Aminoalkyl phosphonate derivatives

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. ... 

Many syntheses of (aminoalkyl)phosphonic derivatives have been listed which rely on the participation of phosphorous acid, H3PO3 this, like its diesters, exists in the quinque-valent phosphonic acid structure, (H0)2P(0)H. Such reactions include Mannich-type aminomethylations Similar types of reactions with the involvement of hypophosphorous acid and primary amines lead to (aminomethyl)phosphinic acids (Scheme 54) (R = H), during which the formation of376 (R = H) undoubtedly occurs initially. However, such products cannot be isolated, and views differ as to the relative importance of the subsequent formation of polymers and that of the bis(aminoalkyl)phosphinic acids (377 R = fj 5S4,585 latter type of acid is available through reactions with pre-... 

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). 

Rees and co-workers have carried out an extensive study of the addition of tri-methylsilyloxy phosphorus(lll) derivatives (phosphites, phosphonites, and phos-phinites, generated in situ) to aldimines to yield a-aminoalkyl-phosphonates, phosphinates and phosphine oxides (respectively, the transferred /V-TMS group being lost during work-up). Competition experiments demonstrated that the addition to imines is faster than that to the parent aldehydes. They found that the presence of electron-withdrawing groups in the imine slows the reaction. 

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. 

One of the many uses to which (nitroalkyl)phosphonic derivatives are put is their reduction to the corresponding (aminoalkyl)phosphonic compound. The reverse reaction, that of oxidation of the amino compound to the nitro analogue, has rarely been adopted, a suprising observation in view of the multitude of procedures available for the preparation of the amino compounds. The oxidation of amino to nitro on C i) has employed KMn04 in acetone or acetic acid, but the yields are low acidic conditions have to be avoided, since (nitroalkyl)phosphonates then break down according to the Nef reaction . ... 

The situation with regard to the (aminoalkyl)phosphonic acids is, however, completely different. Not only have many (aminoalkyl)phosphonic acids, either in the free state or as derivatives, generally esters, been resolved, but also many synthetic procedures have been adapted for potential asymmetric preferment. The latter will be considered under each individual type of reaction, but it is convenient to consider the problem of resolution separately. 

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... 

The oxime from (4-chloro-l-oxobutyl)phosphonic acid has been cyclized to Pro ". An unusual rearrangement based on valence expansion of phosphorus is of interest the treatment of an (oxoalkyl)phosphonic oxime with Ph2PCl initially yields the phosphorus(III) derivative, but this rearranges spontaneously to give a phosphinic amide derivative 300, reduction of which then affords the [(V-diphenylphosphinoylamino)alkyl]phosphonic acid, readily hydrolysable under acid conditions to the free (aminoalkyl)phosphonic diester (Scheme 34)" ". 

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. ... 

In the conversion of derivatives of (l-oxoalkyl)phosphonic diesters into those of the (1-aminoalkyl)phosphonic acid, it may be noted that an improvement to the use of NaBH3CN involves that of sodium triacetoxyborohydride-TiCl3 in aqueous methanol buffered at pH 4 for the reduction of oximes . ... 

By contrast, the reactions of the amino group in (aminoalkyl)phosphonic and related acids are, in principle, relatively simple and few in number, interest in the acids, as a class, residing in their biochemical properties. Their diazotization leads to (diazoalkyl)phos-phonic derivatives, and the protection of the amino group by acylation (as acetyl, benzoyl... 

The action of hot alkali on salts of the acids 195 (R = tert-a kyl) yields the acids 197, whereas nitrous acid at 0-5 °C yields the hydroxy acids 196. (l-Aminoalkyl)phosphonic diesters react with carbonyl chloride to give the corresponding isocyanates, which may be characterized as derived ureas or semicarbazides ... 

In addition to (aminoalkyl)phosphonic diesters, several other, well characterized products have been obtained from the oximes, or derivatives of oximes, of acylphosphonic diesters. Methylation of the oximes 283 [Z = CONHR, COOR (R = Et or Pr ), R = H of undefined geometry] with MeI-K2C03, or with Me2S04, yields the O-methyl oximes 283 (Z = CONHR R = Me) methylation with diazomethane also yields the latter but together with the phosphorylated nitrones 284 (Z = CONHR or COOR), which have been characterized in E and Z forms. The interaction of283 (R = Me) and diazomethane yields the corresponding 285 . Methylene insertion also occurs in reactions between diazomethane and 0-acylated oximes ... 

R = H), derived from (+)-oxopinic acid, and (aminomethyl)phosphonic acid diethyl ester, was alkylated in the usual way and the products hydrolysed to give the (S)-( 1-aminoalkyl)phosphonic diesters with 15. 62, 93, and 92% e.e. for R = Me, Et. Bn. and allyl. The reaction between (347 R = Li) and diethyl vinylphosphonate gave the (lS)-(347 R = CH2CH2P02Et2) which was acidolysed ( aqueous acetic acid) to... 

The use of phenylphosphonous dichloride in the preceding reactions leads to derivatives of the [(1-aminoalkyl)phenyl]phosphinic acids. Oximes of (1-oxoalkyl)phosphonic acids react with Ph2PCl/Et2N to give l-(diphenylphosphinoyliminoalkyl)phosphonates (166) by spontaneous... 

Addition of hypophosphorous acid, PH(OH)2 to Schiff bases, yielding (l-aminoalkyl)phosphorous acids, can also be effected by mixing the three reactants.129 Further, Schiff bases have also been added to dialkyl thiophos-phites,130 phosphonous monoesters,130 secondary phosphine oxides,117 and metal derivatives of secondary phosphines 131 these phosphides, however, give well-defined products only after hydrolytic working up to phosphine oxides. 

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