Phosphonylating agents

Murphy et al. showed that EPHP [25] and L2P(0)H [26] can also be used in radical C-C bond forming reactions (Scheme 8). Recently, Piettre et al. [27] used the sodium salt of hypophosphorous acid as H-donor and the subsequent phosphonyl radical as phosphonylating agent for the preparation of 3-fura-nosyl-6 -furanosylphosphinate (Scheme 9). 

Addition of diethyl phosphite to aldimines bearing less bulky substituents (e.g., CH3 or Et)39 proceeds with very low stereoselectivity and leads to the various diastereomeric products in comparable amounts. For this reason a new phosphonylating agent was introduced, trisftri-methylsilyl) phosphite40. However, the stereoselectivity with this reagent is not much improved, although yields increased by ca. 20 %. 

Fluorinated phosphonates exhibit interesting properties as enzyme inhibitors, chelating agents or as fuel cell electrolytes [29] however, only few methods of preparation for these compounds are available. Burton et al. [30] developed several methods to prepare fluorinated phosphates which involve phosphonyl, and likely phosphoranyl radicals as chain carriers (Scheme 11). 

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 ). 

Hobblger, F. 1963. Reactivation of phosphonylated acetylcholinesterase. In, Koelle, G.B. (ed) 1963 Cholinesterases and Anticholinesterase Agents, Berlin-Gottingen-Heidelberg, Sprlnger-Verlag, pp. 921-988. 

Millard, C.B., Kryger, G., Ordentlich, A., Greenblatt, H.M., Harel, M., Raves, M.L., Segall, Y., Barak, D., Shafferman, A., Silman, I., Sussman, J.L. (1999a). Crystal structures of aged phosphonylated acetylcholinesterase nerve agent reaction products at the atomic level. Biochemistry 38 7032-9. 

The mechanism of AChE inhibition for aU the OP nerve agents is practically the same, i.e. phosphorylation or phosphonylation of the esteratic site of AChE. 

Nerve agents phosphorylate or phosphonylate the serine hydroxyl group at the esteratic part of the active site of the enzyme acetylcholinesterase (AChE EC 3.1.1.7) (Figure 66.2). AChE plays a key role in cholinergic transmission in the peripheral and central nervous system and, consequently, its inhibition is hfe-endangering (Taylor, 1996 Marrs, 1993). 

The oxime HI-6 with atropine is reasonably effective against soman regardless of the choice of experimental animals while currently used oximes (pralidoxime and obidoxime) seem to be practically uneffective to protect mammals poisoned with supralethal dose of soman (Table 4). Presented data confirm that soman appears to be one of the most resistant nerve agent to the antidotal treatment because of the rapid aging of soman-phosphonylated AChE and the existence of a soman depot in the poisoned organisms (31, 54, 55). The soman-AChE complexes age very quickly and this fact prevents the oxime-induced reac-... 

Millard CB, Kryger G, Ordentlich A et al. (1999). Crystal structures of aged phosphonylated acetylcholinesterase nerve agent reaction products at the atomic level. Biochemistry, 38, 7032-7039. 

However, even erythrocyte AChE measurements cannot be expected to be a perfect surrogate for the nervous tissue enzyme this is because pharmacokinetic factors may result in differential access of the inhibitor to the red cell and to neural structures. A further consideration is that, where nerve agents react with the enzyme to produce a phosphonylated structure that does not spontaneously reactivate, red cells of mammals lack the protein synthetic capability to synthesize new AChE. By contrast, in nervous tissue, after inhibition by OPs whose enzyme-inhibitor complex with AChE does not readily reactivate, activity may reappear relatively quickly. Thus, Wehner et al (1985) observed approximately 30% recovery after 24 h in di-isopropylfluorophosphate (DFP)-treated mouse CNS reaggregates, which was clearly due to synthesis de novo of AChE. Another consideration in the interpretation of butyrylcholinesterase activity measurements is that the normal range is relatively wide, rendering interpretation in individual patients difficult unless the results of previous estimations in the patient are available (Swami-nathan and Widdop, 2001). 

The mechanism of AChE inhibition for the all OP and nerve agents is practically the same—the inhibition via phosphorylation or phosphonylation of the esteratic site of AChE. However, reactivation of inhibited AChE by oximes is different for different nerve agents phosphorylated but reactivata-ble AChE is changed to a nonreactivatable complex. The half-times for this reaction described as dealkylation (F5) are different for various OP/nerve agents (B3, Bll). 

Photochemically generated phosphonyl radicals are effeetive reducing agents for Cu VCu reduction in copper complexes. It has been shown that the obtained copper(i) species can rapidly catalyse atom transfer radical polymerisation and azide-alkyne cycloadditions in mild conditions, i.e. at ambient temperature and humidity, under an air atmosphere. 

Phosphonylation of a Carboxylic Acid Polymer. The reaction of a water-soluble polycarboxylic acid with phosphorous acid is said to yield a polymer with hydroxybis(phosphonic acid) structures. These are effective scale-inhibiting agents for aqueous systems (119) but not known to have been commercialized. A similar reaction in a Chinese study is said to result in the replacement of carboxyl groups by phosphonic acid groups (120) to produce pol5uners with similar utility. 

Sawyer, T.W., Weiss, M.T., Boulet, C.A., et al., 1991b. Toxicity of organophosphate nerve agents and related phosphonylated oximes compared to their anticholinesterase activity in neuron cultures. Fundam. Appl. Toxicol 17, 208-214. 

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