Synthesis of unsymmetric diphospho-inositol polyphosphates

Article abstract of DOI:10.1002/anie.201301092

One to rule them all: A novel C₂-symmetric phosphoramidite was developed that can be used to prepare all four unsymmetric diphospho inositol pentaphosphates (PP-InsP₅). The target structures were synthesized in few steps and high enantiomeric ratios. With the obtained compounds, specificity of Ddp1 from yeast (a PP-InsP₅ phosphatase) was studied. Copyright

Full text of DOI:10.1002/anie.201301092

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DOI: 10.1002/anie.201301092
Phosphorylation
Synthesis of Unsymmetric Diphospho-Inositol Polyphosphates**
Samanta Capolicchio, Divyeshsinh T. Thakor, Anthony Linden, and Henning J. Jessen*
The phosphate esters of myo-inositol (1) have long been
recognized as molecules of tremendous biological relevance
in cellular signaling events.[1] Given the already high complex-
ity of the inositol signaling cascade, a striking discovery was
that inositol hexakisphosphate InsP6 can be further phos-
phorylated by inositolhexakisphosphate kinases (IP6K) to
pyrophosphorylated representatives such as 5-diphospho-
inositol-1,2,3,4,6-pentakisphosphate 5-PP-InsP5.[2] Different
positional isomers of diphospho-inositol polyphosphates (X-
PP-InsP5, for example, 2–5) have been discovered and were
found to occur in all domains of biology ranging from archaea
to mammals. Highly conserved enzymes tightly regulate their
production and destruction.[3]
homeostasis, stress responses, viral release, cancer develop-
ment, telomere length control, diabetes, and obesity.[3g,4]
Furthermore, 5-PP-InsP5 has been shown to act as a phosphate
donor in vitro. This special process has been dubbed trans-
phosphorylation, as in contrast to ATP-dependent phosphor-
ylation, it occurs autocatalytically within specific serine-rich
aminoacid sequences and the product of transphosphoryla-
tion is a serine pyrophosphate.[3d,4a,5]
X-PP-InsP5 are difficult synthetic targets owing to their
extreme hydrophilicity that is manifested in up to thirteen
negative charges arranged around the rim of the inositol core
structure. Recent investigations were focused on the synthesis
of the symmetric meso-5-PP-InsP5 and highlight the difficul-
ties associated with obtaining reasonably pure material.[6]
Although preparations of unsymmetric X-PP-InsP5 have
been reported,[1b,7] no unified approach exists to target all
four unsymmetric X-PP-InsP5.
The desymmetrization of myo-inositol (1) can be achieved
in different ways.[8] A very efficient approach would be
a desymmetrization by phosphorylation. Peptide-catalyzed
enantioselective phosphorylations and phosphitylations have
been described.[9] However, so far only phenol and benzyl
protecting groups for the phosphite/phosphate esters are
tolerated in this approach.
C2-symmetric phosphoramidites have not yet been
applied in the desymmetrization event to directly yield
a phosphitylated intermediate. Conceptually, the chiral P-
amidite should fulfil the following criteria: 1) easy accessi-
bility, 2) C2 symmetry to avoid chirality at phosphorous, 3)
stability, and 4) mild removal as an orthogonal protecting
group. With these prerequisites defined, a chiral auxiliary
derived from the b-cyanoethyl protecting group[10] (b-CE, see
Scheme 1, box) seemed to be a promising candidate. Analysis
of the structure revealed a possible straightforward modifi-
cation by introduction of a phenyl ring at C-a (7, Scheme 1).
This novel chiral auxiliary/phosphate protecting group was
derived from mandelic acid (e.r. 99.5:0.5) in a few synthetic
steps but can also be prepared by enantioselective transfer
hydrogenation.[11]
With the chiral P-amidite 7 in hand, different protected
inositol-derived meso building blocks were needed that were
suitable for the envisaged desymmetrization. For the con-
struction of 1- and 3-PP-Ins-P5 (2, 3), a recently described
regioselective ortho-ester cleavage was employed with a modi-
fied pattern of protecting groups.[12] Briefly, myo-inositol (1)
was converted into its ortho-benzoate and subsequently para-
methoxybenzylated (PMB) to ortho-ester 8. Diisobutylalu-
minium hydride (DIBAL-H) was used for a regioselective
reductive scission of the ortho-benzoate, thus releasing the 5-
OH group. PMB-protection and selective acid-catalyzed
rupture of the 1,3 benzylidene acetal without isolation of
the intermediate yielded PMB-protected diol 9.
