Alpha-functionalized phosphonate

The second chapter highlights the past, present and future of the asymmetric phospho-aldol reaction, one of the most powerful method to control the stereochemistry at the alpha-carbon of alpha-functionalized phosphonic systems (T.P. Kee and T.D. Nixon). Attention focused for the future to the design of new catalysts, improved processing and to medicinal chemistry and disease targets. 

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

These compounds were synthesized because it was noticed that several competitive inhibitors of the NMDA receptor had alpha-amino carboxylic acid and phosphonic acid functionalities separated by 3-5 carbons. All of the inhibitors shown in Fig. 11.11 have K- values for inhibition of the NMDA receptor of 10 juM or less. In general, nitrogen substituents larger than those shown decrease receptor affinity. In addition, substitution on the second nitrogen decreases affinity. 

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]. 

FIGURE 11.6 Plot of alpha values for protonated monomers of organophosphate compounds obtained at two fields of 80 (bottom) and 140 (top) Td as a function of moisture. DMMP, dimethyl-methylphosphonate TMP, trimethyl-phosphate DEMP, diethyl-methyl-phosphonate DEEP, diethyl-ethylphosphonate DIMP, di-iso-prophyl-methylphosphonate DEIP, diethyl-iso-prophylphosphonate TEP, triethyl phosphate TPP, tripropyl phosphate DBBP, dibutyl-butylphosphonate TBP, tri-n-butylphosphate. (From Krylova et al., Effect of moisture on high field dependence of mobility for gas phase ions at atmospheric pressure organophosphorus compounds, J. Phys. Chem. 2003. With permission.)... 

---