Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи
Difluoromethylene phosphonates are non-hydrolyzable bioisosteres of phosphates. They have proven their efficiency as inhibitors of the enzymes that specialize in utilizing these essential biogenic molecules. Difluoromethylene phosphonates show a broad spectrum of biological activity and are used as...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
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Ukrainica Bioorganica Acta| _version_ | 1871193548574949376 |
|---|---|
| author | Shevchuk, Mykhailo V. Röschenthaler, Gerd-Volker |
| author_facet | Shevchuk, Mykhailo V. Röschenthaler, Gerd-Volker |
| author_institution_txt_mv | [
{
"author": "Mykhailo V. Shevchuk",
"institution": "Jacobs University Bremen, Life Sciences & Chemistry, Campus Ring 1, 28759, Bremen, Germany"
},
{
"author": "Gerd-Volker Röschenthaler",
"institution": "Jacobs University Bremen, Life Sciences & Chemistry, Campus Ring 1, 28759, Bremen, Germany"
}
] |
| author_sort | Shevchuk, Mykhailo V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | Difluoromethylene phosphonates are non-hydrolyzable bioisosteres of phosphates. They have proven their efficiency as inhibitors of the enzymes that specialize in utilizing these essential biogenic molecules. Difluoromethylene phosphonates show a broad spectrum of biological activity and are used as molecular tools to study enzymes and enzyme-substrate interactions. In this review, we briefly summarize the importance of difluoromethylene phosphonates as a distinct class of synthetic phosphonates resulting from multidisciplinary efforts of the organophosphorus, organofluorine, and bioorganic research communities. We outline the development of the synthetic chemistry of difluoromethylene phosphonates from the historical perspective, discuss the most recent trends in the field, and highlight the existing challenges and unsolved questions   |
| doi_str_mv | 10.15407/bioorganica2022.01.040 |
| first_indexed | 2025-07-17T12:19:23Z |
| format | Article |
| fulltext |
IS ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 547.1´1/.448
DOI: https://doi.org/10.15407/bioorganica2022.01.040
40
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
REVIEW
Chemistry of difluoromethylene phosphonates: history, state of the art,
and prospects
Mykhailo V. Shevchuk*, Gerd-Volker Röschenthaler
Jacobs University Bremen, Life Sciences & Chemistry, Campus Ring 1, Bremen, 28759, Germany
Abstract: Difluoromethylene phosphonates are non-hydrolyzable bioisosteres of phosphates. They have proven their efficiency as
inhibitors of the enzymes that specialize in utilizing these essential biogenic molecules. Difluoromethylene phosphonates show a broad
spectrum of biological activity and are used as molecular tools to study enzymes and enzyme-substrate interactions. In this review, we
briefly summarize the importance of difluoromethylene phosphonates as a distinct class of synthetic phosphonates resulting from
multidisciplinary efforts of the organophosphorus, organofluorine, and bioorganic research communities. We outline the development of
the synthetic chemistry of difluoromethylene phosphonates from the historical perspective, discuss the most recent trends in the field, and
highlight the existing challenges and unsolved questions.
Keywords: difluoromethylene phosphonates; phosphinates; phosphine oxides; phosphoryldifluoromethylation; phosphorylation.
Introduction
Organofluorine сompounds
The elements of the second period show unique
properties compared to their analogs from higher periods.
While nature has used the uniqueness of carbon, oxygen,
and nitrogen to assemble living matter, humankind
extensively exploits the rest, of which fluorine holds a
special place. This element can bond with almost all
chemical elements except helium and neon. Fluorine
chemistry is thus a vibrant and diverse discipline, yet it
becomes fascinating when fluorine combines with carbon to
create organofluorine compounds [1]. Out of more than 164
million compounds with a C-C bond, almost 44 million
chemicals also have at least one C-F bond [2]. Such a
flourishing diversity of organofluorine compounds is also
the result of a constantly growing demand for new materials
from all science, medicine, and technology fields.
Not surprisingly, organofluorine chemicals have
permeated our everyday lives greater than may be
commonly perceived [3]. Today’s healthcare is hardly
imaginable without organofluorine drugs, anesthetics, and
functional organic and inorganic fluorinated materials [4-7].
Modern-scale food production, which sustains almost
8 billion people, heavily depends on fluorine-containing
agrochemicals [8]. Enhanced lipophilicity, high polarity and
low polarizability, resistance to degradation by enzymes,
and emerging conformational control are the properties that
make the C-F bond and fluorinated compounds essential to
life sciences [9, 10].
Organofluorine chemistry is extensively covered in
several books [9-13]. A vital remark is that a fluorine atom
or a fluorinated group in the vicinity of the reaction center
strongly alters the substrate’s reactivity, the reaction
outcome, and the product’s properties [14, 15].
Bioorganic phosphates and phosphonates
Phosphorus is an essential element within modern life,
where it is found mainly in the form of organic and
inorganic phosphates. Organic phosphates – DNA and
RNA, phosphoproteins, and phospholipids – are critical
intermediates in major biochemical processes [16, 17].
Our knowledge of how phosphates function in living
organisms [18] is essential to creating new therapeutic
© M. Shevchuk and G.-V. Röschenthaler. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received:
Revised:
Accepted:
Published online:
05.04.2022
22.04.2022
29.04.2022
30.06.2022
Corresponding author. Tel.: +49-421-200-3267;
e-mail: m.shevchuk@jacobs-university.de (M. Shevchuk)
ORCID: 0000-0001-5426-4018
M. Shevchuk, G.-V. Röschenthaler.
41
agents [19]. More fundamentally, a better understanding of
phosphate chemistry and biochemistry helps us to challenge
the questions of what life is and how it began [20].
Phosphonates are close analogs of phosphates first
identified as natural products more than 60 years ago [21].
Since then, the perception of the role that phosphonates play
in living organisms has shifted remarkably from viewing
them as biochemical oddities characteristic of a few
microbial species to accepting them in the past 20 years as
an integral part of the global biogeochemical phosphorus
cycle [22-25]. Regardless of their origin, the potential of
phosphonates as bioactive compounds was realized long
ago. The development of bioactive phosphonates is an
active research field that attracts serious effort [26].
Phosphonates owe their high biological activity to their
ability to mimic phosphates in interactions with enzymes
that specialize in making or breaking phosphate bonds. As
phosphate bioisosteres, phosphonates have many viable
targets in the most crucial biochemical processes:
polymerases (synthesis of DNA and RNA), phosphatases,
and kinases (cell signaling and regulation of other enzymes)
[27]. Phosphonates can also act as transition state analogs of
carboxylic substrates by forming non-hydrolyzable
tetrahedral intermediates [28]. A classic example is
acetylcholinesterase inhibition by chemical warfare agents
and insecticides [29].
