosphonate scaffolds through hydrogenation of the unsaturated CC bond and through metal mediated addition of aryl boronic acids and indoles provide a wide range of new bisphosphonate products as potential leads to contrast osteoporosis.

Full text of DOI:10.1039/c9nj02504a

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DOI: 10.1039/C9NJ02504A
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Functional Bisphosphonate Synthesis for the Development of New
Anti-Resorption Bone Drug Candidates
Enrica Bortolamiol,a Andrea Chiminazzo,a Laura Sperni,a Giuseppe Borsato,a Fabrizio Fabrisa and
Received 00th January 20xx,
Accepted 00th January 20xx
Alessandro Scarsoa,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
attributed to specific BPs range from anticancer activity,8 to
Herein we present the synthesis of β-mono and β-bisubstituted
vinylidenebisphosphonate esters bearing a carboxylic ester
antibacterial and anti-malarial properties.9
The chemical structure of currently available BPs is
rather limited and the search for more potent and better
tolerated N containing BPs is a highly desirable topic. It is
also worth to underline that, despite the importance of
chiral drugs is nowadays a landmark in drug discovery, the
development of chiral BPs and the investigation of their
biological activity is still a rather unexplored topic10 that
deserve further investigation.11 For this purpose, the
development of new prochiral BP scaffolds to widen the
structure variability of BPs is highly desirable.
moiety to be used as
a building blocks for further
functionalizations. Reactions of these new bisphosphonate
scaffolds through hydrogenation of the unsaturated C=C bond
and through metal mediated addition of aryl boronic acids and
indoles provides a wide range of new bisphosphonate products
as potential leads to contrast osteoporosis
Introduction
Bisphosphonic acids (BPs) are a class of molecules bearing
O O
O O
two phosphonic acid moieties connected through
a
HO
OH
O O
HO
OH
O
O
P
P
P
P
P
P
O
methylene linker whose chemical similarity to
hydroxyapatite, the major mineral component of bones, is
responsible for their specific bone targeting properties1 and
because of this they have been used for decades in
medicinal chemistry2 for the treatment of bone disorders
such as hypocalcemia and osteoporosis. The close
correlation between their chemical structure (R1 and R2
groups in Scheme 1) and the biological activity is still a highly
debated topic;3,4 in particular it has been recognized that
their cellular activity is related to their ability to inhibit
specific enzymes like farnesyl diphosphate synthase (FPPS),
geranylgeranyl diphosphate synthase (GGPPS)5,6 and other
ones7 present in osteoclasts that are the cells deputed for
bone resorption. As long as their chemical structure is
concerned, the presence of a hydroxyl group in position R1
of the BP (Scheme 1) enhances the affinity for
hydroxyapatite in bones. Very important is the presence of N
containing residues on R2 as evidenced by the structures of
the commercially available alendronic and zoledronic acids
clinically used to contrast osteoporosis (Scheme 1). The
combination of N atoms in the side chain together with a
long alkyl chain on R2 provide even more efficient BPs to
contrast bone resorption.5 Other therapeutic effects
HO
OH
HO
OH
R1 R2
O
O
tetraethyl methylene
bisphosphonate ester
(MBP)
bisphosphonic acid
pyrophosphoric acid
O O
O O
HO
OH
OH
HO
OH
P
P
P
P
HO
HO
OH
HO
HO
N
N
NH2
zoledronic acid
alendronic acid
O O
O O
O O
O
O
O
O
O
O
O
O
P
P
P
P
P
P
O
O
O
O
R3
R3
R4
tetraethyl VBP
tetraethyl
monosubstituted-VBP
tetraethyl
bisubstituted-VBP
R3= COOAlk; R4=Ar
Scheme 1. Chemical structure of a generic bisphosphonic acid,
pyrophosphoric acid, tetraethyl methylene bisphosphonate ester
(MBP), alendronic and zoledronic acids, vinylidenebisphosphonate
tetraethyl ester (VBP) and related compounds with one or two
substituents in β position.
