Bis(dimethylamino)phosphorodiamidate: A Reagent for the Regioselective Cyclophosphorylation of cis-Diols Enabling One-Step Access to High-Value Target Cyclophosphates

Article abstract of DOI:10.1021/acs.orglett.9b02694

Bis(dimethylamino)phosphorodiamidate (BDMDAP) enables an efficient and one-pot cyclophosphorylation of vicinal cis-diol moiety of polyol-organics of biological importance without the need for protecting group chemistry and is amenable to large-scale reactions. The utility of this reagent is demonstrated through the synthesis of high-value targets such as cyclic phosphates of myo-inositol, nucleosides, metabolites, and drug molecules.

Full text of DOI:10.1021/acs.orglett.9b02694

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bis(dimethylamino)phosphorodiamidate: A Reagent for the
Regioselective Cyclophosphorylation of cis-Diols Enabling One-Step
Access to High-Value Target Cyclophosphates
Mahipal Yadav†,‡ and Ramanarayanan Krishnamurthy*,†,‡
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United
States
‡NSF-NASA Center for Chemical Evolution, Atlanta, Georgia 30332, United States
S
* Supporting Information
ABSTRACT: Bis(dimethylamino)phosphorodiamidate (BDMDAP) enables an efficient
and one-pot cyclophosphorylation of vicinal cis-diol moiety of polyol-organics of
biological importance without the need for protecting group chemistry and is amenable to
large-scale reactions. The utility of this reagent is demonstrated through the synthesis of
high-value targets such as cyclic phosphates of myo-inositol, nucleosides, metabolites, and
drug molecules.
hosphate esters of organic molecules are ubiquitous in
Pbiochemistry and play a central role in many of the
essential chemical processes of life.1 They are nature’s
preferred modifications of all the four classes of biomolecules,
i.e., carbohydrates, proteins, lipids, and nucleosides.2 They
include phosphate esters in RNA and DNA, phospholipids for
membrane structure, phosphoproteins for regulation of cellular
function, and phosphatidylinositol phosphates for signaling
(Figure 1).2,3 Although these phosphate esters are kinetically
stable in aqueous solution at physiological pH, they are easily
hydrolyzed by appropriate enzymes,4,5 proceeding through the
assistance of an adjacent hydroxyl group, resulting in
cyclophosphate (cP) ester intermediates (Figure 1).6 Many
cyclophosphate intermediates play very important roles in
modern biology.7 For example, myo-inositol-1,2-cyclophos-
phate, produced by the action of enzyme phosphoinositide
specific phospholipase C (PI-PLC) on the sn-3-phosphodiester
Figure 1. Representative biologically and chemically important
molecules that contain a cylcophosphate group.
bond of phosphatidylinositol, gives rise to inositol based
signaling metabolites crucial to signal transductions and
metabolic circuits.8−13
In another example, 2′,3′-cyclic nucleoside monophos-
phates, produced by enzymatic and nonenzymatic hydrolysis
of RNA,14−17 are employed in many biological studies18−20
and synthesis of complex nucleotides.21−25 Moreover, several
glycerolipids containing the 1,2-cyclophosphate moiety form a
unique class of compounds called cyclic phosphatidic acid.26
These compounds affect numerous cellular functions and are
involved in various biological activities.26,27
Apart from these biological roles, the applications of
cyclophosphate compounds in organic synthesis as ligands in
asymmetric synthesis and as insecticides/pesticides are well
recognized (Figure 1).28−33 These cyclophosphate derivatives
are traditionally prepared either by intramolecular dehydra-
Received: August 2, 2019
© XXXX American Chemical Society
A
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tion/cyclization of a monophosphate derivative34−36 or by
treating the starting diol with POCl3 followed by hydrolysis of
the cyclophosphoryl chloride intermediate to cyclophos-
phate37,38 (Figure 2). All of these traditional methods are
As summarized above, each of the cyclophosphorylation
methods have their limits.51 Recently, we discovered a method
for cyclophosphorylation of glycerol and nucleosides in
aqueous medium by diamidophosphate (DAP), without the
need for protecting groups, under plausible prebiotic
conditions.52 Inspired by this result, we began investigating
how best we can take advantage of the moderate reactivity of
diamidophosphates, improve yields, and achieve regioselective
phosphorylation of other polyols containing cis-diol moiety
(particularly inositol) in a regioselective fashion, without any
protection−deprotection chemistry. After several attempts, we
developed the bis(dimethyl) version of DAP (BDMDAP, 3) as
a cyclophosphorylating reagent for the synthesis of cyclo-
phosphates of diols in one step with excellent yields.
