A convenient synthesis of dibenzyl α,α-difluoromethyl-β-ketophosphonates

Article abstract of DOI:10.1002/1099-0690(200208)2002:15<2640::AID-EJOC2640>3.0.CO;2-9

The first synthesis of dibenzyl α,α-difluoro-β-ketophosphonates has been accomplished by an original fluorination reaction, namely addition of the F⁺ ion to the enolate form of the corresponding dibenzyl β-ketophosphonate. After an easy cleavag

Full text of DOI:10.1002/1099-0690(200208)2002:15<2640::AID-EJOC2640>3.0.CO;2-9

FULL PAPER
A Convenient Synthesis of Dibenzyl α,α-Difluoromethyl-β-ketophosphonates
[a]
[a]
`
´ ´[a]
Sylvain Ladame, Michele Willson,* and Jacques Perie
Keywords: Carbenes / Phosphonates / Fluorination
The first synthesis of dibenzyl α,α-difluoro-β-ketophosphon-
to be introduced into multiply functionalised molecules, thus
ates has been accomplished by an original fluorination reac- making the previously described diethyl phosphonate route
tion, namely addition of the F+ ion to the enolate form of the
corresponding dibenzyl β-ketophosphonate. After an easy
cleavage of the benzyloxy protecting groups on the phos-
phorus atom, α-fluoro-β-ketophosphonic acids were sub-
no longer relevant. Moreover, study of their stability under
neutral and basic conditions showed the importance of the
keto-enol equilibrium in the decomposition pathway of
these molecules.
sequently obtained as stable carboxyphosphate mimics. This ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
approach enables α,α-difluoro-β-ketophosphonate moieties
2002)
Introduction
cei. From results accumulated from Blackburn’s work[11Ϫ13]
on the electronic and structural analogy between α,α-di-
fluoromethylphosphonate and the phosphate group,[14] it
has been shown that α,α-difluoromethyl-β-ketophosphon-
ates have higher affinities than their corresponding non-
fluorinated analogues for GAPDH from different organ-
isms (parasite and mammals).[10] This improvement was
ascribed to the effects of the two fluorine atoms on the pKa
of the phosphonate (the pKa2 of an α,α-difluoromethylpho-
sphonate is two units lower than the pKa of the correspond-
ing methylphosphonate), as well as to the narrowing of the
PϪCϪC(O) angle. Thus, α-fluoromethyl-β-ketophosphon-
ate appeared to be a more hydrolytically stable mimic of the
mixed anhydride moiety P(O)OC(O) than the correspond-
ing α-methyl-β-ketophosphonates. The high affinities of
these fluorinated substrate analogues may also be explained
by association of the fluorine atoms with residues of the
targeted protein active site through H-bonding.[15]
The constant need for new drugs displaying high and spe-
cific antiparasitic activity — particularly for new trypanoci-
dal molecules — caused us to focus our attention on sub-
strate analogues of glycolytic enzymes.[1] Carbohydrate
metabolism in trypanomastidae is compartmentalised into
specific organelles called glycosomes, and is the sole energy
source of the bloodstream form of Trypanosoma brucei,[2]
the parasite responsible for sleeping sickness. The inhibition
of any step of the glycolytic pathway should result in the
death of the parasite.[3Ϫ5]
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
from trypanosomastidae[6] was chosen as a promising drug
target[7] for two reasons: i) according to the kinetic model
of trypanosome glycolysis,[8,9] the flux is mainly controlled
by glucose transport and by four glycolytic enzymes,
GAPDH among them, and ii) a cysteine at its active site
plays a key role in the multi-step mechanism of this enzyme.
GAPDH catalyses the oxidative phosphorylation of glycer-
aldehyde-3-phosphate (GAP) into 1,3-bisphospho--
glyceric acid (1,3-diPG) in the presence of NADH and inor-
ganic phosphate. This 1,3-diPG, also the common substrate
of two other glycolytic enzymes, phosphoglycerate kinase
(PGK) and phosphoglycerate mutase (PGM), is one of the
few glycolytic metabolites able to cross the glycosomal
membrane.[2] Consequently, analogues of such a substrate
should offer the advantage of easy uptake into the parasite’s
microbody. Several diphosphonates and phosphono-phos-
phates[10] have already been synthesised and have proved to
be valuable inhibitors of GAPDH from Trypanosoma bru-
To date, α-methyl-β-ketophosphonic acids have mainly
been synthesised via their corresponding diethoxy- or diiso-
propyloxyphosphonate neutral analogues,[16Ϫ18] the dial-
kyloxy protecting groups of which were then cleaved by a
fast hydrolysis of the bis-trimethylsilyl esterphosphonate in-
termediate.[19] This deprotection becomes very slow with
α,α-difluorinated analogues[20,21] and such a long exposure
to an acidic medium is incompatible with numerous chemic-
ally sensitive functions. To synthesise polyfunctionalised
molecules bearing α-fluoro-β-ketophosphonate moieties, di-
benzyl protection on the phosphoryl group appeared to be
the only alternative, since this can easily and quickly be
cleaved by reduction under mild and neutral conditions,
even in the presence of fluorine atoms on the CαϪP. [22]
However, the general route through condensation of the di-
benzyl α,α-difluoromethanephosphonate carbanion with
carboxylic esters or carboxylic acid chlorides would no
[a]
Groupe de Chimie Organique Biologique Ϫ LSPCMIB, UMR-
´
CNRS 5068, Universite Paul Sabatier,
´
118, route de Narbonne, 31062 Toulouse Cedex 4, France
Fax: (internat.) ϩ33-560/556-011
E-mail: willson@chimie.ups-tlse.fr
2640
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0815Ϫ2640 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2640Ϫ2648

A Convenient Synthesis of Dibenzyl α,α-Difluoromethyl-β-ketophosphonates
FULL PAPER
longer be applicable, since this carbanion is too unstable to precursors were synthesised from 1,2;5,6-di-O-isopropylid-
react.[23] Reaction with a triflate group is the only previ- ene--mannitol and β-propionolactone by a previously de-
ously reported successful example, by Berkowitz.[22] Con- scribed procedure.[10] Protection of all hydroxyl groups be-
sequently, no dibenzyl α-fluoromethyl-β-ketophosphonate fore the fluorination step was necessary, since F-TEDA is
has previously been isolated.
known to oxidise hydroxy functions to carbonyl groups.[26]
In this report we describe a novel and convenient method We chose tetrahydropyranyl (THP), ethoxyethyl (EE) and
for the synthesis of dibenzyl α,α-difluoromethyl-β-ketopho- trityloxy (Tr) groups, owing to their stability under alkaline
sphonates resulting from the phosphonylation of com- conditions and their easy cleavage by mild acidic hydrolysis.
pounds bearing chemically sensitive groups such as alco- Tetrahydropyranyl and ethoxyethyl groups were introduced
hols, α-diols, ketones or other phosphoryl groups. More- under anhydrous acidic conditions by use of catalytic
over, the stabilities of such compounds were studied with amounts of pyridinium para-toluenesulfonic acid. The tri-
regard to the number of fluorine atoms introduced onto the tylation reaction was achieved under basic conditions by
methylene group, as well as the nature of the carbonyl sub- addition of the alcohol to trityl chloride in anhydrous pyr-
stituents.
idine (Scheme 2 and 3). Selected representative spectro-
scopic data (13C, 31P, JP,C and JP,F) of all α-monofluoro-
and α,α-difluoro-β-ketophosphonates obtained by this syn-
thetic pathway are presented in Table 1 and compared to
those of the nonfluorinated parent molecules. All the non-
fluorinated phosphonates (1bϪ5b) exist only in their ketone
forms, as attested to by the 13C chemical shifts of their
CαϪP moieties. For the di-O-THP- and di-O-EE-protected
compounds, the diastereoisomers were not isolated and
were only detected by 31P NMR spectroscopy.
