Aminoalkylphosphonic acids —

No reports have appeared of compounds of the formula R— CH(—NH2)—As03H2, and they might have considerable interest in view of the large literature on 1-aminoalkylphosphonic acids, R— CH(—NH2)—P03H2, as well as reports (e.g., 112-114) of 1-aminoal-... 

Optically Active 1-Aminoalkylphosphonic Acids 21 General Procedure 54 ... 

Aminoalkylphosphonic acids are analogues of natural a-aminocarboxylic acids and are designated by generally accepted three-letter abbreviations for the amino acid residue followed by a superscript P. For example, 1-aminoethylphosphonic acid, which is related to alanine, is abbreviated as Alap. Diphenyl [l-(benzyloxycarbonylamino)ethyl]phosphonate, is abbreviated as Z-Alap(OPh)2. The l-aminoalkylphosphonic acids have modest water solubility, which significantly increases in strong acidic and alkali solution. They are not soluble... 

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. 

Peptides with C-Terminal 1-Aminoalkylphosphonic Acid Residues from the Free 1-Aminoalkylphosphonic Acids... 

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 ...

In general, the active ester method gives the better yield because the coupling reaction can be run in a single-phase solvent system such as DMF/H20. In such a solvent system, the active ester and salt of 1-aminoalkylphosphonic acids (sodium or triethylamine) are soluble. 

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 ... 

Scheme 7 Esterification of 1-Aminoalkylphosphonic Acids with Triethyl Orthoformate To Give Diethyl 1-Aminoalkylphosphonate Oxalic Acid Salts 251...

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-... 

Dipeptides of 1-Aminoalkylphosphonic Acids 26 Synthesized via Diphenyl Esters 24 General Procedure 14 1... 

Direct Conversion of Acyl Amino Acids and Peptides into the Corresponding 1-Aminoalkylphosphonic Acid Derivatives... 

Aminoalkyl and Related Acids. Various 1-aminoalkylphosphonic acids (313) have been obtained in high yield by microwave assisted reaction of ammonium hypophosphites (314) with aldehydes (Scheme 83). ... 

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

Treatment of acylphosphonic acids with NaBH4 in aqueous or alcoholic ammonia solution produces 1-aminoalkylphosphonic acids in good yields... 

Ryglowski, A., and Kafarski, P., Preparation of 1-aminoalkylphosphonic acids and 2-aminoalkylphosphonic acids by reductive amination of oxoalkylphosphonates. Tetrahedron, 52, 10685, 1996. 

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%. 

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