Bogdan Iorga

Frédéric Eymery

Philippe Savignac

The Syntheses and Properties of 1,2-Epoxyalkylphosphonates

Keywords: Darzens reaction, halohydrins, haloketones, fosfomycin, opening and rearrangement reactions

The present review article deals with the methods of preparation of dialkyl 1,2epoxyalkylphosphonates as well as synthetically useful reactions of this class of compounds. Four main routes to 1,2-epoxyalkylphosphonates are described, in which new developments adapted to each processes are given, including the choice of the leaving group, new cyclisation methods and stereocontrol induction. Thermal and acid catalyzed rearrangements are also covered, and the use of the oxirane ring by nucleophilic opening is highlighted. Particular emphasis is placed on the synthetic approaches to antibiotic fosfomycin.

Introduction

The discovery of antibiotic fosfomycin 1 [(-) (1R,2S)-(Z)-1,2-epoxypropylphosphonic acid] in 1969 has generated a regular interest in the chemistry of 1,2-epoxyalkylphosphonates and gave rise to a large number of synthetic preparations. It has also given to 1,2epoxyalkylphosphonates and derivatives a biochemical significance. As a consequence of this discovery, a lot of research has resulted in the extensive development of methodologies in order to prepare analogs of fosfomycin and to diversify the syntheses. These techniques have largely contributed to extend the synthetic utility of the epoxyphosphonate function and have greatly diversified the reactions available for the construction of the epoxide ring. As synthetic intermediates, these compounds owe their interest to the presence of the epoxide ring, which participates as an electrophilic site and governs their chemical reactivity. The purpose of this review is to provide a general overview of the synthetic reactions, which have been realized in the epoxyphosphonate field and to help focus attention on these valuable derivatives. In this paper, the various methods of preparation of 1,2-epoxyalkylphosphonates, with an emphasis on the syntheses of fosfomycin, and the types of reactions they undergo are summarized.

Preparations

Several methods of synthesis of dialkyl 1,2-epoxyalkylphosphonates are known, they may be classified into four main categories of reactions including (a) the Darzens reaction of dialkyl chloromethylphosphonates with carbonyl compounds, (b) the reaction of sodium dialkylphosphites with α-haloketones, (c) the reaction of dialkyl halohydrinphosphonates with bases, and (d) the oxidation of 1,2-unsaturated phosphonates with a peroxide. These procedures, which usually involve a one-step operation, allow the coverage of a large variety of dialkyl 1,2-epoxyalkylphosphonates.

The Darzens reaction

The Darzens synthesis of glycidic esters by the condensation of carbonyl compounds with α-haloesters 2 is an important and useful method, which has been extended in phosphorus chemistry. Unquestionably, the most general and perhaps most widely employed method for the synthesis of dialkyl 1,2-epoxyalkylphosphonates involves the reaction of dialkyl chloromethylphosphonates 1 with carbonyl compounds. The synthetically useful dialkyl chloromethylphosphonates 1 were readily obtained by standard alcoholysis under anhydrous conditions of the chloromethylphosphonyl dichloride. 3 The latter was obtained in up to 67% yield from phosphorus trichloride and paraformaldehyde at 250°C. 4 Several variations on the preparation of dialkyl 1,2-epoxyalkylphosphonates 3 from dialkyl chloromethylphosphonates 1 and different carbonyl partners have been reported. The conditions of generating the αmetallated dialkyl chloromethylphosphonates were found to be critical due to their notorious instability. With alkoxide bases, the addition of sodium ethoxide or potassium t-butoxide to an equimolecular amount of dialkyl chloromethylphosphonate and carbonyl compound (aromatic aldehydes or ketones) in diethyl ether or t-butyl alcohol at temperatures varying between -10°C and +10°C leads to dialkyl 1,2-epoxyalkylphosphonates in low to good yields (10-68%). 5 Best yields were obtained when the dialkyl chloromethylphosphonates 1 were metallated by treatment with n-BuLi in THF at low temperature. 6 The resulting carbanions 2 undergo facile addition with carbonyl compounds to give the almost immediate formation of chlorohydrins, which on warming conduce quantitatively to dialkyl 1,2epoxyalkylphosphonates 3 without trace of side products (Scheme 1). These conditions were found to be preferable for preparing dialkyl 1,2-epoxyalkylphosphonates 3 in pure form and in good to excellent yield (50-90%). This method appears to be applicable to a wide range of carbonyl compounds so that aliphatic and aromatic aldehydes as well as aliphatic, cyclic and aromatic ketones may be introduced in the reaction (Table 1). The Darzens process was without side reactions, but was not stereoselective, and mixtures of E and Z isomers were frequently obtained with the E form being preferred. Metallated diethyl chloromethylthiophosphonates have also served as precursors to diethyl 1,2epoxyalkylthiophosphonates. 6 Scheme 1

Diethyl 1,2-epoxyalkanephosphonates 6 : A 1.45 molar solution of n-butyllithium in hexane (0.054 mol + 5%) is placed in a three necked flask equipped with a stirrer, an addition funnel, a low temperature thermometer and a nitrogen inlet tube. An equal volume of tetrahydrofuran (~40 ml) is added to the cooled (-20°) solution. Subsequently diethyl chloromethanephosphonate (10 g, 0.054 mol) in tetrahydrofuran (15 ml) is added dropwise at -70°C. After ~10 min the clear reaction mixture becomes turbid and the carbonyl compound (0.054 mol) in tetrahydrofuran (10 ml) is added at -75° to -70°. The mixture becomes clear, stirring is continued for 1 h at -70°, and then the mixture is allowed to warm to room temperature within a few min. Stirring is continued at room temperature for 17 h, water (40 ml) is added, and the product is extracted into 1:1 ether / dichloromethane (3 x

(R 1 O) 2 P O C H 2 Cl (R 1 O) 2 P O C C (R 1 O) 2 P O C H Cl Li n-BuLi -78°C, THF R 2 C R 3 O -78 to 20°C O R 2 R 3 H 1 2 3 R 1 = Me, Et 50
ml). The combined organic layers are dried with magnesium sulfate, the solvent is removed under reduced pressure and the product is purified by vacuum distillation. Several recent innovations have significantly extended the scope and synthetic utility of the classical Darzens reaction. For example, a useful supplement applicable to the formation of 1substituted-1,2-epoxyalkylphosphonates has been described to convert diethyl alkylphosphonates 4 into diethyl 1-substituted-1,2-epoxyalkylphosphonates 6 by a one-step process. 7 Metallation of diethyl alkylphosphonates 4 with 2 eq. of n-BuLi in THF at low temperature followed by electrophilic chlorination using benzenesulfonyl chloride yields the diethyl 1-lithiochloroalkylphosphonates 5, which were converted into diethyl 1-substituted-1,2-epoxyalkylphosphonates 6 by reaction with carbonyl compounds in moderate to good overall yields (30 to 80%) (Scheme 2).

Scheme 2

Diehyl 1,2-epoxyalkanephosphonates 7 : To a stirred solution of diethyl alkanephosphonate (1 mmol) in dry THF (3 ml) is added n-butyllithium (2.2 mmol, 1.6 M in hexane) at -78°C under nitrogen atmospere. After being stirred for 30 min at same temperature, benzenesulfonyl chloride (1 mmol) and carbonyl compound (1 mmol) are added successively and the mixture is allowed to warm with stirring to room temperature. Stirring is continued at room temperature for 15 h, sat. NH 4 Cl solution (10 ml) is added, and the mixture is extracted with ether (3 x 20 ml). The combined organic layer is dried with MgSO 4 , the solvent is removed under reduced pressure and the product is purified by column chromatography on silica gel (ethyl acetate / hexane = 1 / 1).

The halogen-metal exchange reaction of diethyl 1,1-dichloroalkylphosphonates 7 with n-BuLi provides another convenient preparation of diethyl 1-lithio-1-chloroalkylphosphonates 5. 8 Me

Me (R 1 O) 2 P O C H 2 R 4 (R 1 O) 2 P O C C (R 1 O) 2 P O C R 4 Li 1) 2 n-BuLi -78°C, THF R 2 C R 3 O -78 to 20°C O R 2 R 3 R 4 2) PhSO 2 Cl R 1 = Et R 2 = Ph, 4-Cl-C 6 H 4 , 4-MeO-C 6 H 4 , PhCH=CH R 3 = H, Me, Ph R 4 = Me, Et, PhCH 2 4 5 6 Cl
This gives a somewhat higher yield of carbanion than is obtained by the chlorination procedure. For example, trapping of diethyl 1-lithio-1-chloroethylphosphonate 5 (R 4 =Me) with aliphatic or aromatic aldehydes and aliphatic ketones provides a suitable route to diethyl 1-methyl-1,2-epoxyalkylphosphonates 6 (R 4 =Me) in good yields (61-81%) (Scheme 3) as a mixture of Z and E isomers in approximately equal amounts. 9

Scheme 3

Diethyl 1,2-dimethyl-1,2-epoxypropanephosphonate 9 : A solution of diethyl 1,1-dichloroethane-phosphonate (5.9 g, 25 mmol) in ether (25 ml) and THF (20 ml) is placed in a three necked flask equipped with a stirrer, addition funnel, low temperature thermometer, and nitrogen inlet tube, n-BuLi (21.2 ml of a 1.25 M solution in ether, 5% excess), is added dropwise to the cooled solution (-100°C) under nitrogen (5 min). When the addition is finished the temperature is allowed to reach -85°C for 30 min. Then, at -90°C, a solution of acetone (1.5 g, ~26 mmol) in ether (10 ml) is added and the cooling is removed. When the temperature has reached -50°C, a 1+1 mixture (10 ml) of HMPT-THF is added and stirring is continued for 30 min at 0°C. Then, 2 normal sulfuric acid (20 ml) is rapidly added and the mixture is extracted with ether (3 x 50 ml). The organic phase is washed with 1 normal sulfuric acid (50 ml) and with saturated sodium chloride solution (2 x 100 ml), it is dried with magnesium sulfate, the solvents are removed at reduced pressure, and the oily residue is distilled in vacuo; yield: 4.5 g (80%); b.p. 70°C / 0.25 torr.

A new technique for the formation of 1,2-epoxyalkylphosphonates 3 is based upon the reactivity towards aromatic aldehydes of electrochemically generated carbanion of diethyl chloromethylphosphonate 1 (R 1 =Et) in DMF. 10 The yield of 72% obtained with p-methoxybenzaldehyde was promising. However, the major disadvantage, which attends the use of the electrochemical route is the difficulty that may be encountered in the electrogeneration of species sufficiently basic to deprotonate the chloromethylphosphonates. An interesting and useful variant of the Darzens reaction has been reported for the preparation of fosfomycin from diethyl chloromethylphosphonate 1 (R 1 =Et). 11 Nucleophilic substitution of the chlorine in diethyl chloromethylphosphonate with dimethyl sulfide gives the sulfonium salt 8, which may be further converted into its stable ylide by the use of MeS(O)CH 2 Na. The use of the ylide in addition to acetaldehyde produces the diethyl 1,2-epoxypropylphosphonate 9, thus avoiding the problems associated with stability of chloromethylphosphonate carbanions (Scheme 4).