Results and Discussion
General Procedure for the Synthesis of Dibenzyl α,α-Di-
fluoromethyl-β-ketophosphonates
All syntheses were carried out by a convenient two-step
reaction sequence (Scheme 1).
Of the α-monofluoro-β-ketophosphonates, compounds
1d, 2d and 3d were identified only by 31P NMR spectro-
scopy, while compounds 4d and 5d were isolated and puri-
fied.
All the α,α-difluoro-β-ketophosphonates 1؊5c and 6
were isolated and characterised by NMR spectroscopy and
mass spectrometry. They exist in equilibria with their hy-
Scheme 1
(i) The first step deals with the synthesis of the nonfluor-
inated β-ketophosphonate derivatives by condensation of
the (BnO)2P(O)CH2Li carbanion with the appropriate
methyl ester. The stable intermediates were isolated and
purified.
(ii) In the second step, the fluorination of the α-methyl-
ene group of the β-ketophosphonate framework was carried
out with an Fϩ donor, namely 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-
TEDA), usually employed for fluorination of 1,3-dicar-
bonylated compounds.[24,25] The fluorination process con-
sists of initial deprotonation of the α-methylene group of
the β-ketophosphonate with sodium hydride (2 equiv.) at
low temperature, followed by treatment with the F-TEDA
reagent (2 equiv.). The resulting dibenzyl α,α-difluoro-
methyl-β-ketophosphonates were thus obtained in moderate
to good yields (up to 60%). Whatever the concentration of
NaH (from 0.5 to 3 equiv.), these syntheses always gener-
ated minor amounts of monofluorinated phosphonate (5 to
10%) as side-products, which were systematically charac-
terised by spectral analysis. For a few examples, these were
isolated during the purification of the difluorinated derivat-
ives.
Scheme 2. a) CH3P(O)(OBn)2, nBuLi, THF, Ϫ78 °C, 99%; b) NaH,
F-TEDA, THF/DMF (50:50), 60%; c) HCl, H2O; d) PPTS, ethyl
vinyl ether (or 3,4-dihydro-2H-pyran), CH2Cl2, 73% and 90%; e)
This general method was successfully used for the syn-
thesis of several dibenzyl β-ketophosphonates bearing
either α-diol or monoalcohol moieties as substituents. The H2 Pd/C, CH3OH, 98%
Eur. J. Org. Chem. 2002, 2640Ϫ2648
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S. Ladame, M. Willson, J. Perie
FULL PAPER
drated forms, which account for about 10Ϫ20% by 13C
NMR spectroscopy [C(OH)2 signal, td, δ ϭ 95Ϫ96 ppm].
This equilibrium can be completely displaced towards the
ketone form by azeotropic distillation with anhydrous ben-
zene. The dibenzyloxy protecting groups of the α-mono-
fluoro- and α,α-difluoro-β-ketophosphonates were easily
and completely removed by catalytic hydrogenolysis. The
dibenzyl α,α-difluoro-β-ketophosphonates were thus
quickly converted into their corresponding phosphonic ac-
ids under neutral conditions. The efficiency of such mild
deprotecting conditions was illustrated by the almost
quantitative conversion of the dibenzyl esters 1c and 6 into
their corresponding phosphonic acids 1e and 8.
Fluorination Mechanism
A few electrophilic fluorinations have already been de-
scribed in the literature, all of them involving a specific syn-
thetic approach:
(i) The fluorination of nonfunctionalised diethyl phosphon-
ates has been reported to involve the addition of the fluor-
ine ion Fϩ to
a ‘‘stabilized’’ α-phosphoryl anion
(EtO)2P(O)YRCϪ, in which the stabilizing groups Y were
either aryl,[27] trialkylsilyl[28,29] or arenesulfonyl.[30,24]
(ii) For β-diketones, electrophilic fluorination occurs at an
enolic intermediate.[24] Under neutral conditions, the β-di-
ketones exist almost completely as enols,[31] and treatment
with one equivalent of F-TEDA afforded the corresponding
α-monofluoro derivative in excellent yield. Under the same
conditions, the fluorination of keto-esters (8 to 10% of en-
Scheme 3. a) NaOH, MeOH; b) TrCl, pyridine; c) 3,4-dihydro-2H-
pyran, PPTS, CH2Cl; d) CH3P(O)(OBn)2, nBuLi, THF, Ϫ78 °C; e)
NaH, F-TEDA, THF/DMF (50:50), 4c 48%, 4d 5%, 5c 55%, 5d
5%; f) Et2O/HCOOH; g) PPTS, MeOH, 6 72%, 7 83%; h) H2
Pd/C, CH3OH, 96%
Table 1. NMR spectral data of the fluorinated and non-fluorinated dibenzyl-β-ketophosphonates
2642
Eur. J. Org. Chem. 2002, 2640Ϫ2648

A Convenient Synthesis of Dibenzyl α,α-Difluoromethyl-β-ketophosphonates
FULL PAPER
olic form) occurred much more slowly, but could rapidly be PϪO phosphoric ester bond and thus facilitating hydro-
accomplished by complete displacement of the equilibrium lysis.[32,33,34]
towards the enolate species under basic conditions.
For the protected α-diols 1c, 2c and 3c (Scheme 2), the
The fluorination method we report here was successfully complete hydrolysis of both primary and secondary alcohol
achieved only in the presence of at least one equivalent of protecting groups (THP, EE, isopropylidene bridge) did not
base (NaH), no fluorination of dibenzyl β-ketophosphon- produce the expected dibenzyl (3R)-1,1-difluoro-3,4-dihy-
ates being observed under neutral conditions. This caused droxy-2-oxobutylphosphonate, regardless of whether the
us to postulate that the fluorination mechanism involved an conditions of cleavage employed mild acidic conditions or
enolate intermediate resulting from the deprotonation of specific catalysts such as [PdCl2(CH3CN)2][35] or FeCl3 ad-
the β-ketophosphonate moiety. This enolisation was de- sorbed on silica gel.[34] In parallel, partial hydrolysis of the
tected for dibenzyl 2-oxopropyl-phosphonate, the enolate benzyloxy groups around the phosphorus atom was ob-
species being unambiguously identified by 13C NMR spec- served. Replacement of the benzyloxy groups by ethoxy
1
troscopy [δ ϭ 63.8 ppm (d, JC-P ϭ 196 Hz, ϭCH-P)] and groups, which are less sensitive to acidic hydrolysis, gave a
IR spectroscopy (disappearance of νCϭO ϭ 1714 cmϪ1).
similar result.