Difluoromethylene phosphonates
The idea of phosphate-phosphonate bioisosterism has
gained a lot of theoretical and experimental support by the
end of the 1970s. However, it has also become evident that
in many cases, the differences between the phosphate and
the analogous phosphonate functions are too significant to
have an adequate predictive power [30]. For example, the
pKa2 of phosphonates is higher than that of phosphates, ~7.6
vs. ~6.4. Consequently, phosphonates, unlike phosphates,
remain singly ionized at physiological pH values (pH of
blood is 7.4) [27]. In 1981, Blackburn suggested that
α-halogenated alkylphosphonates could mimic phosphates
better than their non-halogenated analogs [31, 32].
Difluoromethylene phosphonates (CF2-phosphonates,
DFMPs) often appear to be the best match for the phosphate
group in terms of C-X-P angles (X = O, 118.7°; CF2,
116.5°; CH2, 112.1°) and pKa2 values (~5.4) as well as other
properties [1, 15, 27].
Today, CF2-phosphonates are essential biochemical tools
for studying ligand binding and substrate-enzyme
interactions [33-36]. Phosphonodifluoromethyl phenyl-
alanine (F2Pmp) derivatives are potent inhibitors of protein
tyrosine phosphatases (PTPs) [37, 38], an enzyme central to
type 2 diabetes, obesity, and cancer (Figure 1) [39]. Other
identified targets for CF2-phosphonates are SH2 domains of
signal transducer and activator of transcription proteins
STAT6 and STAT3 [40], purine nucleoside phosphorylase
(PNP) [41], sphingomyelinase [42], phosphoribosyl-
transferase [43], lysophosphatidic acid receptors [44], and
polo-like kinase 1 (Plk1) [45]. The enzymes responsible for
synthesizing or utilizing biogenic phosphonates are novel
and exciting targets. Phosphonate pathways are unknown in
humans and higher plants and animals but are characteristic
of many pathogenic microbes. Targeting such pathways is a
promising direction toward novel antibacterial agents that
are less harmful to higher organisms [46].
Biomedicinal opportunities for CF2-phosphonates that
are not related directly to enzyme inhibition include using
them for affinity purification of kinases [47], as molecular
anchors to improve adsorption [48], as monomers for dental
applications [49], and as NMR reagents for assessing pH of
biological samples [50]. Artificial nucleosides featuring
CF2-bisphosphonate fragments are candidates for extending
the genetic alphabet (Figure 1) [51].
The chemistry of CF2-phosphonates can be tracked
through several discrete historical stages that have been
dominated by specific biologically focused ideas (or the
absence thereof) and by chemical methods to try these
ideas.
Figure 1. Select examples of bioactive CF2-phosphonates.
IS ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
42
Substances formally defined as CF2-phosphonates have
been known occasionally since the 1950s. In the early
1980s, Blackburn’s idea of α-fluorinated phosphonates as
fully synthetic, better than the parent phosphonates analogs
of phosphates, marked the birth of the bioorganic chemistry
of these compounds, setting a framework for new ideas
[31, 32]. However, the original Blackburn compounds,
difluoromethylene bisphosphonates, have conceptually
always been a separate class of compounds despite being a
subclass of CF2-phosphonates in a strict chemical sense.
Their chemistry has recently been reviewed in several
publications by Romanenko and Kukhar and will not be
discussed here [52-54]. In some cases, the closely related
monofluoromethylene phosphonates have been proven
superior to CF2-phosphonates, but chemical methods for
their preparation, apart from fluorination, are usually
specific to them [55]. We will not focus here on these
compounds either.
After gaining the initial momentum in the 1980s, the
bioorganic chemistry of CF2-phosphonates blossomed
through the 1990s and the first half of the 2000s.
Romanenko and Kukhar extensively discussed the
achievements of this period in several sections of their now
classical review from 2006 on fluorinated phosphonates in
general [55]. A 2010 review by Chkanikov and co-workers
also summarized this period, focusing explicitly on CF2-
phosphonates [56].
Although the biological research in this area continued at
the same pace into the 2010s and 2020s and not without
significant results, it can hardly be described as inspired by
excitingly new ideas. Indeed, one can sometimes feel an
unuttered sense of disappointment: after 40 years of intense
research, there is still no single CF2-phosphonate derivative
on the drug market. At the same time, the synthetic
chemistry of CF2-phosphonates has seen a second birth in
the early 2010s. On the one side, this period is characterized
by the rapid progress in radical and transition metal-assisted
phosphoryldifluoromethylation methods, a development
well understood from a broader perspective of modern
fluoroalkylation chemistry. On the other side, much effort
has been devoted to developing environmentally friendly
chemistry of CF2-phosphonates that would not depend on
ozone-depleting precursors such as CHF2Cl. In 2016,
Poisson and co-workers presented an excellent concept
outlook of these emerging trends [57]. Our group recently
contributed a comprehensive review of CF2-phosphonates
for biological applications embracing the period after 2006
[58].
In the past ten years, certain aspects of the CF2-
phosphonate chemistry have also appeared in phosphonate-
centric discussions [59-63] and organofluorine topics
[13, 64-68].
Synthetic approaches toward difluoromethylene
phosphonates
There are three principal approaches to installing the
CF2-phosphonate functional group: phosphorylation,
fluorination, and phosphoryldifluoromethylation. The
building block approach is a fourth distinct category, but
any building block itself relies on one of the three primary
strategies (Figure 2) [58].
Figure 2. General synthetic approaches to CF2-phosphonates.
Historically, the phosphorylation strategy is the oldest
one dating back to the 1950s [69, 70]. Those early works
focused on exploring the reactivity of alkyl phosphites
toward perfluorinated compounds. Potential practical
applications of CF2-phosphonates were scarcely known, and
there was little incentive to develop this chemistry until the
biological prospects of CF2-phosphonates came into focus
at the beginning of the 1980s.
In 1980, a year before Blackburn’s first publications on
the topic, which assumably was already a subject for
discussions in the community, Burton and Flynn published
the first synthesis of CF2-bisphosphonates,
(RO)2P(O)CF2P(O)(OR)2, by the reaction of
BrCF2P(O)(OR)2 with NaP(O)(OR)2 thus also formally
using phosphoryldifluoromethylation for the first time [71].