A concise synthetic approach allowing for the synthesis of
all positional isomers of the X-PP-InsP5 would enable the
assignment of the specificity of the enzymes involved in X-PP-
InsP5 turnover. The possibility to generate derivatives as tools
for chemical biology studies would open up new ways to
understand their rich biological functions. X-PP-InsP5 are
involved in the regulation of such diverse processes as energy
[*] S. Capolicchio, D. T. Thakor, Priv.-Doz. Dr. A. Linden, Dr. H. J. Jessen
Organic Chemistry Institute, University of Zꢀrich (UZH)
Winterthurerstrasse 190, 8057 Zꢀrich (Switzerland)
E-mail: Henningjacob.jessen@uzh.ch
[**] The authors are grateful to Prof. J. Siegel for continuous support,
and the NMR and MS facilities at UZH (O. Zerbe, L. Bigler). We
thank A. Saiardi for kindly providing the plasmid encoding Ddp1.
This work was supported by the Fonds der Chemischen Industrie
(FCI, Liebig Stipend to H.J.J.) and the Swiss National Science
Foundation (SNF, Ambizione Grant PZ00P2_136816 to H.J.J.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301092.
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which the optical rotations are known (see Supporting
Information).[8d]
Cleavage of the PMB groups resulted in the diastereo-
meric protected inositol-phosphates 12 and 13 that were
subjected to exhaustive phosphitylation with an o-xylylene-
derived phosphoramidite (XEP-amidite)[6c] followed by
in situ oxidation yielding hexaphosphates 14 and 15.
The next challenge was the mild removal of the chiral
auxiliary and the generation of the phosphoanhydride bond.
Although mono-deprotection was readily achieved by addi-
tion of one equivalent of DBU under elimination of
cinnamonitrile (thus proving equivalence to the b-CE pro-
tecting group; see Scheme 2), the second group was not as
easily removed. With the assumption that the generated
negative charge at phosphorous after cleavage of the first
Scheme 1. Synthesis of unsymmetric hexaphosphates 14 and 15.
a) Cl2PN(iPr)2, NEt3, 3 d; b) PhC(OMe)3, CSA, DMSO, then recryst.;
c) NaH, PMB-Cl, DMF, then recryst.; d) 2.7 equiv DIBAL-H, DCM,
À788C; e) NaH, PMB-Cl, DMF; f) cat. pTsOH, H2O/MeOH, 5 min
reflux, then recryst.; g) 3 equiv 9, 1 equiv 7, 5-(para-F-phenyl)1H-
tetrazole in MeCN, then 08C, mCPBA; 1:1 mixture of 10 and 11,
separated by recryst. and FC. Excess starting material recovered, yield
based on 7; h) 2.5% TFA in CHCl3; i) 10 equiv XEP-amidite, 15 equiv
DCI, 08C, MeCN, then 10 equiv mCPBA, 08C, then recryst. CSA=cam-
phorsulfonic acid; DCI=4,5-dicyanoimidazole; DCM=dichlorome-
thane; DMF=dimethylformamide; DMSO=dimethylsulfoxide; DIBAL-
H=diisobutylaluminium hydride; mCPBA=meta-chloro perbenzoic
acid; PMB-Cl=para-methoxybenzyl chloride; pTsOH=para-toluene
sulfonic acid; TFA=trifluoroacetic acid; XEP-amidite=o-xylylene N,N-
diisopropylamino phosphoramidite.
Scheme 2. One-pot deprotection/P-anhydride formation sequence fol-
lowed by global reductive deprotection yielding the natural products
(2–5) as sodium salts. a) 1. DBU, BSTFA in MeCN (A), then 2. TFA in
MeOH, then 3. remove solvents in vacuo (B), then 4. dibenzyl
diisopropylamino phosphoramidite, 1H-tetrazole in MeCN, then 5.
mCPBA (C), recryst., then RP-FC (C18); b) 80 bar H2, PtO2 or Pd
(black) in tBuOH/H2O 4:1 to 1:1, NaHCO3, 3 h, then recryst.
DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene; BSTFA=N,O-bis(trimethyl-
silyl) trifluoroacetamide, RP-FC=reversed phase flash chromatogra-
phy.
Meso-compound 9 with free 1- and 3-OH groups was now
set for desymmetrization by phosphitylation. As an activator,
5-(para-F-phenyl)1H-tetrazole was used and the PIII inter-
mediates were oxidized in situ. This procedure resulted in
a 1:1 mixture of both the 1- and 3- phosphorylated products 10
and 11 according to 31P NMR analysis. No attempts were
undertaken to bias the selectivity, as both products were
needed in the following steps.
Diastereomer 11 was separated from the mixture by
crystallization resulting in a diastereomeric ratio of > 99:1 as
judged by proton decoupled 31P NMR spectroscopy. The
other diastereomer 10 was purified to a ratio 98:2 by normal
flash column chromatography (FC). The regioselectivity was
assigned by cleavage of the protecting groups giving the
enantiomeric inositol-1-phosphate or inositol-3-phosphate for
protecting group is blocking the cleavage of the second
protecting group due to repulsive coulombic interaction,
a transient masking of the negative charge with a trimethylsilyl
(TMS) group should enable cleavage of the second chiral
auxiliary.[13]
N,O-Bis(trimethylsilyl) trifluoroacetamide (BSTFA)
proved to be a suitable, mild TMS donor in this trans-
formation and produced the bis-TMS-protected phosphate
(A, Scheme 2) within a few minutes in the presence of excess
DBU. The bis-TMS phosphate was then directly methano-
lyzed to the monophosphate. Suppression of an immediate
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attack of the strongly nucleophilic dibasic phosphate to the
adjacent phosphate triesters was achieved by addition of
trifluoroacetic acid (TFA) during methanolysis (B, Scheme 2)
resulting in the less nucleophilic monobasic phosphate. This
intermediate was then directly converted into the mixed P-
anhydride with bis-benzyl-N,N-diisopropylamino phosphor-
amidite in the presence of 1H-tetrazole, subsequently oxi-
dized, and the product was crystallized in excellent yield (C,
Scheme 2).
This transformation allowed the P-anhydride bond to be
set up in a one-pot reaction starting from both hexaphos-
phates 14 and 15, respectively. It underscores the multiple
utilities of the new chiral phosphate protecting group and is
the first example for the application of PIII chemistry in the
generation of phosphoanhydrides on the way to diphospho-
inositol polyphosphates. It opens up the possibility of
introducing, for example, thiopyrophosphates (see the Sup-
porting Information for proof of concept, compound 17b) and
boranopyrophosphates as chemical probes for inositol metab-
olism and provides a highly streamlined access to protected
PP-InsP5 derivatives.
A global deprotection of phosphoanhydrides 16 and 17 by
hydrogenation[7a] led to the natural products 2 and 3,
respectively, after recrystallization from water/acetone in
only ten steps. No further purification was necessary, as
testified by the recorded NMR spectra (Supporting Informa-
tion). Treatment of the material with ion exchange resin
(Dowex Na+) usually led to a significant improvement of the
recorded spectra that tend to show very broad resonances
both in the 31P NMR as well as in the 1H NMR spectra,
blurring impurities that can be problematic in biological
studies.[6c,7a] The high quality of this material will be helpful in
understanding the binding specificity of X-PP-InsP5 to
proteins and the IP6Ks in unprecedented detail.
Next, application of the same chemistry to the synthesis of
the two enantiomorphous 4- and 6-PP-InsP5 isomers (4, 5) was
envisaged. Analysis of orthogonally protected derivatives
with free hydroxy functions in the 4- and 6-positions revealed
ortho-formates as suitable starting materials. These com-
pounds are accessible from myo-inositol (1) by ortho-ester
formation followed by selective silyl protection of the
equatorial hydroxy function.[14] This procedure leaves the
axial 4- and 6-positions available for desymmetrization as in
20 (Scheme 3).