(R 1 O) 2 P O CCl 2 R 4 (R 1 O) 2 P O C C (R 1 O) 2 P O C R 4 Li -78°C, THF R 2 C R 3 O -78 to 20°C O R 2 R 3 R 4 R 1 = Et R 2 = H, Me, n-Bu R 3 = Me, Et, i-Pr, CH(Et) 2 , i-Bu, Ph R 4 = Me n-BuLi HMPT 7 5 6 Cl Scheme 4
The use of diazomethane derivatives represents another modification of the Darzens reaction (Scheme 5). However, the reaction was not effective enough and remains undeveloped. 12 Diphenyldiazomethane on reaction with dimethyl α-ketophosphonates 10 undergoes reactions typical of carbonyl compounds to give the corresponding dimethyl 1-substituted-

The reaction of sodium dialkylphosphite with α-haloketones

In connection with the reaction of α-haloketones with nucleophiles, which is a standard epoxide synthesis, [START_REF] Rosowsky | Heterocyclic Compounds with Three and Four Member Rings[END_REF] it is well recognized that reaction of α-haloketones 13 with the appropriate phosphorus nucleophiles can constitute an interesting but somewhat limited method of synthesis of dialkyl 1,2-epoxyalkylphosphonates 6. Effectively, the conditions required for this procedure may not be compatible with the sensitive functionalities of αhaloketones, and the reaction sometimes proceeds with a lack of regiospecificity to produce a mixture of phosphorus compounds. Thus, this reaction has been reported to give the epoxide alone, 24,28 the vinyl phosphate alone, 25,36 a mixture of the epoxide and vinyl phosphate, 20,21,23 or a mixture of the epoxide and β-ketophosphonate. 22,26,27,29 A large number of investigations have led to propose four types of mechanisms involving an initial attack of the phosphorus on: the halogen, 31 the carbonyl oxygen, 32 the α-carbon bound to the halogen 33 or on the carbonyl carbon. 34,35 phosphorus at the carbonyl carbon. Formation of the β-ketophosphonate results from attack at the α-halo carbon. Alkali metal derivatives of dialkylphosphites 12 (M=Na, K) attack αhaloketones 13 (X=Cl, Br) primarily at the carbonyl carbon atom forming an alkoxide anion 14, which displaces the β-halogen to give the dialkyl 1,2-epoxyalkylphosphonates 6 (Scheme 6) with reasonable yields in the range 55 to 71% (Table 2). In some cases, however, formation of vinyl phosphate 15 can be a competing reaction. 20,21,23,30 This procedure appears to be limited to the synthesis of epoxides having only one non-hydrogen β-substituent since the αhalo carbon cannot be tertiary, the vinyl phosphate being the main product. 20-22,36,37 An alternative procedure for the preparation of dialkyl 1,2-epoxyalkylphosphonates 6 from αhaloketones is the action of sodium methoxide (1 eq.) on a mixture of α-chloroketones 13

(R 1 O) 2 P O (R 1 O) 2 P O C C O R 2 R 3 R 4 M M = Na, K R 4 C O C X R 2 R 3 + (R 1 O) 2 P C O C X R 4 R 2 O M R 3 (R 1 O) 2 P O O C C R 2 R 3
(X=Cl) and dimethyl-or diethylphosphite (1 eq.) in methanol at room temperature. 37 The reproductible yields of 53 to 84% obtained by this technique represent a significant improvement over the yields of 30 and 63% reported for the one-step reaction of αchloroketones with sodium diethylphosphite. This procedure appears to give only the epoxides with aliphatic α-chloroketones and attempts to form the epoxide by reaction of αchloroacetophenone with dimethylphosphite resulted in the formation of dimethyl 1phenylvinylphosphate. However, in spite of the difficulties frequently encountered in the choice of the α-chloroketones, this facile and convenient procedure is a useful variant of the classical approach as illustrated by the results gathered in the Table 3. Dimethyl 1,2-epoxy-2-propylphosphonate 37 : A solution of sodium methoxide was prepared by dissolving 0.06 mol (1.37 g) of sodium in 25 ml of methanol. The sodium methoxide was then added dropwise over a period of 15 min to a mixture of 0.06 mol (5.55 g) of chloroacetone and 0.06 mol (6.60 g) of dimethyl phosphite in 5 ml of methanol at room temperature. After stirring for 1h the solution was filtered, distilled to remove methanol, and refiltered. Ether was then added to precipitate any remaining sodium chloride. The solution was filtered again and ether evaporated off. A short-pass distillation gave the title compound: b.p. 75-76°C (0.7 mm Hg).

The reaction between diethylphosphite and α-chloroketones 13 (X=Cl) can also be accomplished by fluoride ion-deprotonation reaction in DMF (dry KF or KF . 2H 2 O are fluoride ion source), which proves a non-basic route to diethyl 1,2-epoxyalkylphosphonates. However, the application of this technique provides a mixture of 1,2-epoxyphosphonate (about 50%) and vinyl phosphate (about 30%) whatever the α-chloroketones. 38 The reaction conditions required for the preparation of halogenoketones frequently may not be compatible with the sensitive functionalities that are present in complex polyfunctional molecules. Recent innovations in the standard synthetic procedure using α-haloketones have featured the use of a new class of leaving groups, α-tosyloxyketones. [39][40][41][42][43] For example, a relatively general procedure for the quantitative generation of dialkyl 1,2-epoxyphosphonates 17 possessing a sugar or a steroid appendage using α-tosyloxyketones 16 has been employed.

Generation of the epoxides may be conveniently executed under a variety of reaction conditions. They include sodium diethylphosphite in EtOH at reflux (69%), 39 diethylphosphite in the two-phase system CH 2 Cl 2 /NaOH 50%/TBAC at room temperature 41 or diethylphosphite in MeOH in the presence of DBU at 0°C (62-90%) 42a,42b,43 (Scheme 7). This attractive procedure appears as a useful modification having a great synthetic utility since the leaving group is introduced in mild conditions by merely treating the sensitive substrat containing a primary alcohol with TsCl in the presence of pyridine. 43

Scheme 7

(5R or 5S)-5,6-anhydro-3-O-benzyl-5-C-(dimethoxyphosphinyl)-1,2-O-isopropylidene-α-D-xylo- hexofuranose 42 : To a mixture of 3-O-benzyl-1,2-O-isopropylidene-6-O-p-tolylsulfonyl-α-D-xylo-hexofuranose
(5.6 g) and dimethyl phosphite (1.5 g) in methanol (10 ml) was added DBU (2.1 g) during 1 h at 0°C, and the solution was kept in a refrigerator for 48 h. The methanol and unreacted dimethyl phosphite were removed in vacuo, and then a solution of the residue in chloroforme was successively washed with aqueous sodium hydrogencarbonate and water, dried (sodium sulfate), and evaporated, to afford a syrup, which was chromatographied in a column of silica gel, using 1:2 (v/v) ethyl acetate-petroleum ether as the eluant. The fractions were suitably pooled, and evaporated in vacuo to give a syrup (3.4 g, 70%), which crystallized after 2 days; m.p. 107-108°C (ethyl acetate-hexane).

Another variation reports a one-pot synthesis of diethyl 1-(perfluoroalkyl)-1,2epoxyalkylphosphonates 19 using the nucleophilic attack of lithium diethylphosphite on the carbonyl carbon atom of the perfluorinated β-oxophosphonium salts 18 (Scheme 8). 44 The resulting intermediate can eliminate in two directions. When the oxygen anion with the least sterically hindered position attacks the neighbouring carbon atom it gives, after elimination of triphenylphosphine (anti fashion), the diethyl 1-(perfluoroalkyl)-1,2-epoxyalkylphosphonates 19 in moderate yields (42-51%). The formation of the α-(perfluoroalkyl)vinylphosphonates 20 by attack at phosphorus (syn fashion) can be a competing reaction. The results indicate that the selectivity could be controlled to produce exclusively either epoxyphosphonates or vinylphosphonates depending on steric factors (R 2 , R 3 ) and the base used. 16 17

(EtO) 2 P O (EtO) 2 P O C C H 2 O R 4 H R 4 C H C H 2 O H O H R 4 C H C H 2 OTs O H R 4 C C H 2 OTs O TsCl rt, Py PCC DBU / MeOH rt, CH 2 Cl 2
R 4 = Me, O O R O O Me Me O O O O Me Me , , Scheme 8
Diethyl (3,3-dimethyl-2-pentafluoroethyloxiran-2-yl)phosphonate 44 : n-Butyllithium (3.0 mmol) or methyllithium (3.0 mmol) in dry tetrahydrofuran (THF) was added dropwise to a stirred suspension of the phosphonium salt 18 (3.0 mmol) in absolute THF (30 ml) at -20°C under nitrogen. The mixture was stirred for 30 min at 0°C and cooled to -78°C; the perfluoroalkanoic anhydride (2.5 mmol) was slowly added until the characteristic ylidic colour had disappeared. The mixture was stirred at -78°C for 5 min and a solution of diethyl lithium phosphite [prepared by the reaction of ethyl hydrogen phosphite (0.41 g, 3.0 mmol) and methyllithium (3.0 mmol) in THF (10 ml) for 30 min at -78°C] was slowly added. The mixture was allowed to warm to room temperature, stirred for a further 2 h, and diluted with light petroleum (b.p. 60-90°C). Filtration and evaporation of filtrate gave a residue, which was purified by column chromatography on silica gel with light petroleum (b.p. 60-90°C)-ethyl acetate (10:1) as eluant to give the title product: yield 42%; b.p. 84°C / 2 mm Hg.

The most recent development in the field has featured the use of phase transfer catalyst conditions in the preparation of dialkyl 1,2-epoxyalkylphosphonates from dialkylphosphites and α-haloketones 13 (X=Cl). 45 A first procedure uses potassium carbonate in excess as base, and a second a mixture of potassium carbonate and sodium hydrogen carbonate, TBAB being introduced as phase transfer catalyst. Each reaction was carried out in the absence of solvent, the liquid phase being formed by the starting reagents. This method does not improve the yields of dialkyl 1,2-epoxyalkylphosphonates, which are roughly comparable to those previous reported. However, the absence of undesired side products, which usually accompany this reaction renders this methodology a viable alternative to the methods, which require the use of a solvent.

The reaction of dialkyl halohydrinphosphonates and related structure with bases

In addition to the two previous methodologies, there is a technique, which employs the conversion of halohydrinphosphonates into epoxyphosphonates by formation of an alkoxide anion. This two-step procedure appears to be limited to the synthesis of dialkyl 1,2epoxyethylphosphonates having hydrogens or only one non-hydrogen substituent. Formation of halohydrinphosphonates can be accomplished by two procedures, which exploit either the condensation of a dialkylphosphite with an α-chlorocarbonyl compound or the halohydroxylation of a vinylphosphonate. The reaction of dialkylphosphites proceeds upon heating for a long time with α-chloroketones at 100-165°C with a catalyst (MeONa/MeOH) [START_REF] Arbuzov | [END_REF] (EtO

) 2 P O (EtO) 2 P O C C O R 2 R 3 R 4 Li Ph 3 P C R 2 R 3 C R 4 O R 4 C O 2 + + R 4 = CF 3 , C 2 F 5 R 2 = R 3 = Me 18 19 (EtO) 2 P O C C R 2 R 3 R 4 20 R 2 = Me, R 3 = Ph
or at 100-120°C without catalyst, 47 and with chloroacetaldehyde 46 at 100°C without any catalyst to give, in 50 to 100% yields, the chlorohydrinphosphonates having the hydroxyl group in the α position. The reaction between diethylphosphite and chloroacetaldehyde can proceed also at room temperature in the presence of catalytic amount of triethylamine. 48 Diethyl 2-chloro-1-hydroxyethylphosphonate 48 : A mixture of diethyl phosphite (27.6 g) and chloroacetaldehyde (15.6 g) was stirred at room temperature for 3 h in the presence of a few drops of triethylamine. Distillation in vacuo of the resultant reaction mixture gave 23.7 g (63%) of the title compound; b.p.=116-118°C / 0.06 mm Hg.

The halohydroxylation method has been developed for exploiting the reactivity of the double bond present in the dialkyl vinyl-and propenylphosphonates. The preparation of the halohydrins of diethyl vinylphosphonate 21, which failed to be accomplished using Nbromosuccinimide or N-bromoacetamide, was achieved on large scale by treatment of diethyl vinylphosphonate 21 with sodium hypochlorite or hypobromite in aqueous medium at pH<3 to give the halohydrins 22 with the hydroxyl group in the β position (anti Markovnikoff addition) having a 95% purity for the chlorohydrin and a 65-85% purity for the bromohydrin (Scheme 9). 49 As a consequence of the acid conditions, the preparation of halohydrins 22 was generally accompanied by the formation of undesired diethyl 1,2-dihalogenophosphonates 23. Synthetic reactions, which result in the bromohydroxylation of the monoester of propenylphosphonate 50 with N-bromoacetamide in water at 15°C and in the chloro-or bromohydroxylation of the diacid with N-chloro-or bromosuccinimide, were particularly useful to provide in good conditions the two isomeric threo-halohydrins, which can be separated prior to epoxidation. For example, crystallization from acetone of the mixture of diastereomeric bromohydrins prepared by bromohydroxylation of the monoester of propenylphosphonate provided the preferred threo-bromohydrin in diastereomerically pure form. 50 A variety of procedures have been developed to effect the conversion of α-or β-hydroxy The phase transfert catalysis using the chlorohydrin 22 (X=Cl) of diethyl vinylphosphonate and concentrated (50%) sodium hydroxyde at room temperature has been found to be the method of choice for preparing the diethyl 1,2-epoxyethylphosphonate 24 (74%) on large scale (Scheme 9). 49 The methods using alkoxide anion or KOH in alcohol tend to be accompanied by important monodealkylation at carbon ester. The preferred threobromohydrin obtained from propenylphosphonic acid was converted to epoxide by reaction with MeONa in MeOH at 40°C. 50

halohydrins
Diethyl 1,2-epoxyethylphosphonate 48 . Method A : An ethanolic solution of 32 g of potassium hydroxide was added dropwise with stirring to a solution of the chlorohydrin (124 g) in ethanol (300 ml) at 4-6°C. Stirring was continued at room temperature for 10 h. The mixture was then filtered, concentrated, and distilled in vacuo; yield: 57.6 g (54%). Method B : An ethanolic solution of 19.2 g of sodium ethoxide was added dropwise with stirring to a solution of the chlorohydrin (60 g) in ethanol (300 ml) at 10-18°C. Stirring was continued at room temperature for 7 h. The mixture was then filtered, concentrated, and distilled in vacuo; yield: 28.6 g (56%). Method C : An aqueous solution of 10 g of potassium hydroxide was added dropwise with stirring to the chlorohydrin (30.5 g) at room temperature. Stirring was continued for 5 h. The mixture was then concentrated, extracted with ether, the ether distilled, and the residue distilled in vacuo; yield: 5.7 g (23%), b.p.=86-89°C / 2 mm Hg.

