Combined Phosphoramidite-Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates

Article abstract of DOI:10.1002/anie.201611878

A new class of phosphanylmethylphosphonate reagents has been developed to enable the controlled synthesis of methylene bisphosphonate mono- and diesters. Condensation of such reagents with an alcohol of choice through azole-mediated phosphoramidite chemistry followed by in situ oxidation provides orthogonally protected methylene bisphosphonate tetraesters. Global deprotection of the tetraester leads to terminal methylene bisphosphonates. Alternatively, selective deprotection at the terminal phosphonate followed by a condensation between the acquired methylene bisphosphonate triester and a second alcohol leads to methylene bisphosphonates diesters.

Full text of DOI:10.1002/anie.201611878

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611878
German Edition: DOI: 10.1002/ange.201611878
Phosphorylation
Hot Paper
Combined Phosphoramidite-Phosphodiester Reagents for the
Synthesis of Methylene Bisphosphonates
Sander B. Engelsma, Nico J. Meeuwenoord, Hermen S. Overkleeft, Gijsbert A. van der Marel,*
and Dmitri V. Filippov*
Abstract: A new class of phosphanylmethylphosphonate
reagents has been developed to enable the controlled synthesis
of methylene bisphosphonate mono- and diesters. Condensa-
tion of such reagents with an alcohol of choice through azole-
mediated phosphoramidite chemistry followed by in situ
oxidation provides orthogonally protected methylene
bisphosphonate tetraesters. Global deprotection of the tet-
raester leads to terminal methylene bisphosphonates. Alter-
natively, selective deprotection at the terminal phosphonate
followed by a condensation between the acquired methylene
bisphosphonate triester and a second alcohol leads to methyl-
ene bisphosphonates diesters.
Moreover, no generic strategy exists that readily allows for
the introduction of methylene bisphosphonate moieties in
structurally diverse pyrophosphate-containing (bio)mole-
cules. The development of such a strategy and its application
to methylene bisphosphonate analogues of natural products
(ATP, NAD, FAD) is reported here.
We envisioned that generic reagents capable of providing
access to both terminal and unsymmetric methylene
bisphosphonates had to be orthogonally protected to allow
two sequential condensations under conditions compatible
with common biomolecules, and that these requirements
could be met through the application of phosphanylmethyl-
phosphonate reagents (3; Figure 1). Azole-mediated conden-
sation between an alcohol and 3 followed by in situ oxidation
would give fully protected methylene bisphosphonate tet-
raester 4. Global deprotection of 4 would provide terminal
methylene bisphosphonate molecules. Alternatively, selective
deprotection of 4 to bisphosphonotriester 5 and consecutive
PV condensation with a second alcohol would give bisphos-
phonotetraester 6, and removal of the protecting groups in 6
would provide unsymmetric methylene bisphosphonates. We
herein describe several reagents of type 3 and their applica-
tion in the synthesis of terminal and unsymmetric methylene
bisphosphonates, both in solution and on solid support.
To evaluate the proposed method, phosphanylmethyl-
phosphonate 9 was chosen as a reagent suitable for the
introduction of terminal methylene bisphosphonate mono-
esters (Scheme 1). Lithiation of di-tert-butyl methylphospho-
nate (7) with 1 equiv of nBuLi followed by the addition of
phosphoramidite 8 provided the desired phosphanylmethyl-
phosphonate 9 in 37% yield.[18] The phosphorylating proper-
ties of reagent 9 were investigated by exploring the synthesis
of known adenosine-5’-methylene bisphosphonate (13).[19]
Condensation of phosphoramidite 9 with partially protected
adenosine 10[20] was accomplished using 1H-tetrazole as the
activator. Subsequent in situ tBuOOH-mediated oxidation of
the phosphonite-phosphonate intermediate afforded a meth-
ylene bisphosphonate of adenosine 11 in 37% yield. Treat-
ment of 11 with thiophenol and TEA resulted in complete
demethylation within 16 hours, as determined by LCMS and
31P NMR spectroscopy. After extractive work-up, consecutive
deprotection of the tert-butyl groups was accomplished with
10% trifluoroacetic acid (TFA) in dichloromethane (DCM)
within 30 min (Supporting Information, Figure S2). Final
ammonia-mediated deacylation provided me-ADP (13) in
quantitative yield. It is of interest to note that demethylation
proceeded sluggishly when the tert-butyl groups were
removed beforehand, taking up to 48 hours to complete.