The synthesis of BPs bearing the OH moiety on R1 is
usually accomplished starting from a carboxylic acid12,13 or
an acyl chloride derivative,14 conversely BPs lacking the OH
on R1 are more commonly prepared by Michael addition of
nucleophiles to vinylidenebisphosphonate tetraethylester
(VBP)15 as a typical electrophilic building block (Scheme 1).
a. Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca’ Foscari di
Venezia, via Torino 155, 30172, Mestre (Ve),:+39-041-234-8569; Fax: +39-041-
234-8517; E-mail: alesca@unive.it
Electronic Supplementary Information (ESI) available: full experimental procedures
and characterization spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Addition reactions to the electron poor C=C of VBP enabled
the preparation of several classes of BPs containing thio-
ether units,16 heterocycles17 steroid conjugates as well as
cycloaddition derivatives through reaction with dienes18,19
and nitrones.20,21 Recently, metal catalyzed addition of
indoles and boronic acid to VBP led to a further enrichment
of the structure variability of BPs.22,23
endowed with one aromatic and one ester substituVeienwt,AtrthicelelOanttliener
useful for further functionalization.
DOI: 10.1039/C9NJ02504A
O
TiCl4
NEt3
O O
O
O
O O
O
O
O
P
P
R1
P
P
O
O
O
0°C
CH2Cl2
O
O
O
R2
R1
R2
In continuation of our effort in the field,24 we focused
our attention on the development of new unsaturated BP
precursors,25 in particular herein we describe the synthesis
of β-mono-substituted and β-bis-substituted VBP prochiral
precursors bearing a carboxylic ester unit in the side chain R3
(Scheme 1). Examples of disubstituted VBP precursors are
very limited in the literature, in particular worth of mention
are the structures bearing two identical substituents in the
β-position like in Scheme 2A.26,27 Abdou and co-workers
recently reported a one-pot procedure to obtain a series of
branched N-heterocyclic-substituted VBPs (Scheme 2B).28
Another example was reported using copper-promoted
domino condensation/S-arylation/heterocyclization process
for the synthesis of series of 2-C-substituted benzothiazoles
containing gem-BPs (Scheme 2C).29 In the latter two
examples both substituents on the vinyl position are part of
the same heterocyclic ring. By reaction of MBP with N1- and
O
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Scheme 3. Condensation reaction of glyoxylate derivatives with
MBP catalyzed by TiCl4 and TEA.
Synthesis of Substituted VBP
A solution of ethyl glyoxylate in toluene was used for the
reaction with MBP mediated by TEA and TiCl4 (Scheme 4) leading
to the formation in high yield of the corresponding condensation
product.
The
latter
was
identified
as
ethyl-3,3-
bis(diethoxyphosphoryl)acrylate 1a, a new mono-substituted-VBP
precursor bearing an ester substituents in the β-position, while
known mono-substituted-VBP presents exclusively aryl, alkenyl or
alkyl moieties in the same position.33 The 1H NMR spectrum of 1a
was characterized by the presence of the resonance of the β-
hydrogen at 7.43 ppm as a doublet of doublets (J = 44.4, 27.7 Hz)
due to the coupling with the two diastereotopic P atoms.
Accordingly, the 31P NMR spectrum showed two resonances at
N3-allyl-2-thiouracils
under
phase-transfer
catalysis
conditions, the products reported in Scheme 2D and E were
obtained.30 A useful synthetic route for the formation of
enamino keto esters that use nitriles and ethyl acetoacetate
has been reported recently by Pei and collaborators
(Scheme 2F).31
2
13.01 and 9.22 ppm with JP-P of 42.2 Hz. The new substituted
VBP derivative turned out to be stable at 0°C for weeks.
Commercially available molecules structurally similar to ethyl
phenylglyoxylate are methyl and ethyl pyruvates. The latter were
tested under the above reported experimental conditions but
unfortunately did not provide any product formation probably
because possible enolate species can be formed due to the
presence of α hydrogen atoms in the α-keto ester units that
could be further involved in aldol condensation side-reactions. t-
butyl pyruvate and diethyl oxalate under experimental conditions
of Scheme 4 also failed to provide the corresponding desired
product.