Primarily motivated by the importance of inositol
phosphates, we started our study to identify optimal conditions
for cyclophosphorylation of myo-inositol by using diamido-
phosphate (DAP) as a phosphorylating reagent. All attempts
toward regioselective 1,2-cyclophosphorylation of myo-inositol
1 by using our previously developed standard phosphorylation
conditions with diamidophosphate (DAP)52 in H2O were
unsuccessful; myo-inositol was unchanged, but DAP was
hydrolyzed to various inorganic phosphates (Supporting
Information (SI), Table 1). myo-Inositol and DAP under the
low water activity “paste conditions” showed some formation
of cyclophosphates (according to 31P NMR), but conversion to
the product was poor (SI, Table 1).
Figure 2. Traditional methods for the preparation of 1,2-cyclo-
phosphates.
Then we explored variants of DAP with better leaving
groups for the phosphorylation reaction. Because the
phosphorylation is initiated by protonation of the NH2
group on DAP, we reasoned that making the amino group
more basic would make it more reactive. Therefore, we
synthesized bis(dimethylamino)-phosphorodiamidate
(BDMDAP) by the aq NaOH mediated hydrolysis of
commercially available bis(dimethylamino) phosphorochlor-
idate (Scheme 1). BDMDAP has been known in the literature,
however, its utility as a phosphorylating reagent has never been
explored.53
multistep processes, require anhydrous reaction conditions,
and afford the final cyclic phosphodiesters in moderate to poor
yields (Figure 2). Other methods have been developed over
the years to address the efficiency and streamline the
protocol,39−42 however, these also require many steps for the
synthesis of cyclophosphates and yields are low based on
starting diols.
The problem of cyclophosphorylation becomes more acute
when it comes to structures such as myo-inositol and
carbohydrates, which have inherent structural complexity
with many free hydroxyl groups. For example, there is no
report of a single-step synthesis of inositol-1,2-cyclic phosphate
(IcP) to date. However, considering the central role of myo-
inositol phosphates in metabolism and signaling pathways, they
are highly valuable targets for synthetic chemists.11,43−45
Despite significant advances, most of the synthetic methods
described for inositol phosphates still take more than 10 steps
starting from inositol involving protection−deprotection
chemistry.11,43,45−47
Scheme 1. Synthesis of
a b
,
Bis(dimethylamino)phosphorodiamidate (BDMDAP)
Because of its structural complexity, only a few (but
unsuccessful) efforts have been made to explore the
chemical-phosphorylation of unprotected inositol in one
step.48,49 Bruzik et al.10 and Vishwakarma and co-workers50
have demonstrated the enzymatic synthesis of various of O-
alkyl inositol phosphates via inositol-1,2-cyclic phosphate (IcP)
by using the PI-PLC enzyme. Because the enzymatic synthesis
of inositol-1,2-cyclic phosphate involves the isolation of
inositol phospholipids and PI-PLC from biological sources,
which is not always straightforward, it is still a much sought-
after goal to chemically synthesize inositol-1,2-cyclic phosphate
from unprotected inositol in a single step. Similarly, all current
methods for the preparation of 2′,3′-cyclic nucleoside
monophosphates also have either low yield or high price,
which greatly limits their further exploration and application.
The easy availability of cyclic phosphates of defined structure
would further biochemical investigations.
a
Reagents and conditions: 2 (10 mmol), aq NaOH (2 M solution, 21
b
mmol, 2.1 equiv) for 1 h. Conversion yields were calculated based on
1H, 13C, and 31P NMR.
We determined the pKa of BDMDAP to be 6.6 (SI, Figure
1), which suggested that it may be suitable for phosphorylation
when compared to DAP (pKa 5.5).52 The phosphorylation of
myo-inositol 1 with BDMDAP 3 in aqueous solution or under
“paste conditions”, under various pH (5.5−7.0) and with
imidazole, however, did not afford the cyclic product 4 (SI,
Table 2, entries 1−4) and exploration of other solvents (NMP:
N-methyl-2-pyrrolidone) and Lewis acids resulted in meager
conversion to 4 or gave complex mixtures of cyclic phosphates
(SI, Table 2, entries 5−10).