P
yrophosphates are present in numerous natural products
that are involved in a wide variety of fundamental physio-
logical processes, including cell metabolism as well as
immunity and genome maintenance.[1–5] Consequently, pyro-
phosphates are important components of molecular tools or
probes that aim to study and influence these events.[6–8]
Pyrophosphates are inherently susceptible to hydrolysis,
transesterification, and enzymatic cleavage.[9,10] If a higher
stability is desired, methylene bisphosphonates are attractive
pyrophosphate bioisosteres that are less prone to undergo
hydrolysis both during synthesis and in physiological sur-
roundings.[11] The use of methylene bisphosphonate isosteres
of sugar nucleotides and nucleoside di- and triphosphates in
studies on the function of a wide variety of enzymes is well
documented.[8,12,13] Terminal methylene bisphosphonates
have been synthesized in the past using either methylene
bisphosphonic dichloride or partially protected monochlor-
idite derivatives as the phosphonylation agent.[14,15] Unsym-
metric methylene bisphosphonates can be accessed using
Mitsunobu chemistry or by condensing the hydroxy group of
a target (bio)molecule with an independently prepared
terminal methylene bisphosphonate.[16,17] The published
methods use unselective reagents, which limits the regiose-
lectivity of substitution reactions at the bisphosphonate core.
[*] S. B. Engelsma, N. J. Meeuwenoord, Prof. Dr. H. S. Overkleeft,
Prof. Dr. G. A. van der Marel, Dr. D. V. Filippov
Leiden Institute of Chemistry
Department of Bioorganic Synthesis
Leiden University
Einsteinweg 55, 2333 CC Leiden (The Netherlands)
E-mail: marel_g@lic.leidenuniv.nl
filippov@chem.leidenuniv.nl
Homepage: http://biosyn.lic.leidenuniv.nl/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611878.
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Figure 1. Method for the synthesis of terminal and unsymmetric methylene bisphosphates. Reagent 3 features orthogonally removable protecting
groups PG and PG* and can be prepared from methylphosphonate 1 and chlorophosphoramidite 2. The reagent is coupled to an alcohol-
containing substrate (R1OH) in a PIII phosphoramidite coupling/oxidation sequence (PCO) to give protected intermediate 4, a precursor for
terminal methylene bisphosphonates. Alternatively, after selective PG* removal (5), a second alcohol (R2OH) can be introduced through
phosphodiester condensation (PDC), leading to protected intermediate 6, a precursor of unsymmetric methylene bisphosphates.
Scheme 2. Synthesis of phosphanylmethylphosphonates 15 and 18.
Reagents and conditions: a) 1) nBuLi, THF, ꢀ788C, 0.5 h, 2) 8,
ꢀ788C, 15 min; b) 1) LDA, THF, ꢀ788C, 0.5 h, 2) 16, ꢀ788C!RT,
16 h; c) DCI, 2-cyanoethanol, DCM, 3.5 h.
neutralizing the reactant. This problem was circumvented
by switching to an excess of lithium diisopropylamide (LDA;
2.1 equiv), which increased the yield to 45%. Second, we
found that commercially available 8 was contaminated with
diisopropylamine hydrochloride (DIPA·HCl), another spe-
cies capable of quenching the lithiated methylphosphonate
14. Removal of DIPA·HCl, by precipitation in n-hexane prior
to addition, further increased the yield of 15 to 70%
(Figure S3).