Oxidation of the tetraethyl ethenylidene-1,1-diphosphonate 25 with aqueous NaOCl gives directly the tetraethyl oxiranylidene-1,1-diphosphonate 26 via nucleophilic Michael βaddition of the hypochlorite anion followed by ring closure (Scheme 10). 51 Preparation of the tetrasodium salt 28 of the corresponding epoxide was accomplished in a two step process through the bromohydrin 27. The latter was prepared from 25 by treatment of the double bond with Br 2 / H 2 O, followed by ring closure by addition to a concentrated solution of NaOH. briefly to black; when the mixture again became yellow, more alkene was added in the same manner. After 10 min, addition of alkene was complete (10 g; 42 mmol) and the two phases were separated. The organic layer was treated with isopropanol (1 ml), then filtered through Celite, dried (MgSO 4 ), re-filtered, and evaporated under reduced pressure. The pale brown, oily residue was distilled under reduced pressure to give 7.49 g (71%) of the product as a colorless oil, b.p. 92-94°C (0.002 mm).

In the steroid field, 53 bromohydroxylation of the vinylphosphonate derived from cholestanone was carried out with bromine in aqueous acetic acid to afford a mixture of products containing the desired bromohydrin, which was converted to the epoxide by further treatment with MeONa in MeOH.

One ingenious procedure for the construction of a nucleoside epoxyphosphonate from a 1,2-dihydroxyalkylphosphonate exploits the properties of triflates, which serve as a good leaving groups (Scheme 12). 54 was added dropwise triflyl chloride (30 µl, 0.28 mmol) under N 2 . The reaction mixture was allowed to warm to r.t. over 1 h with stirring, and then poured into water (20 ml). After separation of the layers, the water phase was extracted with CH 2 Cl 2 (15 ml x 3), and the combined organic phase was washed with brine (20 ml x 2), and water (20 ml x 2) and then dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was purified by radial chromatography (CHCl 3 : MeOH, 95 : 5) to give the title compound (105 mg, 74%). The most attractive and potentially most general route for the synthesis of dialkyl 1,2-epoxyalkylphosphonates and its various α-and β-substituted analogs 6 appears to be the direct epoxidation of the corresponding dialkyl vinylphosphonates 36 (Scheme 13). The syntheses of dialkyl vinyphosphonates with essentially any desired combination of α and β substituents can be achieved readily by a number of procedures. 55 The use of vinylphosphonates offers appreciable advantages. Not only are the two isomeric unsaturated phosphonates formed when R 2 or R 3 ≠ H readily separable prior to cis-or trans-epoxidation of the appropriate isomer, but the use of these unsaturated intermediates permits an acidcatalyzed hydrolysis of the ester functions prior to epoxidation.

Scheme 13

In view of the relative weak electrophilicity of the double bond of vinylphosphonates and the tendencies of these compounds to undergo nucleophilic addition (Michael addition), epoxidations with either strongly electrophilic peracids or nucleophilic oxidants (akaline hydrogen peroxide and t-butylhydroperoxide) were experimented. Full utilization of peracids is often handicapped by the apparition of competing side reaction resulting in addition on the double bond or opening of epoxide ring. 56 For example, when a buffered trifluoroperacetic acid solution in CH 2 Cl 2 was used as oxidant, ring opening of the so formed epoxide could observed. The use of t-butylhydroperoxide in benzene with Triton B as catalyst has been shown to result in the Michael addition product of the butoxide to the olefin. 56 In a further example of a Mo(CO) 6 catalyzed reaction, t-butylhydroperoxide in 1,2-dichloroethane at reflux fails to react with diethyl 2-methyl-and 1-methylvinylphosphonate. 57 These disadvantages were overcome when these reagents were replaced by an alkaline hydrogen peroxide solution (30% solution) in alcohol. Alkaline hydroperoxide is recognized as the most common and perhaps most generally useful reagent for epoxidation of double bonds conjugated with electron-withdrawing groups. Although hydroperoxide has proved to be uneffective at pH 4.7 in the oxidation of diethyl 2-methyl-and 1-methylvinylphosphonate in the presence of Na

/ (R 1 O) 2 P O (R 1 O) 2 P O C C O C C R 4 R 2 R 3 R 4 R 2 R 3 36 6
NaHCO 3 / EtOH / rt, 2h. 61 The epoxidation of 25 (Scheme 10) was achieved very efficiently in 95% EtOH with the use of 30% aqueous H 2 O 2 and sodium bicarbonate for 2h at room temperature, instead of NaOCl, to give 26 as a pure product in excellent yield (93%). 61

Tetraethyl oxiranylidenebis(phosphonate) 61 : A solution of tetraethyl ethenylidene-1,1-bis(phosphonate) (1.510 g, 0.0050 mol), 30% aqueous H 2 O 2 (1 ml), and NaHCO 3 (0.424 g) in 95% EtOH (5 ml) was stirred at rt for 2 h, diluted with brine, and extracted twice with CH 2 Cl 2 . The combined organic extracts were dried (MgSO 4 ) and concentrated under reduced pressure to give the title compound as a clear, colorless oil (1.472 g, 0.00465 mol, 93%). A sample of the oil was distilled, b.p.=121-123°C (0.07 mm Hg).

Similarly, the dimethyl 3-oxo-1-cycloalkenylphosphonates Very recently, a variety of diethyl vinylphosphonates 36 (R 1 =Et) were oxidized in moderate to good yields (19-84%) using dioxirane generated in situ from buffered monopersulfate (oxone) and a ketone in a two-phase (CH 2 Cl 2 / H 2 O) reaction mixture. 62 On account of the pH dependence of the dioxirane stability, the process needs an acurate control of the pH at 7.4. However, the reaction is often very sluggish, requiring regular addition of fresh portions of oxone and lengthy reaction times.

Preparations of fosfomycin

Fosfomycin 39, formerly called phosphonomycin, is a low molecular weight antibiotic of unusual structure, which was originally isolated in 1969 from used culture medium of Streptomyces fradiae. 1,[START_REF] Horiguchi | In Biochemistry of Natural C-P Compounds[END_REF] The structure was established by NMR and IR, by MS of its dimethylester, and by direct comparison of the monobenzylammonium salt of the natural and synthetic products. 64 The absolute configuration was determined chemically as (-)(1R,2S)-(Z)-1,2-epoxypropylphosphonic acid. Fosfomycin is also produced by various species of Pseudomonas such as Pseudomonas syringae 65 or Pseudomonas viridiflava. 66 Fosfomycin is a broad spectrum antibiotic effective against both Gram-positive and Gram-negative infections in mammals, and its effectiveness is comparable with that of tetracycline or chloramphenicol. 67 The antibiotic irreversibly inactivates the uridine-5'-diphospho-Nacetylglucosamine-3-O-enolpyruvyltransferase (MurA), the enzyme which catalyzes the first committed step in cell wall biosynthesis. 68 The inactivation occurs through alkylation of a cysteine residue (Cys 115 of the enzyme from Escherichia coli ) in the active site of MurA. 68,69 The antibiotic, whose action has been investigated in depth 70 , can be administrated orally or by intravenous way and shows little toxicity to humans. Early reported works using isotope labelling techniques have shown that labelling of carbons C1 and C2 was provided by [1,6-14 C]glucose, which primarily labels C1, [2-14 C]glucose, which labels C2 and [2-14 C]acetate, which labels both C1 and C2 in equal amounts. 71 From these data, phosphoenolpyruvate was suggested as the most likely precursor of carbons C1 and C2 of fosfomycin. 71 More recently reported works have shown that when 1,1-dideuterio-2hydroxyethylphosphonic acid is fed to Streptomyces fradiae the deuterium is incorporated into the fosfomycin derived therefrom, via phosphonoacetaldehyde. 72 Fosfomycin is thought to be produced from phosphoenolpyruvate via phosphonopyruvate and phosphonoacetaldehyde through the addition of a one carbon species to the pro-(S) face of the carbonyl group. 73 Only the (S) form of 2-hydroxy-[2-2 H 1 ]ethylphosphonic acid was incorporated into the fosfomycin of Streptomyces fradiae. 74 Fosfomycin is present on the pharmaceutical market as the disodium, 75 calcium, [START_REF]Merck Index[END_REF] and tris(hydroxymethyl)ammonium salts. [START_REF][END_REF] The structure of the diester, monoester, disodium, calcium and phenethylammonium salts of fosfomycin have been studied by 1 H, 13 C, 31 P NMR, IR and Raman spectroscopy, and X-ray crystallography. 78 Presently a number of methods are available for its synthesis and we selected the more attractive ones. The first racemic synthesis of fosfomycin 39 described in 1969 was based on the oxidation of the (±) (Z)-1-propenylphosphonic acid 42 (Scheme 15). 64 The reaction was effectively achieved using an excess of H 2 O 2 (30% solution) at 60°C in the presence of Na 2 WO 4 as catalyst (2%) at pH 5.5. The (Z)-1-propenylphosphonic acid 42 was obtained by stereospecific reduction, with Lindlar catalyst, of the dibutyl 1-propynylphosphonate 40 into dibutyl (Z)-1-propenylphosphonate 41 followed by hydrolysis with concentrated hydrochloric acid of the ester functions. Optical resolution of the racemic (±) (Z)-1,2epoxypropylphosphonic acid to fosfomycin was accomplished by way of the quinine salt.

Scheme 15

Latter, the synthesis has been improved using the acid sensitive t-butyl alcohol as blocking group instead of n-butyl alcohol and propargyl alcohol instead of propyne. A sequence of reactions for the conversion of propargyl alcohol into (±) (Z)-1-propenylphosphonic acid, which proceeds in 81% overall yield via the alkadienylphosphonate has been developed (Scheme 16). 58,79 After rearrangement of the alkynylphosphite into alkadienylphosphonate 43 (Boisselle and Meinhardt rearrangement), 80 this one was selectively and stereospecifically hydrogenated in benzene with Pd/C, with hydrogen attacking only the terminal double bond of the allene moiety, to give the di-t-butyl (Z)-1-propenylphosphonate 44. The rapid removal of the two t-butyl groups was accomplished by refluxing the benzene solution with a strong acid catalyst. An elegant procedure was to use (Z)-1-propenylphosphonic acid as catalyst to avoid contaminating the product with a foreign acid. Removal of the solvent leaves (Z)-1propenylphosphonic acid 42 in 81% overall yield after five reactions in the same pot. Conversion of (±) (Z)-1-propenylphosphonic acid 42 to fosfomycin 39 was accomplished by using (+)-α-phenethylamine as resolving base in propanol, followed by treatment at pH of (+)-α-Phenethylammonium (-)-cis-1,2-epoxypropylphosphonate 58 : cis-Propenylphosphonic acid having C=C purity of 83% (148 g, 1.00 mol "pure") was dissolved in propanol (800 ml) . To the stirred solution was added (+)-α-phenethylamine (80.5 g, 0.665 mol), followed by enough triethylamine (56 g, 0.553 mol) to reach a pH of 5.8-5.9. The resulting warm solution was treated in one portion with sodium tungstate dihydrate (5.0 g, 0.015 mol) and disodium ethylenediaminetetraacetic acid (1.0 g) dissolved together in 15 ml of warm (65-70°C) water.