B
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To resolve the regioselectivity issue, we employed the Sn
(IV) catalysts because Sn (IV) catalysts are known to form the
complex with cis-diols in a regioselective manner and increase
their reactivity.54 After systematic exploratory experiments
(varying the equivalents of BDMDAP, temperature, solvents,
and activators; SI, Table 2), we found that 1 equiv of
BDMDAP in NMP as solvent at 80 °C afforded 75%
conversion to cyclophosphate product 4 (SI, Table 2, entry
19). The use of tin catalyst Me2SnCl2 in place of Bu2SnO
improved the conversion to 4 (80%) (Scheme 2 and SI, Table
removal of the NMP solvent in vacuo) and loaded directly on
the ion-exchange column and eluted with buffer to afford pure
cyclophosphate products.
To understand the scope of this BDMDAP-phosphorylation
protocol, cis-diols having different ring sizes, acid-sensitive
functional groups, and phenolic groups, with varying
reactivities, were investigated as substrates (Scheme 4). All
Scheme 4. Cyclophosphorylation of cis-Diol Containing
a b c
, ,
Molecules with BDMDAP
Scheme 2. Regioselective Cyclophosphorylation of myo-
a b
,
Inositol with BDMDAP
a
Reagents and conditions: 1 (0.2 mmol), BDMDAP (1 equiv) and
b
Me2SnCl2 (0.1 equiv) in NMP solvent (1.0 mL) for 12 h. Isolated
yield.
2, entry 20); reaction under argon atmosphere did not show
any further improvement in yield of the reaction, suggesting
that the reaction is insensitive to presence of air-moisture (SI,
Table 2, entry 21). No extra precautions (such as dry solvents
or oven-dried flasks) were found to be necessary for the
reaction to proceed in an efficient manner.
With the optimized conditions for myo-inositol cyclo-
phosphorylation in hand, we applied the protocol to RNA
nucleosides to investigate the general applicability of our
method. Satisfyingly, all four canonical nucleosides afforded
the corresponding 2′,3′-cylcophosphates 5−8 in excellent
(88−92%) isolated yields without the need for any further
optimization of the reaction conditions (Scheme 3). We did
a
Reagents and conditions: substrate (0.2−0.5 mmol), BDMDAP (1
equiv), Me2SnCl2 (0.1 equiv) in NMP as solvent (1.0 mL) at 80 °C
b
c
for 12 h. Isolated yields after column chromatography. Conversion
yield based upon 31P and H NMR.
1
of the compounds underwent the desired transformation
smoothly and furnished the corresponding cyclophosphate
products. For example, cis-diols with or without heteroatoms in
the rings were cyclo-phosphorylated with the same ease to give
9−11 in very good (>90%) yields (Scheme 4). In the case of
carbohydrates, cis-diols of furanosides and pyranosides formed
their respective cyclophosphates in very good yields (Scheme
4). Cyclophosphates of cis-diols in 6-membered rings were also
easily formed using BDMDAP under the optimized protocol.
Saligenin cyclic phosphate esters have remarkable insectici-
dal and fungicidal activities,55 and their synthesis has been
challenging.51 Our method overcomes this synthetic problem
and provides a concise route to saligenin cyclic phosphates.
When saligenin was reacted with BDMDAP, it afforded the
desired product 18 in an excellent yield of 94% (Scheme 4).
2,2′-Biphenol also afforded the cyclophosphorylated product
19 in 85% yield. For reaction with catechol, the BDMDAP was
found to hydrolyze to phosphate faster than the cyclo-
phosphate formation, giving less than 10% conversion. We
suppose that because phenolic compounds are more acidic
than regular alcohols, the acidic proton of phenols protonates
the amino group in BDMDAP and hydrolyzes it to
orthophosphate in the reaction mixture. Therefore, we
prepared BDMDAP with slightly higher pH ∼13 (pH
determined in aq soln) and observed that it could be
successfully used for the phosphorylation of phenolic
compounds. Although the cyclophosphorylation at the higher
pH was efficient (80% conversion by NMR of crude reaction
Scheme 3. Cyclophosphorylation of Ribonucleosides with
a b
,
BDMDAP
a
Reagents and conditions: nucleoside (0.5 mmol), BDMDAP (1
equiv), Me2SnCl2 (0.1 equiv) in NMP as solvent (1.0 mL) at 80 °C
b
for 8 h. Isolated yields from ion-exchange column chromatography.
not observe any phosphorylation at the sterically less hindered
5′-OH position nor on the nucleobases, thus eliminating the
need for protecting group manipulations. Notably, because of
the clean reaction and high conversion, the purification
(Sephadex, ion-exchange column chromatography) of all the
cyclophosphate products was straightforward. The reaction
mixture was dissolved in an equal amount of H2O (without
C
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mixture), the cyclophosphate product 20 was sensitive, and we
could isolate only the catechol-monophosphate 20a (see SI).