Scheme 1. Synthesis of me-ADP 13. Reagents and conditions:
a) 1) nBuLi, THF, ꢀ788C, 0.5 h, 2) 8, 15 min; b) 1) 9, 1H-tetrazole,
MeCN, 10 min, 2) tBuOOH, 15 min; c) PhSH/Et3N/dioxane (1:2:2),
16 h; d) 1) 10% TFA in DCM, 0.5 h, 2) NH4OH, 16 h. [*] Yields based
on 31P NMR and LCMS analysis. Bz=benzoyl.
Reagent 18, which features a cyanoethyl protecting group,
was prepared by a similar method. Di-tert-butyl methyl-
phosphonate (7) was deprotonated and reacted with bis(di-
isopropylamino)chlorophosphoramidite 16 to afford bis-
(amidite) 17 in 76% yield. Selective substitution of one of
the diisopropylamine groups with 2-cyanoethanol in the
presence of 4,5-dicyanoimidazole (DCI, 0.6 equiv) provided
reagent 18 in 82% yield. It should be noted that bis(amidite)
17 is a versatile precursor that allows for other relevant
protecting groups (such as benzyl) to be installed, and thus
a variety of reagents of type 3 (Figure 1) are within reach.
With the reagents in hand, the synthesis of the methylene
bisphosphonate analogues of adenosine di- and triphos-
phate[21] (me-ADP (13) and me-ATP (21); Scheme 3) with
reagent 18 was undertaken. Condensation of 18 with adeno-
sine derivative 10 in the presence of DCI and subsequent
oxidation of the PIII/PV intermediate gave protected me-ADP
19 in 93% yield after isolation. Removal of the terminal tert-
With the proposed method validated, efforts were
directed towards phosphanylmethylphosphonate reagents 15
and 18 (Scheme 2). The terminal tert-butyl group in 15 can be
selectively cleaved to allow for consecutive PV condensation,
leading to unsymmetric methylene bisphosphonate diesters.
Reagent 18 contains the base-labile 2-cyanoethanol protect-
ing group to enable the synthesis of terminal methylene
bisphosphonate monoesters both in solution and on solid
supports.
Lithiation of methylphosphonate 14 with 1 equiv of nBuLi
was followed by the addition of chlorophosphine 8, providing
target phosphoramidite 15 in 32% yield. During refinement
of this reaction, we found that the relatively low yield could be
attributed to two forms of quenching. The diminished yield
was partially caused by proton exchange between emerging
bisphosphonate 15 and lithiated methylphosphonate 14,
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Scheme 4. Automated solid-phase synthesis of methylene bisphospho-
nate nucleotides. Reagents and conditions: a) 4ꢀHCl (50 mm), HFIP,
1 min; b) 1) 2ꢀETT and 18, MeCN, 5 min, 2) 2ꢀCSO, MeCN, 5 min;
c) 1) 4ꢀHCl (50 mm), HFIP, 1 min, d) 1) 2ꢀDBU, DMF, 2 min,
2) NH4OH (35%), 1 h. CE=2-cyanoethanol, Tac=(4-tert-butylphen-
oxy)acetyl.
Scheme 3. Solution-phase synthesis of me-ADP (13) and the methylene
analogue of ATP 21. Reagents and conditions: a) 1) 18, DCI, MeCN,
15 min, 2) tBuOOH, 15 min; b) HCl (1.2 equiv, 0.5m), HFIP, 4 h ;
c) ammonia, 16 h; d) 1) 22, ETT, MeCN, 15 min, 2) tBuOOH, 15 min,
3) DBU, 0.5 h, 4) ammonia, 16 h.
with ETT as the activating agent. Subsequent oxidation with
(1S)-(+)-(10-camphorsulfonyl)oxaziridine (CSO) yielded
protected, resin-bound methylene bisphosphonate nucleo-
tides 24. The terminal tert-butyl groups in intermediate 24
were cleaved with HCl in HFIP (25), which was followed by
DBU-mediated removal of the 2-cyanoethyl group. Final
aminolysis of the acyl protecting groups with concomitant
release from the solid support was effected by treatment with
aqueous ammonia. The crude products were purified by gel
filtration, providing methylene bisphosphonate nucleotides
13 (39%), 26 (46%), 27 (44%), and 28 (52%).