In 1981, Blackburn et al. disclosed an alternative synthesis
of (RO)2P(O)CF2P(O)(OR)2 by fluorination of
(RO)2P(O)CH2P(O)(OR)2 with FClO3 [31, 32]. McKenna
and Shen published essentially the same synthesis of
(EtO)2P(O)CF2P(O)(OEt)2 just a few months later [72]. In
1982, Obayashi et al. reported the preparation of
LiCF2P(O)(OEt)2 from HCF2P(O)(OEt)2 and the first
nucleophilic phosphoryldifluoromethylation reactions using
this reagent [73].
A significant milestone of the 1990s was the introduction
of Cu-mediated Ullmann-type cross-coupling reactions of
BrCdCF2P(O)(OEt)2 and BrZnCF2P(O)(OEt)2 with aryl
iodides developed by the groups of Burton [74] and
Shibuya [75]. These protocols allowed for convenient and
versatile preparations of α,α-difluorobenzylphosphonates
leading to a boom in bioorganic and medicinal chemistry of
CF2-phosphonates.
Over the past 15 years, various radical
phosphoryldifluoromethylation methods employing
M. Shevchuk, G.-V. Röschenthaler.
43
photoredox and transition metal catalysis have emerged.
Besides, Me3SiCF2P(O)(OEt)2 has been explored as a more
environmentally friendly alternative to HCF2P(O)(OEt)2
and BrCF2P(O)(OEt)2. At the same time, the fluorination
and phosphorylation strategies have enjoyed far less
attention [58].
Phosphorylation
Substitution reactions
Phosphorylation might seem to be a natural choice for
the synthesis of CF2-phosphonates. The Michaelis-Arbuzov
rearrangement and Michaelis-Becker reaction are the
cornerstone transformations in organophosphorus
chemistry. However, they have found limited application as
general methods for preparing CF2-phosphonates due to
either inertness or unusual reactivity of α,α-difluoroalkyl
halides toward phosphorus-based nucleophiles [76].
One of the earliest examples and indeed the beginning of
the CF2-phosphonate chemistry proper can be traced back to
1959 when Soborovskii and Baina published the pre-
paration of diethyl difluoromethylphosphonate,
HCF2P(O)(OEt)2, by the reaction of CHF2Cl with
NaP(O)(OEt)2 [70]. Their synthetic procedure remained
unchanged apart from minor improvements by Obayashi et
al. (Scheme 1) [73].
HCF2Cl P
O
Na
OR
OR
P
O
OR
OR
H
F F
+
THF, rt
77%
HCF2Cl
P
O
OR
OR
HCF2
–
P
O
Cl
OR
OR
–Cl–
P
O
OR
OR
H
F F
P
O
H
OR
OR
X-philic mechanism
difluorocarbene mechansim
Soborovskii and Baina (1959)
Kondo et al. (1982)
Blackburn and Taylor (1988)
Burton and Flynn (1977)
:CF2
–Cl–
Scheme 1. Synthesis of HCF2P(O)(OR)2 and the suggested
reaction mechanisms.
Soborovskii and Baina suggested the classical SN2
Michaelis-Becker substitution at the phosphorus atom, but
the reaction likely proceeds through the X-philic
mechanism [77] involving a halogen-metal exchange
followed by phosphorylation of the resulting difluoromethyl
carbanion, HCF2
–, as suggested by Blackburn and Taylor
[78]. Burton instead advocated the difluorocarbene route by
analogy with reactions of CHF2Cl with other strong bases
(Scheme 1) [79, 80].
The formal Michaelis-Arbuzov reaction of CF2Br2 with
P(OEt)3 provides access to another critical reagent for
phosphoryldifluoromethylation, BrCF2P(O)(OEt)2. Its syn-
thesis was developed by Burton and Flynn in 1977 [79] and
is believed to proceed through a rather complex mechanistic
sequence involving an X-philic attack on one of the CF2Br2
bromines and the subsequent generation and trapping of
difluorocarbene (Scheme 2) [81, 82].
P
O
OEt
OEt
Br
F F
P
EtO OEt
OEt Br–CF2Br
– Br–
PEtO
OEt
OEt
Br
:CF2
P
EtO OEt
OEt
PEtO
OEt
OEt
CF2
–
PEtO
OEt
OEt
CF2Br
+ Br–
– EtBr
95%
P(OEt)3
Burton and Flynn (1977)
Scheme 2. Synthesis of BrCF2P(O)(OR)2 and the suggested
reaction mechanism.
A practical consequence of this “fluorine” mode of reac-
tivity is that the Michaelis-Becker and Michaelis-Arbuzov
reactions are limited to CHF2Cl, CF2Br2, and similar halo-
methanes. Higher homologs are inert toward phosphorus
nucleophiles or do not give the anticipated products [76].
Direct phosphorylation of higher fluorinated haloalkanes is
possible under radical or electrophilic conditions. Still, such
methods have not gained much popularity because of
several limitations. The Burton and Kato groups studied the
radical phosphorylation of perfluorinated iodoalkanes with
tetraethyl pyrophosphite in the 1980s and 1990s [80, 83].
RCF2CF2Br RCF2CF2P(OEt)2
1. i-PrMgCl·LiCl
2. ClP(O)(OEt)2
THF, –78 °C, 3-4 h
F
O
CF2CF2P(OEt)2
O
CF2CF2P(OEt)2
O
X
78%
X = Br (37%)
X = OTs (48%)
O
Beier et al. (2016)
ON
Ph
CF2Br
Me
1. n-BuLi
2. ClP(O)(OEt)2
2,5-Me2THF, –130 °C, 1 h
ON
Ph
CF2P(OEt)2
Me
O
42%
Toste et al. (2020)
RCF2I RCF2P(OEt)2
1. PhMgCl
2. ClP(O)(OEt)2
Et2O, –50 °C, 30 min
R = C5F9, Cl(CF2)3, Cl(CF2)5, Cl(CF2)7, FO2S(CF2)2O(CF2)3
O
1, 31–58%
Cen and Shen (1991)
2
3
Scheme 3. Electrophilic phosphorylations of in situ generated
difluoromethylcarbanions.