Hydrogen peroxide (1.53 mol, 157 ml of a 30% solution) was then added dropwise with stirring over a 15 min period while maintaining the temperature between 40 and 55°C. After the addition was complete, the reaction was kept at 50-55°C for 1 h to complete the epoxidation. The solution was then cooled to -5°C over a 30 min period to initiate crystallization. After stirring for 2 h at -5°C, the product was filtered and the cake washed with cold propanol (four 50 ml portions). This salt when dried weighed 106 g, and was about 92% optically pure. To complete the resolution, the salt was dissolved in 770 ml of hot (75-80°C) propanol. The slightly turbid solution was charcoal treated (2.5 g) and filtered while hot throgh a preheated funnel. To the hot filtrate was added 80 ml of warm (60-70°C) water. Crystallization of the monohydrate began within a few minutes. After stirring the mixture at 0°C for 2 h the product was filtered, washed with cold propanol (three 25 ml portions), and dried in vacuo at 45°C. The yield of phosphonomycin salt was 90.1 g (32.5%): m.p. 132-134°C (dec.).

An alternative synthesis of fosfomycin 39 has also been realized by the halohydrin route. 81 Treatment of (±) (Z)-1-propenylphosphonic acid 42 in aqueous solution with t-butyl-or sodium hypochlorite afforded threo-1-chloro-2-hydroxypropylphosphonic acid (85%).

Resolution was accomplished with (-) α-phenylethylamine to yield (+)-chlorohydrin (80%), which was converted to (-) fosfomycin 39 (85-90%) in 10 M aqueous sodium hydroxide.

With the aim in view to cover the access to fosfomycin, several important and attractive synthetic methods were reported in patents. They include, for example, precursors such as dimethyl hydroxymethylphosphonate, 82 dimethyl, dibenzyl, and diallyl formylphosphonate, 83 trimethylphosphite and 2-cyano-1-hydroxypropene, 84 trialkylphosphite and 2chloropropionaldehyde or 2-acetoxypropionaldehyde, 85 diethyl chloromethylphosphonate, 11 dibenzylphosphite and 1-chloro-1,2-propylene oxide, 86 propynylphosphonic acid, 87 propenylphosphonic acid, 88 2-chloro-(cis-1,2-epoxypropyl)phosphonic acid, 89 and extrusion reactions upon thermolysis. 90 The resolution of racemic acids has also been reported. 91 The first nonmicrobial asymmetric synthesis of fosfomycin 39 was based on the use of tartaric acid as a chiral auxiliary in directing an appropriate bifunctionalization of prochiral (Z)-1-propenylphosphonic acid (Scheme 17). 50 Thus, the reaction of (2S,3S)-tartaric acid derivatives with (Z)-1-propenylphosphonic dichloride 113 in CH 2 Cl 2 at -10°C gave rise to the cyclic phosphonates that after ring opening and crystallization afforded the monoesters (70%). The bromohydroxylation, carried out in water at 15°C under neutral or acidic conditions with N-bromoacetamide (NBA) is highly chemoselective, regiospecific and stereospecific providing threo-bromohydrins (1R,2S) and (1S,2R) in a 70:30 ratio with yields higher than 90%. Crystallization of the mixture of diastereomeric bromohydrins provided the preferred (1R,2S) in diastereomerically pure form. After elimination of tartaric acid, the threobromohydrin was easily converted to fosfomycin as the sodium salt 50 by reaction with MeONa in MeOH at 40°C for 3 h.

Scheme 17

(1R,2S)-(1,2-Epoxypropyl)phosphonic acid, disodium salt 50 : A solution of 46% aqueous HBr (26.5 ml) was added to a solution of 48 (5.69 g, 13.12 mmol) in water (26.5 ml). The solution was kept at 100°C for 16 h. The solvent was removed by distillation under reduced pressure. Ethyl acetate (285 ml) was added and the mixture was kept at reflux for 2 h, cooled to ambient temperature, and filtered. Evaporation of the solvent under reduced pressure gave a residue that was added to acetone. The precipitate was filtered off. Evaporation of the solvent under reduced pressure gave crude containing (1-bromo-2-hydroxypropyl)phosphonic acid 49 and tartaric acid. The crude 49, thus obtained, was dissolved in methanol (50 ml) and the solution was added dropwise at 40°C under nitrogen to a solution of sodium methoxide in methanol (5.55 M, ca. 15 ml), in such a way as to maintain the pH at 12.5-13. At complete conversion of 49, the reaction mixture was cooled to ambient temperature and filtered. The pH of the solution was brought to pH 9-10 with methanesulfonic acid. The mixture was concentrated under reduced pressure to half volume and filtered. Evaporation of the solvent under reduced pressure gave a residue (3.38 g) containing 63% w/w of the title compound (2.13 g, 11.7 mmol) as determined by HPLC. The residue was dissolved in methanol (18 ml) and added, under stirring at ambient temperature, to 2propanol (90 ml). Methanesulfonic acid (2.5 g, 26 mmol) was added to the suspension at 15°C. The mixture was kept at 15°C for 15 min and filtered. The solution was added at 15°C to a solution of sodium methoxide in methanol (5.55 M, 4.32 ml) and kept at 15°C for 2 h. The precipitate was filtered and dried at 50°C under reduced pressure to yield (1R,2S)-(1,2-epoxypropyl)phosphonic acid, disodium salt 50 (1.91 g, 10.5 mmol).

Me

C C O H P(ONa) 2 H Me C C H P(OH) 2 H O O Br O H Me C C H PCl 2 H O Me C C H P H O O O C O R C O R Me C C H P H O O H O C O R C O R O H Me C C H P H O O H O C O R C O R

2) resolution

Recently the conditions for a large scale synthesis of fosfomycin 39 based on the enantioselective formation of the (1R, 2S) threo-bromohydrin by enantioselective hydrogenation of prochiral β-ketophosphonates have been described (Scheme 18). 92 The starting racemic dimethyl α-bromo-β-ketophosphonate 51 was prepared by the reaction of dimethyl 2-oxopropylphosphonate with hydrogen bromide (8.8 M) and H 2 O 2 (30%) in THF at 25°C. Hydrogenation of a racemic α-substituted-β-ketophosphonate usually gives four possible stereoisomers. The lability of the α-stereogenic center allows for the stereoselective synthesis of a single isomer via dynamic kinetic resolution utilizing in situ stereoinversion.

The stereoinversion to hydrogenation of racemic α-bromo-β-ketophosphonate 51 depends on the determination of suitable stereochemical and kinetic parameters by computer-aided analysis of experimental conditions. In this way, the (S)-BINAP-Ru(II) complex formed in situ by simple heating of a mixture of [RuCl 2 (benzene)] 2 and (S)-BINAP in DMF acts as an excellent catalyst for the enantioselective hydrogenation of prochiral 51, leading to the dimethyl (1R,2S)-1-bromo-2-hydroxypropyl-phosphonate 52 in 98% ee and 84% yield. The reaction takes place smoothly in MeOH under 4 atm at 25°C during 100 h. With these conditions, a partial (15%) hydrogenolytic debromination was observed, which can be completely achieved using Pd/CaCO 3 -90% MeOH. The fosfomycin, as the sodium salt 50, can be obtained by acid-catalyzed hydrolysis of the hydrogenation product, followed by treatment with sodium hydroxide.

Scheme 18

Another recent asymmetric synthesis of fosfomycin was based on the formation of a protected 1,2-dihydroxyphosphonate by stereoselective addition of trimethylsilyl-dibenzylphosphite 54 to the (S)-triisopropylsilyloxylactaldehyde 53 at low temperature (Scheme 19). 93 The crude reaction mixture afforded the protected α-hydroxyphosphonates 55, which on reaction with methanesulfonyl chloride followed by flash chromatography gave the methanesulfonate 56.

The latter was treated with TBAF in THF with the aim to simultaneously deprotect the hydroxy group and to achieve the ring closure to give 57 as a single diastereoisomer (77%). After deprotection at phosphorus, fosfomycin was isolated as the sodium salt 50 in 76% yield. 51 52

Me P(OMe) 2 O O Br Me P(OMe) 2 O O H Br H 2 (S)-BINAP-Ru MeOH, 25°C (1R, 2S) (±)

Scheme 19

The oxidation of (Z)-propenylphosphonic acid 42 to fosfomycin 39 by a fermentation process has also been investigated. 94 Thus, it has been demonstrated that Penicillium spinolusum may be effectively employed to transform the biologically inactive (Z)-propenylphosphonic acid 42 into biologically active fosfomycin 39. At optimum levels of glucose, used as the carbon source, an epoxidation efficiency in olefin approaching 90% was obtained after 10 days of incubation at 28°C and at pH 5.6. It is not known if this reaction is involved in the biosynthesis of the antibiotic by Streptomyces. Moreover, the epoxidizing systems show substrate specificity since (E)-propenylphosphonic acid was not epoxidized.

Rearrangements of 1,2-epoxyalkylphosphonates

A variety of skeletal rearrangements of organophosphorus compounds involving migration of a phosphorus substituent are well established reactions. The ability of a phosphorus substituent to migrate from carbon to oxygen, 95 oxygen to carbon, 80,96 carbon to nitrogen, 97 nitrogen to carbon 98 and nitrogen to oxygen [START_REF] Sasse | Methoden der Organischen Chemie[END_REF] has been reported by several workers. The first example of thermal and acid-catalyzed shifts from carbon to carbon was reported in 1966. 13 It has been reported that diethyl 2,2-disubstituted-1,2-epoxyethylphosphonates 58 readily undergo specific rearrangement to yield, as a result of the phosphoryl group migration, diethyl 1,1-disubstituted-1-formylmethylphosphonate 59 (Scheme 20). The thermal specificity and hence applicability was limited to those substrates, which can rearrange at a temperature not exceeding 170°C (0.7 mm) and evidence for an efficient reaction was obtained in only one instance. 13 In other cases, the rearranged products were frequently unstable at the temperature (270-300°C, 0.6-0.7 mm) required for rearrangement and only the dephosphorylated aldehydes were isolated accompanied by polymeric material. The thermal technique has largely been supplanted in recent years by the use of Lewis acids, which are much more generally useful in this reaction. 13,14,17,56a,100-103 The preferred catalyst for this reaction was found to be boron trifluoride etherate (BF 3 . Et 2 O). Its use increases reaction rates and yields. Rearrangement of readily available diethyl 2,2disubstituted-1,2-epoxyethylphosphonates 58 to diethyl 1,1-disubstituted-1formylmethylphosphonates 59 can be effected on large scale in benzene or CH 2 Cl 2 at room temperature in few minutes. In every instance, only the carbonyl compound was isolated. It necessarely involved formation of a carbonium ion 60 and migration of the phosphoryl group rather than the hydrogen atom to the carbonium ion. The boron trifluoride-catalyzed rearragement of β-disubstituted epoxyphosphonates constitutes an expeditious route for the synthesis of diethyl 1-formylalkylphosphonates (Scheme 21), 102 and a large variety of 1,1disubstituted phosphonoacetaldehydes have been synthesized on preparative scale and in excellent yields from symmetrical or unsymmetrical ketones as outlined in Table 4. The preferred catalyst for this rearrangement was found to be BF . Et 2 O (3.6 g; 0.025 mol) in CH 2 Cl 2 (50 ml). After 30 min at 0°C the reaction mixture is kept for two hours at room temperature then tranferred in a separatory funnel and washed with an aqueous NaHCO 3 solution (3 x 20 ml) and water (20 ml). The organic layer is dried over sodium sulfate. After removal of the solvent under reduced pressure we obtained a colourless liquid purified by vacuum distillation: yield 72%, b.p. 112-114°C / 2 torr. 102 and consequently give a mixture of diethyl 1,1-disubstituted-1-formylphosphonates 62 (70%) and diethyl 1-hydroxyallylphosphonates 63 (30%).

