Phosphoramidates

Phosphoramidates (14) are a type of modification which - like triphosphates - offers further options for functionalization of oligonucleotides. They may be synthesized using phosphora-midite technology with oxidation of the phosphite triester with iodine in the presence of alkylamines [91]. t-Butylamine in methanol at 45 °C is used for their deprotection and cleavage from the support. The protocol allows modification of a single linkage for attachment of functional groups. 

Alternative methods for the synthesis of phosphoramidates are presented in Table 6. Suitability for these techniques has been reviewed in [91]. 

In NaHPOa(NH2) there are zwitterions H3N.PO3 , (d), analogous to the isoelectronic sulphamic acid, (e), H3N. SOJ (p. 586). The N-H-0 bonds link the ions into a 3-dimensional framework, in the interstices of which are located the Na ions. Replacement of one 0 by S in PO3NH2 gives the ion [P02S(NH2)] in which the bond lengths shown at (f) come from a study of the di-ammonium salt. There are similar bond lengths in the diamidothiophosphate ion, studied in NH4 [P0S(NH2)2].  

In this subclass, the phosphorus bonds to a nitrogen. Acephate is a typical phosphoramidate. 

Acephate is a systemic insecticide with contact and stomach poison activity for control of a wide range of chewing and sucking insects on fruits, cotton, soybeans, peanuts, beets, potatoes, ornamentals, and others. Its oral LD50 in rats is 866-945 mg/kg. 

Methamidophos is an insecticide and acaricide for control of chewing and sucking insects and spider mites such as aphids, flea beetles, whiteflies, cabbage loopers, thrips, cutworms, Colorado potato beetles, armyworms, mites, leafhoppers, and others on vegetables, cotton, potatoes, and fruits. It has an oral LD50 in rats of 250-500 mg/kg. 

The OP compounds are difficult to generalize with respect to their physical properties. They have moderate-to-considerable water solubility. Some organophosphate insecticides are water soluble, e.g., oxydemeton-methyl, azodrin, phosdrin, trichlorfon, and phosph-amidon. They also have moderate-to-considerable vapor pressures, generally in the range 10 3-10-5 mm Hg. Some organophosphate insecticides such as naled and dichlorvos are very volatile. This combination of physical and chemical properties makes the entire class of insecticides biodegradable and nonpersistent. 

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Pentamethylphosphorotriamide. Of the phosphoramide derivatives, pentamethylphosphorotriamide [10159-46-3] is the most effective finish when appHed to fabric in conjunction with dimethylolmelamine and an amine hydrochloride catalyst. The finished fabric passes the FF3-71 flammabihty test. Its main appHcation is for use on heavyweight clothes since the finish imparts a harsh hand to lightweight fabrics (99). 

Both phosphoramidate and phosphate triester derivatives have been used as linkers to attach reporter groups to oligonucleotides. These derivatives are not entirely resistant to nucleases and they possess a chiral center. They have not been widely iavestigated as antisense dmgs. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Phosphonium hexafluorophosphate, benzotriazolyl-N-hydroxytris(dimethylamino)-in peptide synthesis, 5, 728 Phosphonium salts chromene synthesis from, 3, 753 reactions, 1, 531 Phosphonium salts, vinyl-in pyrrole synthesis, 4, 343 Phosphonium ylides in heterocyclic synthesis, 5, 165 Phosphoramide, triethylene-as pharmaceutical, 1, 157 Phosphoramide, triethylenethio-as pharmaceutical, 1, 157 Phosphorane, pentaphenyl-synthesis, 1, 532 Phosphoranes, 1, 527-537 Berry pseudorotation, 1, 529 bonding, 1, 528... 

ATHERTON TODD Phosphoramidate Synihasis Synthesis of phosphoramidates from formamides and dialkyl phosphite. 

Phosphoramidates are cleaved with HCl saturated THE (70-94% yield). Their Stability is dependent on the alkyl group, the methyl derivative being the least stable. They also have good stability to organic acids and Lewis acids. ... 

Dibenzyl phosphoramidates have been prepared from amino acids and the j)hos-phoryl chloride, (Bn0)2P(0)Cl. ° A diphenyl phosphoramidate has been prepared from a glucosamine it is converted by transesterification into a dibenzyl derivative to facilitate cleavage. ... 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

The high reactivity of N-H bonds has also been exploited to produce N-F denvatives without significant substitution on neighbonng C-H bonds, Diethyl-phosphoramidates of ammonia, alkylammes, and a,polar solvents to produce difluoroamine [57], N,N-difluoroalkylamines, and a,to-bis(At,7V-difluoroamino)alkanes [52] Acetamide undergoes fluonnation to give modest yields of N,N difluoroacetatnide and acetyl fluonde when fluorinated... 

Condensation of sodium phenoxide witli 2,2,2-trifluoroethyl iodide gives a product of direct substitution in a low yield, several other ethers are formed by eliminatton-addition reactions [7] Use of mesylate as a leaving group and hex amethyl phosphoramide (HMPA) as a solvent increases the yield of the substitution [S] Even chlorine can be replaced when the condensation is performed with potassium fluoride and acetic acid at a high temperature [9] (equations 6-8)... 

TBDMSCl, imidazole, DMF, 25°, 10 h, high yields. This is the most common method for the introduction of the TBDMS group on alcohols with low steric demand. The method works best when the reactions are run in very concentrated solutions. This combination of reagents also silylates phenols, hydroperoxides," and hydroxylamines. Thiols, amines, and carboxylic acids are not effectively silylated under these conditions. Tertiary alcohols can be silylated with the phosphoramidate... 

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