Despite its usefulness in preparing perfluorinated
phosphonates, the method is generally limited by the
availability of α,α-difluoroiodoalkanes, and harsh reactio
IS ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
44
conditions. More recent developments of this method have
not been documented. The electrophilic phosphorylation of
α,α-difluoroalkyl carbanions is inherently limited by the
stability of these intermediates. First examples of such
reactions were reported in 1991 by Cen and Shen, who
prepared perfluoroalkyl phosphonates 1 in reasonable yields
[84]. The recent findings by the groups of Beier [85] and
Toste [86], who briefly studied phosphorylation of carba-
nions derived from bromides 2 and 3, provide a hint for
further elaboration of this strategy (Scheme 3).
Addition reactions
Reactions of P(III) nucleophiles with gem-difluoro-
alkenes lead to fluoroalkenyl phosphonates through the
formal Michaelis-Arbuzov reaction at the terminal sp2
carbon rather than to the anticipated addition products
[55, 76]. To the best of our knowledge, addition reactions of
P(V) nucleophiles to gem-difluoroalkenes have not been
described in the literature.
At the same time, the radical addition of phosphites to a
double bond containing a terminal CF2 group has been
much more successful. Its roots go back to a 1951 patent
assigned to DuPont that describes the telomerization of
tetrafluoroethylene in the presence of diethyl phosphite and
a peroxide initiator [69]. Systematic studies of this method
were launched by Piettre [87, 88] and independently by
Motherwell and co-workers [89, 90] only in 1996. These
groups developed efficient protocols for preparing CF2-
phosphonates 4 and 6 of varying complexity (Scheme 4).
Scheme 4. Radical phosphorylation of gem-difluoroalkenes.
In some instances, hydrogen atom transfer to the
phosphoryl radical may proceed faster than the radical
addition to the gem-difluoroalkene, leading to no net
reaction [91]. Such substrate sensitivity of the method,
when a transformation fails with a structurally similar
substrate (compare difluoroalkenes 5 and 7), lowers the
predictive power of this otherwise attractive approach.
It should be noted that the transition metal-catalyzed
radical phosphorylation of non-fluorinated alkenes has been
extensively explored recently [92]. It may be anticipated
that some of these reactions may also work with gem-
difluorinated alkenes.
Environmental concerns and latest developments
Despite all the limitations, the phosphorylation strategy
still holds the key to the CF2-phosphonate chemistry, which
ultimately relies on HCF2P(O)(OR)2 and BrCF2P(O)(OR)2.
These phosphoryldifluoromethylating reagents are produced
through phosphorylation of industrial halomethanes CHF2Cl
and CF2Br2, respectively.
Chlorodifluoromethane (CHF2Cl, freon R-22) is a class
II ozone-depleting substance. Despite being a critical
industrial chemical – CHF2Cl is a precursor to
tetrafluoroethylene – its free circulation on the market has
been banned in the EU, US, and China. In research
laboratories, it now shares the fate of the once-ubiquitous
solvent CCl4, being either difficult or impossible to acquire.
Dibromodifluoromethane (CF2Br2, freon 12B2) is available
commercially. However, it is a controlled substance within
the EU and is much more expensive than CHF2Cl. Thus,
despite being a mature field, the chemistry of
HCF2P(O)(OEt)2 and BrCF2P(O)(OEt)2 has become
unattractive to many laboratories. Recently, significant
effort has been put into Me3SiCF2P(O)(OEt)2 as an
alternative reagent for nucleophilic and Ullmann-type
chemistry. Yet it is itself prepared from either
HCF2P(O)(OEt)2 or BrCF2P(O)(OEt)2 (Scheme 5)
[50, 73, 93, 94].
P
O
OEt
OEt
H
F F
1. RLi
2. Me3SiCl
P
O
OEt
OEt
Me3Si
F F
P
O
OEt
OEt
Br
F F
1. Mg or Cd
or RLi
2. Me3SiCl
2.
1. LiH (1.2 equiv), LiCl (1.2 equiv)
DMF, 10-30 min, rt
Me3SiCF3 (4.0 equiv)
10-30 min, rt
P
O
H
OR2
OR1
P
O
OR2
OR1
Me3Si
F F
P
O
OR2
OR1
Me3Si
F F
P
O
O
OMe3Si
F F
P
O
OtBu
NEt2Me3Si
F F
Me
MeR1, R2 = Et, i-Pr, t-Bu
P
O
H
R
R
P
O
Li
R
R P O
R
R
SiMe3
P O
R
R
SiMe3
CF2
P O
R
R
F2C
SiMe3
Me3SiCF3
CF3 CF2
LiH
F +
8, 48–99%
Prakash et al. (2019)
Classical preparations of Me3SiCF2P(O)(OR)2
Scheme 5. Electrophilic phosphorylations of in situ generated
difluoromethylcarbanions.
M. Shevchuk, G.-V. Röschenthaler.
45
Given this, the 2019 report by Prakash et al. looks
encouraging [95]. The group has developed a direct method
for preparing Me3SiCF2P(O)(OR)2 compounds of general
formula 8 by a formal Michaelis-Becker reaction of lithio
dialkyl phosphonates with Me3SiCF3 (Scheme 5). Consi-
dering that the same group has earlier reported a direct
synthesis of Me3SiCF3 from fluoroform, an industrial waste
product [96], it may look like the problem has now been
solved. Unfortunately, only conceptionally. From a prac-
tical point of view, the synthetic route “Me3SiCF3 →
Me3SiCF2P(O)(OR)2 → product” is the least economical
one: the second step typically requires a 2 to 3-fold excess
of the reagent relative to the substrate, and the
Me3SiCF2P(O)(OR)2 from Me3SiCF3 step requires, in turn,
another 2.5 to 4-fold excess of Me3SiCF3. For comparison,
HCF2P(O)(OR)2 is typically employed in stoichiometric
amounts, and BrCF2P(O)(OR)2 is used in a 1.5 to 2-fold
excess; both reagents are prepared stoichiometrically from
CHF2Cl or CF2Br2, respectively.
Fluorination
Electrophilic fluorination
In the 1990s, several research groups successfully used
the electrophilic fluorination approach to access CF2-phos-
phonate building blocks such as 9 and 10 for biomedicinal
studies (Scheme 6) [97-99]. This period coincided with the
general interest in electrophilic fluorination.
Scheme 6. Synthesis of CF2-phosphonates by electrophilic
fluorination.
Nucleophilic fluorination
First syntheses of benzylic α-monofluorophosphonates
by nucleophilic fluorination of α-hydroxyphosphonates with
diethylaminosulfur trifluoride (DAST) were achieved by
Blackburn and Kent in 1981 [100]. About ten years later,
Burke et al. applied this method to diethyl benzoyl-
phosphonate, PhC(O)P(O)(OEt)2, to prepare diethyl α,α-di-
fluorobenzylphosphonate, PhCF2P(O)(OEt)2, the first
example of this iconic class of compounds (Scheme 7)
[101]. Expanding the protocol to substituted benzoyl-
phosphonates culminated in the synthesis of 4-phos-
phonodifluoromethylalanine (F2Pmp), which they reported
simultaneously with the group of Wrobel [102-104].