A)
B)
C)
O O
O O
O O
O
O
O
O
O
O
P
P
P
P
P
P
O
O
O
O
O
O
HN
N
N
S
S
S
NH
R1
O
TiCl4
NEt3
R1
O O
O
O
O O
O
O
O
P
P
H
P
P
O
O
O
0°C
CH2Cl2
O
O
O
D)
E)
F)
H
O
O O
O O
O O
P
O
O
O
O
O
O
O
1a
, 90%
P
P
P
P
P
Scheme 4. Condensation reaction of ethyl glyoxylate catalyzed by
TiCl4 and NEt3 with MBP forming the corresponding product 1a.
O
O
O
O
O
O
Et
Et
N
N
NH2
Spurred by the positive result observed with ethyl glyoxylate,
we thus investigated a wide spectrum of commercially available
and synthetic -keto esters with different steric and electronic
properties and characterized by the presence of sensitive
functional groups to test the generality of the synthetic method.
The results obtained are reported in Table 1. The reaction
between MBP and ethyl phenylglyoxylate in the presence of TEA
as organic base and TiCl4 as hard-Lewis acid led to the formation
N
H
S
O
N
S
H
Scheme 2. Examples of bis-substituted VBP structures recently
reported in the literature.
Results and discussion
of the desired product 1b in a 90% yield (Table 1, entry 1). The 31
P
Inspired by the recent publication reporting the reactivity of
benzylidene malonate intermediate with α-keto ester reagents32
catalyzed by TiCl4, we decided to investigate the condensation of
MBP with glyoxylate derivatives catalyzed by TiCl4 and NEt3
aiming at obtaining bis-substituted VBP precursors (Scheme 3)
NMR spectrum showed the presence of two distinct resonances
2
at 11.28 and 10.13 ppm for the P atoms with a JP-P coupling
constant of 44.5 Hz (see supporting information). The ethoxy
residues of the carboxylic ester and the two of the different
phosphonic esters were all characterized by different chemical
shift both for the methylene and the methyl residues, as
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confirmed by the COSY spectrum of 1b (see supporting
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information). As expected, the use of methyl phenylglyoxalate led
to the formation of the corresponding product with yield similar
to the ethyl derivative (Table 1, entry 2). The use of numerous
aryl glyoxylates synthesized according to the procedures reported
in the literature,34,35 allowed to study the scope of the reaction
varying the steric and electronic properties of the reagent. The
presence of electron-donating groups on the aryl residue led to
slightly lower yields compared to those bearing electron-
withdrawing groups (Table 1, entries 3-5). The reaction proved to
be very sensitive to the steric properties of the reagent, in fact
the presence of substituents in the ortho position of the phenyl
group led to a decrease of the reaction yield (Table 1, entries 4, 5
and 6).
DOI: 10.1039/C9NJ02504A
P
O
O
O
P
COOEt
O
7
8
64
O
COOEt
CF3
F3C
O
1h
10
11
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O O
O
O
O
P
O
P
O
COOEt
22
COOEt
Cl
Cl
1i
Bis-substituted VBP
product
Yield
O O
#
α-keto ester
(%)a
O
O
P
P
F
F
O
O
O
F
F
F
O O
COOEt
O
O
F
F
9
28
COOEt
O
P
P
F
O
O
1
90
COOEt
F
COOEt
F
1j
1b
O O
O
O
O
O O
P
P
O
O
O
P
P
O
O
COOEt
10
11
92
40
O
O
2
3
4
5
6
84
73
58
63
60
COOEt
COOMe
O2N
COOMe
O2N
1k
1c
O O
O O
O
O
O
O
O
O
P
O
P
P
P
O
O
O
COOEt
COOEt
COOEt
COOEt
N
O
N
O
1l
1d
Table 1: Synthesis of bis-substituted VBP 1b-1l. Reaction conditions: 1
mmol MBP, 1 mmol α-keto esters, 4 mmol NEt3, 1 mmol TiCl4, 25 mL
CH2Cl2, 0°C. [a] Isolated yield. The products were all obtained in hundreds
mg scale, purified by flash chromatography.