To explore the practical utility and application of BDMDAP
under the present phosphorylation protocol, we also
performed two representative reactions on larger scale.
Reaction of myo-inositol (540 mg) and uridine (1 g) smoothly
underwent phosphorylation and afforded the desired cyclo-
phosphate products in isolated yields of 80% and 90%,
respectively.
As alluded to in the introduction, phosphorylation is one of
the most common and physiologically important modifications
and phosphorylation of natural products/drugs provide
important analogues for structure−activity relationship
(SAR), which play a crucial role in a number of biochemical
interactions.56−59 Therefore, we applied our BDMDAP
cyclophosphorylation protocols to produce cyclophosphates
of three representatives of natural product and drug molecules
(Scheme 5). Mupirocin is an antibiotic that targets tRNA
cyclic stannylene acetal or the dichlorostannane complex with
the cis-diol, which then exchanges in a stepwise fashion with
the P−N(Me)2 bonds of BDMDAP to form the cyclicphos-
phate with the release of methylamine, regenerating the
Me2SnCl to start the next cycle of reaction.
In conclusion, we have developed BDMDAP as an efficient
reagent for regioselective and one-step cyclophosphorylation of
cis-diol containing polyhydroxy compounds. This method
affords excellent yields of cyclophophorylated products from a
wide variety of high value target substrates including myo-
inositol and nucleosides. The optimized conditions presented
herein are operationally simple (no protecting groups are
necessary), scalable, and provide a convenient choice when
compared to conventional phosphorylating reagents such as
phosphoryl chloride and its derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02694.
Scheme 5. Cyclophosphorylation of cis-Diol Containing
Natural Products and Drug Molecules with BDMDAP
a b
,
Experimental procedures, compound characterization
data, mechanistic hypothesis, and 1H, 13C, and 31P
NMR (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rkrishna@scripps.edu.
ORCID
Mahipal Yadav: 0000-0003-4394-9737
Ramanarayanan Krishnamurthy: 0000-0001-5238-610X
Author Contributions
a
Reagents and conditions: substrate (0.05−0.5 mmol), BDMDAP 3
(1 equiv), Me2SnCl2 (0.1 equiv) in NMP as solvent (1.0 mL) at 80
°C for 12 h. Isolated yields.
b
The manuscript was written through contributions of all
authors.
Notes
synthetase and is a complex molecule and has several
functional groups, i.e., carboxylate, ester, epoxide, and an
unsaturated double bond.60 Using the optimized BDMDAP
protocol, the corresponding cyclophosphorylated derivative of
mupirocin, 21 was formed in a good yield of 80% (Scheme 5),
reflecting the wide range of functional group compatible with,
and tolerated under, the phosphorylation protocol. The next
target raffinose, a naturally occurring trisaccharide (serving
many functions in plants)61 with a myriad of secondary and
primary hydroxyl groups, ketal/acetal linkages and a cis-diol
was investigated with BDMDAP. Phosphorylation of raffinose
produced the cyclophosphate product 22 in an excellent yield
and highly regioselective fashion (Scheme 5). The last target
was shikimic acid, an important metabolite found in plants and
microorganisms (but not in animals), connecting carbohy-
drates and essential aromatic amino acids in a metabolic
pathway, which involves phosphorylation of shikimate at 3-
hydroxyl group as an important step.62 BDMDAP treatment of
sodium shikimate also delivered the cyclophosphate product
23 in a high yield (Scheme 5). Shikimate cyclophosphate could
serve as a starting point, as a potential candidate, for various
biological and medicinal studies. It is noteworthy that only the
cis-diols of 22 and 23 are reactive toward BDMDAP under
these conditions.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was jointly supported by NSF and the NASA
Astrobiology Program under the NSF Center for Chemical
Evolution (CHE-1504217).
DEDICATION
■
Dedicated to Professor Albert Eschenmoser on his 94th
birthday.
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