Incorporating this artificial amino acid into an oligopeptide
chain led to the first exceptionally potent inhibitor of
protein tyrosine phosphates (PTPs) 11 [105].
Scheme 7. Nucleophilic fluorination in the synthesis of F2Pmp
and the first potent inhibitor of PTPs.
Not only was their work a remarkable proof of
Blackburn’s concept on structurally very different objects –
Blackburn’s pyrophosphate mimetics vs. Burke’s
phosphotyrosine mimetics – but it had also instigated much
interest in CF2-phosphonates within the bioorganic
community and largely shaped the next 10-15 years of
research in this field. In 2010, it was retrospectively named
the first major medicinal chemistry breakthrough in the
design of phosphatase inhibitors [106].
Limitations and latest developments
In the past 15 years, only a few works have been
dedicated to fluorination as a route toward CF2-phos-
phonates [107-111]. This strategy is still relevant to α-mo-
nofluorinated alkylphosphonates, whereas α,α-difluoro-
alkylphosphonates are often the unwanted reaction by-
products resulting from excessive non-selective fluori-
nation. Besides, the necessity to handle toxic, aggressive,
potentially explosive reagents is another reason for the lack
of interest in this approach.
Phosphoryldifluoromethylation
Phosphoryldifluoromethylation is the most versatile
approach to the construction of CF2-phosphonates. It relies
on several reagents, of which HCF2P(O)(OR)2,
BrCF2P(O)(OR)2, and since recently, Me3SiCF2P(O)(OR)2
are the most important ones. As outlined in Scheme 8, these
reagents and the less widely used R1XCF2P(O)(OR)2
(R1 = Me, Ph, X = S, Se) and ICF2P(O)(OR)2 form transient
organometallic or radical species, which then react through
three principal modes of reactivity: nucleophilic, radical,
and transitional metal-mediated cross-coupling [58]. Here,
we group the material chronologically rather than according
to the above classification to illustrate the historical line of
thought.
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46
Scheme 8. Phosphoryldifluoromethylating reagents and the reactive species they can produce in three different modes of reactivity.
The early 1980s to mid-1990s
The reaction of BrCF2P(O)(OEt)2 with NaP(O)(OEt)2
described by Burton and Flynn in 1980 is the first formal
example of phosphoryldifluoromethylation (Scheme 9)
[71]. Presumably, BrCF2P(O)(OEt)2 was considered a
reagent for electrophilic alkylation. However, investigations
of the reaction mechanism revealed that NaP(O)(OEt)2
attacks the bromine atom in an X-philic fashion inducing
the halogen-metal exchange and formation of the
intermediate carbanion (EtO)2P(O)CF2
– [71]. Halogen-
metal exchange reactions between BrCF2P(O)(OR)2 and
organometallic reagents belong to the standard inventory
for generating carbanions (RO)2P(O)CF2
– (Scheme 8)
[93, 112, 113]. The hydroxide ion and other oxygen bases
attack the phosphorus atom instead, promoting the
C-P bond cleavage and formation of difluorocarbene
(Scheme 9). This fact can be exploited for difluoro-
methylation [114], but it hinders the CF2-phosphonate
chemistry: non-radical electrophilic phosphoryldifluoro-
methylation has not been reported to date.
Scheme 9. Specific reactivity of BrCF2P(O)(OEt)2 toward bases.
Scheme 10. Early nucleophilic phosphoryldifluoromethylations
with HCF2P(O)(OEt)2 and Me3SiCF2P(O)(OEt)2.
Phosphonodifluoromethyl carbanions react with various
electrophiles in substitution and addition reactions and are
paramount to the CF2-phosphonate chemistry. The
carbanion (EtO)2P(O)CF2
– was first prepared by Obayashi
et al. in 1982 by the deprotonation of HCF2P(O)(OEt)2 with
LDA (Scheme 10) [73]. The group has demonstrated its
utility in reactions with common electrophiles leading to
products 12. Adding (EtO)2P(O)CF2
– to aldehydes and
ketones produces the expected hydroxyphosphonates 14.
However, the intermediate lithium alkoxides 13 are
thermally unstable and quickly decompose to gem-difluoro-
M. Shevchuk, G.-V. Röschenthaler.
47
alkenes 15 even at sub-zero temperatures. The authors have
also noticed that in the case of electron-poor aromatic
aldehydes, the addition to the C=O bond can be complicated
by phosphonate-phosphate rearrangement induced by the
newly formed β-alkoxide group leading to products 16. In a
follow-up article, they showed that “this defect can readily
be overcome by the use of Me3SiCF2P(O)(OEt)2 and CsF as
a catalyst, which generates (EtO)2P(O)CF2
– species under
neutral conditions” [115].
On a side note, although Me3SiCF2P(O)(OEt)2 is
sometimes referred to as an analog of Me3SiCF3,
chronologically, its synthesis and first reactions were
reported two years before Ruppert et al. disclosed the
preparation of Me3SiCF3 [116] and seven years before
Prakash et al. used Me3SiCF3 for trifluoromethylation [117].
An essential practical difference between the two
methods for generating nucleophilic CF2-phosphonate
intermediates is that LiCF2P(O)(OR)2 is stable only below –
60 °C. On the contrary, the reactions of
Me3SiCF2P(O)(OR)2 can be conducted at room or even
elevated temperatures. This is because the pentacoordinate
silicon species [Me3SiFCF2P(O)(OR)2] – rather than the free
carbanion (RO)2P(O)CF2
– is the presumable reactive
intermediate [118]. Besides the difference in stability, this
silicon species also has a different, typically lower
reactivity.
Other notable developments of this period include
the preparations of BrZnCF2P(O)(OEt)2 and
ZnBr2·CuCF2P(O)(OEt)2 and the first insights into the
reactivities of these reagents by the Burton group [119, 120]
as well as the first transition metal-assisted generation
(RO)2P(O)CF2
• radicals by the groups of Burton [121] and
Hu [122].