O O
O
O
O
O
P
P
O
O
COOEt
COOEt
The presence of a halogen substituent such as chlorine in the
ortho position of the phenyl ring turned out to be detrimental for
the yield of the corresponding products (Table 1, entry 8). An
electron-withdrawing group like nitro in the para position of the
aromatic ring led to good yield for the corresponding product 1k
(Table 1, entry 10) while other two aryl glyoxylate reagents
bearing electron poor aryl units like pentafluoro phenyl or pyridyl
led to low or moderate yields for the corresponding products 1j
and 1l (Table 1 entry 9 and 11).
O
1e
O
O O
O
O
P
P
COOEt
O
O
COOEt
O
O
O
O
1f
O O
O
O
Hydrogenation of bis-substituted VBP products 1b-l
O
P
P
O
O
In the literature several examples of hydrogenation reactions
of phosphonate monosubstituted alkenes have been
reported,36,37 most of which employing Pd supported on carbon
as catalyst. There are also examples of hydrogenation of double
bonds substituted with one phosphonate groups using sodium
borohydride as reducing reagent.38,39 We decided to investigate
the use of Pd/C as heterogeneous catalyst for the hydrogenation
COOEt
COOEt
1g
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of some of the bis-substituted VBP products reported in Table 1
to obtain the corresponding racemic products 2b-l (Scheme 5 and
Table 2).
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DOI: 10.1039/C9NJ02504A
O O
O
O
P
P
O
O
6
1g
>98
6
COOEt
7
8
9
2g
1 atm. H2
O O
O O
O
O
O
O
20 mol% Pd/C (5% w/w)
P
P
P
P
O O
10
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O
O
O
O
O
O
O
O
P
P
r.t.
MeOH
O
O
R1
R1
7
8
1h
1i
>98
COOEt
O
O
F3C
R
R
O
1b-l
2b-l
2h
R1 = Me, Et
O O
Scheme 5. Pd/C catalyzed hydrogenation of Bi-substituted VBP
precursors.
O
O
P
O
P
O
0
COOEt
Cl
bis-
2i
Yield
#
substituted
VBP
BP product
(%)a
O O
O
O
P
P
O
O
F
O O
O
O
P
P
F
F
9
1j
>98
COOEt
O
O
1
1b
1c
1d
1e
1f
>98
COOEt
F
F
2j
2b
O O
O O
O
O
O
O
P
P
O
P
P
O
O
O
18a
2
3
4
5
>98
>98
>98
>98
COOEt
COOMe
O2N
2c
2k
10
1k
O O
O O
O
O
O
O
P
P
P
P
O
O
O
O
82a
COOEt
COOEt
O
H2N
2d
2k’
O O
O O
O
O
O
O
O
P
P
P
P
O
O
O
11
1l
>98
COOEt
COOEt
O
N
2e
2l
Table 2: Pd/C catalyzed hydrogenation of bis-substituted VBP
precursors. Reaction conditions: 1 mmol of VBP, 20 mol% of 5 %
w/w Pd/C, 1 atm H2, MeOH, r.t., t=overnight. [a] Isolated yield.
O O
O
O
P
P
O
O
COOEt
As long as the structure of the substrates is concerned, all the
substrates led to the corresponding saturated hydrogenation
product in quantitative yields, while the reaction on 1k led
predominantly to the reduction also of the nitro group to amino
group as main product (Table 2, entry 10 product 2k’) with only
18% of 2k (Table 2, entry 10). The structures of the two products
O
O
2f
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2k and 2k’ were confirmed by mass spectrometry analysis and
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the 31P NMR spectra clearly showed two different pairs of
doublets downfield shifted with respect to the starting prochiral
VBP attributed to the two reduced products. Differently from
what observed with the other substrates, the hydrogenation of 1i
under identical experimental conditions not only led to the
hydrogenation of the double bond but also to the hydro-
dechlorination of the aromatic unit, leading to the formation of
2b as main product while 2i was not observed (Table 2, entry 8).
