A-heterosubstituted phosphonate

Koenigkramer, R.E. and Zimmer, H., a-Heterosubstituted phosphonate car-banions. IX. Diethyl 1-phenyl-l-trimethylsiloxymethane phosphonate as an acyl anion equivalent a novel method for the preparation of a-hydroxyke-tones, Tetrahedron Lett., 1017, 1980. 

Z4.8 a-HETEROSUBSTITUTED PHOSPHONATE CARBANIONS AS ACYL ANION EQUIVALENTS... 

Zimmer. H.. Hickey, K.R., and Schumacher, R., Syntheses with a-heterosubstituted phosphonate cai banions. Part 3. Diacetylenes and substituted vinyl chlorides, Chimia, 28, 656, 1974. 

This is particularly so with a-heterosubstituted derivatives, as shown by a number of recent examples in which oxide derived ylids have been found to give vinyl derivatives in circumstances where the corresponding phosphonate derived ylids do not (2-5). It was therefore decided to prepare the parent (unsubstituted) a-methoxy-allyl phosphorus compounds 1, 2 and 3, in order to investigate their Wittig-type chemistry. 

An interesting variation of this reaction that made use of a three-component, one-pot solventless procedure with the corresponding trialkyl phosphites gave dramatically improved yields of many heterosubstituted glyphosate phosphonate diesters (37). When exactly one equivalent of water, 25, and tris-p-chloroethyl phosphite were mixed and heated under neat conditions for a few hours, nearly quantitative yields of displaced p-chloroethanol and the desired triester product 27 were obtained. If desired, the displaced alcohol was first removed by vacuum distillation, or the mixture could be hydrolyzed directly to GLYH3. Various oxygen, sulfur, nitrogen, cyano, and carboxylate functionalities were similarly accommodated in the trialkyl phosphite. 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

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