Aminoalkyl -phosphonic Acids and

An improved synthesis has been developed for the synthesis of tetraalkyl 

Sulphur and selenium-containing compounds-Jht enzyme, phosphoenolpyruvate phosphomutase, from Tetrahymena pyriformis, catalyses the tran.sformation of phosphoenolpyruvate (PEP) into its P-C bond-containing metabolite, phosphonopyruvate. 

During the course of a study of the mechanistic details of this process using isotope 

Reagents i. (S)-PhCHMeNHMe, HPLC ii. BuLi, Cul, CICOCOOR iii, CsF, 18-crown-6, MeCN iv, Ha  

4-nitrophenacyl bromide. The 0-2-(trimethylsilyl)ethyl protecting groups in (355) were 

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In an investigation into the relative spatial requirements of phosphono and amino groups in (aminoalkyl)phosphonic acids and phosphinic acids vis-a-vis their behaviour towards NMDA, several q-. 

As an example of developments in the phosphorus-containing peptide field, the syntheses of (285), a tripeptidic (l-hydroxy-2-aminoalkyl)phosphonic acid, and some analogues, have been reported the compound (285) itself is a good inhibitor of human renin. ... 

In principle, the reactions employed to bring about peptide formation between an (aminoalkyl)phosphonic acid and an aminocarboxylic acid are similar to those used in conventional peptide chemistry. Thus, a diester of the (aminoalkyl)phosphonic acid is brought into contact with the A-protected aminocarboxylic acid in the presence of dicy-clohexylcarbodiimide (Scheme 60) or the carboxylic acid may be activated by preliminary reaction (mixed anhydride formation) with an appropriate reagent, e.g. Bu COCl , ClCOOEt or ClCOOCHMeEt , or by the use of A-hydroxysuccinimide The... 

Scheme 21 summarizes further reactions leading to phosphonic acid analogues of amino acids. Treatment of the nitrone (138 R =Me or Pr ) with a dialkyl hydrogen phosphonate (best as the Li derivative which shows greater diastereoselectivity than the Na or K salts), and subsequent steps involving acidolysis of the oximino compound (139) lead to the free (ot-aminoalkyl)-phosphonic acids (140)(phosphonoalanine, phosphonova1ine). 

The methodology of the catalytic asymmetric aldol reaction has been further extended to the aldol-type condensation of (isocyanomethyl)phosphonates (12) with aldehydes, providing a useful method for the synthesis of optically active (l-aminoalkyl)phosphonic acids, which are a class of biologically interesting phosphorous analogs of a-amino acids (Scheme 8B1.6) [21,22], Higher enantioselectivity and reactivity are obtained with diphenyl ester 12b than with diethyl ester 12a (Table 8B1.6). 

Optically active (1-aminoalkyl)phosphonic acids have also been obtained using a methodology based on the chemistry of 1,3,2-oxazaphospholidines (Scheme 9). The diastereoisomers (l73 a) and (l73 b) afe separated by column chromatography, then alkylated and hydrolysed to the (S) and (B) acids (174). ... 

Aminoethyl)phosphonic acid (AEP) has been prepared, together with other (u-aminoalkyl)phosphonic acids, by the borane-Me2S reduction of oo-(dialkoxyphosphiny 1) carboxamides, and also via its N,0,0-tris(trimethylsilyl) derivative (248) obtained from an N-acylaziridine. 

In planning a general enantioselective route to (l-aminoalkyl)phosphonic acids, French workers originally considered the alkylation of (212) (R = H), but this procedure led to products of only moderate e.e.s. Newer work has now considered the preparation and use of the perhydro-l,4,2-oxazaphosphorine... 

Further esterification of monobenzyl benzylphosphonate may be carried through the Mitsunobu procedure, the best yields being achieved using the potassium salt of the substrate. Monoesters of iV-protected (1-aminoalkyl)phosphonic acids are further esterified by alcohols in the presence of BOP-type reagents [(l-aminoalkyl)alkylj- and [(l-aminoalkyl)aryl]-phosphinic acids, again as their potassium salts, have been converted into esters by reactive alkyl halides in the presence of 18-crown-6 ether (see also reference The... 