The experimental procedure was optimised to favour the
These diethoxy analogues were synthesised as previously
synthesis of the α,α-difluoro-β-ketophosphonates (2 equiva- described, by condensation of the diethylmethylphosphon-
lents of base). Nevertheless, the fluorination reaction does ate carbanion (Scheme 4). Unfortunately, the hydrolysis of
not seem to depend on the amount of base, since the α,α- the isopropylidene bridge was no more successful for diethyl
difluorophosphonate is always the main product whatever α,α-difluoromethyl-β-ketophosphonate 9a (Scheme 4) than
the quantity of sodium hydride added, varying from 0.5 to it had been for its dibenzyl ester analogue 1b. The ortho-
3 equivalents relative to the β-ketophosphonate. This pre- gonal protection of both primary and secondary hydroxyl
dominant difluorination reaction occurs through an initial groups allowed the isolation of the stable monoalcohol 10e
addition of F-TEDA to the enolate tautomer, followed by (Scheme 4). However, the removal of the benzyl ether by
a fast gem fluorination of the more stable enolate resulting hydrogenolysis under neutral conditions did not enable
from the monofluoro derivative. For the latter, as in the case isolation of the corresponding α-diol. This seems to indicate
of β-diketones, the enol form is able to exist in the absence that the overall instability of this series of molecules prob-
of base, and can therefore give rise to the difluoro derivative ably involves the α-hydroxy ketone moiety. In all the at-
despite the use of less than one equivalent of base.
tempts described above, the degradation of the α,α-di-
fluoromethylphosphonate moiety was clearly evident in the
31P, 13C and 19F NMR spectra. Indeed, PϪF coupling was
no longer observed in the crude material, and the main
Stability of Dibenzyl α-Fluoro-β-ketophosphonates
In order to achieve the synthesis of the 1,3-diPG ana- phosphorylated product was the appropriate dialkyl phos-
logues 4,4-difluoro-3-oxo-4-phosphonobutyl phosphates phite (RO)2P(O)H, as confirmed by 31P NMR spectroscopy
deprotection of the hydroxyl groups was required in order (δ ϭ 7.2 ppm, JP-H ϭ 690 Hz).
to phosphorylate the primary alcohol selectively. This could
be effected by a recently reported procedure already suc- difluoromethyl-γ-hydroxy-β-ketodiesterphosphonates are
cessfully applied to nonfluorinated analogues.[10]
intrinsically unstable whatever the pH conditions, whereas
From these experimental results, it appears that the α,α-
At first, the reaction was studied with the monohydroxyl- the decomposition of the α,α-difluoromethyl-δ-hydroxy-β-
ated derivatives 4c,d and 5c,d (Scheme 3). The tritylhydroxy ketophosphonates (such as 6 in Scheme 3) is only observed
(4c and 4d) and tetrahydropyranyl (5c and 5d) protecting under alkaline conditions. Both sensitivities can be ac-
groups were removed, affording the corresponding mono-
and difluorinated alcohols 7 (from 4d and 5d) and 6 (from
4c and 5c) as stable compounds. Whereas the cleavage of
the hydroxyl protecting groups by acidic hydrolysis was
complete in nearly quantitative yields for the monofluorin-
ated dibenzylphosphonates 4d and 5d, use of the same ex-
perimental conditions for the difluorinated compounds 4c
and 5c resulted in the hydrolysis of a single benzyloxy
group. Consequently, for the two difluorophosphonates 4c
and 5c, cleavage of the THP or Tr groups must have oc-
curred simultaneously with a partial benzyloxy cleavage,
which could be taken to completion by hydrogenolysis to
afford the completely deprotected phosphoric acid 8. This
increased sensitivity of the dibenzyl difluoro-β-keto-phos-
phonates towards acidic hydrolysis relative to their α-mono-
fluorinated analogues can be explained by the electron-
withdrawing effect of the two fluorine atoms, the introduc-
tion of a second fluorine atom on the CαϪP weakening the HCOOH
Scheme 4. a) (EtO)2P(O)CF2H, LDA, THF, Ϫ78 °C; b) HCl, H2O;
c) TrCl, pyridine, CH2Cl2; d) BnBr, Ag2O, benzene; e) Et2O/
Eur. J. Org. Chem. 2002, 2640Ϫ2648
2643

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S. Ladame, M. Willson, J. Perie
FULL PAPER
counted for by the easy enolisation of the ketone moiety ponding enolate for the first fluorination, and eventually
induced by the two fluorine atoms (Scheme 5). Indeed, through the enolic form for the second. The synthetic pro-
these α,α-difluoro-β-ketophosphonates are only enolisable cess we describe here has been successfully applied to a set
towards the C-3 atom, and are easily and irreversibly de- of protected β-hydroxy or α,β-dihydroxy esters. It appears
composed from this enolic form into stable compounds.
to be the best alternative for the introduction of α,α-di-
fluoro-β-keto-phosphonates into pH-sensitive molecules for
which the previously described diethyl difluoromethylphos-
phonate route cannot be used.
While the use of the dibenzyl difluoromethanephosphon-
ate carbanion is not applicable because of the low stability
of this species (contrary to what has been observed with
dialkyl difluoromethanephosphonate anion), stabilization
by the carbonyl group allows the electrophilic fluorination
of the β-ketophosphonate system. The removal of the
benzyl groups under mild conditions offers access to the
targeted compounds. We have demonstrated that the meth-
odology we describe here is of general applicability and in-
dicated why the α,α-difluorophosphono-phosphate 1,3-
diPG isosteric analogue cannot exist, because of the in-
trinsic instability of the α,α-difluoro-γ-hydroxy-β-ketophos-
phonate scaffold.
Experimental Section
Before use, tetrahydrofuran and diethyl ether were distilled from
over sodium and benzophenone, dichloromethane was distilled
from over P2O5, and pyridine and triethylamine from over KOH.
1H, 13C, 19F and 31P NMR spectra were obtained on Bruker Instru-
ments AC 250, AC 50, AC 188 and AC 81 machines, respectively.
Chemical shifts (δ) reported for signal centres are expressed in ppm
from the internal standard references: TMS (1H and 13C),
CF3COOH (19F) and H3PO4 (31P). Coupling constants (J) are
given in Hz. IR spectra were recorded on a PerkinϪElmer 1600
series FTIR spectrophotometer. Mass spectra (chemical ionisation)
were recorded on a Nermag R10Ϫ10 quadrupolar spectrometer
and performed by the ‘‘service commun’’ of the Institute of Mo-
lecular Chemistry Paul Sabatier (ICMPC, IR-1744). Preparative
column chromatography was performed on 70Ϫ230 mesh Merck
silica gel.
Scheme 5
For the γ-hydroxy derivatives, this enolisation results in
the displacement of the carbonyl group from the β- to the
γ-position, with the corresponding α,α-difluoro-β-hydroxy-
γ-ketophosphonates then spontaneously decomposing into
the appropriate aldehyde, dibenzylphosphite and CF2 car-
bene.