After phosphitylation with P-amidite 7, the desired
products 21 and 22 were obtained as a 1.0:0.8 mixture,
which were separated by FC, yielding both monophosphory-
lated isomers 21 and 22 in excellent diastereomeric ratios
(> 99:1). Single crystals of diastereomer 21 were obtained and
an X-ray diffraction analysis[15] (Scheme 2, Supporting Infor-
mation) revealed that phosphorylation had taken place at the
4-position and thus allowed assignment of the other isomer as
the 6-modified phosphate triester 22. Upon treatment with
catalytic amounts of acid, first the TES group was smoothly
removed, releasing the 2-OH group. It is well documented
that this group is involved in the cleavage mechanism of
ortho-esters of inositols.[16] Thus, in a second event, the ortho-
ester was cleaved through the intermediacy of a 2 formyl-
modified scaffold that eventually released the 4- and 6-
Scheme 3. a) HC(OMe)3, pTsOH, DMSO, then recryst.; b) TES-Cl,
lutidine, DCM, then recryst.; c) 3 equiv 20, 1 equiv 7, DCI in MeCN,
08C, then tBuOOH (5.5m in nonane) 1.0:0.8 mixture of 21 and 22,
separated by FC and recryst.; d.r. >99:1; excess starting material
recovered, yield based on 7; d) cat. pTsOH, MeOH/DCM, then recryst.;
e) 10 equiv XEP-amidite, 15 equiv DCI, 08C, MeCN, then 10 equiv
mCPBA, 08C, then recryst. Abbreviations: DCI=4,5-dicyanoimidazole;
TES-Cl=triethylsilyl-chloride.
modified phosphate triesters 23 and 24, respectively. The
products were exhaustively phosphitylated with XEP-amidite
followed by in situ oxidation yielding hexaphosphates 25 and
26.
The P-anhydride was established as previously described
for the 1- and 3-isomers 16 and 17 in a one-pot sequence
(Scheme 2). The protected natural products 18 and 19 were
unveiled by hydrogenations yielding the corresponding 4- and
6-PP inositol pentaphosphates 4 and 5 in good quality after
strong anion exchange chromatography in only seven con-
secutive steps.
X-PP-InsP5 are metabolized by different enzymes, for
example, phosphatases that cleave the pyrophosphate group.
The assignment of the regioisomeric preference of diadeno-
sine and diphosphoinositol polyphosphate phosphohydrolase
1 from yeast (Ddp1) is an interesting application of synthetic
X-PP-InsP5.[17] A modified malachite green assay (Supporting
Information)[17c] to measure phosphate release from the
isomers 2–5 in the presence or absence of recombinant
purified Ddp1 was employed (Figure 1). This data shows, that
Ddp1 is a selective 1-PP-InsP5 phosphatase. Ddp1 dephos-
phorylates the product of Vip1,[17c] a kinase that phosphor-
ylates InsP6 in the 1/3 position. More recently, the human
diphosphoinositol pentakisphosphate kinases PPIP5K (Vip1
is the yeast homolog) were assigned to be InsP6 1-kinases.[3k]
The obtained data support this assignment, as only one out of
the four analyzed isomers, namely 1-PP-InsP5, is a substrate of
Ddp1.
In summary, a novel approach for a unified synthesis of
unsymmetric diphosphoinositol polyphosphates has been
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Figure 1. Measurement of phosphate release from nonsymmetric X-PP-
IP5 in the presence of recombinant 6ꢁHis-Ddp1 from yeast. 100 mm
solutions of 2–5 were incubated with 100 ng Ddp1 at 378C for 10 min.
Absorbance was quantified at 650 nm after addition of malachite green
reagent. All assays were conducted in triplicate and corrected for
nonenzymatic hydrolysis of 2–5 under the assay conditions.
developed. The application of one single C2-symmetric
phosphoramidite allows inositol to be desymmetrized, accom-
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tected phosphate triester, in all four relevant positions. It was
shown that this approach is complementary to usually applied
desymmetrizations with camphor acetals and is more efficient
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auxiliary was cleanly removed upon treatment with base
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of the vital P–anhydride bond. This method can readily be
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Received: February 6, 2013
Revised: March 29, 2013
Published online: May 27, 2013
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Keywords: chiral auxiliaries · cyclitols · natural products ·
phosphorylation · polyanions
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