Aminoalkyl phosphonic derivatives examined include (2-amino-1-fluoroethyl)-phosphonic acid [(3-amino-2-hydroxypropyl)methyl]phosphinic acid (guanidinophenylmethyl)phosphonic acid (2-amino-2-phenylethyl)phosphonic acid and (—)-(aminocyclohexylmethyl)phosphonic acid and its Mosher derivative. ... 

With the possible exception of the (diazoalkyl)phosphonic acids, all other functionalized phosphonic acids have, at some stage, been employed as precursors in the synthesis of aminoalkyl phosphonic acids, with various degrees of success many such methods (in the context of Chapter 6, reactions of the precursors) will be considered as syntheses by modification , and reference should be made to the appropriate sections in this or the previous chapter for the preparation of those precursors. 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

Currently, the most widely practised procedure for the quantitative estimation of diastereoisomeric purity (d.e.) and thus of enantiomeric purity (e.e.) consists in the derivatization of the aminoalkyl phosphonic acid as the A-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl) derivative the latter is prepared from (R)-(+)-(3,3,3-trifluoro-2-methoxy-2-phenyl)propanoyl chloride (the so-called Mosher reagent) Although the diastereoisomeric derivatives 123 may also be separable by HPLC (e.g. on Zorbax-Sil) and which can be separately characterized [the derivative from (+)-Val was shown by X-ray... 

Amongst additionally functionalized aminoalkyl phosphonic acids, of which the hydroxy- and oxo-derivatized compounds are the more important, (haloaminoalkyl)-phosphonic acids have been very seldom reported. In the reactions between trialkyl phosphites and the aminotetrachloroethanes 161, the integrity of the trichloromethyl group is, surprisinglv, retained, with the (l-amino-2,2,2-trichloroethyl)phosphonates 162 as the products, e.g. with R = Such compounds may be reduced by Bu3SnH, but the... 

Several studies have been concerned with the Michaelis-Arbuzov reactions of halogen-containing imido compounds and which, in addition to their intrinsic interest, are of potential interest for the preparation of more unusual (aminoalkyl)phosphonic acids. Some of the reactions between trialkyl phosphites and imidoyl chlorides are entirely conventional thus, the compounds 163 (R = Me or Ph) give the corresponding esters 164 however, the similar transformation of 165 (R = Ac, PhCO or COOEt) into 166 does not take place ... 

In addition to aldimines, reactions between dialkyl hydrogenphosphonates and ketoximes are reported to give low yields of (aminoalkyl)phosphonic acids when treated with hypophosphorous acid. ... 

Reactions similar to those just described are well known for the phosphinic acid series ". Maier has described similar aminomethylation reactions which lead to products such as 246 (R = Me, Et, Pr, Bu or CH2OH), and also other reactions, to be discussed later, which afford bis(co-aminoalkyl)phosphonic acids. 

The synthesis of phosphonic acid derivatives by the direct oxidation of those of the corresponding phosphonous acid has been afforded very little interest (Chapter 2, Section VI.c), unlike the more controllable synthesis of derivatives of the thio- or seleno-phos-phonic acid derivatives (Chapter 5, Section II.B.4). In the present instance, the oxidation of A -protected (fmoc) (l-aminoalkyl)phosphinic esters has been carried out with NaI04 with high yields. Quantitative yields of (aminoalkyl)phosphonic acids were obtained in oxidation reactions with bromine water and with HgCl2-H20. In an alternative approach (Scheme 59), the A -protected (cbz) ethyl(l-aminoalkyl)phosphinate is initially converted into a (l-aminoalkyl)phosphonous acid diester, which is then subjected to the Atherton procedure to achieve change in valence at phosphorus. ... 

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