For the non-hydroxylated β-ketophosphonates, which are
stable under acidic or neutral conditions, the corresponding
enolate, formed only under basic conditions, decomposes
into an unstable ketene, which is probably hydrolysed in-
stantaneously.
For both series of compounds, the decomposition reac-
tions affording dibenzylphosphite imply the formation of a
very reactive carbene, CF2, which has also been detected
previously in decomposition reactions of difluorometh-
anes.[37,38] In this present study, we were able to characterise
the concomitantly formed dibenzylphosphite by phos-
phorus NMR spectroscopy, thus corroborating our mech-
anistic hypothesis.
General Procedure for Phosphorylation: A solution of nBuLi (1.6
, 4.4 mL, 6.9 mmol) was slowly added at Ϫ78 °C to a solution of
the dibenzyl methylphosphonate (1.76 g, 6.4 mmol) in THF
(20 mL). After stirring for 30 min at Ϫ78 °C, this solution was
slowly added at Ϫ78 °C, by cannula, to a solution of carboxylic
ester (5.8 mmol) in THF (20 mL). After one hour at Ϫ78 °C, the
mixture was allowed to warm to room temperature overnight. The
organic layer was then neutralised with a saturated aqueous solu-
tion of NH4Cl and, after evaporation of THF, the residue was ex-
tracted with EtOAc (3 ϫ 100 mL). The combined organic layers
were dried (MgSO4), filtered and evaporated, and the residue was
purified by flash chromatography (CH2Cl2/MeOH), affording the
expected β-ketophosphonate. This procedure was successfully ap-
plied for the synthesis of compounds 1b, 4b and 5b.
General Procedure for Fluorination: NaH (50 mg, 2 mmol) was
slowly added at 0 °C to a solution of the β-ketophosphonate
(1.3 mmol) in THF (20 mL). After stirring the mixture for 15 min
at 0 °C, F-TEDA (1 g, 2.8 mmol) and DMF (20 mL) were added
successively. Stirring was continued for two hours at room temper-
Conclusion
The synthesis of stable α,α-difluorinated analogues of
1,3-diphosphoglycerate can be achieved by fluorination of
dibenzyl β-ketophosphonate esters, through the corres- ature, and the reaction was quenched by addition of Et2O and
2644 Eur. J. Org. Chem. 2002, 2640Ϫ2648

A Convenient Synthesis of Dibenzyl α,α-Difluoromethyl-β-ketophosphonates
FULL PAPER
NH4Cl (aq). The organic layer was washed with NaCl (aq) and
water, dried (MgSO4) and filtered, and the solvents were evapor-
ated. The residue was purified by flash chromatography (CH2Cl2/
(250 MHz, CDCl3): δ ϭ 1.0Ϫ1.4 (m, 12 H, CH3 EE), 3.1Ϫ3.7 (m,
10 H, CH2-CO, CH2 et CH-O EE), 4.15 (m, 0.5 H, CH-O), 4.30
(m, 0.5 H, CH-O), 4.65 (m, 2 H, CH2-O), 5.05 (m, CH2 Bn), 7.29
MeOH), affording dibenzyl (α,α-difluoro)-β-ketophosphonate (m, 10 H, Ph) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ 21.5,
(from 40 to 60%). Some starting material (20 to 30%) was also
recovered. This method was successfully applied for the synthesis
of compounds 1c, 2c, 3c, 4c, 5c, 4d and 5d.
22.4 ppm. MS (DCI, NH3): m/z ϭ 509 [MHϩ], 526 [MNH4ϩ].
Dibenzyl [(3R)-1,1-Difluoro-2-oxo-3,4-bis(tetrahydro-2H-2-pyranyl-
oxy)butyl]phosphonate (2c): This compound (yield 52%) was syn-
thesised from 2b (438 mg, 0.82 mmol). 31P NMR (81 MHz,
CDCl3): δ ϭ 3.3 (t, JP-F ϭ 95 Hz), 3.5 (t, JP-F ϭ 95 Hz) ppm.
MS (DCI, NH3): m/z ϭ 569 [MHϩ], 586 [MNH4ϩ]. C28H35F2O8P
(568.2): calcd. C 59.15, H 6.20; found C 59.04, H 6.27.
General Procedure for Dibenzyl Hydrogenolysis: Pd/C (10%, 60 mg)
was added to a solution of the dibenzyl phosphonate (1 mmol) in
MeOH (20 mL), and the heterogeneous solution was stirred under
an H2 atmosphere for half an hour at room temperature. The Pd/
C was then filtered off and washed with MeOH, and the solvent
was evaporated off, quantitatively affording the corresponding di-
hydroxyphosphonate as a colourless oil (yield around 98%). This
method was successfully applied for the synthesis of compounds 1e
and 8.
Dibenzyl [(3R)-3,4-Bis(1-ethoxyethyl)-1,1-difluoro-2-oxobutyl]phos-
phonate (3c): This compound (yield 50%) was synthesised from 3b.
31P NMR (81 MHz, CDCl3): δ ϭ 3.2 (t, JP-F ϭ 95.2 Hz), 3.6 (t,
JP-F ϭ 95.2 Hz) ppm. MS (DCI, NH3): m/z ϭ 545 [MHϩ], 562
[MNH4ϩ].
Dibenzyl
{2-[(1R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1,1-difluoro-2-
Methyl 3-Trityloxypropanoate (4a): Chlorotriphenylmethane
(7.77 g, 27.9 mmol) was added at 0 °C to a solution of methyl 3-
hydroxypropanoate[27] (2.9 g, 27.9 mmol) in anhydrous pyridine
(60 mL). After stirring the mixture overnight at room temperature,
the pyridine was evaporated off. The oily residue was chromato-
graphed (CH2Cl2/petroleum ether 50:50), to afford compound 4a
(6.95 g, 72%) as a white powder. 1H NMR (250 MHz, CDCl3): δ ϭ
2.62 (t, 2 H, CH2-CO), 3.44 (t, 2 H, CH2-O), 3.72 (s, 3 H, CH3),
7.23Ϫ7.50 (m, 15 H, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
35.4 (CH2-CO), 51.7 (CH3), 59.6 (CH2-O), 86.8 [C(Ph)3], 127.2
(Ph), 128.0 (Ph), 128.8 (Ph), 144.1 (Cq Ph), 172.3 (CϭO) ppm. MS
(DCI, NH3): m/z ϭ 347 [MHϩ], 364 [MNH4ϩ].