(EtO) 2 P O C C O R 2 R 3 (EtO) 2 P O C C R 3 R 2 O H H 58 59 Δ (EtO) 2 P O C C O R 2 R 3 (EtO) 2 P O C C R 3 R 2 O H B F 3 .Et 2 O H (EtO) 2 P O C H C O R 2 R 3 + 0°C,

Scheme 22

The occurence of rearrangement being dependent upon the stability of the incipient carbonium ion at the β position, the unsubstituted dialkyl 1,2-epoxyphosphonates upon treatment with BF hydroxy-2-ethoxyethylphosphonates in 55-62% yields. 56a However, it has been reported, and proofs were given by means of mass spectrometry, that diethyl 1-methyl-1,2epoxyethylphosphonate 6c under conditions of acid-catalysis (BF 3 . Et 2 O or H 2 SO 4 ) was attacked at the α position by alcohols to give the diethyl 1-alkoxy-1-methyl-2hydroxyethylphosphonate. 104 An attractive procedure for the preparation of phosphorylated amino alcohols from 1,2epoxyphosphonates involves the oxirane ring opening by amines. The reaction follows the general pattern of nucleophilic attack at C2 established with electronegative substituents at C1. The structures of reaction products demonstrate that ring opening in 1,2epoxyphosphonates 6c and 24 was directionally specific and results of attack at C2 by ammonia or amines. Analysis of the isolated products failed to produce any information for production of isomers resulting from attack at C1. Thus, the 1-hydroxy-2aminoethylphosphonic acids 66 were obtained by reaction of diethyl 1,2epoxyethylphosphonate 24 or diethyl 1-methyl-1,2-epoxyethylphosphonate 6c with aqueous ammonia at 0°C for 24 h or amines at room temperature for 48 h, followed by acid hydrolysis (Scheme 24). 105 By contrast, ring opening of 24 with aniline was realized in 90% yield by heating at 120°C for 24h. 56a

Scheme 24

1-Hydroxy-1-methyl-2-N-benzylaminoethanephosphonic acid 105 : Equimolar mixture of diethyl 1,2-epoxy-1methylphosphonate and benzylamine (0.05 mol scale) was kept for 48 h at room temperature and the resulting mixture was hydrolyzed by refluxing in concentrated HCl for 7 h. The solution after hydrolysis was decolorized with carbon (when necessary), evaporated to dryness and the residue was dissolved in ethanol. Treatment with propylene oxide precipitated crude product, which was purified by crystallization from water-ethanol mixtures: yield 64.8%, m.p. 237-240°C.

The reaction of tetraethyl oxiranylidene-1,1-diphosphonate 26 with several primary amines, including n-propylamine, cyclohexylamine, benzylamine and allylamine has been examined. From the reaction of 26 and primary amines, the phosphinyl phosphates 67 were isolated as the major products in 40-63% yields (Scheme 25). 61 It seems very likely that the formation of 67 was the result of a rearrangement either in concert with (path a) or subsequent to opening of the epoxide with amine and generation of an intermediate alkoxide (path b). When di-n- propylamine was used, a second product, ethylidene-1-phosphinyl-1-phosphate, corresponding to the loss of the amine by elimination, was formed (32%) in addition to the phosphinyl phosphate (20% Under normal physiologic conditions, it is established that opening of fosfomycin can occur either at C2 or at C1. Thus, the inactivation of enzyme MurA by fosfomycin 39 occurs through alkylation by the thiol of a cysteine residue at C2 of the antibiotic in the active site of MurA. By contrast, the plasmid-mediated resistance to the antibiotic involves the reaction catalyzed by FosA 107 (fosfomycin-specific metalloglutathione transferase) of fosfomycin 39 with glutathione by attack of the thiol of glutathione at C1 of the antibiotic. The latter addition is somewhat surprising in that nucleophilic substitutions α to phosphoryl are difficult. Very recently it has been shown that L-cysteine can act as an alternative thiol substrate for FosA (Scheme 27). 108 The regiochemistry of the reaction was the same as that exhibited with normal substrate, glutathione, with addition of the nucleophile at the most hindered carbon, C1. The stereochemical course of the reaction was shown to occur with inversion of configuration at C1 of 39, suggesting that the enzyme catalyzes the reaction via an S N 2 or borderline S N 2 mechanism.

(EtO) 2 P O C C H 2 O (HO) 2 P O C C H 2 O H R 4 R 4 NH-R 5 1) H 2 N-R 5 R 4 = H, 24 R 4 = Me, 6c R 5 = H, Et, n-Pr, n-Bu, i-Bu, s-Bu, n-C 5 H 11 , i-C 5 H

Scheme 27

Treatment of diethyl 1,2-epoxyethylphosphonate 24 with an alkylmagnesiumbromide failed to result in the formation of the expected hydroxyalkylphosphonate. The oxirane ring was opened by reaction with magnesium bromide to yield the halohydrin, which was hydrolyzed to the glycol during product isolation. 56a The readily available diethyl 1,2-epoxyalkylphosphonates 69 have proved to be valuable synthetic intermediates. On treatment with sodium dialkylphosphites in ethanolic solution they undergo a rearrangement via an oxirane opening reaction. The sodium dialkylphosphite attacks on the β carbon atom of the epoxide ring to give unstable sodium α- FosA, Mn 2+ L-Cys 4 4

Scheme 28

Diethyl 2-oxopropylphosphonate 109 : To diethyl 1,2-epoxypropanephosphonate (19.4 g, 0.1 mol) an ethanol solution of sodium diethyl phosphite [0.1 mol, prepared from sodium (2.3 g) in ethanol (80 ml)] is added with stirring at 20°C. After the addition is completed, the reaction mixture is heated under reflux for 2-5 h. It is then hydrolysed by addition of water (50 ml). The aqueous solution is extracted with chloroform, the organic phases are combined, and dried with sodium sulfate. The organic solvent is removed under reduced pressure to give an oil, which is distilled in vacuo: yield 85%, b.p. 90°C / 0.1 torr.

The diisopropyl (E)-1,2-epoxy-3-oxoalkylphosphonates 72, which were easily prepared by epoxidation of the corresponding alkenyl compounds, underwent heterocyclisation with various 1,3-bidentate nucleophiles, such as ethyl 2-pyridylacetate, 2-aminopyridine, 2-aminopyrimidine, thiourea, and thiocarboxamides (Scheme 29) 59,110 to produce 73 and 74, arising from regioselective oxirane opening and subsequent dehydration. α-Metallated 1,2-epoxyethylphosphonate 111 75 can serve as precursor to higher homologues (Scheme 30). Reaction of diethyl 1,2-epoxyethylphosphonate 24 with LDA in THF at very low temperature resulted in deprotonation at the α position giving high yield of diethyl αlithioepoxy-ethylphosphonate 75, which can be captured under internal quench conditions by electrophiles R 4 X (R 4 =Me 3 Si, 91% and R 4 =Me, 57%), as illustrated by the obtention of 76.

Scheme 30

Diethyl 1-trimethylsilyl-1,2-epoxyethylphosphonate 111 : A solution of 1.08 g (6 mmol) of diethyl 1,2epoxyethylphosphonate and 1.14 ml (9 mmol) of chlorotrimethylsilane dissolved in 18 ml of THF, 4 ml of ether and 4 ml of hexane was cooled to -115°C and then treated with 8.3 mmol of lithium diisopropylamide in 6 ml of THF and 5 ml of hexane (generated from diisopropylamine (8.3 mmol) and 8.3 mmol of n-butyllithium in hexane) over 40 min. After an additional 15 min the solution was allowed to warm to 0°C and then quenched with 3 ml of water. The usual workup and the removal of volatiles under reduced pressure gave the crude trimethylsilyl derivative in 91% yield (1.85 g). Distillation yielded 1.72 g (84%) of title compound: b.p. 115-120°C (0.1 mm Hg).

When diethyl 1-methyl-1,2-epoxyethylphosphonate 19 (R 2 =R 3 =H, R 4 =Me) was subjected to the action of n-BuLi in excess in THF at low temperature for two hours, the 1-hydroxy-2methyl-2-hexene was obtained in 45% yield (Scheme 31). 112 This reaction has been extended to a variety of 1-or 2-substituted 1,2-epoxyphosphonates to give in each case the allylic alcohols 77 in low yields (15-32%) as a mixture of E and Z isomers.

Scheme 31

The reverse oxidation reaction of vinylphosphonates was also described. When dialkyl 1alkyl-1,2-epoxyethylphosphonates 6 were treated with an excess of thiourea in MeOH at reflux, dialkyl 1-alkylvinylphosphonates 79 were produced in generally good yields (Scheme 32). 42c

Conclusion

The 1,2-epoxyalkylphosphonates constitute a valuable class of phosphorus compounds. The popularity of these molecules emanates from their simplicity, access and efficiency. The fosfomycin phenomenon has largely contributed to their popularity. Fosfomycin is still present on the pharmaceutical market owing to several drugs, 114 such as Fosfocine ® , Monuril ® and Uridoz ® , employed in the treatment of acute cystisis. It has induced a systematic study of epoxidation reactions, resulting in various attempts to arrive at satisfying syntheses and to extend the family. Among the four classes of reaction, which resume almost all the ways of access to 1,2-epoxyphosphonates, the halohydrins and α,β unsaturated intermediates are the most efficient precursors in terms of stereoselectivity. Undoubtedly, significant progress have been achieved. However, the efforts being largely confined to fosfomycin or analogs, most of these investigations have captured the energy of chemists to the detriment of the search of new phosphonic structures containing the epoxide moiety. The prochiral vinylphosphonates of controlled geometry being easily available, it would be interesting to develop the asymmetric functionalization of these attractive intermediates by employing both the halohydrin and peroxide approaches with chiral ester substituents at phosphorus or chiral epoxidation reagents. The exploration of new mild epoxidation processes with the aim to introduce biologically active groups would be a useful improvement. Careful investigations of α-metallated epoxyalkyl-phosphonates may also afford some unusual compounds.

We are grateful to the Centre National de la Recherche Scientifique (CNRS) and Ecole Polytechnique for financial support to B. I.

(

54 :

 54 Scheme 12

2 . 4 .

 24 The direct epoxidation of α,β-unsaturated phosphonates

Figure 1

 1 Figure 1

Scheme 21 O

 21 Scheme 21

hydroxyphosphonates 70 ,

 70 which eliminate sodium diethylphosphite to produce the dialkyl 1formylethyl-(R 4 = H) or 2-oxoalkyl-(R 4 =Me) phosphonates 71 in 50-85% yield (Scheme 28

  Scheme 29

  Scheme 32

Table 1 .

 1 Synthesis of dialkyl 1,2-epoxyalkylphosphonates by the Darzens reaction.

	3	R 1	R 2	R 3	Base/Solvent	Yield (%) Ref.
	a	Et	Me	Me	n-BuLi/THF		6
					NaH/DMSO		16
	b	Et	Et	Et	n-BuLi/THF		6
	c	Et	i-Pr	i-Pr	n-BuLi/THF		6
	d	Et	Me	Et	n-BuLi/THF		6
	e	Et	Me	i-Pr	n-BuLi/THF		6
	f	Et	Me	t-Bu	n-BuLi/THF		6
	g	Et	Me	i-Bu	n-BuLi/THF		6
	h	Et	Me	CH CH 2	n-BuLi/THF		6
	i	Et	Me	C CH 2	n-BuLi/THF		6
				Me
	j	Et	Me	CH(OMe) 2	n-BuLi/THF		6
	k	Et	Me		n-BuLi/THF		6
	l	Et	Me		n-BuLi/THF		6
					NaH/DMSO	-	13
	m	Et	H	Me	n-BuLi/THF		6
	n	Et	H	i-Pr	n-BuLi/THF		6
	o	Et	H	i-Bu	n-BuLi/THF		6
	p	Et		-(CH 2 ) 4 -	n-BuLi/THF		6
	q	Me	Me	-(CH 2 ) 2 CH(Me) 2	EtONa/ether		5
	r	Et	H		EtONa/ether		5
					t-BuOK/t-BuOH		5
	s	Me	Me		EtONa/ether		5
					t-BuOK/t-BuOH		5
	t	Me	H		t-BuOK/t-BuOH		5
					EtONa/ether		5
	u	Et	H		t-BuOK/t-BuOH		5
					NaH/DMSO	-	13
	v	Me	Me	Me	NaH/DMSO	-	13

  Formation of the vinyl phosphate, epoxyphosphonate and phosphate halohydrin is believed to result from attack by the

	(EtO) 2 P	C H 2 Cl	Me 2 S	(EtO) 2 P	C H 2	+ SMe 2
	O	10			O	8
					2) MeCHO 1) MeS(O)CH 2 Na	(EtO) 2 P	C H CHMe
							O	O
								9
								R 4	Ph
	(MeO) 2 P O	C R 4 O	+	Ph 2 C N 2	(MeO) 2 P O	C C O	Ph
		10						11
	R 4 = Me, Ph, 4-MeO-C 6 H 4 , 4-Me-C 6 H 4 , 4-Cl-C 6 H 4 , 4-CN-C 6 H 4

Scheme 6 1-Méthyl-1,2-epoxyéthylphosphonate de diéthyle 24 : Dans

	un tricol de 500 ml muni d'une ampoule isobare,
	d'un agitateur, d'un thermomètre, et isolé de l'extérieur par un tube à CaCl 2 , on place 0,3 M de phosphite sodé en
	solution éthérée. On refroidit à -70°C à l'aide d'un mélange carboglace-acétone. On ajoute alors goutte à goutte
	une solution 0,3 M de chloracétone diluée dans son volume d'éther anhydre. On maintient le Dewar toute la nuit.
	Le lendemain matin, la température est de 30°C. On supprime le refroidissement, on laisse le mélange revenir
	progressivement à température ordinaire. On chauffe ensuite 2 h à reflux. La minéralisation qui devait se
	produire n'apparaît pas. La solution laiteuse est très difficile à centrifuger. On ajoute 150 ml de DMF et ayant
	placé une petite colonne, l'éther est distillé jusqu'à ce que la température atteigne 110°C. On adapte alors un
	réfrigérant ascendant, et cette température est maintenue pendant 1 h. Il se forme une importante minéralisation.
	Après refroidissement, on centrifuge, on chasse le DMF à la trompe et distille. Une rectification soignée donne
	E.b.=75°C / 0,6 mm Hg; Pds=35 g.