As a typical example, in Figure 1 are reported the 1H-NMR (A) and
1H {31P}-NMR (B) spectra of 2e. In the latter spectrum the H-P
coupling is not observed, and this provides a simplification of the
resonances of the  and  protons that are characterized only by
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3
H-H coupling with a J of 9.8 Hz. The 31P {1H}-NMR of 2e showed
the presence of two doublets downfield shifted with respect to
1e with a small coupling constant of 0.8 Hz (Figure 2).
Figure 2: (A) 31P {1H}-NMR of 2e and (B) 31P {1H}-NMR of 1e.
Asymmetric Hydrogenation of bis-substituted VBP
Rh(I) complexes bearing chiral ligands appears to be the best
choice for the catalytic asymmetric hydrogenation of olefin or
α,β-unsaturated compounds as demonstrated by
a vast
literature.40 As long as the stereoselective hydrogenation of
alkenes bearing the phosphonate moiety is concerned, previous
studies demonstrated that best ligands were chiral phosphines.41
Substrate 1b was used for the stereoselective Rh(I) catalyzed
hydrogenation screening a range of chiral enantiopure di-
Figure 1: (A) 1H-NMR and (B) 1H {31P}-NMR of 2e.
phosphine ligands. The use of 0.5 mol
%
of
(acetylacetonato)dicarbonylrhodium(I) coupled with (S)-BINAP or
(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]-
ethyldicyclohexylphosphine ((R)-JOSIPHOS) with respect 1b did
not lead to any formation of the desired hydrogenation product
at room temperature and 10 bar pressure of H2. The same
catalytic systems under forced reaction conditions (50 bar and
50°C) led to the same results. These drastic reaction conditions
were used also with the metal precursor chloro(1,5-
cyclooctadiene)rhodium(I) dimer without ligands showing that
Rh(I) cannot catalyze the hydrogenation of the double bond of
the bis-substituted BP precursor.
Metal catalysis was therefore abandoned, and other reducing
agents were considered. We focused our attention on the use of
NaBH4 in combination with enantiopure organocatalysts. In the
absence of any organocatalyst, NABH4 hydrogenation of 1b
resulted in the quantitative formation of saturated product 2b.
The asymmetric version of the reaction was therefore performed
with quinine-thiourea and quinidine-thiourea as organocatalyst42
as commonly used H-bonding organocatalysts for Michael type
addition reactions known to be active on phosphonate
compounds43 and previously tested by our group in the
stereoselective synthesis of chiral isatin containing BPs.24c The
organocatalyzed hydrogenation of 1b led to quantitative yields of
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the hydrogenated product 2b but unfortunately, chiral HPLC
analyses showed however no asymmetric induction. We tested
also the reduction with the Hantzsch ester known for its high
degree of stereo-control in the reduction of α,β-unsaturated
carbonyl compounds, cyclic/acyclic imines and activated olefins.44
Experimental tests for the asymmetric hydrogenation of 1b with
the Hantzsch ester mediated by L-proline in apolar solvent at
room temperature as well as at 60 °C resulted in no formation of
the expected hydrogenated product. Overall the asymmetric
hydrogenation of the disubstituted VBP substrates turned out to
be a still open challenge45,46 due to the high steric hindrance
present on the C=C double bond and its electron poor character.
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OH
O O
O O
O
O
DOI: 10.1039/C9NJ02504A
B
Cu(OTf)2
O
O
P
P
P
P
O
O
O
O
O
O
Toluene
70°C, 18 h
S
O
O
S
1a
3a
85%
Scheme 7. Addition of 3-thienylboronic acid to 1a leading to the
corresponding addition product 3a.
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1
Figure 3 reports the comparison between the H (A) and the
1H {31P} (B) NMR spectra of 3a showing the simplification of the
resonance peaks in the latter spectrum. 31P {1H}-NMR of 3a
showed formation of two doublets typically downfield shifted
with respect to the resonances of the reagent 1a as commonly
observed for addition products on VBP and characterized by a
much smaller JP-P coupling constant of 2.4 Hz (see supporting
information). Attempts to induce asymmetry in the reaction using
Box and PyBox as chiral ligands turned out to be inefficient
forming only racemic product 3a.
