Phosphorothiolate derivatives

The methylphosphonates differ from the phosphodiesters and phosphorothiolates in that the methyl derivatives are uncharged and are thus less water soluble. Moreover, compared to the naturally occurring phosphodiesters, the methylphosphonates form slightly less stable duplexes with complementary DNA and RNA sequences. This effect has been ascribed to the iaevitable chiraUty problem that is, if one isomer biads less well, the overall binding is decreased. Methylphosphonates can enter cell membranes by a passive mechanism and are completely resistant to nucleases. 

Biooxidation is an essential activation process for some organothiophosphorus neurotoxicants (1). m-Chloroperoxybenzoic acid (MCPBA) has been used to mimic some of these reactions but without identifying the products derived from phosphorothiolates (.2,3). We observed that S-alkyl phosphorothiolates react with MCPBA to form a new and unexpected class of phosphinyloxysulfonates via a novel rearrangement process (Eq. 1). 

Different OP compounds have structural similarities within classes. The phosphorus compounds have the characteristic phosphoryl bond, P=0. Most OP compounds have a phosphoryl bond or a thiophosphoryl bond (P=S). All OP compounds are esters of phosphorus with varying combinations of oxygen, carbon, sulfur, and nitrogen attached. These are classified as (1) phosphates (2) phos-phonates (3) phosphorothioates (4) phosphorodithioates (5) phosphorothiolates and (6) phosphoramidates. Further, the OP compounds are categorized as (1) aliphatic (2) phenyl and (3) heterocyclic derivatives. The aliphatic are carbon chainlike in structure. TEPP, which was used in agriculture for the first time in 1946, is a member of this group. Others include malathion, trichlorfon, monocrotophos, dimethoate, oxydemetonmethyl, dimethoate, dicrotophos, disulfoton, dichlorvos, mevinphos, methamidophos, and acephate. 

Several uimatural nucleoside phosphate modifications (Fig. 2e) have been generated, which include phosphorothioate, phosphoroamidate, phosphorothiolate, and methylphosphonate derivatives. The syntheses of these modifications have been reviewed by Verma and Eckstein (19). A modification of those procedures can be used for the generation of phosphoroselenoate RNAs (20). 

Dimethyl-S-ethylthioethyl phosphorothiolate Sulfonium derivative, sulfoxide, and sulfone H20... 

An important group of insecticides of the phosphorus ester type are those compounds in which the sulfur atom of the phosphorothiolic acid or of the phosphorodithioic acid is linked through a methylene bridge to a heteroaromatic ring. They are mostly prepared by the reaction of the sodium, salt of the desired phosphorothiolic acid or phosphorodithioic acid with the chloromethyl derivative of the respective heterocyclic compound. 

The most important of the phosphorothiolic acid derivatives within this group is 0,0-dimethyl-S-[(5-methoxy-4-oxo-4H-pyran-2-yl)methyl] phosphorothioate (endothion, 77) prepared by Metivier (1955a 1955b) by the reaction of 2-chloromethyl-5-methoxy-4-oxo-4H-pyran with the sodium salt of 0,0-dimethyl phosphorothioate ... 

Modifications at the phosphorous center, including the phosphorothiolate, methylphos-phonate, and phosphoramidate derivatives, have generally shown reduced binding affinity for their RNA targets [19]. Replacement of the phosphate generally destabilizes bind-... 

The use of the Michaelis-Arbuzov reaction has been made in the synthesis of dinucleoside-3 -5-phosphorothiolates using disulphides (73) and nucleoside 5 -dialkylphosphite derivatives. Particularly efficient reactions were achieved using a 5 -Wj(trimethylsilyl)phosphite (74) which afforded the phosphorothiolate directly after aqueous work up. Derivative (74) was obtained by treating the corresponding nucleoside H-phosphonate with chlorotrimethylsilane in pyridine in the presence of triethylamine. 

Various 1,2-bifunctionalized alkenes containing heteroatoms are prepared by addition to alkynes. Thiophosphorylation of 1-octyne with phosphorothiolate 131 provided (Z)-l-(diphenoxyphosphinyl)-2-(phenylthio)-l-octene in good yield [40]. A useful synthetic method for (Z)-3-phenylthioacrylate derivative is the Pd-catalyzed thioesterification of 1-alkynes with 6)-methyl S-phenyl thiocarbonate (132). Addition of 132 to 1-octyne using Pd(PCy3)2 as a catalyst afforded methyl (Z)-3-phenylthio-2-nonenoate in 86% yield [41]. (Z)-l,2-Bis(phenylthio)alkene was prepared in good yield by stereoselective Pd-catalyzed addition of (PhS)2 (3) to 1-alkyne [2]. 

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