As a final research objective, the synthesis of two
unsymmetric methylene bisphosphonates, namely adenosine
bisphosphonate ribose (ADPR) analogue 33 and flavin
adenine dinucleotide (FAD) analogue 36 (Scheme 5), was
undertaken. The condensation efficiency of reagent 15 with
adenosine derivative 10 was evaluated using various activa-
tors. Based on 31P NMR spectroscopic analysis and the
obtained yields, ETT and 1H-tetrazole performed equally
well whereas DCI gave cleaner and more reproducible results.
Subsequent oxidation gave clean conversion into me-ADP
(29) as monitored by 31P NMR spectroscopy (Figure S4).
Unexpectedly, using DCI, me-ADP (29) was isolated in yields
not exceeding 55%. Exclusion of product loss during column
purification and washing steps led to the tentative conclusion
that the methylene bisphosphonate moiety in 29 binds Mg2+
from magnesium sulfate. Indeed, switching to the use of
sodium sulfate as a drying agent resulted in the isolation of 29
in significantly higher yields (76–85%). Subsequent removal
of the tert-butyl group in 29 to give 30 would permit the next
condensation with the 5-hydroxy group from ribose 31.
Cleavage of the tert-butyl group using 10% TFA in DCM
cleanly provided phosphonic acid 30 as determined by 31P and
1H NMR spectroscopy. Surprisingly, all attempts to condense
30 with 31 in the presence of 2-mesitylenesulfonyl chloride
(TMBSC) and 4-methoxypyridine N-oxide (MNO) were
unsuccessful.[28] Based on model studies, it became evident
butyl protecting groups was carried out with HCl in hexa-
fluoroisopropanol (HFIP) to obtain the partially protected
ADP analogue 20 in 97% yield. Global deprotection of 20 by
treatment with aqueous ammonia provided adenosine meth-
ylene bisphosphonate (13) in 73% yield. The synthesis of
adenosine methylene triphosphate 21 was accomplished by
the modification of a method developed by us[22–24] and others
for native pyrophosphates.[25] Partially protected methylene
bisphosphonate 20 was first condensed with known bis[(me-
thylsulfonyl)ethyl]diisopropylphosphoramidite (22)[26] in the
presence of 5-ethylthiotetrazole (ETT) followed by in situ
oxidation of the phosphonite-phosphonate anhydride inter-
mediate by tBuOOH to give the protected precursor of 21.
All steps could be monitored by 31P NMR spectroscopy.
Subsequent elimination of the (methylsulfonyl)ethyl and
cyanoethyl protecting groups with DBU was followed by
deacylation with ammonia. Purification by size-exclusion and
anion-exchange chromatography gave me-ATP (21).
Next, we decided to test our newly developed method in
an automated solid-phase synthesis to allow for future
extension of the phosphonite-phosphonate chemistry to the
synthesis of biomolecules containing multiple pyrophosphate
bridges. In addition, the solid-phase approach could prove
useful for poorly soluble compounds, such as guanosine
derivatives. For this purpose, the methylene bisphosphonate
analogues of all nucleosides (me-ADP (13), me-CDP (26),
me-GDP (27), and me-UDP (28); Scheme 4) were selected as
target molecules. Commercially available controlled pore
glass (CPG), preloaded with the respective suitably protected
nucleoside through a succinyl linker (23),[27] was loaded into
an automated solid-phase oligonucleotide synthesizer. The
four-cycle procedure started with coupling of the immobilized
nucleoside with phosphanylmethylphosphonate reagent 18,
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54% yield. Ensuing two-step deprotection fol-
lowed by purification by size-exclusion chroma-
tography gave me-FAD (36) in 43% yield after
isolation. The synthesis of me-FAD proved to be
challenging as the poor solubility of the flavin
moiety reduced the conversion rate and compli-
cated the purification.