Cu(II)-Catalyzed Addition of Aryl Boronic Acids to Substituted
VBP
In order to investigate the synthesis of more elaborated BP
products, we tested the asymmetric addition of aryl boronic acids
to β-disubstituted VBP in the presence of Cu(II) as catalyst with
the aid of chiral N based bidentate ligands (Scheme 6).
R2
O
R2
O
R2
O
R2
O
Catalyst
Solvent
O O
O O
OH
B
P
P
P
P
R2
O
O
O R2
R1
OH
R2
O
O
O R2
Ar
Ar
R1
O
O
Scheme 6. Asymmetric addition of boronic acids to β-bisubstituted VBP.
The desired product was not obtained even with the use of
the highly electrophilic bis-substituted substrate 1k in
combination with the chiral bis(oxazoline) ligands (+)-2,2’-
isopropylidenebis[(4R)-4-benzyl-2-oxazoline] (Box) and 2,6-
bis[(4S)-(-)-isopropyl-2-oxazolin-2-yl]pyridine (PyBox), following
the results recently reported for the asymmetric Cu(II) catalyzed
1,4-addition of phenyl boronate to electron deficient olefins.47
Differently, the Rh(I) catalyzed addition led to some reactivity,
but only causing the elimination of a phosphonate group from
the BP reagent, regardless the electron-withdrawing or electron-
donating properties of the aryl-boronic acid employed. The
reaction did not proceed even in the absence of the chiral ligands
probably due to the high steric hindrance present on the
electrophilic -C atom.
Figure 3: (A) 1H-NMR and (B) 1H {31P}-NMR of 3a.
Friedel–Crafts Reaction between indoles and 1a
Several attempts were made to investigate the asymmetric
version of the Friedel-Crafts reaction between indole and the
substituted bisphosphonate precursors (Scheme 8) characterized
by different electronic properties under the above optimized
catalytic conditions.
The reaction was then extended to the less hindered β-mono-
substituted VBP 1a showing that product formation was largely
influenced by the size of the boronic reagent. While Cu(II)
addition of phenylboronic acid to 1a did not lead to the desired
product, the use of a less hindered reagent like 3-thienyl boronic
acid led to the corresponding addition product in excellent yield
(Scheme 7). Alkyl boronic acids like isopropyl boronic acid led
only to decomposition of 1a by loss of a phosphonate moiety.
O O
P
O O
Cu(OTf)2
O
O
O
O
P
P
P
NH
O
O
O
O
O
O
DCE
70°C
12 h
R1
HN
O
O
R1
1a
4aa-4ah
Scheme 8. General Friedel-Crafts reaction indole substrates to 1a.
Tests on 1b and the electron-poor 1k precursors were
performed with free Cu(OTf)2 as well as in the presence of chiral
ligands like (+)-2,2′-Isopropylidenebis[(4R)-4-benzyl-2-oxazoline]
(Box) or 2,6-bis[(4S)-(−)-isopropyl-2-oxazolin-2-yl]pyridine (PyBox)
but unfortunately, no evidence of product formation was
obtained, recovering in both cases only the unconverted
prochiral bisphosphonate reagent. The lack of reactivity is
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probably due to intrinsic steric hindrance present in the β-
position of the aromatic substituted BP precursors.
4af
View Article Online
DOI: 10.1039/C9NJ02504A
Cl
O O
Yielda
(%)
O
O
P
P
#
BP
1a
Indole
Product
HN
O
O
7
1a
13
COOEt
O O
O
O
HN
P
P
O
O
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43d
1
Cl
COOEt
N
H
HN
4ag
Cl
O O
O
O
4aa
P
O
P
O
O O
8
22
O
COOEt
Cl
O
O
N
1a
P
P
HN
O
O
O
2
3
4
1a
64
N
COOEt
N
H3C
4ah
CH3
Table 3: Addition of indoles to substituted VBP precursor 1a mediated by
Cu(OTf)2. Reaction conditions: 1 mmol monosubstituted VBP, 1.5 mmol
indole, 10 mol% Cu(OTf)2 in DCE, T=70°C, t=12h. [a] Isolated yield, [b] 2
mol% of Box, [c] 2 mol% PyBox, [d] [SDS]=100 mM in water at 70°C.