From the mid-1990s to the early 2010s
The 1994 work of Burke et al., in which they reported
α,α-difluorobenzylphosphonates as successful phospho-
tyrosine mimetics and potent inhibitors of PTPs (see
Section “Fluorination” and Scheme 7) [105], revealed a
bottleneck situation from the chemist’s perspective: the
only method to access these compounds relied on
fluorination of labile benzoylphosphonates with harmful
and potentially explosive DAST.
This situation was addressed in 1996 by the Burton
group, who had been studying the chemistry of
BrZnCF2P(O)(OEt)2 and CuCF2P(O)(OEt)2 for more than
ten years by then. They showed that the cadmium reagent
BrCdCF2P(O)(OEt)2, a somewhat more stable analog of
their earlier zinc reagent, reacts with aryl iodides in a CuCl-
mediated Ullmann-type coupling reaction providing
straightforward access to α,α-difluorobenzylphosphonates
17 (Scheme 11) [74].
In 1997, the Shibuya group disclosed essentially the
same procedure using Burton’s original zinc reagent
[119, 120] in the presence of CuBr [75]. The same year,
Kahn and co-workers used the Burton method to prepare
F2Pmp in one step from commercially available protected
4-iodophenylalanine 18 (Scheme 11) [123]. However, the
Shibuya variation gained much popularity in the following
years, presumably because of the lower toxicity of zinc. It
became the standard procedure for multigram preparations
of bioactive α,α-difluorobenzylphosphonates. It should be
mentioned that CuCF2P(O)(OR)2 is the actual reactive
intermediate in both cases [58].
Scheme 11. Ullmann-type coupling reactions of BrCF2P(O)(OEt)2
with iodoarenes.
In the carbanionic chemistry, the development of the
LiCF2P(O)(OR)2/CeCl3 reagent by the Percy group allowed
to tackle the addition reactions to the C=O bond that had
failed previously, opening straightforward access to
bioactive α,α-difluoro-β-ketophosphonates 19 (Scheme 12)
[124, 125]. This reagent also expanded the reaction scope to
the conjugated C=C bond [126, 127].
Scheme 12. CeCl3-mediated acylation of (EtO)2P(O)CF2
– with
carboxylic esters prevents double addition.
Scheme 13. Stereoselective synthesis of β-amino-α,α-
difluoroalkylphosphonates.
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48
Besides that, stereoselective syntheses involving
phosphonodifluoromethyl carbanions became a vital
research direction as exemplified by the preparations of
enantiomerically pure β-amino-α,α-difluorophosphonates
20 by Sorochinksy, Kukhar, and co-workers in collabora-
tion with Röschenthaler (Scheme 13) [128, 129].
In the 2000s, the Leqeux group emphasized the need to
minimize the dependence on freon precursors in the
CF2-phosphonate chemistry. These researchers developed a
freon-free route to MeSCF2P(O)(OEt)2, which could be
used to generate LiCF2P(O)(OR)2 upon treatment with
t-BuLi [130]. They also began studying the chemistry of
(RO)2P(O)CF2
• radicals, which was still in its infancy at that
time [131].
From the early 2010s until the present
By the first half of the 2010s, the field of organofluorine
chemistry had accumulated solid experimental evidence on
the reactivity of perfluorinated halides under the conditions
of photoredox catalysis. Photoredox-catalyzed reactions are
powered by visible light, a green and low-cost energy
source. These transformations enable a direct and selective
late-stage functionalization with small functional groups
such as fluoroalkyl residues [132, 133].
Liu and co-workers reported in 2014 the first example of
photoredox-catalyzed phosphoryldifluoromethylation. They
found that arenes and heteroarenes reacted with
BrCF2P(O)(OEt)2 in the presence of Ir(ppy)3 catalyst and
irradiation from the blue LED lamps to give the
corresponding α,α-difluorobenzylphosphonates 21 (Scheme
14). Electron-rich substrates were more reactive than the
electron-poor ones, and the radical species preferably
attacked the electron-rich sites of the aromatic rings. The
authors concluded the electrophilic nature of
(EtO)2P(O)CF2
• [134].
Scheme 14. Photoredox-catalyzed phosphoryldifluoromethylation
of arenes and the suggested reaction mechanism.
Apart from phosphoryldifluoromethylation of aromatic
substrates [134, 135], this methodology was also used to
add (RO)2P(O)CF2
• radicals to double bond [136-141] as
well as for Heck [142] and Sonogashira-type [143] cross-
couplings. One of the notable limitations of photoredox-
catalyzed reactions is their dependence on a particular
experimental setup due to the need for an efficiently
illuminated surface-to-volume ratio: positioning of the light
source and its intensity, as well as the absolute volume of
the reaction vessel, can significantly affect the reaction
outcome [133]. Consequently, these reactions are not
readily scalable for larger applications; reproducibility of
the results obtained by different groups may also become an
issue [58].
In 1992, Yang and Burton demonstrated that
ICF2P(O)(OEt)2 produced (EtO)2P(O)CF2
• radicals in the
presence of Pd(PPh3)4 [121]. The conceptually similar
chemistry of BrCF2P(O)(OEt)2 and a Co(III)/Zn redox
system was reported by Hu and Chen a year later [122].
However, this approach to the generation of (EtO)2P(O)CF2
•
radicals had not been explored further for more than 20
years until Zhang and co-workers disclosed a Suzuki-type
reaction of BrCF2P(O)(OEt)2 with boronic acids in 2014
(Scheme 15) [144]. The intrinsic difference between the
reaction reported by the Zhang group and the classical
Suzuki reaction is that the activation of an alkyl halide,
BrCF2P(O)(OEt)2 in this case, proceeds through a
Pd-assisted generation of (EtO)2P(O)CF2
• rather than
through the SN2-type oxidative addition. The radical then
recombines with Pd(I) species 23, formed by the oxidation
of the initial Pd(0) complex 22. The resulting Pd(II)
σ-complex 24 transmetalates the boronic substrate 25 giving
Pd(II) complex 26. The subsequent reductive elimination of
26 leads to the target product 27. This type of
transformation termed “transitional metal radical involved
reactions” [145] has gained much attention during the past
decade; several other reactions that may be classified as
such have been reported for BrCF2P(O)(OR)2 [146-148].
Scheme 15. Pd-catalyzed phosphoryldifluoromethylation of
arylboronic acids with BrCF2P(O)(OEt)2 and the suggested
reaction mechanism that involves the generation of
(EtO)2P(O)CF2
•.
As mentioned earlier, reactions involving a nucleophilic
attack on the central carbon atom of BrCF2P(O)(OR)2 are
unknown. The above transformation shows that the
transition metal-assisted generation of electrophilic
(RO)2P(O)CF2
• radicals is a viable means to overcome this
limitation.
