A-Hydroxyphosphonates

It is worthy of note that a-sulfanyl phosphonic acids, which can now be obtained enantioselectively from corresponding a-hydroxyphosphonates, are analogues of the a-sulfanyl carboxylic acids, which, for some of them, are metallo- -lactamases inhibitors [ 112]. To our knowledge, it does not seem that biological activities of a-sulfanyl phosphonic acids have been examined so far. 

Reaction of a phosphorus halide with a 2-alkynol and subsequent rearrangement to generate a hydroxyphosphonate... 

Of course, the use of tris(trimethylsilyl) phosphite213 214 provides facile access to the free a-hydroxyphosphonic acids. These silyl reagents have been used for the preparation of a wide range of a-substituted phosphonates and -phosphonic acids, starting with ketene,215 a-ketophosphonates,216 ketoesters,217 218 and a,P-unsaturated carbonyl compounds,207/219-221 as well as simple aldehydes and ketones.205 210/219 224 Their use for the preparation of compounds of significant biological interest has been reviewed.125... 

Two reports have been made of the preparation of P-chiral phosphine oxides through reaction of chiral f-butylphenylphosphine oxide treated with LDA and electrophiles. The electrophiles included aldehydes,355 ketones,355 and benzylic-type halides.356 Optically active a-hydroxyphosphonate products have also been generated from aldehydes and dialkyl phosphites using an asymmetric induction approach with LiAl-BINOL.357... 

Texier-Boullet, F., Synthesis of a-hydroxyphosphonates in a heterogeneous solid-liquid medium and at the surface of inorganic solids. Study of factors of their formation in some two-phase systems, Bull. Soc. Sci. Bretagne, 56, 57, 1984. 

Schultz s group employed an a-hydroxyphosphonate hapten [99] and subsequently isolated 20 cell lines of which 5 catalysed the hydrolysis of the model substrate p-nitrophenyl phosphate [100] above background (Fig. 34) (Scanlan et al., 1991). Antibody 38E1 was characterized in more detail and kinetic parameters were afforded by Lineweaver-Burke analysis. This antibody exhibited 11 turnovers per binding site with no change in Vmax, and thus acted as a true catalyst. Moreover, examination of substrate specificity showed that catalysis was entirely selective for p-substituted species (Appendix entry 6.6). 

Fig. 34 (above) Antibody 38E1, generated from the a-hydroxyphosphonate hapten [99], catalysed the hydrolysis of p-nitrophenyl phosphate [100]. 

The oxidation of alcohols with metal dichromates, other than sodium or potassium dichromate, has been little explored. Hydrated zinc dichromate (ZnCr207 3H20)367 368a and ferric dichromate [Fe2(Cr207)3],368b—which are very easy to prepare as stable solids—are able to oxidize alcohols in organic solvents.368 Zinc dichromate is particularly efficient in the transformation of a-hydroxyphosphonates into a-ketophosphonates.369... 

Hammerschmidt, F. Schmidt, S. Deprotonation of secondary benzylic phosphates. Configurationally stable benzylic carbanions with a diethoxyphosphoryloxy substituent and their rearrangement to optically active tertiary a-hydroxyphosphonates. Chem. Ber. 1996, 329, 1503-1508. 

As expected, the reaction of the lithium salts of phosphonates with oxygen results in the formation of dialkyl phosphoric acids-8 and carbonyl products i.e. the cleavage of the C-P bond takes place (, 5). However, when the halomagnesiurn salts of phosphonates Z were oxidized, a-hydroxyphosphonates 2 were formed. 

Using these reagents, resolutions of various types of racemic alcohols, including alkylarylcarbinols, alkylthienyl-carbinols, cyanohydrins, a-hydroxyalkynes, and a-hydroxyphosphonates, and also of a thiol and an amine, have been performed. 

It has been shown that metallation of diisopropyl phosphates derived from primary aliphatic alcohols, except methanol, takes place at the alkyl as well as the isopropyl group in a ratio which is strongly influenced by steric effects. It was proposed that short-lived alkyllithium compounds were configurationally stable up to — 50°C and rearrange, with retention of configuration, into the corresponding a-hydroxyphosphonates (phosphate-phosphonate rearrangement) (Scheme 21). ... 

Oxoalkyl Acids. Various types of readily available a-hydroxyphosphon-ates have been converted to a-ketophosphonates in high yield by potassium... 

Diethyl a-hydroxyphosphonates (448) were converted into the corresponding a-thiocyanatophosphonates (449) using triphenyl phosphine, 2,3-dichloro-5,6-dicyanobenzoquinone and ammonium thiocyanate under neutral conditions (Figure 85). °°... 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

Consistently good enantioselectivity in the catalyzed addition of MOjSiCN to aldehydes is observed with 33 as chiral ligand, while fluctuating results are obtained in the formation of a-hydroxyphosphonate esters by an analogous addition using chiral lanthanide alkoxides. ... 

When performed in ether at —70 °C containing HCl, the reaction between triethyl phosphite and either chloral or bromoacetone affords higher yields of the a-hydroxyphosphonates (34), relative to vinyl phosphate, than are normally obtained. The rate-determining step in the formation of the phosphonate (35) from chloroacetone and dimethyl hydrogen phosphonate appears to be the tautomerism of dialkyl phosphonate to phosphite. ... 

The addition of diethyl phosphite to 3-cyanopropionaldehyde yields l-hydroxy-3-cyanopropylphos-phonatc. " Triethyl phosphite reacts with 2,2-dimethyl-4-cyanobutyraldehyde in tlie presence of McgSiCl to give the protected a-hydroxyphosphonate in 67% yicld.- - -... 

Firouzabadi, H., Iranpoor, N., Sobhani, S., and Sardarian, A.R., High yield preparation of a-keto-phosphonates by oxidation of a-hydroxyphosphonates with zinc dichromate trihydrate (ZnCr2O7 SHjO) under solvent-free conditions. Tetrahedron Lett., 42, 4369, 2001. 

Pudovik, A.N., Konovalova, I.V, and Dedova, L.V., Reanangement of a-hydroxyphosphonic and a-hydroxyphosphonothioic esters into phosphonates and phosphorothioates, Dokl. Akad. Nauk SSSR, 153, 616, 1963 Chem. Abstr, 60, 8060a, 1964. 

Ohler, E., and Kotzinger, S., Thermal reanangement of trichloroacetimidic esters of allylic a-hydroxyphosphonates. A convenient way to (3-amino-1-alkenylphosphonic acids, Synthesis, 497, 1993. 

Because of their biological activity, optically active a-hydroxyphosphonates have received increasing interest. Enantio-enriched dialkyl a-hydroxyphosphonates were obtained by the oxazaborolidine catalyzed reduction of a-ketophospho-nates with catecholborane (Scheme 11) [96]. 

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