oxoethyl}phosphonate (1c): This compound (yield 59%) was syn-
thesised from dibenzyl {2-[(1R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
oxoethyl}phosphonate (564 mg, 1.4 mmol).[10] 1H NMR
(250 MHz, CDCl3): δ ϭ 1.42 (s, 3 H, CH3), 1.50 (s, 3 H, CH3),
4.13 (dd, 2 H, CH2-O hydrated form), 4.28 (dd, 2 H, CH2-O ketone
form), 4.46 (t, 1 H, CH-O hydrated form), 4.60 (t, 1 H, CH-O
ketone form), 5.2 (m, 4 H, CH2 Bn), 7.35 (m, 10 H, Ph) ppm. 13C
NMR (50 MHz, CDCl3) ketone form: δ ϭ 25.4 (s, CH3), 25.7 (s,
CH3), 65.7 (CH2-O), 70.8 (d, JC-P ϭ 6.3 Hz, CH2 Bn), 77.2 (d,
JC-P ϭ 7.2 Hz, CH-O), 116.8 (td, CF2), 128Ϫ129 (m, Ph), 135.2 (d,
JC-P ϭ 6.6 Hz, Cq Bn), 207.1 (m, CO); hydrated form: δ ϭ 25.4 (s,
CH3), 25.7 (s, CH3), 65.3 (CH2-O), 70.4 (d, JC-P ϭ 6.2 Hz, CH2
Bn), 74.7 (d, JC-P ϭ 7.2 Hz, CH-O), 93.9 [td, C(OH)2], 116.8 (td,
CF2), 128Ϫ129 (m, Ph), 135.2 (d, JC-P ϭ 6.6 Hz, Cq Bn) ppm. 19F
Methyl 3-(Tetrahydro-2H-pyranyloxy)propanoate (5a): 3,4-Dihydro-
2H-pyran (9.6 mL, 105 mmol) and pyridinium p-toluenesulfonate
(1.75 g, 7 mmol) were added to a solution of methyl 3-hydroxypro-
panoate[39] (7.75 g, 47.5 mmol) in anhydrous CH2Cl2 (40 mL).
After stirring the mixture overnight at room temperature, diethyl
ether (150 mL) was added and the organic layer was washed with
semisaturated brine (50 mL), dried (MgSO4) and filtered. After dis-
tillation (b.p. ϭ 115 °C, 16 Torr), compound 5a was obtained pure
NMR (188 MHz, CDCl3) ketone form: δ ϭ Ϫ43.1 (d, JP-F
ϭ
96 Hz); hydrated form: δ ϭ Ϫ39.5 (d, JP-F ϭ 96 Hz) ppm. 31P
NMR (81 MHz, CDCl3) ketone form: δ ϭ 3.29 (t, JP-F ϭ 96 Hz);
hydrated form: δ ϭ 7.30 (t, JP-F ϭ 96 Hz) ppm.
Dibenzyl [(3R)-2-Oxo-3,4-bis(tetrahydro-2H-2-pyranyloxy)butyl]-
phosphonate (2b): 3,4-Dihydro-2H-pyran (0.82 mL, 9.0 mmol) and
pyridinium p-toluenesulfonate (75 mg, 0.3 mmol) were added to a
solution of dibenzyl [(3R)-3,4-dihydroxybutyl]-2-oxophosphon-
ate[10] (542 mg, 1.49 mmol) in anhydrous CH2Cl2 (15 mL). After
stirring the mixture at room temperature for 5 days, diethyl ether
(100 mL) was added, and the organic mixture was washed with
semisaturated brine (30 mL), dried (MgSO4) and filtered, and the
solvents were evaporated. The residue was then purified by chroma-
tography (CH2Cl2/MeOH, 99:1) to give 2b as a colourless oil (yield:
73%). 13C NMR (50 MHz, CDCl3): δ ϭ 18.8Ϫ20.2 (m, CH2 THP),
25.2 (m, CH2 THP), 61.9 (m, CH2-O), 67.9 (m, CH2 Bn), 81.3 (m,
1
as a colourless liquid (11.5 g, 82%). H NMR (250 MHz, CDCl3):
δ ϭ 1.4Ϫ1.8 (m, 6 H, 3 ϫ CH2 THP), 2.56 (t, 2 H, CH2-CO), 3.4
(m, 1 H, CH2-O THP), 3.6 (td, 1 H, CH2-O), 3.64 (s, 3 H, CH3),
3.78 (m, 1 H, CH2-O THP), 3.93 (td, 1 H, CH2-O), 4.57 (t, 1 H,
O-CH-O) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 19.3 (CH2 THP),
25.4 (CH2 THP), 30.5 (CH2 THP), 34.9 (CH2-CO), 51.5 (CH3),
62.0 (CH2-OH), 62.8 (CH2-O THP), 98.8 (O-CH-O), 172.0 (CO)
ppm. MS (DCI, NH3): m/z ϭ 189 [MHϩ], 206 [MNH4ϩ].
Dibenzyl (2-Oxo-4-trityloxybutyl)phosphonate (4b): This compound
(3.75 g, 55%) was synthesised from compound 4a (4.0 g,
11.6 mmol). It was obtained as a colourless oil after flash chroma-
CH-O), 99.0 (m, O-CH-O), 128Ϫ129 (m, Ph), 135.9 (d, JC-P
ϭ
6.5 Hz, Cq Bn), 204.0 (m, CϭO) ppm. 31P NMR (81 MHz, CDCl3):
δ ϭ 21.6, 22.5 ppm. MS (DCI, NH3): m/z ϭ 533 [MHϩ], 550
[MNH4ϩ]. C28H37O8P (532.2): calcd. C 63.15, H 7.00; found C
63.09, H 6.97.
1
tography (CHCl3/MeOH 99:1). H NMR (250 MHz, CDCl3): δ ϭ
2.82 (t, 2 H, CH2-CO), 3.13 (d, JP-C ϭ 22.6 Hz, 2 H, CH2-P), 3.41
(t, 2 H, CH2-O), 5.01Ϫ5.13 (m, 4 H, CH2-Ph), 7.25Ϫ7.47 (m, 25
H, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 42.6 (d, JP-C
128.5 Hz, CH2-P), 44.4 (CH2-CO), 58.9 (CH2-O), 68.1 (d, JP-C
ϭ
ϭ
Dibenzyl [(3R)-3,4-Bis(1-ethoxyethyl)-2-oxobutyl]phosphonate (3b):
Ethyl vinyl ether (0.38 mL, 4.0 mmol) and pyridinium p-toluene-
sulfonate (63 mg, 0.25 mmol) were added to a solution of di-
benzyl [(3R)-3,4-dihydroxy-2-oxobutyl]phosphonate[10] (410 mg,
1.1 mmol) in anhydrous CH2Cl2 (15 mL). After stirring the mixture
at room temperature for 3 hours, diethyl ether (150 mL) was added,
and the organic mixture was washed with brine (30 mL), dried
6.3 Hz, CH2-Ph), 86.9 [Cq-(Ph)3], 127.1 (Ph), 127.9 (Ph), 128.2
(Ph), 128.7 (Ph), 135.8 (d, JP-C ϭ 6.2 Hz, Cq-Ph Bn), 143.9 (Cq-Ph
Tr), 200.4 (d, JP-C ϭ 6.3 Hz, CϭO) ppm. 31P NMR (81 MHz,
CDCl3): δ ϭ 21.2 ppm. MS (DCI, NH3): m/z ϭ 591 [MHϩ], 608
[MNH4ϩ].