M. Shevchuk, G.-V. Röschenthaler.
49
Finally, here should be mentioned works by the groups
of Qing and Poisson, who during the 2010s extensively
studied Me3SiCF2P(O)(OEt)2 as an alternative to
BrCF2P(O)(OEt)2 source of CuCF2P(O)(OEt)2. According
to their findings, the copper reagent forms upon treating
Me3SiCF2P(O)(OEt)2 with CsF in the presence of a Cu(I)
salt such as CuCl or CuSCN in a polar solvent. This copper
species participates in Ullmann-type reactions [149, 150],
coupling reactions with iodonium salts [151], and oxi-
dative couplings with arylboronic acids [152] and
terminal acetylenes [153]. As mentioned earlier,
Me3SiCF2P(O)(OEt)2 can also replace HCF2P(O)(OEt)2 in
nucleophilic chemistry [94, 115] and there is a freon-free
way of producing it from Me3SiCF3 [95]. All this together
makes Me3SiCF2P(O)(OEt)2 one of the most versatile
phosphoryldifluoromethylating reagents.
Building block approach
Phosphoryldifluoromethylation is arguably the most
straightforward way of synthesizing CF2-phosphonate-
containing molecules. It is essentially a variation of
fluoroalkylation. However, it is not always possible to tell
whether a published fluoroalkylation procedure will work
for phosphoryldifluoromethylation. This is where the
building block approach offers additional flexibility. A
small molecule with a CF2-phosphonate moiety and a
reactive functional group has better chances in a known
functional group transformation. Scheme 16 provides
examples of CF2-phosphonate building blocks 28 and 29
developed recently in the Röschenthaler group [154, 155].
Scheme 16. Select examples of the application of CF2-
phosphonate building blocks.
Select Subclasses of difluoromethylene phosphona-
tes and their analogs
Phosphoryldifluoromethyl thioethers
Fluoroalkyl thioethers attract much attention due to their
uniquely high lipophilicity, an essential parameter in
designing bioactive compounds [156, 157].
However, the
variety of phosphoryldifluoromethyl thioethers was limited
to only a few representatives as there was no general
method for their preparation until recently [58].
In 2016, Besset and co-workers developed the efficient
bench-stable phosphoryldifluoromethylthiolating reagent
30. Compound 30 could be prepared on a gram scale and
was reactive toward electron-rich arenes and heteroarenes,
enolizable ketones, anilines, and thiols producing the
corresponding RSCF2P(O)(OEt)2 derivatives 31 in good to
excellent yields (Scheme 17) [158].
In the follow-up works, this chemistry was expanded to
other classes of compounds, new reagents, and methods
[149,159-163].
It should be noted that the biological properties of
phosphoryldifluoromethyl thioethers remain unexplored.
Scheme 17. Synthesis and exemplary applications of the first
general reagent for phosphoryldifluoromethylthiolation.
Phosphoryldifluoromethyl ethers
The situation is different for phosphoryldifluoromethyl
ethers. Only three compounds featuring a ROCF2P(O)(OR)2
structural unit can be with a certain degree of confidence
said of as being known. They are products of trapping
(RO)2P(O)CF2
• radicals with radical scavengers TEMPO
and BHT detected by mass spectrometry or 19F NMR in
mechanistic studies of other reactions (Figure 3) [134, 136,
139, 141].
Figure 3. Known representatives of compounds featuring the
OCF2P(O)(OR)2 structural unit.
One more ArOCF2P(O)(OR)2 molecule has been
claimed in the patent literature to have been prepared by
alkylation of a functionalized sodium phenolate with
BrCF2P(O)(OEt)2 [164]. This result is highly doubtful
because, as discussed earlier, the phosphorus atom or, in
some cases, the bromine atom – but not the carbon atom in
BrCF2P(O)(OEt)2 – are the primary targets for a
nucleophilic attack.
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50
Several monofluorinated oxymethylphosphonates of type
R1OCHFP(O)(OR2)2 were prepared and characterized in the
1990s by electrophilic fluorination of the respective
carbanions [165, 166]. The question remains whether this
method will also work for difluorinated derivatives. In any
case, fluorination and radical phosphoryldifluoro-
methylation are viable approaches to these biologically and
otherwise interesting compounds [167].
Difluoromethylene Phosphonic Amides, Phosphinates,
and Phosphine Oxides
Although the phosphoryldifluoromethylation strategy has
been shown to work for various reagents of the general
formula XCF2P(O)R2, including phosphinates and
phosphine oxides [139, 141, 168], the prevailing amount of
work is being performed with phosphonic esters
(R = OAlk). Conceivably, to introduce a new substituent
onto the phosphorus atom, one must develop and study a
new phosphoryldifluoromethylating reagent, even though
several viable approaches have been demonstrated for
phosphonic amides and phosphinates [169-171]. From this
point of view, the phosphorylation strategy offers a
meaningful advantage over phosphoryldifluoromethylation
since many appropriate phosphorylating reagents are readily
available.
Our group has recently reported a general method for the
preparation of difluoromethylene phosphonic and
phosphinic amides and phosphine oxides 33 based on the
formal [2,3]-sigmatropic rearrangement of fluoroallylic
P(III) derivatives 32 (Scheme 18) [172]. Although not
especially well explored, the earliest precedents of such an
allyl phosphite – allyl phosphonate Arbuzov rearrangement
of non-fluorinated substrates can be traced back to the 1963
work by Pudovik and Aladzyeva [173] and the 1964 work
by Lemper and Tieckelmann [174]. Other researchers have
made several improvements over the years [175-177]. In
1996, Percy and co-workers disclosed three examples of
rearrangements of 3,3-difluoroallyl phosphinites leading to
difluoromethylene phosphine oxides [178], but no further
developments followed until now.
It is believed that the rearrangement proceeds in a
concerted fashion with partial charge separation in the
transition state. The reaction follows the first-order kinetics,
and no cross-products could be detected when two different
fluoroallyl amidophosphites were allowed to rearrange in a
mixture. These observations support the concerted
intramolecular mechanism, although the heterolytic or
homolytic bond cleavage leading to intimate ion or radical
pairs cannot be entirely excluded [179].
The P(III) fluoroallyl substrates 32 are formed in situ
from readily available starting materials and do not require
isolation. The reactions can be easily scaled up.
Furthermore, the developed protocol does not depend on
ozone-depleting precursors CHF2Cl and CF2Br2.
