1- aminoalkyl phosphonate

Keywords primary amine, diethyl phosphite, aldehyde, alumina, microwave irradiation, 1-aminoalkyl phosphonate... 

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). ... 

In the presence of sodium methoxide, alkyl N-alkyl-(1-chloroalkyl)phosphonamidates rearrange to (1-aminoalkyl)-phosphonates ( a reaction previously observed) together with phosphoramidates-the latter a new feature of mechanistic significance.The use of methoxide did lead, however, to complications due to the further degradation of the products, and the use of benzyltrlmethylammonium methoxide was found to be more satisfactory. This brought about the conversion of... 

The addition of lithium diethyl phosphite to the imines (201) from (/ )-(—)- -amino-l-phenyl-2-methoxyethane gave mixtures of (202) and (203) in the ratios of >110 1 to 7 1, but mostly around 50 1. The sequence was completed by hydrogenolytic removal of the benzylic group, when the product (1-aminoalkyl)-phosphonic diesters had e.e.s of 96-99%. The diastereoisomeric ratios within (205), obtained from the chiral sulfoxides (204) and diethyl (lithiomethyl)phos-phonate, varied from 4.9 1 (R = PhCH=CH) to 9.2 1 (R = 2-thienyl), but the ratio also depended, to some extent, on the nature of the phosphonate alkyl group. ... 

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... 

A very large amount of NMR spectroscopic data has been collected during the year under review. The presentation of data in addition to data is now almost routine. NMR spectroscopic studies have now been presented for phosphonocarboxylic acids and their esters,some new phosphinic amides, and for Lawesson s reagent (solid and solution data). A spectroscopic study of the dimer of the nitrile oxide (401) suggested the structure (402). 1-(1-Naphthalenyl)ethylamine and ephedrine are recommended for the NMR spectroscopic determination of the enantiomeric composition of (1-aminoalkyl)-phosphonates, but of quinine and rert-butylphenylphosphinothioic acid, only the former was effective for the chiral resolution of the diethyl esters in the determination of e.e.s of (2-hydroxyalkyl)phosphonates. Conformational analyses, based on NMR spectroscopic data, have been carried out for dialkyl (2-hydroxyalkyl)phosphonates. ... 

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 . ... 

Reduction methods-Thtix. have included the reduction of oximes of the esters of (I-oxoalkyl)phosphonic acids, and of (l-azidoalkyl)phosphonic acids. in both cases to (1 -aminoalkyl)phosphonic diesters. and the reduction of nitro groups at C(2) with hydrogen/Pt02 or Raney nickel. ... 

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... 

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 addition of compounds of type 3 to C=N double bond systems leads to O-alkyl(aminoalkyl) O-silylphosphonates 9. Monoalkyl esters of aminoalkyl phosphonous acids 10 are formed in excellent yield by solvolysis of 9 [3]. 

To avoid the problems with kinetic control of a reaction during peptide bond formation, it is recommended that longer peptide phosphonates be synthesized stepwise by extension in the N-terminal direction, starting with diphenyl l-(aminoalkyl)phosphonates. The longer coupling time will provide peptide products that are usually an equivalent (or close to equivalent) mixture of diastereomers. The synthesis of longer peptides is demonstrated by the synthesis of Boc-Val-Pro-Valp(OPh)2, which is an excellent inhibitor of human neutrophil elastase (kobs/[I] = 27,000 M 1s 1)J38 ... 

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). 

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. 

Isocyanomethyl)phosphonate 97 is also a beneficial pronucleophile leading to optically active (l-aminoalkyl)phosphonic acids, phosphonic acid analogs of a-amino acids via tra s-5-alkyl-2-oxazoline-4-phosphonates 98 (E = PO(OPh)2, Sch. 25) [50]. ... 

The gold-catalyzed aldol reaction has been successfully applied to the asymmetric synthesis of (l-aminoalkyl)phosphonic acids, phosphonic analogs of a-amino acids (Scheme 2-57) [80, 81]. The reaction of (isocyanomethyl)phosphonates 65 with... 

For such inactivators to be effective both in vitro and in vivo, there are several conditions which must be met. First, they must be sufficiently stable that they are not spontaneously hydrolyzed or cleaved by esterases. Second, the acyl-enzymes which they form must be relatively stable to deacylation. Third, they should have good enzyme selectivity. Both the phosphofluoridates and sulphonyl fluorides are too hydrolytically reactive and non-selective to be examined in in vivo models. Recently, several (a-aminoalkyl)phosphonate diphenyl esters were explored [169] in order to address some of these issues. However, as no in vivo results were reported with them, neither they, nor the phosphonyl fluorides nor the sulphonyl fluorides will be discussed further in this review. 

Other (4-aminoalkyl)phosphonic acids (181) have been... 

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-. 

Gajda, T. Nowalinska. M.. Zawadzki, S., and Zwierzak, A., New approach to diethyl 2-aminoalkyl-phosphonates, Pho.sphorus. Sulfur Silicon Relat. Elem., 105, 45, 1995. 

The [a-(cyanoguanidino)alkyl]phosphonic diesters (247) can be made from the (a-aminoalkyl)phosphonic esters (246) through the two steps illustraced. 

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. 

Aminoalkyl and Related Acids. - Diethyl (l-aminoalkyl)phosphonates have been prepared by reduction of the oximes of (l-oxoalkyl)phosphonates with NaBH4 in the presence of NiCla or MoOa and diethyl (2-amino-2-arylethyl)-phosphonates by hydrogenation of the methyl ethers or acetates of the oximes of the corresponding 2-oxo esters. ... 

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... 

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. ... 

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. ... 

E. (Aminoalkyl)phosphonous Acids [(Aminoalkyl)phosphinic Acids]. 374... 

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 . ... 

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