Dibenzyl
[2-Oxo-4-(tetrahydro-2H-pyranyloxy)butyl]phosphonate
(MgSO4) and filtered, and the solvents were evaporated to afford (5b): This compound (7.1 g, 57%) was synthesised from compound
compound 3b as a colourless oil (516 mg, 90%). 1H NMR
5a (5.5 g, 29 mmol). It was obtained as a colourless oil after puri-
Eur. J. Org. Chem. 2002, 2640Ϫ2648
2645

´
´
S. Ladame, M. Willson, J. Perie
FULL PAPER
fication by flash chromatography (petroleum ether/diethyl ether
3.64 (m, 1 H, CH2-O), 3.80 (m, 1 H, CH2-O THP), 3.96 (m, 1 H,
CH2-O), 4.57 (t, 1 H, O-CH-O), 5.15 (m, 4 H, CH2-Ph), 5.20 (dd,
30:70). 1H NMR (250 MHz, CDCl3): δ ϭ 1.4Ϫ1.7 (m, 6 H, 3 ϫ
CH2 THP), 2.80 (t, 2 H, CH2-CO), 3.15 (d, 2 H, JH-P ϭ 22.6 Hz, JH-P ϭ 14.2 Hz, JH-F ϭ 48.2 Hz, 1 H, CHF), 7.33 (m, 10 H, Ph)
CH2-P), 3.45 (td, 1 H, CH2-O THP), 3.62 (td, 1 H, CH2-O), 3.76
(m, 1 H, CH2-O THP), 3.93 (td, 1 H, CH2-O), 4.55 (t, 1 H, O-CH-
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 19.3 (CH2 THP), 25.4
(CH2 THP), 30.5 (CH2 THP), 39.5 (d, JC-P ϭ 5.0 Hz, CH2-CO),
O), 5.05 (m, 4 H, CH2-Ph), 7.33 (m, 10 H, Ph) ppm. 13C NMR 61.5 (d, JC-P ϭ 5.1 Hz, CH2-O), 62.1 (CH2-O THP), 69.4 (dd, JC-
(50 MHz, CDCl3): δ ϭ 19.4 (CH2 THP), 25.4 (CH2 THP), 30.5
(CH2 THP), 43.1 (d, JC-P ϭ 128.7 Hz, CH2-P), 44.1 (CH2-CO), CHF), 99.0 (O-CH-O), 127.9 (Ph), 128.5 (Ph), 135.2 (d, JC-P
62.0 (CH2-O), 62.2 (CH2-O THP), 68.0 (d, JC-P ϭ 6.2 Hz, CH2-Ph), 5.6 Hz, Cq Bn), 200.7 (dd, JC-P ϭ 16.7 Hz, JC-F ϭ 2.6 Hz, CϭO)
ϭ 6.2 Hz, CH2 Bn), 91.8 (dd, JC-P ϭ 153.0 Hz, JC-F ϭ 198.4 Hz,
P
ϭ
99.0 (O-CH-O), 128.1 (Ph), 128.6 (Ph), 135.8 (d, JC-P ϭ 6.2 Hz, Cq
ppm. 19F NMR (188 MHz, CDCl3): δ ϭ Ϫ29.5 (dd, JP-F
ϭ
Bn), 200.2 (d, JC-P ϭ 6.3 Hz, CϭO) ppm. 31P NMR (81 MHz, 71.2 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ 11.1 (d, JP-F
ϭ
CDCl3): δ ϭ 21.1 ppm. MS (DCI, NH3): m/z ϭ 433 [MHϩ], 450 71.2 Hz) ppm. MS (DCI, NH3): m/z ϭ 451 [MHϩ], 468 [MNH4ϩ].
[MNH4ϩ].
Dibenzyl (1,1-Difluoro-4-hydroxy-2-oxobutyl)phosphonate (6): This
Dibenzyl (1,1-Difluoro-2-oxo-4-trityloxybutyl)phosphonate (4c):
This compound (yield 48%) was synthesised from compound 4b
(3 g, 5.1 mmol). It was obtained as a colourless oil after purifica-
tion by flash chromatography (CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 3.11 (t, 2 H, CH2-CO), 3.56 (t, 2 H, CH2-O), 5.2Ϫ5.3
(m, 4 H, CH2-Ph), 7.27Ϫ7.58 (m, 25 H, Ph) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 38.4 (CH2-CO), 57.6 (CH2-OTr), 70.5 (d,
compound was obtained from both compounds 4c and 5c.
(i) Formic acid (10 mL) was added to a solution of 4c in diethyl
ether (10 mL). After stirring the mixture for 4 hours, the solvent
was evaporated off and the residue was purified by chromato-
graphy (CH2Cl2).
(ii) Pyridinium p-toluenesulfonate (63 mg, 0.19 mmol) was added
to a solution of 5c (870 mg, 1.86 mmol) in ethanol (15 mL). After
stirring the mixture for 3 hours at 55 °C, the ethanol was evapor-
ated off and the residue was purified by chromatography (CHCl3
and then EtOAc). Compound 6 (740 mg, 72%) was obtained pure
JC-P ϭ 6.5 Hz, CH2-Ph), 87.1 [Cq-(Ph)3], 113.2 (td, JC-P
ϭ
197.9 Hz, JC-F ϭ 274.2 Hz, CF2), 127.2Ϫ129.7 (Ph), 134.9 (d, JP-
C ϭ 6.1 Hz, Cq-Ph Bn), 143.9 (Cq-Ph Tr), 197.0 (td, JP-C ϭ 16.3 Hz,
JC-F ϭ 2.6 Hz, CϭO) ppm. 19F NMR (188 MHz, CDCl3): δ ϭ
Ϫ42.0 (d, JP-F ϭ 98.2 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ
4.07 (t, JP-F ϭ 98.2 Hz) ppm. MS (DCI, NH3): m/z ϭ 627 [MHϩ],
644 [MNH4ϩ]. C37H33F2O5P (626.2): calcd. C 70.92, H 5.31; found
C 71.04, H 5.23.
1
as a colourless oil. H NMR (250 MHz, CDCl3): δ ϭ 2.56 (s, 1 H,
OH), 2.99 (t, 2 H, CH2-CO), 3.90 (t, 2 H, CH2-O), 5.18 (m, 4 H,
CH2-Ph Bn), 7.35 (m, 10 H, Ph) ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 40.6 (CH2-CO), 57.0 (CH2-O), 70.7 (d, JC-P ϭ 6.1 Hz, CH2-
Ph), 113.0 (td, JC-P ϭ 197.0 Hz, JC-F ϭ 265.8 Hz, CF2), 128.1 (Ph),
128.7 (Ph), 129.1 (Ph), 134.7 (d, JC-P ϭ 5.5 Hz, Cq Bn), 199.0 (d,
JC-P ϭ 11.3 Hz, CϭO) ppm. 19F NMR (188 MHz, CDCl3): δ ϭ
Ϫ42.1 (d, JP-F ϭ 97.0 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ
3.8 (t, JP-F ϭ 97.0 Hz) ppm. MS (DCI, NH3): m/z ϭ 385 [MHϩ],
402 [MNH4ϩ].