O-protected 2,2,2-trifluoroethanol 34 can be used as
starting material in the one-pot multistep preparation of
α,α-difluoro-β-ketophosphonate, -phosphinate, and phos-
phine oxide derivatives 35 (Scheme 19).
Scheme 18. [2,3]-Sigmatropic rearrangements of fluoroallyl P(III)
substrates leading to difluoromethylene phosphonic and
phosphinic amides and phosphine oxides.
Scheme 19. One-pot synthesis of α,α-difluoro-β-
ketophosphonates, -phosphinates and -phosphine oxides starting
from THP-protected 2,2,2-trifluoroethanol.
Finally, the rearrangement products 33 can be used as
building blocks in further syntheses, as exemplified by pre-
paring the pyrrolidine derivative 36. Furthermore, phos-
phonic amides such as 36 could be easily converted into the
biologically relevant phosphonic acid 37 (Scheme 20).
Scheme 20. Functionalization of [2,3]-rearrangement products.
M. Shevchuk, G.-V. Röschenthaler.
51
Conclusions
In this review, we have shown that the chemistry of
CF2-phosphonates is a mature yet dynamic research field
that continues to stimulate the researchers' interest. One of
the considerable challenges in the area is the reliance of a
more substantial part of this chemistry on ozone-depleting
reagents. Difluoromethylene phosphonic amides, phos-
phonates, and phosphine oxides are still relatively
unexplored, while phosphoryldifluoromethyl ethers are
virtually unknown. It is anticipated that these problems will
be solved in the coming years. We hope this review, which
traces the current state of the art through its historical
development up to the still unresolved questions, will help
the readers get a structured impression of the CF2-phos-
phonate chemistry and identify promising research goals.
Notes
Acknowledgments and finances. This work was funded
by the Bundesministerium für Wirtschaft und Energie
(German Federal Ministry of Economic Affairs and Energy)
through the “GO3” project (No. 03ETE002C). M.S. is also
grateful to Prof. Vadim Romanenko for fruitful discussions.
The authors declare no conflict of interest.
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Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи
М. В. Шевчук*, Ґ.-Ф. Рошенталєр
Бременський університет Якобса, Кампус Рінг 1, Бремен, 28759, Німеччина.
Резюме: Дифлуорометиленфосфонати є негідролізовними біоізостерами фосфатів. Вони довели свою ефективність як ігібітори ферментів, що
спеціалізуються на використанні цих важливих біогенних молекул. Дифлуорометиленфосфонати виявляють широкий спектр біологічної
активності та використовуються як молекулярні інструменти для вивчення ферментів та ферментно-субстратних взаємодій. У цьому огляді ми
коротко підсумовуємо важливість дифлуорометиленфосфонатів як окремого класу синтетичних фосфонатів, що є результатом міждисциплі-
нарних зусиль фосфорорганічної, фторорганічної та біоорганічної наукових спільнот. Ми окреслюємо розвиток синтетичної хімії
дифлуорометиленфосфонатів з історичної точки зору, обговорюємо останні тенденції в цій галузі та висвітлюємо існуючі проблеми та
невирішені питання.
Ключові слова: дифлуорометиленфосфонати; фосфінати; фосфіноксиди; фосфорилдифлуорометилювання; фосфорилювання.
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| id | oai:ojs2.bioorganica.com.ua:article-12 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:28Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/ab/4e01565944544938e58af6e9d03869ab.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-122026-07-19T14:56:52Z Chemistry of difluoromethylene phosphonates: history, state of the art, and prospects Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи Shevchuk, Mykhailo V. Röschenthaler, Gerd-Volker difluoromethylene phosphonates phosphinates phosphine oxides phosphoryldifluoromethylation phosphorylation дифлуорометиленфосфонати фосфінати фосфіноксиди фосфорилдифлуорометилювання фосфорилювання Difluoromethylene phosphonates are non-hydrolyzable bioisosteres of phosphates. They have proven their efficiency as inhibitors of the enzymes that specialize in utilizing these essential biogenic molecules. Difluoromethylene phosphonates show a broad spectrum of biological activity and are used as molecular tools to study enzymes and enzyme-substrate interactions. In this review, we briefly summarize the importance of difluoromethylene phosphonates as a distinct class of synthetic phosphonates resulting from multidisciplinary efforts of the organophosphorus, organofluorine, and bioorganic research communities. We outline the development of the synthetic chemistry of difluoromethylene phosphonates from the historical perspective, discuss the most recent trends in the field, and highlight the existing challenges and unsolved questions   Дифлуорометиленфосфонати є негідролізовними біоізостерами фосфатів. Вони довели свою ефективність як ігібітори ферментів, що спеціалізуються на використанні цих важливих біогенних молекул. Дифлуорометиленфосфонати виявляють широкий спектр біологічної активності та використовуються як молекулярні інструменти для вивчення ферментів та ферментно-субстратних взаємодій. У цьому огляді ми коротко підсумовуємо важливість дифлуорометиленфосфонатів як окремого класу синтетичних фосфонатів, що є результатом міждисциплі-нарних зусиль фосфорорганічної, фторорганічної та біоорганічної наукових спільнот. Ми окреслюємо розвиток синтетичної хімії дифлуорометиленфосфонатів з історичної точки зору, обговорюємо останні тенденції в цій галузі та висвітлюємо існуючі проблеми та невирішені питання. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/12 10.15407/bioorganica2022.01.040 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 40-55 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 40-55 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/12/13 Copyright (c) 2022 Mykhailo V. Shevchuk, Gerd-Volker Röschenthaler https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | дифлуорометиленфосфонати фосфінати фосфіноксиди фосфорилдифлуорометилювання фосфорилювання Shevchuk, Mykhailo V. Röschenthaler, Gerd-Volker Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title | Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title_alt | Chemistry of difluoromethylene phosphonates: history, state of the art, and prospects |
| title_full | Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title_fullStr | Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title_full_unstemmed | Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title_short | Хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| title_sort | хімія дифлуорометиленфосфонатів: історія, сучасний стан і перспективи |
| topic | дифлуорометиленфосфонати фосфінати фосфіноксиди фосфорилдифлуорометилювання фосфорилювання |
| topic_facet | difluoromethylene phosphonates phosphinates phosphine oxides phosphoryldifluoromethylation phosphorylation дифлуорометиленфосфонати фосфінати фосфіноксиди фосфорилдифлуорометилювання фосфорилювання |
| url | https://bioorganica.com.ua/index.php/journal/article/view/12 |
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