Phosphonylation with

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

Diphenyl H-phosphonate represents an inexpensive, commercially available reagent suitable for the convenient and efficient conversion of partially protected deoxyribo- and ribonucleotides into the corresponding 3 -phosphonate monoesters. The reagent is stable, easy to handle, and affords H-phosphonate monoesters of purity usually better than 95% even without column chromatography. Considering that phosphonylation with diphenyl phosphonate occurred effectively in rather mild conditions, it could be expected that this procedure will find applications outside the nucleotide field, for example, peptides, carbohydrates, etc. 

The thienamycin precursor is then prepared by phosphonylation with phosphorohalidates in a substantially inert solvent containing a suitable tertiary amine. The function of the base is to keep the reaction medium... 

Without additional reagents Phosphonylation with phosphonyl oxides... 

CLAY - KINNEAR - PERREN Phosphonyl Chloride Synthesis Synthesis ol alkyl phosphonyl chlorides Irom alkyl chlorides or from ethers with PCI3 AICI3... 

A general synthesis of phosphonyl thiadiazoles has been recently disclosed starting from the hydrazone 55. The hydrazones were prepared from acyl phosphonates, which in turn were made from acid chlorides 54. Thus treatment of the hydrazone 55 with thionyl chloride in the presence of DMF and sodium chloride provided the thiadiazoles in... 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

Recently, Fossum et al. prepared several phosphine-oxide-containing monomers (Scheme 6.23).163 These monomers were used to prepare hyperbranched polymers in a typical aromatic nucleophilic substitution. However, only oligomers with M lower than 2500 g/mol were obtained. These results did not surprise us, since our previous work demonstrated that the para-hydroxyl group of the phosphonyl group is not very reactive and would require higher reaction temperatures.11... 

Various cyclic phosphonate esters 36 and 37 have been described previously as products from the HHT reaction of 25 with the appropriate cyclic phosphite. A complementary method has also been developed from the V-protected phosphonyl chloride 84, which was readily prepared from the corresponding phosphonic acid 83. Subsequent reaction of 84 with the appropriate diol produced the cyclic phosphonate esters 85 (63). Higher homologs of 85 have also been prepared from the analogous propane or butane diols. 

Addition of phosphonyl radicals onto alkenes or alkynes has been known since the sixties [14]. Nevertheless, because of the interest in organic synthesis and in the initiation of free radical polymerizations [15], the modes of generation of phosphonyl radicals [16] and their addition rate constants onto alkenes [9,12,17] has continued to be intensively studied over the last decade. Narasaka et al. [18] and Romakhin et al. [19] showed that phosphonyl radicals, generated either in the presence of manganese salts or anodically, add to alkenes with good yields. 

Scheme 10 Reductive cyclization involving phosphonyl radicals. Reprinted with permission from [28a]. Copyright 2001 Pergamon Press...

The p-scission of a phosphoniumyl radical yields a cation and a phosphonyl radical, while its reaction with a nucleophile generates a phosphoranyl radical which can undergo SET reactions and a- or p-fragmentations (Scheme 14). 

Esters of a-diazoalkylphosphonic acids (95) show considerable thermal stability but react with acids, dienophiles, and triphenylphosphine to give the expected products. With olefinic compounds in the presence of copper they give cyclopropane derivatives (96), but with no such compounds present vinylphosphonic esters are formed by 1,2-hydrogen shift, or, when this route is not available, products such as (97) or (98) are formed, resulting from insertion of a carbenoid intermediate into C—C or C—H bonds. The related phosphonyl (and phosphoryl) azides (99) add to electron-rich alkynes to give 1,2,3-triazoles, from which the phosphoryl group is readily removed by hydrolysis. 

Reaction of perthiophosphonic anhydrides (64) with amines leads first to (105) and then, by further attack, to (106). With ammonia itself the second addition proceeds at the same phosphorus atom as the initial attack, giving (107) and (108). The anhydride (64) is also reported to react with 1,3-dioIs to give cyclic phosphonyl disulphides (109). Thermal decomposition of phenylphosphinic anhydride (110) may lead to the formation of PhP since in the presence of benzil the formation of the phosphorane (111) was observed. ... 

The intermediate N-acylpyridinium salt is highly stabilized by the electron donating ability of the dimethylamino group. The increased stability of the N-acylpyridinium ion has been postulated to lead to increased separation of the ion pair resulting in an easier attack by the nucleophile with general base catalysis provided by the loosely bound carboxylate anion. Dialkylamino-pyridines have been shown to be excellent catalysts for acylation (of amines, alcohols, phenols, enolates), tritylation, silylation, lactonization, phosphonylation, and carbomylation and as transfer agents of cyano, arylsulfonyl, and arylsulfinyl groups (lj-3 ). 

J-Oxenols[14] and oximes[15] can also be phosphonylated successfully in this way. In the reaction with diols, selective monophosphonylation has been achieved.[14]... 

On the basis of NMR and derivatisation studies, the configuration at phosphorus in 48 was shown to be S. It phosphonylates aldehydes readily via the Abramov reaction to afford a-siloxyimidophosphonate esters 50 (Scheme 18) [41 13] with diastereomeric excess (de) up to 96% (for R=/-Bu). The reactions proceed smoothly... 

The phosphonyl adduct 300 reacted with a dilute solution of anhydrous hydrogen chloride in ethanol or with sodium ethoxide to afford an essentially quantitative yield of the P-N cleaved product 304 with inversion of configuration. Addition of sodium ethoxide to a solution of 304 in methanol resulted in the formation of enantiomerically pure (+)-(.V)-ethyl methyl phenylphosphonate (305). It also reacted quantitatively with methylmagnesium iodide at room temperature to give the product of P-S bond cleavage 306, which upon acid catalyzed methanolysis afforded enantiomerically pure (+)-(R)- methyl methylphenylphosphinate (307) (Scheme 72) [108],... 

The rate of appearance of p-nitrophenolate ion from p-nitrophenyl methylphosphonate (7), an anionic substrate, is moderately accelerated in the presence of cycloheptaamylose (Brass and Bender, 1972). The kinetics and pH dependence of the reaction are consistent with nucleophilic displacement of p-nitrophenolate ion by an alkoxide ion derived from a cycloheptaamylose hydroxyl group to form, presumably, a phosphonylated cycloheptaamylose. At 60.9° and pH 10, the cycloheptaamylose-induced rate acceleration is approximately five. Interestingly, the rate of hydrolysis of m-nitrophenyl methylphosphonate is not affected by cycloheptaamylose. Hence, in contrast to carboxylate esters, the specificity of cycloheptaamylose toward these phosphonate esters is reversed. As noted by Brass and Bender (1972), the low reactivity of the meta-isomer may, in this case, be determined by a disadvantageous location of the center of negative charge of this substrate near the potentially anionic cycloheptaamylose secondary hydroxyl groups. 

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