In conclusion, we have developed a new and
broadly applicable strategy for the synthesis of
methylene bisphosphonate esters that is based on
the combination of phosphoramidite and phospho-
triester chemistry. A new class of orthogonally
protected phosphanylmethylphosphonate reagents
was developed, which are accessible by reacting
a
lithiated methylphosphonate diester with
a chlorophosphoramidite. Relevant examples are
reagents 15, 17, and 18, in which the tert-butyl
groups are selectively removable. Bis(amidite) 17
should enable the installation of other relevant
protecting groups. The efficiency of our procedure
to prepare methylene bisphosphonates was dem-
onstrated by the solution-phase synthesis of ana-
logues of adenosine di- and triphosphates (me-
ADP (13) and me-ATP (21)) as well as analogues
of adenosine bisphosphonate ribose me-ADPR
(33) and flavin adenine dinucleotide me-FAD (36).
In addition, the method is suitable for solid-phase
synthesis, as shown for nucleotide methylene
bisphosphonates (13, 26–28). Our method is
based on classical methods of nucleic acid chemis-
try, and we expect it to be compatible with a broad
range of biomolecules.
Scheme 5. Synthesis of Me-ADPR (33) and Me-FAD (36). Reagents and conditions:
a) 1) DCI, MeCN, 15 min, 2) tBuOOH, 15 min; b) HCl (1.5 equiv, 0.2m), HFIP;
c) PyNTP, 31, 2,6-lutidine, MeCN, 2 h or PyNTP, 34, 2,6-lutidine, MeCN, 1 h;
d) 1) PhSH/Et3N/MeCN (3:2:3), 358C, 4.5 h, 2) 30% NH4OH, 16 h.
that the one equivalent of TFA used during tert-butyl
deprotection remains adhered to 30. During the condensation
reaction, an unproductive mixed anhydride of TFA and the
bisphosphonate is formed. Switching to 1.5 equiv of HCl in
hexafluoroisopropanol (HFIP) effectively cleaved the tert-
butyl group, providing 30 in quantitative yield. Indeed, the
subsequent key PV coupling reaction of 30 with 34 under the
agency of TMBSC and MNO afforded a mixture of the fully
protected target compound me-ADPR (32) and its mono-
demethylated analogue in a combined yield of 60%. Pre-
viously, Wada and co-workers had shown that phosphonium
reagents are selective activators and effective agents for the
condensation of methylphosphonates with alcohols.[29] Using
3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium
hexafluorophosphate (PyNTP) as the condensation agent
further improved the yield of protected me-ADPR (32) to
84% (Figure S5). Two-step removal of all protecting groups
in 32 (demethylation with thiophenol in MeCN/TEA fol-
lowed by deacylation using aqueous ammonia) and purifica-
tion of the crude product by gel filtration provided the desired
product me-ADPR (33) in 52% yield (Figure S6). The thus
determined optimal method for the installation of unsym-
metric methylene bisphosphonates was implemented in the
synthesis of 36, a known bioisostere for FAD, which is an
essential redox cofactor in cellular metabolism.[30] Riboflavin
building block 34 was condensed with 30 under the agency of
PyNTP to furnish the protected me-FAD derivative 35 in
Acknowledgements
This research was financially supported by the Netherlands
Organization for Scientific Research (NWO).
Conflict of interest
The authors declare no conflict of interest.
Keywords: methylene bisphosphonates ·
phosphanylmethylphosphonate · phosphorylation ·
pyrophosphate bioisosteres · solid-phase synthesis
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Manuscript received: December 6, 2016
Final Article published: && &&, &&&&
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Communications
Phosphorylation
S. B. Engelsma, N. J. Meeuwenoord,
H. S. Overkleeft, G. A. van der Marel,*
D. V. Filippov*
&&& — &&&
Combined Phosphoramidite-
Phosphodiester Reagents for the
Synthesis of Methylene Bisphosphonates
The condensation of novel phosphanyl-
methylphosphonate reagents with an
alcohol of choice followed by oxidation
provides orthogonally protected methyl-
ene bisphosphonate tetraesters. Global
deprotection of the tetraester leads to
terminal methylene bisphosphonates
whereas selective deprotection at the
terminal phosphonate followed by con-
densation with a second alcohol yields
methylene bisphosphonate diesters.
6
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