4ab
O O
The addition of indole on the less sterically hindered
substrate 1a confirmed the formulated hypothesis observing the
reaction on position 3 of the indole unit. It is also worth to note
that, as previously reported for the addition of indoles to VBP,
the reaction could be carried out also in aqueous micellar media
(Table 3, entry 8) obtaining yields similar to those obtained in
DCE as organic solvent. 1a was then reacted with a wide range of
indoles with different electronic and steric properties applying
the optimized catalytic system (Table 3, entries 1-8). In general
the presence of electron-donating groups as substituents in the
nitrogen containing five membered ring of indole led to higher
reaction yields (Table 3, entries 2 and 3) compared to the
presence of electron withdrawing groups on the six-membered
ring (Table 3, entries 4 and 5). Moreover, with sterically hindered
indoles containing phenyl substituents, a lowering of the reaction
yields was observed (Table 3, entries 6 and 7). With 1-(tert-
butoxycarbonyl)-5-chloroindole (Table 3, entry 8) partial loss of
the tert-butoxycarbonyl group occurred during the reaction,
leading to the completely deprotected product after
chromatographic purification, presumably because of the acid
character of silica. The results were confirmed by EI-MS analysis
O
O
O
P
P
O
1a
37
N
CH3
COOEt
N
4ac
O O
O
O
P
P
Br
O
O
COOEt
H3C
HN
28
1a
HN
Br
O
4ad
O O
O
P
P
H3CO
O
O
1
O
and H NMR that showed the presence of signals typical of the
COOEt
HN
indolyl nitrogen proton. Comparing the results for the addition of
indoles to 1a with those previously reported for the reaction on
VBP,22 generally lower yields were observed most likely due to
steric effects at the β-position. In Figure 4 the 31P {1H}-NMR of
4aa is reported showing two doublets with a really small coupling
constant (J = 2.4 Hz) down-field shifted compared to 1a.
5
18
1a
HN
O
O
4ae
O O
O
O
P
P
HN
O
O
6
26
1a
COOEt
HN
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provided free BPs characterized by solubility in water and some
surfactant like properties due to their amphiphilic nVaiteuwrAer.ticle Online
DOI: 10.1039/C9NJ02504A
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
The authors acknowledge Università Ca’ Foscari Venezia and
MIUR for support.
Notes and references
Figure 4: (A) 31P {1H}-NMR of 4aa and (B) 31P {1H}-NMR of 1a.
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Deprotection of the phosphoric ester moiety
In order to obtain the final version of the BP products with
free phosphonic acid units, some of the newly synthesized
products, 1a, 2b and the indolyl-containing BP products 4aa were
deprotected with trimethylsilyl bromide following an improved
procedure compared to that reported in the literature.20 The
corresponding deprotected bisphosphonic acid 5a, 5b and 5aa
1
were isolated in quantitative yields and characterized by H and
31P-NMR spectroscopy in D2O. In particular, the acids bearing
aromatic units showed surfactant like properties due to their
amphiphilic nature, confirmed by the appearance of broad
resonances in the 31P NMR spectra (see supporting information).
Further detailed biological evaluation on osteoclast bone cells
activity will be carried out in order to investigate the anti-
resorption properties of the new classes of BPs synthesized in the
present work.
Conclusions
In conclusion, herein we reported about the synthesis of a
new class of prochiral β-mono-substituted and β-bis-substituted
vinylidenebisphosphonate esters 1a-k as building blocks for
further functionalizations to widen the range of structures for the
preparation of bisphosphonic acids as potential leads to contrast
osteoporosis and bone related diseases. Further functionalization
through metal mediated addition of aryl boronic acids and
indoles on 1a led to the formation of new BPs bearing
heterocyclic units in the β position. Conversely, the addition
reactions on bis-substituted vinylidenebisphosphonate 1b-k
turned out to be hampered by steric interactions, while
hydrogenation of 1b-l provided a large series of racemic products
2b-l. Further deprotection of the phosphoric ethyl ester units
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Widening the bisphosphonate toolbox: new bisphosphonate scaffolds enable new functionalizations