P-aminophosphonic acid

Phosphonylated. V-bciizyI enamine, formed from benzylamine and diethyl 2-oxopropylphosphonate, undergoes aza-annulation with acryloyl chloride in refluxing THF to provide a phosphonylated unsaturated lactam in 72% yield. - Subsequent hydrogenation generates a 78 22 ratio of diastereomeric products in 67% yield (Scheme 7.114). These compounds represent an interesting class of rotationally constrained P-aminophosphonic acid analogues. 

A. Aminophosphonic Acids.— The Michael addition of a dialkyl phosphite to acrylonitrile leads to C—P bond formation and the production in high yield of derivatives of 2-aminoethylphosphonic acid (45). This synthetic method appears to be preferable to those already described. ... 

Chiral P-Hydroxy-a-Aminophosphonic Acids. An enan-tioselective synthesis of substituted dihydrooxazolin-4-yl phos-phonates was reported by the reaction of an aldehyde with a-isocyanomethylphosphonate ester catalyzed by (i )-(5)-(l) (eq 12). The enantiomeric purity of the product was determined by P H NMR spectroscopy using the chiral solvating reagent (.S)-(+)-2,2,2-trifluoro-l-(9-anthryl)ethanol. Independently, an asymmetric synthesis of ot-aminophosphonic acids was reported using the chiral ferrocenylamine catalyst (R)-(S)-(3) (eq 13). ... 

Although initially prepared and evaluated as a racemate, the NMDA antagonist activity was likely to reside primarily in a single enantiomer. The stereoselective nature of the NDMA receptor is well established, albeit not completely understood. Consequently, several attempts have been undertaken to develop synthetic protocols that would allow preparation of optically active compounds. Early reports of preparation of optically active co-amino-o-carboxyalkylphosphonic acids describe the preparation of (.S )-A P-3 from an optically active amino nitrile prepared by reaction of diethyl 1-formylphosphonate with hydrogen cyanide and (5)-(-)-a-methylbenzylamine. Acid hydrolysis, enrichment of the diastereomers by fractional recrystaUization, and debenzylation lead to the isolation of (.S )-A P-3 in 86% enantiomeric excess. " Recently reported procedures, which use chemoenzymatic processes, offer a more convenient and mild approach for the production of optically pure aminophosphonic acids. Enzymatic hydrolysis of amides using penicillinacylase (EC... 

C-P bond have been the subjects of reviews. In the latter publication the synthesis, including enantioselective synthesis, of 2-aminophosphonic acid derivatives, phospholipids, aminomethylphosphonic acid, fosfomycin, phos-phonopyruvic acid, and a variety of other, often complex, structures is described. 

For the addition of diethyl hydrogenphosphonate, the composition (estimated from the NMR signals for the anomeric carbons) of the reaction product was p S P-R (x-S a-R = 83 5.5 10.3 1.2, but this ratio can be altered by a careful choice in the adopted experimental procedure. The major isomer may be isolated by crystallization or HPLC and the cleavage of those adducts by 1 m HCL in MeOH yields the ( -aminophosphonic acid. The Schiff base from D-arabinopyranosylamine, 200, reacts to form selectively the R adduct (the ratio of R to 5 products is 5 1). By a careful choice of the carbohydrate nucleus, the major diastereoisomer adduct is formed with a purity sufficient to allow crystallization in pure form, as with the glucosylamine derivative 198 which afforded the adducts in the... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

The rather low yields of the aminophosphonic acids can be fairly substantially improved over those reported by Kabachnik and Medved if anhydrons ammonia and the aldehyde are premixed in alcohol solution. Using this procedure, a few amino-substituted phosphonic acids are prepared a-aminobenzylphosphonic acid (benzaldehyde, dibutyl H-phosphonate, solution of dry ammonia in absolute ethyl alcohol) a-amino-propylphosphonic acid propionaldehyde, diethyl H-phosphonate, and a solntion of dry ammonia in absolute ethyl alcohol) p-methoxybenzyl-a-aminophosphonic acid (p-hydroxybenzaldehyde, diethyl H-phosphonate, and solution of dry ammonia in absolute ethyl alcohol). 

Aminophosphonic acids containing groups sensitive to hydrolysis and hydrogenation are obtained easily from aldimines by addition of di(p-methylbenzyl) H-phosphonate followed by selective removal of p-methylbenzyl group by solvolysis with formic acid [54],... 

Despite the high level of interest in the asymmetric synthesis of a-aminophosphonic acids, not much is known about the cyclic a-aminophosphonates. The pharmaceutically interesting cyclic a-aminophosphonates are synthesized by the hydrophosphonylation of cyclic imines (thiazoUnes) in the presence of chiral lanthanoid-potassium-binaphtoxide complexes (LnPB) (Ln = lantanoid metal, P = potassium, B = binaphtol) [77],... 

The P-C cleavage is not only characteristic for aminophosphonate esters. The corresponding aminophosphonic acids also nndergo a similar cleavage. 

Peptides containing a P-terminal aminophosphonic acid have been prepared by coupling protected amino acids with dialkyl or diaryl esters of aminoalkanephosphonic acids or free acids. Protection of the amino phosphonic acid groups is an important step in the phospho-nopeptide synthesis. Aminophosphonates based on the H-phosphonate diesters are used directly for the preparation of phosphonopeptides. Diphenyl aminoalkanephosphonates are attractive starting materials for phosphonopeptide synthesis because they are readily available, and efficient coupling is easily achieved by most methods used in peptide chemistry. 

Figure 3 The separation of Ba(ll) 1.5 ppm, Ni(ll) 1 ppm, Co(ll) 2 ppm, