Aminoalkylphosphonic acids, synthesis

Some Aspects of Aminoalkylphosphonic Acids Synthesis by the Reductive Amination Approach... 

Savignac, P., and Collignon, N., Some aspects of aminoalkylphosphonic acids. Synthesis by the reductive amination approach, ACS Symp. Ser. (Phosphorus Chem.), 171, 255, 1981 Chem. Abstr, 96, 35344, 1982. 

Scheme 62 Synthesis of enantiomerically pure a-aminoalkylphosphonic acids 259a and 259b...

Kowalik, J., Kupczyk-Subotkowska, L., and Mastalerz, P., Preparation of dialkyl 1-aminoalkylphosphonates by reduction of dialkyl 1-hydroxyiminoal-kanephosphonates with zinc in formic acid, Synthesis, 57, 1981. 

Scheme 11 Recently Described Methods for Stereoselective Synthesis of a-Aminoalkylphosphonic Acid Derivatives 5-171...

By analogy to the Strecker-like synthesis of a-aminoalkylphosphonic acids (Section 10.10.1.1.1), alkyl phosphonites can be added to AMritylimines 66 in refluxing toluene to form aminoalkyl(alkyl)phosphinates 67 (Scheme 22, Table 10).[33] The addition of a catalytic amount of Lewis acid, such as BF3 OEt2, dramatically improves the chemical yield for this process. Moreover, alkyl phosphonites can be added to acylating agents, such as alkyl isocyanates 68, to form acyl(alkyl)phosphinates 69 (Scheme 22)J103l... 

Before 1975, peptides with C-terminal l-aminoalkylphosphonic acid residues (1-APA) or their esters 1 were essentially unknown. In 1978, the antibacterial properties of phospho-nopeptides incorporating C-terminal 1-aminoethylphosphonic and aminomethylphosphonic acids were reported1 1 and this stimulated interest in this class of compounds. Alaphosphalin [2, alaphosphin, l-(L-alanylamino)ethylphosphonic acid] is probably the first example of a rationally designed synthetic antibiotic. Alaphosphalin did not reach the market, however its discovery increased interest in the development of new synthetic methods for the synthesis of l-aminoalkylphosphonic adds as well as their esters and peptides. 

For the synthesis of peptides, the phosphonic moiety in most cases should be masked as a diester. Diesters of 1-aminoalkylphosphonic acids can be synthesized directly or by esterification of 1-aminoalkylphosphonic acids. If peptides with the free phosphonic moiety are the desired products, then methods are available for the selective removal of both ester groups. Peptides with a free C-terminal phosphonic acid functionality can be synthesized directly from the free 1-aminoalkylphosphonic acids. In addition, methods for synthesis of the peptides with C-terminal phosphonates directly from the peptides are also available. In general, most methods for the synthesis of peptide bonds work well for the synthesis of peptides with C-terminal phosphonates if diesters of 1-aminoalkylphosphonic acids are used. Bulky diaryl esters give yields similar to the diethyl esters. Therefore, the most challenging step in the synthesis of peptide phosphonates is the synthesis of 1-aminoalkylphosphonic acids and/or their esters. It is not possible in this section to review all of the literature data and only examples of several general methods are included. This will still provide a variety of methods for the efficient synthesis 1-aminoalkylphosphonic acids, their esters, and related peptide derivatives. 

Although some investigators consider free 1-aminoalkylphosphonic adds as poor substrates for the synthesis of peptides with a C-terminal 1-aminoalkylphosphonic acid moiety, successful procedures are reported in the literature with yields higher than 80% J6 7 The competitive formation of a mixed anhydride between the 1-aminoalkylphosphonic acid and the acylating agent (e.g., N-protected active ester of an amino acid) followed by its fast hydrolysis could be minimized in some solvent systems. The free 1-aminoalkylphosphonic acids could also be N-protected and esterified to provide various esters suitable for the peptide synthesis. 

Scheme 2 Synthesis of 1-Aminoalkylphosphonic Acids by Amidoalkylation of Phosphorus Trichloride in Acetic Acid 9 13 16-18 ...

Synthesis of Peptides with C-Terminal l-Aminoalkylphosphonic Acid Residues... 

Dipeptides with C-terminal 1-aminoalkylphosphonic acids such as L-Ala-L-Alap (8), can be coupled to another amino acid active ester using the same methods used in the synthesis of dipeptides. The dipeptide can be extended from the N-terminal up to hexapeptides. Generally, the yield for each step is >60% J7 ... 

A few methods for the esterification of 1-aminoalkylphosphonic adds have been developed for use when diesters of 1-aminoalkylphosphonic acids are the preferred starting materials for peptide synthesis. 8 In general, 1-aminoalkylphosphonic acids cannot be esterified under conditions that work for amino acids, and protection of the amino group is absolutely essential. Diethyl 1-aminoethylphosphonate [9, Alap(OEt)2] is synthesized from Alap in two steps (Scheme 6). Orthoformates are highly recommended because esterification is almost quantitative. 24 ... 

Synthesis of Diesters of 1-Aminoalkylphosphonic Acids by the Kabachnik-Fieids Method... 

Peptides with C-terminal diphenyl 1-aminoalkylphosphonates can also be used as a starting material for the synthesis of peptides with free C-terminal 1-aminoalkylphosphonic acids. In the earlier attempts, 45 diphenyl esters of Z-dipeptides 24 were transesterified to dimethyl esters 25 and these were hydrolyzed simultaneously with the Z group by HBr/ AcOH, to give the dipeptides of 1-aminoalkylphosphonic acids 26 (Scheme 17).[451 The overall yields are quite good. It is worth mentioning that diphenyl 1-aminomethylphos-... 

Moc-Thr(OTBDMS)p(OMe)2 Oxidative Decarboxylation of Amino Acids Derivatives and Synthesis of l-Aminoalkylphosphonic Acid Esters 28 Typical Procedure 148 ... 

Peptides of aminoalkanephosphonic acids (Phosphono-peptides 4,are now receiving considerable interest because some representatives of this class were found to repress,bacterial growth at very low concentration levels 1. Literature data on the synthesis of dipeptides containing aminoalkylphosphonic acids are scarce and very little information is avaiable,on blocking and deblocking of the phosphonate moiety ... 

In this communication we report synthesis of dipeptides containing P-terminal aminoalkylphosphonic acids related structurally to glycine,alanine,nor-vallne,valine, leucine,phenylglycine and phenylalanine,while the N-terminal residues include glycine,alanine,valine,leucine,pro line,methionine,beta -alanine,phenylalanine, tyrosine, lysine and glutamine. 

Dingwall, J.G., Ehrenfreund, J., and Hall, R.G., Diethoxymethylphosphonites and phosphinates. Intermediates for the synthesis of a,P- and y-aminoalkylphosphonous acids. Tetrahedron, 45, 3787, 1989. Mohrle, H., and Vetter, W., Participation of phosphonate neighbour groups with dehydrogenations of amines, Z. Naturforsch., 43b, 1662, 1988. 

The Hofmann degradation is applicable to the synthesis of 2-aminoalkylphosphonic acids." " For example, 2-aminoethylphosphonic acid has been obtained by this method in 75% yield (Scheme 8.94). To avoid the drastic conditions required by the hypobromite method, two new Hofmann-like reagents, iodosobenzene and /-hydroxy-Z-p-tolucnesulfonyloxyiodobcnzcnc (HTIB), have been introduced. Under these conditions, the rearrangement takes place smoothly to produce the desired aminoalkylphosphonic acids in high yields (65-93%). ... 

Considerable research effort has been focused on the preparation of compounds of biochemical interest, using electrophilic reactions of phosphoramidites and phosphorochloridites to prepare modified phosphates of nucleosides or lipids. Intense interest has been shown in the synthesis of myoinositol phosphates, and also of aminoalkylphosphonic acids and their derivatives and analogues. Away from the biological emphasis, however, the first (recorded) syntheses of acetylenic phosphates have been described, and so have the first 1-alkoxyphosphole, the first cis amino-iminophosphine, and the first dithiaphospholium ions ex Phosphorus semper aliquid novi The use of silyl phosphites for synthetic purposes seems to be an increasing trend, while the number of papers on metaphosphate seems to be in decline. 

A simple synthesis of y-aminoalkylphosphonic acids (77) involves addition of a nitroalkane to vinylphosphonic esters, followed by catalytic hydrogenation. j3-Aldehydophosphonic acids (78) are conveniently prepared by acidic hydrolysis of the readily accessible j3-alkoxyvinyl-phosphonates. Oxidation of (2-pyridyl)methyl phosphonic acid (79) with... 

The reactions of phosphorous acid are paralleled still further by the additions of hypophosphorus acid to azomethines in practice, mixtures of amines and carbonyl reactants may be employed ", but the drawbacks to the procedure found for the synthesis of aminoalkylphosphonic acids may well apply here also. In a valuable publication, Dingwall and coworkers described the syntheses of (aminoalkyl)phosphinic acid analogues of many of the naturally occurring aminocarboxylic acids by the simple treatment of the benzyhydrylimine derivatives of the necessary amines with hypophosphorous acid, formed in situ when diphenylmethylammonium hypophosphite is treated with an appropriate aldehyde this step is followed by removal of the A -protection with 48% aqueous HBr, with 18% aqueous HCl or with trifluoroacetic acid in boiling methoxybenzene any second amino group was protected as the phthalimido derivative. 

Oximes, which are valuable intermediates for the conversion of oxoalkyl phosphonic diesters into those of aminoalkylphosphonic acids (Chapter 4, Section IV.C. 1. d), are also readily available, although it is necessary to prepare them with some care. Nevertheless, the feature of interest here is their ready degradability, particularly under aqueous conditions, and which has been intensively investigated by Breuer and coworkers. The necessity for care in the preparation of oximes of acylphosphonic diesters, is illustrated by the synthesis of dimethyl [a-(hydroxyimino)benzyl]phosphonate this compound exists in the thermodynamically more stable ( ) form which, under the influence of acid is converted into the less stable (Z) form, and both forms have been separately characterized by X-ray crystallography. The geometric isomers of the oxime differ in their behaviour under basic conditions with NaOH-MeOH, the ( ) form undergoes monodealkylation, whereas the (Z) isomer decomposes to dimethyl phosphate and benzonitrile. In aqueous solution, ( )-[a-(hydroxyimino)benzyl]phosphonic acid also decomposes into benzonitrile together with phosphoric acid, in a manner which is pH dependent, and consistent with a dissociative mechanism that involves the early formation of monomeric metaphosphate. ... 

One of the very first methods for the preparation of a-aminophosphonic acids appears to be the one described by Kabachnik and Medved [8]. The Kabachnik-Fields reaction is still very useful, especially for the preparation of dialkyl 1-aminoalkanephosphonates. According to this method, a-aminophosphonates were obtained reacting ammonia, carbonyl compounds (aldehydes and ketones), and dialkyl H-phosphonate. A little later. Fields [9] presented a method of synthesis of 1-aminoalkylphosphonic acids by replacing ammonia with amine—reacting both (aldehydes and ketones) with ammonia, or amine and dialkyl H-phosphonate to give dialkyl esters of 1-aminoalkylphosphonic acid (see Appendix). Hydrolysis of the esters produced free aminoalkylphosphonic acids. Yields of aminophosphonates vary from 40 to 47%. 

The biological properties of phosphorus amino acid analogues (and their derivatives) depend upon their stereochemistry. Consequently, numerous methods for obtaining these compounds in stereochemically pure form have been developed. Two excellent review articles summarize the work performed prior to 1993. 3,4 Resolution of racemates continues to be a useful approach for obtaining optically pure aminoalkylphosphonic and -phosphinic acid derivatives (vide infra), but most of the newer literature describes asymmetric syntheses of these compounds.15-17 Two methods for resolution and one for asymmetric synthesis are described (vide infra) they have been selected since they are relatively easy to perform, work with a variety of side chains, can be carried out on a reasonable scale with readily available starting materials, and produce products of high stereopurity. However, just as in traditional amino acid chemistry, each side chain introduces its own complications, and in many cases, especially for more complex analogues, other methods may be preferred. 

The condensation of an aldehyde, benzyl carbamate, and triphenyl phosphite, first described by Oleksyszyn et al., 25,26 affords a direct route to a-aminoalkylphosphonates 4 that are conveniently protected for subsequent reactions (Scheme 4). Since dealkylation of the quaternary phosphonium intermediate 3 is not possible in this case, formation of the pen-tavalent product 4 presumably involves activation of the solvent and formation of phenyl acetate. This method is useful for the synthesis of aliphatic and aromatic amino acid analogues. However, monomers with more elaborate side chains are often incompatible with the reaction conditions. The free amine can be liberated by treatment with HBr/AcOH or by hydrogenolysis after removal of the phenyl esters. The phosphonate moiety can be manipulated by ready exchange of the phenyl esters in alkaline MeOH and activation as described in Section 10.10.2.1.1. Related condensations with other trivalent phosphite derivatives have been reported. 27-30 ... 

---