Dibenzyl
[1,1-difluoro-2-oxo-4-(tetrahydro-2H-pyranyloxy)butyl]-
phosphonate (5c): This compound (yield: 55%) was synthesised
from compound 5b (4.5 g, 10.4 mmol). It was obtained as a colour-
less oil after purification by flash chromatography (petroleum
ether/diethyl ether 30:70). 1H NMR (250 MHz, CDCl3): δ ϭ
1.4Ϫ1.7 (m, 6 H, 3 ϫ CH2 THP), 2.91 (t, 2 H, CH2-CO), 3.49 (m,
2 H, CH2-O THP), 3.96 (m, 1 H, CH2-O), 4.57 (t, 1 H, O-CH-O),
5.15 (m, 4 H, CH2 Bn), 7.33 (m, 10 H, Ph) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 19.3 (CH2 THP), 25.3 (CH2 THP), 30.5
(CH2 THP), 38.1 (CH2-CO), 61.0 (d, JC-P ϭ 5.2 Hz, CH2-O), 62.0
(CH2-O THP), 70.4 (dd, JC-P ϭ 6.2 Hz, CH2-Ph), 98.9 (O-CH-O),
113.0 (td, JC-P ϭ 197.4 Hz, JC-F ϭ 273.8 Hz, CF2), 127.9 (Ph),
Dibenzyl (1-Fluoro-4-hydroxy-2-oxobutyl)phosphonate (7): Pyridin-
ium p-toluenesulfonate (10 mg, 0.03 mmol) was added to a solution
of 5d (130 mg, 0.29 mmol) in ethanol (5 mL). After stirring the
mixture for 3 hours at 55 °C, the ethanol was evaporated off and
the residue was purified by chromatography (CHCl3 and than
EtOAc). Compound 7 (88 mg, 83%) was obtained pure as a colour-
128.5 (Ph), 134.9 (d, JC-P ϭ 5.5 Hz, Cq Bn), 197.0 (td, JC-P
ϭ
1
less oil. H NMR (250 MHz, CDCl3): δ ϭ 2.43 (s, 1 H, OH), 2.87
16.7 Hz, JC-F ϭ 2.6 Hz, CϭO) ppm. 19F NMR (188 MHz, CDCl3):
δ ϭ Ϫ42.1 (d, JP-F ϭ 98.1 Hz) ppm. 31P NMR (81 MHz, CDCl3):
δ ϭ 4.0 (t, JP-F ϭ 98.1 Hz) ppm. MS (DCI, NH3): m/z ϭ 469
[MHϩ], 486 [MNH4ϩ].
(m, 2 H, CH2-CO), 3.88 (t, 2 H, CH2-O), 5.10 (m, 4 H, CH2-Ph),
5.15 (dd, 1 H, JH-P ϭ 14.6 Hz, JH-F ϭ 47.6 Hz, CHF), 7.35 (m, 10
H, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 41.9 (CH2-CO),
57.0 (d, JC-P ϭ 1.6 Hz, CH2-O), 69.6 (dd, JC-P ϭ 6.2 Hz, CH2-Ph),
91.8 (dd, JC-P ϭ 153.1 Hz, JC-F ϭ 198.8 Hz, CHF), 127.9 (Ph),
Dibenzyl (1-Fluoro-2-oxo-4-trityloxybutyl)phosphonate (4d): This
compound (yield: 5%) was synthesised from compound 4b (3 g,
5.1 mmol). It was obtained as a colourless oil after flash chromato-
128.5 (Ph), 135.1 (d, JC-P ϭ 5.5 Hz, Cq Bn), 203.0 (d, JC-P
ϭ
19.5 Hz, CϭO) ppm. 19F NMR (188 MHz, CDCl3): δ ϭ Ϫ29.5
(dd, JP-F ϭ 71.7 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ 11.0
(d, JP-F ϭ 71.7 Hz) ppm. MS (DCI, NH3): m/z ϭ 367 [MHϩ], 384
[MNH4ϩ]. C18H20FO5P (366.1): calcd. C 59.02, H 5.50; found C
58.90, H 5.44.
1
graphy (CH2Cl2). H NMR (250 MHz, CDCl3): δ ϭ 2.89 (t, 2 H,
CH2-CO), 3.37 (t, 2 H, CH2-O), 5.05Ϫ5.13 (m, 4 H, CH2-Ph), 5.15
(dd, JH-P ϭ 14.6 Hz, JH-F ϭ 47.6 Hz, 1 H, CHF), 7.22Ϫ7.42 (m,
25 H, Ph) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ 11.0 (t, JP-F
ϭ
71.7 Hz) ppm. 19F NMR (188 MHz, CDCl3): δ ϭ Ϫ29.7 (d, JP-F ϭ
71.7 Hz) ppm. MS (DCI, NH3): m/z ϭ 609 [MHϩ], 626 [MNH4ϩ].
C37H34FO5P (608.2): calcd. C 73.02, H 5.63; found C 73.11, H 5.70.
{2-[1(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1,1-difluoro-2-oxoethyl}
phosphonic Acid, Hydrated Form (1e): This compound (105 mg,
98%) was synthesised from dibenzyl {2-[(1R)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-1,1-difluoro-2-oxoethyl}phosphonate 1c (180 mg,
Dibenzyl [1-Fluoro-2-oxo-4-(tetrahydro-2H-pyranyloxy)butyl]phos-
phonate (5d): This compound (235 mg, 5%) was synthesised from 0.4 mmol). 1H NMR (250 MHz, D2O): δ ϭ 1.39 (s, 3 H, CH3),
compound 5b (4.5 g, 10.4 mmol). It was obtained pure as a colour-
less oil after flash chromatography (petroleum ether/diethyl ether
1.47 (s, 3 H, CH3), 4.02 (dd, 2 H, CH2-O), 4.30 (t, 1 H, CH-O)
ppm. 13C NMR (50 MHz, D2O): δ ϭ 25.0 (s, CH3), 25.3 (s, CH3),
50:50). 1H NMR (250 MHz, CDCl3): δ ϭ 1.4Ϫ1.7 (m, 6 H, 3 ϫ 64.2 (s, CH2-O), 72.3 (d, JC-P ϭ 7.5 Hz, CH-O), 91.2 (td, C(OH)2],
CH2 THP), 2.91 (t, 2 H, CH2-CO), 3.49 (m, 1 H, CH2-O THP), 113.9 (td, CF2) ppm. 19F NMR (188 MHz, D2O): δ ϭ Ϫ38.4 (d,
2646
Eur. J. Org. Chem. 2002, 2640Ϫ2648

A Convenient Synthesis of Dibenzyl α,α-Difluoromethyl-β-ketophosphonates
FULL PAPER
JF-P ϭ 98 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ ϭ 7.05 (t, JF- Bn) 143.8 (Cq Tr), 171.4 (CϭO) ppm. IR (film): νCϭO ϭ 1750 cmϪ1
ϭ 98 Hz) ppm.
ppm. MS (DCI, NH3): m/z ϭ 453 [MHϩ], 470 [MNH4ϩ]. C30H28O4
P
(452.2): calcd. C 79.62, H 6.24; found C 79.54, H 6.32.
(1,1-Difluoro-4-hydroxy-2-oxobutyl)phosphonic acid (8): This com-
pound (210 mg, 96%) was synthesised from compound 6 (355 mg,
0.73 mmol). 1H NMR (250 MHz, CD3OD): δ ϭ 4.12 (t, 2 H, CH2-
O), 4.62 (t, 1 H, O-CH-O) ppm. 13C NMR (50 MHz, CD3OD):
δ ϭ 36.8 (s, CH2-CO), 58.9 (d, JC-P ϭ 5.5 Hz, CH2-O), 108.8 (td,
Diethyl [(3R)-3-Benzyloxy-1,1-difluoro-2-oxo-4-trityloxybutyl]phos-
phonate (10d): A solution of diethyl difluoromethylphosphonate
(0.85 mL, 5.3 mmol) in anhydrous THF (5 mL) was slowly added
at Ϫ80 °C to a solution of LDA (2 , 2.65 mL, 5.3 mmol) in anhyd-
rous THF (10 mL). After stirring the mixture for 30 min at Ϫ80
°C, a solution of 10c (2 g, 4.4 mmol) in anhydrous THF (10 mL)
was added. After stirring for 2 h at Ϫ80 °C, the mixture was neut-
ralised with glacial acetic acid (0.54 mL, 5.3 mmol), a saturated
aqueous solution of NH4Cl (30 mL) was added, and the mixture
was extracted with EtOAc (2 ϫ 50 mL). The organic layer was
washed with water, dried (MgSO4) and filtered, and the solvents
were evaporated.
J
C-P ϭ 196.6 Hz, JC-F ϭ 273.5 Hz, CF2), 195.3 (td, JC-P ϭ 16.2 Hz,
J
C-F ϭ 2.7 Hz, CϭO) ppm. 19F NMR (188 MHz, D2O): δ ϭ Ϫ38.6
(d, JF-P ϭ 97 Hz) ppm. 31P NMR (81 MHz, CD3OD): δ ϭ 3.44 (t,
JF-P ϭ 97 Hz) ppm. C4H7F2O5P (204.00): calcd. C 23.54, H 3.46;
found C 23.66, H 3.60.
Diethyl
{2-[1(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1,1-difluoro-2-
oxoethyl}phosphonate (9a): A solution of diethyl difluoromethyl-
phosphonate (1.0 mL, 6.4 mmol) in anhydrous THF (8 mL) was
slowly added at Ϫ80 °C to a 2  solution of LDA (3.2 mL,
6.4 mmol) in anhydrous THF (5 mL). After stirring the mixture for
30 min at Ϫ80 °C, a solution of 1a (1.0 g, 6.4 mmol) in anhydrous
THF (10 mL) was added. After stirring for 2 h at Ϫ80 °C, the mix-
ture was neutralised with glacial acetic acid (0.66 mL, 6.4 mmol),
a saturated aqueous solution of NH4Cl (30 mL) was added, and
the mixture was extracted with EtOAc (2 ϫ 50 mL). The organic
layer was washed with water, dried (MgSO4) and filtered, and the
solvents were evaporated. After purification by flash chromato-
graphy (CH2Cl2/MeOH 98:2), compound 9a was obtained pure as
a colourless oil (85%).
Diethyl [(3R)-3-Benzyloxy-1,1-difluoro-2-oxo-4-hydroxybutyl]phos-
phonate (10e): Formic acid (10 mL) was added to a solution of 10d
(2.7 g, 4.4 mmol) in diethyl ether (10 mL). After stirring the mix-
ture for 3 hours at room temperature, the solvents were evaporated
off and the remaining crude oil was purified by flash chromato-
graphy (CH2Cl2/MeOH 98:2). Compound 10e (1.19 g, 74%) was
obtained pure as a colourless oil. 1H NMR (250 MHz, CDCl3):
δ ϭ 1.35 (td, 6 H, CH3 Et), 3.94 (m, 2 H, CH2OH), 4.27 (m, 4 H,
CH2 Et), 4.52 (dd, 2 H, CH2 Bn), 4.63 (m, 1 H, CH-OBn), 7.32
(m, 5 H, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 16.3 (d,
JC-P ϭ 5.5, CH2 Et), 62.1 (CH2-OH), 65.9 (d, JC-P ϭ 6.2 Hz, CH2
Et), 72.5 (CH2-Ph Bn), 82.1 (CH-O), 113.5 (td, JC-P ϭ 194.9 Hz,
Methyl (2R)-2,3-Dihydroxypropanoate (10a): A solution of HCl (1
, 2 mL) was added to a solution of 1a (4 g, 25 mmol) in a THF/
H2O mixture (1:1, 50 mL). After stirring the mixture at room tem-
perature for 24 hours, the aqueous layer was washed with EtOAc
(20 mL), neutralised with a 1  solution of NaOH and then ly-
ophilised. CH2Cl2 was added, and the resulting salts were filtered
to afford, after evaporation, a colourless oil (1.74 g, 58%). 1H
NMR (250 MHz, CDCl3): δ ϭ 3.70 (s, 3 H, CH3), 3.80 (m, 2 H,
CH2-O), 4.2 (t, 1 H, CH-O), 4.4 (OH) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 52.5 (CH3-O), 64.0 (CH2-O), 71.9 (CH-O), 173.5 (Cϭ
O) ppm. MS (DCI, NH3): m/z ϭ 121 [MHϩ], 138 [MNH4ϩ].
JC-F ϭ 274.9 Hz, CF2), 127.8 (Ph), 128.5 (Ph), 136.9 (Cq Bn), 197.6
(td, JC-P ϭ 12.5 Hz, JC-F ϭ 23.4 Hz, CϭO) ppm. 19F NMR
(188 MHz, CDCl3): δ ϭ Ϫ41.9 (d, JP-F ϭ 94 Hz) ppm. 31P NMR
(81 MHz, CDCl3): δ ϭ Ϫ2.92 (t, JP-F ϭ 94.1 Hz) ppm. MS (DCI,
NH3): m/z ϭ 367 [MHϩ], 384 [MNH4ϩ]. C15H21F2O6P (366.1):
calcd. C 49.18, H 5.78; found C 49.09, H 5.86.
Acknowledgments
We acknowledge the European Science Research and Development
´ ´
Commission (IC 18CT 970220) and ‘‘La Societe de Secours des
Amis des Sciences’’ for their financial support.
Methyl (2R)-2-Hydroxy-3-trityloxypropanoate (10b): Anhydrous
pyridine (1.05 mL, 16.6 mmol) and chlorotriphenylmethane (2.6 g,
9.3 mmol) were added successively to a solution of 10a (1 g,
8.4 mmol) in anhydrous THF (30 mL). After stirring the mixture
overnight at room temperature, the THF was evaporated off and
the residue was purified by chromatography (CHCl3). Compound
10b (1.9 g, 62%) was obtained pure as a white powder. 1H NMR
(250 MHz, CDCl3): δ ϭ 3.6 (m, 2 H, CH2), 3.80 (s, 3 H, CH3), 4.4
(m, 1 H, CH-O), 7.2Ϫ7.7 (m, 15 H, Ph) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 52.5 (CH3-O), 65.6 (CH2-O), 70.9 (CH-O), 86.6
[C(Ph)3], 127.3 (Ph), 128.1 (Ph), 128.8 (Ph), 143.8 (Cq Ph), 173.7
(CϭO) ppm. MS (DCI, NH3): m/z ϭ 363 [MHϩ], 380 [MNH4ϩ].
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