Table 2 .

 2 Synthesis

			of dialkyl 1,2-epoxyalkylphosphonates from sodium dialkylphosphites and
	α-haloketones.
	6	R 1	R 2	R 3	R 4	X	Yield (%)	Ref.
	a	Me	H	H	Me	Cl	74.4	45
	b	Me	C 6 H 5	H	C 6 H 5	Cl	-	14
	c	Me	C 6 H 5	H	4-MeO-C 6 H 4	Cl	-	14
	d	Et	H	H	C 6 H 5	Cl	56	23

Table 3 .

 3 Synthesis

		of dialkyl 1,2-epoxyphosphonates from dialkylphosphites,
	α-chloroketones and sodium methoxide.
	6	R 1	R 2	R 3	R 4	Yield (%) Ref.
	a	Me	H	H	Me	84	37
	e	Et	H	H	Me	83	37
	p	C 6 H 5 CH 2	H	H	Me	48	37

  into 1,2-epoxyalkylphosphonates (NaH / THF; 49 KOH / THF; 49 EtO -/ EtOH; 49 KOH / EtOH; 19,46,47,49 K 2 CO 3 / MeOH or EtOH; 49 NaOH / CH 2 Cl 2 / TBAS 49 ). Generally, bromohydrinphosphonates give better results than corresponding chlorohydrinphosphonates.

  Oxidation of the methylidene double bond in triethyl α-phosphonoacrylate 29 has been investigated in details using O 2 , catalytic RuO 4 (made in situ from RuO 2 / NaOCl or RuO 2 / NaIO 4 ) or stoichiometric RuO 4 (Scheme 11).

	(EtO) 2 P		P(OEt) 2	NaOCl / H 2 O	(EtO) 2 P	P(OEt) 2 O
	O	25	O				O	26	O
			1) TMBS, NaOH / MeOH
			2) Br 2 / H 2 O
				O H
										O
	(NaO) 2 P	Br	P(ONa) 2	NaOH	(NaO) 2 P	P(ONa) 2
		O		O					O	O
			27						28
	Scheme 10
						NaOCl+/-RuO 2 H 2 O/CCl 4	(EtO) 2	P O	O O C	OEt
										30
	(EtO) 2	P		C	OEt
		O	29	O		H 2 O/CHCl 3 NaIO 4 /RuO 2	(EtO) 2	P O	O H C O H	O C	OEt
										31

52

Treatment of triethyl α-phosphonoacrylate 29 on large scale in a two-phase (CCl 4 / H 2 O) reaction mixture with catalytic RuO 4 using NaOCl as co-oxidant or with NaOCl alone at room temperature produces triethyl αphosphonoacrylate oxide 30 in up to 79% isolated yield. As above, epoxidation of the double bond would begin with nucleophilic addition of the ClOfollowed by ring closure. When NaOCl was replaced with NaIO 4 as the RuO 2 reoxidant in a two-phase (CHCl 3 / H 2 O) reaction mixture, the major product in the aqueous phase was the triethyl dihydroxyphosphonoacetate 31, the hydrate of triethyl oxophosphonoacetate.

Scheme 11

dl-Triethyl α-phosphonoacrylate oxide 52 : A 1 l flask was charged with CCl 4 (altenatively, CHCl 3 ) (250 ml) and 5.25% sodium hypochlorite solution (400 ml; 282 mmol). RuO 2 (11 mg; 0.08 mmol) was added, and observed to immediately oxidize to RuO 4 (yellow organic phase). A small portion of triethyl α-phosphonoacrylate was added with vigorous shaking, causing the color of the reaction mixture to change

  2 WO 4 at 55-60°C without solvent, the hydroperoxide in alcoholic solution at more basic pH appears to have a great synthetic utility in the epoxidation of phosphonate diesters or diacids having electron-withdrawing groups. Several oxidizing systems have been developed with success including H 2 O 2 / Na 2 WO 4 / NEt 3 / n-PrOH / pH 5.8-5.9 / 40-55°C, 1h; 58 H 2 O 2 / Na 2 CO 3 / MeOH / 15°C, 3-12h; 59 H 2 O 2 / NaOH / MeOH / rt, 1h; 60 H 2 O 2

  -5.9 with H 2 O 2 in the presence of Na 2 WO 4 at 50-55°C. A single recrystallization from aqueous propanol afforded fosfomycin salt of 100% optical purity.

	C C O S R 39 5.8Scheme 16 H Me	H P O	O H O H
	Cl Me	P(OBu) 2 O + C CMgBr		C 6 H 6 /THF	Me	40 C C P(OBu) 2 O	H 2 Lindlar
	Me H	C C 41	H P(OBu) 2 HCl O	H Me	C C 42	H P(OH) 2 O	1) H 2 O 2 2) resolution	Me H	C C O 39	H P(OH) 2 O

  3 . Et 2 O since diethyl 2,2disubstituted-1,2-epoxymethylphosphonates 58 on treatment with other Lewis acids such as SnCl 4 , SnBr 2 , ZnCl 2 , ZnBr 2 , or TaF 5 in C 6 H 6 or CH 2 Cl 2 gave mixture of products in which 59 was the major compound.

Table 4 .

 4 Synthesis of diethyl 1,1-dialkyl-1-formylmethylphosphonates

	CH 2 Cl 2
	58	60
		59

  3 . Et 2 O undergo ring opening without rearrangement. From the results of the rearrangement studies, the following order of migratory aptitudes has been established 17 : panisyl > p-tolyl > phenyl ≥ (RO) 2 P(O) > H > alkyl. For example, 1,2-epoxyphosphonates substituted in the α-and β-position with aryl groups give on treatment with BF 3 . Et 2 O a mixture of α-and β-ketophosphonates.

	Whereas the α-halohydrinphosphonates were converted to 1,2-epoxyphosphonates by
	treatment with base, the corresponding β-halohydrinphosphonates 64 rearranged
	instantaneously in the presence of aqueous sodium bicarbonate and slowly in water alone to
	give the 1-formylethyl-phosphonic acid 65 (Scheme 23). 81
	(HO) 2 P O	C C H O H Me X	H	NaHCO 3 H 2 O	(HO) 2 P O	C H C O X Me	H
		64						Me	H
	X = Cl, Br				(HO) 2 P O	C H C 65	O
	Scheme 23
	5. Reactions of 1,2-epoxyalkylphosphonates
	Most of the applications of dialkyl 1,2-epoxyalkylphosphonates are based on the ring opening
	reactions with nucleophiles, which provide a convenient method for incorporating functional
	group into the molecule. Generally, the openings of the oxirane ring are directionally specific
	at the C2 carbon and in unusual instance was evidence obtained for the formation of the
	isomeric products resulting from attack of nucleophile at the C1 carbon. Nucleophilic addition
	in α position to the phosphoryl group is generally difficult due to both steric and electronic
	O factors. The formation of α,β-difunctionalized alkylphosphonates was achieved readily by H B F 3. Et 2 O both acid-catalyzed and non-catalyzed openings of the oxirane ring. Preferred nucleophiles (EtO) 2 P C 0°C, CH 2 Cl 2 ( ) n are water, alcohols, phenols, aqueous ammonia, amines and phosphites. Treatment of diethyl O (EtO) 2 P + ( ) n (EtO) 2 P C n = 1-3 61 1,2-epoxyethylphosphonate 24 with aqueous H 2 SO 4 at reflux leads to the formation of the H ( ) n 1,2-dihydroxyethylphosphonate (55%). 56a
	O Diethyl 1,2-dihydroxyethylphosphonate 56a : A solution of 3 g of epoxide diethyl 1,2-epoxyethylphosphonate in C H O O O H
	62 25 ml of water containing 6 drops of concentrated H 2 SO 4 was refluxed for 2.5 h, allowed to cool to room 63 temperature, and adjusted to pH 7.0 by addition of aqueous sodium bicarbonate. The solution was concentrated
	under reduced pressure to yield a thick liquid, which was extracted with CHCl 3 . The CHCl 3 extracts were dried
	(MgSO 4 ) and concentrated to give a residue, which was distilled to yield the product. b.p.=140°C / 0.3 mmHg,
	55%.
	The opening of the epoxide with MeOH or EtOH containing H 2 SO 4 resulted from attack of
	nucleophile at the β carbon to give the two glycol monoethers, 1-hydroxy-2-methoxy or 1-

  ). Exposed to hydrolytic conditions at different pH (2, 6, 10), 26 reacts with water very slowly.61

						O
			path b	(EtO) 2 P		O	path b
						(EtO) 2 P		H 2 N R 5
	(EtO) 2 P O	a	O	b	O	path a	O (EtO) 2 P	O
	(EtO) 2 P O	26	H 2 N R 5	O			(EtO) 2 P O	H 2 N R 5
					(EtO) 2 P	O
						(EtO) 2 P	H N R 5
						O	67
	Scheme 25
	Phosphoric acid, 1-(diethoxyphosphinyl)-2-(2-propen-1-ylamino)ethyl diethyl ester 61 : A solution of
	allylamine (2.855 g, 0.05 mol) and tetraethyl oxiranylidenebis(phosphonate) (3.00 g, 0.0095 mol) in methanol
	(20 ml) was cooled to 0-5°C by means of an ice-water bath. The mixture was stirred while the low temperature
	bath came to r.t. and then stirring was continued overnight at r.t. TLC (10% of a 10% NH 3 /CH 3 OH solution in
	CH 2 Cl 2 ) indicated that starting material was consumed. The solvent and excess of allylamine were removed in
	vacuo to give 3.621 g of crude material from which 1.025 g was chromatographed (flash, 160 g, 0.0403-0.063
	mm silica gel, 4 cm wide, 20-30% acetone in CH 2 Cl 2 ) to give the title compound (0.635 g, 63% overall yield) as
	a clear oil.
	Fosfomycin 39 on treatment with saturated aqueous ammonia for 3 days at 55-60°C gives as
	major component the (-) (1R,2R)-(2-amino-1-hydroxypropyl)phosphonic acid 68 resulting
	from preferential attack of nucleophile at the C2 carbon (Scheme 26). 72,106 Similarly,
	treatment of 39 on an acid Dowex 50 column with 0.1N H 2 SO 4 delivers the corresponding
	diol. 72
	H M e	C C O	H P(OH) 2 N H 3 H 2 O	H 2 N M e H		H O H P(O)(OH) 2	+	H H O M e	N H 2 H P(O)(OH) 2
		39		O		58%	68	23%
	Scheme 26

  1) Hendlin, D.; Stapley, E. O.; Jackson, M.; Wallick, H.; Miller, A. K.; Wolf, F. J.; Miller, T. W.; Chaier, L.; Kahan, F. M.; Foltz, E. L.; Woodruff, H. B.; Mata, J. M.; Hernandez, S.; Mochales, S. Science 1969, 166, 122-123.

Chaiet, L.; Miller, T. W.; Goegelman, R. T.; Kempf, A. J.; Wolf, F. J. J. Antibiotics 1970,

23, 336-347.

1-Chloro-2-hydroxyéthylphosphonate de diéthyle49 : Dans un erlenmeyer muni d'une vive agitation magnétique, on place 0,1 mole de diéthyl vinylphosphonate dissous dans 700 ml d'eau. La solution est portée à un pH <3 par addition d'HCl concentré (d=1,19). On ajoute alors par petites portions (~15 ml) la solution d'hypochlorite de sodium, tout en maintenant le pH de la solution ≤3 par addition simultanée d'HCl concentré. La réaction est considérée comme terminée lorsque le test à l'IK est positif après 15 mn d'attente après la dernière addition de NaOCl. (test à l'iodure de potassium dans un tube à essai, verser 1 ml du milieu réactionnel et 1 ml d'une solution à 10% d'IK. L'apparition d'une coloration jaune-brun atteste la présence d'acide hypohalogéneux). La quantité habituelle d'hypochlorite de sodium additionnée est de l'ordre de 50 à 55 ml et celle de HCl environ 10 ml. Une fois l'addition de NaOCl terminée, le milieu est extrait par 6 x 50 ml de CH 2 Cl 2 et 100 ml de CHCl 3 . Les phases organiques sont rassemblées et séchées sur Na 2 SO 4 anhydre. Après évaporation des solvants, le résidu est distillé sous vide de la pompe. Le distillat est identifié comme un mélange des composés 22 et 23. 22: Eb.=105-108°C / 0,05 mmHg; Rdt=86%. 23: Eb.=92°C / 0,05 mmHg.

Biographical Sketches


Bogdan Iorga

Duncan Carmichael

Philippe Savignac
email: savignac@poly.polytechnique.fr

Phosphonate-Phosphonochloridate Conversion

This review deals with the phosphonate-phosphonochloridate conversion. The different phosphorus-chlorine bond forming reagents (COCl 2 , (COCl) 2 , SOCl 2 , PCl 5 , POCl 3 , Ph 3 PCl 2 , trichloro(o-phenylenedioxy)phosphorane) and the reaction conditions which they impose are considered. Phosphonates / Phosphonochloridates / Chlorinating Agents Version française abrégée -Conversion des dialkyl alkylphosphonates en alkyl chloroalkylphosphonates. La transformation des alkylphosphonates en chloroalkylphosphonates est une réaction très utile en chimie du phosphore. Les chloroalkylphosphonates sont de précieux intermédiaires dans la préparation de dérivés phosphorés plus élaborés tels que, fluoroalkylphosphonates, diesters mixtes, phosphoramideester, thiophosphonates et phosphinates. Plusieurs agents de chloration ont été introduits pour réaliser cette transformation: le phosgène, COCl 2 , le chlorure d'oxalyle, (COCl) 2 , le chlorure de thionyle, SOCl 2 , le pentachlorure de phosphore, PCl 5 , l'oxychlorure de phosphore, POCl 3 , Ph 3 PCl 2 et le trichloro(ο-phenylenedioxy)phosphorane. Les avantages et inconvénients de chaque réactif sont examinés en fonction des critères suivants: disponibilité, efficacité, tolérance, conditions d'emploi, solvant, température, nature des sous-produits. Trois réactifs se détachent, le chlorure d'oxalyle, le pentachlorure et l'oxychlorure de phosphore. Ils réalisent la transformation alkylphosphonates-chloroalkylphosphonates avec efficacité dans des conditions non destructrices et avec des phosphonates d'une grande variété structurale.

Phosphonates / Chlorophosphonates / Agents de Chloration

The reaction conditions for direct substitution of an alkoxy group by nucleophiles (alcohols, phenols, amines, Grignard reagents) in dialkyl alkylphosphonates 1 are sufficiently drastic that this method is not currently used. Procedures which involve the intermediacy of the highly reactive alkyl alkylphosphonochloridates 2 appear to have greater synthetic utility. For this reason, there has been significant interest in developing efficient procedures for Before considering the different phosphorus-chlorine bond-forming reagents and the reaction conditions which they impose, it seems appropriate to briefly review the processes described for preparing alkyl alkylphosphonochloridates 2 from alcohols and alkylphosphonic dichlorides 10. The difficulties associated with these syntheses illustrate the importance of the phosphonate-phosphonochloridate conversion.

The preparation of alkyl alkylphosphonochloridates 2 from alkylphosphonic dichlorides 10 by selective alcoholysis (1 eq.) of only one phosphorus-chlorine bond presents certain difficulties. [48][49][50][51][52][53] The reaction is generally too rapid to allow selective mono esterification and experiments have confirmed that alkyl alkylphosphonochloridates 2 are at least as reactive than the starting alkylphosphonic dichlorides 10. Additionally, many other factors including the nature of alcohols, primary or secondary, hindered or not, the nature of tertiary amine, the solvent and the reaction temperature all influence the degree of the mono esterification at phosphorus. The effect of catalytic amount of base has been investigated and neither imidazole or pyridine have an effect on the ease or course of the reaction. By contrast,

P O R R 1 O HO P O R R 1 O Cl P O R R 1 O R 2 O P O R R 1 O (R 2 ) 2 N P O R R 1 O F P O R R 1 O R 2 P O R R 1 O ArO P O R R 1 O R 1 O 1 2 4 5 6 7 9 3 P O R R 1 O R 2 S
a catalytic amount of 1H-tetrazole was found to increase the rate of alcoholysis in the same way for primary or secondary alcohols and hindered alcohols such as menthol or testosterone. [53] Under these conditions the mixed diesters 5 can be obtained almost exclusively via alkyl alkylphosphonochloridates 2 (Scheme 2) and the formation of symmetrical diesters 5 (R 1 = R 2 ) was reduced to negligible amounts. 1H-tetrazole enhances the reactivity of the phosphonic dichloride 10, probably by nucleophilic catalysis, but apparently less effectively catalyses reaction of the alkyl alkylphosphonochloridates 2, perhaps due to increased steric requirements. The alkylphosphonic dichloride route, however, suffers from another drawback in that the synthesis of the starting materials 10 is restricted to compounds bearing a non sensitive R functionality bound to phosphorus (R = alkyl or aryl).

Scheme 2.

Another approach to alkyl alkylphosphonochloridates 2 exploits the Kinnear-Perren procedure. Early preparations of alkylphosphonic dichlorides This reaction sequence permits a simple one-pot conversion of PCl 3 into the readily obtained complexes 11 with subsequent transformation into the alkyl alkylphosphonochloridates 2 (R = Me, Et, i-Pr) in acceptable yields (32-79%) (Scheme 3). Unfortunately, the potential of this procedure is often handicapped by the sensitivity of the substrates R to the highly acidic reaction conditions and the method appears to have limited synthetic potential. Other more straightforward reaction systems are needed and the phosphonatephosphonochloridate conversion methodology appears to offer a more direct and facile approach to alkyl alkylphosphonochloridates 2 bearing widely varied, functionalised alkyl appendages.

+ P O R Cl Cl P O R R 1 O Cl R 1 OH P O R R 1 O R 2 O R 2 OH 1H-tetrazole i-Pr 2 NEt

Carbonyl chloride, (phosgene), COCl 2

At the beginning of the 1960's most investigations of the reaction of dialkyl alkylphosphonates 1 with phosgene were directed towards the preparation of products having potent anticholinesterase properties (pesticides, chemical warfare agents). Several alkyl

RP(O)OR 1 AlCl 4 R 1 OH R 1 OH P O R R 1 O Cl H 2 O 1 1 1 2 2 RPCl 3 AlCl 4 RP(O)Cl AlCl 4 + + + - - - P O R MeO MeO P O R MeO Cl P O R HO R 1 O NaOH P O R R 2 O R 1 O "Cl -" P O R MeO HO P O R MeO R 1 O P O R Cl R 1 O "Cl -" NaOH R 1 OH R 2 OH 13 2
alkylphosphonochloridates 2 were prepared by simply bubbling dried phosgene through neat dialkyl alkylphosphonates 1, at a temperature below 25°C for relatively long periods (10 to 24 h). [61,62] Scheme 5.

To isolate a pure product cleanly the dialkyl alkylphosphonates 1 must be transformed completely into the target alkyl alkylphosphonochloridates 2; separation by fractional distillation is difficult because the two compounds have very similar boiling points. Several variations on the preparation of isopropyl alkylphosphonochloridates 2 (R 1 = i-Pr) from diisopropyl alkylphosphonates 1 (R 1 = i-Pr) and phosgene have been reported. [63] The best yields are obtained when the R alkyl group has no more than three carbom atoms. Thus, when R = Me, Et, n-Pr, reactions were complete in 24 h and gave uniformly high yields (90%) of pure distilled product. The use of longer chain or more hindered alkyl groups, R = i-Pr, n-Bu, i-Bu, s-Bu, n-C 5 H 11 , implies longer reaction time (four days) and lower yields (26-70%). An influence of the ester group (R 1 = Et, n-Pr, i-Pr, n-Bu, n-C 5 H 11 ) has also been observed with several derivatives containing a methyl group bounded to phosphorus. [62] All the corresponding alkyl methylphosphonochloridates 2 (R = Me) were isolated with roughly comparable yields and considered as sufficiently pure to be used without distillation. This chlorination method appears to be fairly general and has been used for the large-scale synthesis of isopropyl methylphosphonochloridate 15, an intermediate in the synthesis of isopropyl methylphosphonofluoridate (Sarin), in 91% distilled yield from the reaction of diisopropyl methylphosphonate 14 with phosgene (Scheme 6). [START_REF] Bryant | [END_REF] Generally, this method allows alkylphosphonochloridates 2 to be isolated in sufficiently pure form to be used without distillation because the only by-products are one equivalent of alkyl chloride R 1 Cl and carbon dioxide. Hence, phosgene cleanly and specifically removes only one ester group to give the alkylphosphonochloridates 2 from the corresponding phosphonates. However, the reaction

+ P O R R 1 O R 1 O P O R R 1 O Cl COCl 2 -CO 2 neat 1 2 20-30°C -R 1 Cl
has been limited to phosphonates containing R alkyl groups and is relatively slow, so it has not been frequently used. Furthermore, the use of phosgene, which requires sophisticated equipment and great care, is strictly controlled in many countries.

Scheme 6

It seems clear that the reaction occurs by a succession of nucleophilic displacement from a preliminary attack by the phosphoryl oxygen atom, which is the more nucleophilic centre, on the phosgene carbonyl group. After, it was not possible to make a definite decision between the two mechanisms involving either attack at phosphorus or attack on an ester group.

However, the first mechanism has appeared as the more probable pathway (Scheme 7). The reaction then evolves by loss of chloroformate ion which rapidly decomposes into carbon dioxide. The final stage of the reaction, which involves the removal of an alkyl group from the quasi-phosphonium intermediate, is similar to the last stage of the Michaelis-Arbuzov reaction. [64] The relative reactivity of a series of phosphoryl oxygen atom has been shown to be: R

P O R R 1 O R 1 O P O R R 1 O R 1 O + COCl 2 C O Cl + P O R R 1 O Cl + P Cl R R 1 O R 1 O -CO 2 -R 1 Cl -Cl - Scheme 8.
In contrast, the corresponding thiolate esters, such as the diethyl methylphosphonothiolate 17, react with carbonyl chloride to give the S-ethyl methylphosphonochloridothiolate 18 and carbon dioxide in good yield (Scheme 9). [65] Scheme 9.

Oxalyl chloride, (COCl) 2

In the search for a more user-friendly reagent, oxalyl chloride has been introduced as an The trimethylsilyl ester of the phosphorus analogue of protected 3-deoxy-β-D-mannooctulopyranosonic acid (β-Kdo) has been found to react smoothly with oxalyl chloride to produce the corresponding phosphonochloridate 24. In this one-pot reaction sequence, the ethyl ester of the phosphorus analogue of protected 3-deoxy-β-D-manno-octulopyranosonic acid 22 was first converted into the silyl ester 23, by reaction with bromotrimethylsilane at 50°C for 2.5 h, then treated overnight at room temperature with oxalyl chloride in the

P O R R 1 O R 1 O P O R R 1 O Cl + (COCl) 2 , r.t.
-CO 2 -CO -R

Thionyl chloride, SOCl 2

The reaction of dialkyl alkylphosphonates 1 with thionyl chloride to give the alkyl alkylphosphonochloridates 2, generally requires heating, with the thionyl chloride being used as solvent and reagent (Scheme 14). [66,78] A variation using benzene as the solvent has also been reported. [66] In spite of heating the chlorination of diakyl alkylphosphonates 1 stops at the half-ester. However, some sensitive akylphosphonochloridates 2 do not survive the necessary reaction conditions, and polymeric mixtures frequently result, thereby excluding this conversion for synthetic purposes.

Scheme 14.

This method, having only limited utility for the synthesis of alkylphosphonochloridates 2, has found applications in the transformation of dialkyl alkylphosphonates 1 into alkylphosphonic dichlorides 10 (R = Me, Et, CH 2 CH 2 Cl, n-C 12 H 25 ), provided that excess of thionyl chloride, prolonged reaction time and suitable catalysts such as DMF, N-formylpyrrolidine or Nformylpiperidine are used. [START_REF] Maier | Phosphorus[END_REF] Phosphorus pentachloride, PCl 5

Historically, phosphorus pentachloride was the first halogenating reagent to be introduced in phosphonate chemistry. It is the most frequently used and most widely known chlorinating reagent and undoubtedly PCl 5 has several advantages. Treatment of phosphonates with this reagent gives a rather rapid reaction with removal of only one of the ester groups. However, whilst removal of the second ester group is difficult, the treatment can proceed too far to give the dichloridate. Thus, the major difficulty in this reaction often arises from the formation of mixtures containing phosphonochloridates and dichloridates. Only two of the chlorides of PCl 5 are used in this conversion, so this difficulty is overcome when the chlorinating agent and the phosphonates 1 are used in stoichiometric amounts with reaction temperatures held between 30-35°C. However, when PCl 5 is introduced in excess, it can be destroyed by bubbling SO 2 into the reaction mixture. [16,17,21,37,[80][81][82] The role played by reaction solvents is important in progressively solubilising solid PCl 5 as the reaction evolves. For example, CCl 4 , in which PCl 5 is soluble, is the most convenient and more frequently used solvent (Scheme 15); [9,10,12,[17][18][19][24][25][26]28,29,31,37,41,[83][84][85][86] benzene and toluene are

+ P O R R 1 O R 1 O P O R R 1 O Cl SOCl 2 1 2 -SO 2 -R 1 Cl
also frequently employed [14,15,23,27,[32][33][34]39,40,43,87] but CH 2 Cl 2 and CHCl 3 are used more rarely. [11,16,22,36,38,42] The chlorination has been also described in the absence of solvent. [5][6][7][8]13,20,21,80,81,[88][89][90] In that case the reagents are mixed then heated for about 4 h at temperatures between 60 and 90°C, but yields are a little lower and less predictable. No important variations have been made with the ester groups which are invariably methyl or ethyl groups, scarcely higher homologues, and sometimes benzyl groups. [34] The use of cyclic esters has also been reported. The reaction of 2-butoxymethyl-4-methyl-2-oxo-1,3,2dioxaphospholane with solid PCl 5 in benzene goes exothermically and leads to the phosphonochloridate in 81% yield by spontaneous opening of the dioxaphospholane ring.

[82] The R groups bound to phosphorus are represented by alkyl, [9,[13][14][15]18,34,[38][39][40]42,84,85,88] aryl, [32] benzyl, [16,26,28,36,43] norbornyl, [87] halogenoalkyl, [8,12,22,24,31,41,83],vinyl, [11,37,42] phtalimido-methyl [23,30] andethyl, [27,33,35] phosphonoethyl, [19] formic,[

and butanoic [29] esters, ethyl- [25] and benzylisocyanate, [7] enamides [90] and alcoxymethyl. [6,82] Also formed in this reaction are an equivalent of the corresponding alkyl chloride and phosphorus oxychloride.

Scheme 15.

The best yields, between 70 and 95%, are generally obtained by working in CCl 4 with one equivalent of PCl 5 for one equivalent of phosphonate. The reaction is initiated at 30-35°C during the addition of PCl 5 , then heated at reflux (from 1 to 5 h) to complete the reaction (Scheme 16). The use of benzene also requires heating at reflux for few hours and the yields are roughly comparable to those obtained with CCl 4 ( 80 to 90%). In these conditions, the reaction generally proceeds in good yields and generates the expected phosphonochloridate.

For example, the symmetrical dichloride of the diethyl ester of ethylene-1,2-diphosphonic

+ P O R R 1 O R 1 O P O R R

Scheme 17.

A relatively general procedure for the conversion of diethyl alkylphosphonates 1 (R 1 = Et) to alkylphosphonochloridates 2, in yields ranging from 38 to 86%, has been developed from POCl 3 and the method has been applied to a large variety of substrates whose R groups comprise alkyl, halogenoalkyl, benzyl, alkenyl, alkynyl and carboxyl groups. In a typical reaction, diethyl 1-propynylphosphonate 31 (1 eq.) was mixed with an excess of freshly purified POCl 3 (1.5 eq.) and heated at 70-80°C for 3-4 h, to cleanly give ethyl 1-

+ P O R R 1 O R 1 O P O R R 1 O Cl POCl 3 + PCl 2 O R 1 O 70°C neat 1 2 3
P O R R 1 O R 1 O P O R R 1 O Cl (C 6 H 5 ) 3 PCl 2 + + R 1 Cl + (C 6 H 5 ) 3 PO CHCl 3 r.t. 1 2 3 3
ethyl diphenylphosphonite in toluene. The ensuing Michaelis-Arbuzov reaction results in the formation of a polymer-linked diphenylphosphine oxide which may be converted to the tertiary phosphine dichloride by treatment with phosgene. Using one equivalent amount of the polymer reagent in chloroform solution, conversions of 76% and 97% were found for various dimethyl alkylphosphonates after 4 h. Once more, the method suffers from the difficulties encountered in separating the product alkylphosphonochloridate 2 from the o-phenylene chlorophosphate 36 by-product. Whilst this may be achieved by fractional distillation, the difference in boiling points is relatively small and a mixture of products may be obtained. The general synthetic utility of phosphorane 35

remains to be demonstrated.

Conclusion

Three chlorinating reagents, (COCl) 2 , PCl 5 and POCl 3 , appear particularly valuable for the phosphonate-phosphonochloridate conversion. Oxalyl chloride is clearly preferable to phosgene, whose desirability in purely chemical terms is compromised by practical difficulties when working at higher tempetatures and by its very high toxicity. The versatility of PCl 5 is well documented and it seems likely that this reagent will continue to find applications. Whilst phosphoryl chloride has not been widely employed to date, it seems to have great potential and may eventually become the reagent of choice for this conversion.

2 .[ 1 - 3 ]thiolophosphonates 8 [ 13 , 15 , 37 , 38 ]

 213813153738 Scheme 1.

  Scheme 3.Another methodology commonly used for the synthesis of alkyl alkylphosphonochloridates 2 involves the selective esterification of phosphonic acids as summarized in Scheme 4. Starting from a dimethyl alkylphosphonate 13, it proceeds by sequential alkaline hydrolysis, chlorination and esterification to produce mixed diesters 5 via the monoesters 2.[57][58][59][60]

  alternative to phosgene. It shows similar reactivity and, being a liquid reagent and more practical to use, has gradually replaced phosgene in laboratory experiments. At room temperature, either neat or in dry solvent (Et 2 O, CH 2 Cl 2 ), oxalyl chloride reacts with diakyl methylphosphonates 1 (R 1 = Me, Et, n-Pr, i-Pr, n-Bu) to give exclusively the corresponding alkyl methylphosphonochloridates 2 in excellent yields (Scheme 10).[66][67][68][69][70] An excess of oxalyl chloride is generally used. As with phosgene, the reaction is relatively long, from 20 to 70 h, but mild and selective. For example, it has been shown that treatment of phosphonates containing the cyclotetrasiloxane ring with PCl 5 or SOCl 2 gave cyclotetrasiloxane cleavage rather than formation of the desired alkylphosphonochloridate. It was only when these phosphonates were treated with oxalyl chloride under mild conditions that the monoesters were successfully prepared with yields of 80-90%.[71] The by-products of the reaction are the alkyl chloride R 1 Cl along with carbon monoxide and dioxide, resulting from the decomposition of the chlorooxalate ion. Formation of carbon monoxide necessitates the use of well ventilated hoods. The reaction mechanism is the same as for phosgene. Dimethyl benzylphosphonate was submited to a comparative treatment with phosphorus pentachloride

[ 93 ] 36 (

 9336 Scheme 20.

  and phosgene in CCl 4 at room temperature. The same methyl chlorobenzylphosphonate was obtained in each case but after 12 h for PCl 5 and 48 h for (COCl) 2 .[26] One of the most important applications of oxalyl chloride is the use in the synthesis of haptenic phosphonate transition-state analogues. For example, haptens that possess a phosphonate group 21 bearing a five-carbon spacer as the linker were prepared by phosphorylation of the glycerol derivative. Obtention of the intermediate phosphonochloridate 20 was accomplished in quantitative yield by treatment of dimethyl carboxypentylphosphonates 19 with oxalyl chloride in CH 2 Cl 2 at room temperature (Scheme 11).[72,73]

	R 1 O R 1 O	P S	+ 1 6 Me	neat COCl 2 r.t. -COS	R 1 O Cl	P O	Me 2
					-R 1 Cl
	Scheme 10.
	EtS EtO	P O	Me 1 7	+	neat COCl 2 r.t. -CO 2	EtS Cl	P O	Me 1 8
					-EtCl
	Scheme 11.

  acid 29 was produced in 94.5% yield by the reaction of the tetraethyl ester of ethylene-1,2diphosphonic acid 28 with PCl 5 in refluxing CCl 4 .[19] Phosphorus pentachloride, whilst being a useful reagent, is often handicapped by its notorious aggressiveness and suffers from a tendency to give disubstitution products if reaction conditions are not carefully controlled. These problems may be overcome if it is replaced by POCl 3 being used as solvent and reagent.[44][45][46][47]91,92] Only one of the chlorines of this reagent is used in the phosphonate-phosphonochloridate conversion and the monochlorination reactions render it a safe and convenient substitute to PCl 5 . The by-product is one equivalent of the corresponding alkyl dichlorophosphate 30 (Scheme 17).

	Scheme 16.
	Phosphorus oxychloride, POCl 3
	1		PCl 5	CCl 4 30-35°C then reflux
	1 O Cl	+	POCl 3	+	R 1 Cl

Triphenylphosphine dichloride, Ph 3 PCl 2 Triphenylphosphine

  0 propynylphosphonochloridate 32 in pure form with 79% yield (Scheme 18). After elimination of the excess of POCl 3 and ethyl dichlorophosphate 30 (R 1 = Et), the 1propynylphosphonochloridate 32 was purified by fractional distillation.[91]

	EtO EtO	P O	C	C Me 3 1	POCl 3 60°C, 3 h
	EtO
	Cl	P O	C	C Me 3 2
				79%
	Scheme 18.
	Scheme 19.
	The formation of Ph 3 PO 34 as a by-product of these reactions presents a fundamental

dichloride 33 is a monochlorination reagent which was introduced in 1988. The reactions between dialkyl alkylphosphonates 1 and triphenylphosphine dichloride 33 were conducted in CHCl 3 solution at room temperature with reaction times from 2 to 22 h. Other solvents such as THF, CCl 4 and Et 2 O were found to give less favorable results. A series of dimethyl alkylphosphonates 1 (R 1 = Me) involving simple R alkyl groups or more sophisticated groups (R = Me, n-Pr, CH 2 CH=CH 2 , CO 2 Me, CO 2 i-Pr, CO 2 Ph) bound to phosphorus have been studied (Scheme 19).[93] Conversions were found to vary between 73 and 97%. No formation of dihalide product was detected. experimental drawback and poses serious difficulties in isolating the pure alkylphosphonochloridates 2. To obviate this difficulty a polymer-bound tertiary phosphine dichloride reagent was used. Chloromethylated polystyrene was treated with an excess of

Acknowledgements

We are grateful to ATO-FINA for financial support to B. I., M. Multan from the Ecole Polytechnique (BCX) for assistance in collecting the literature and the Centre National de la Recherche Scientifique (CNRS).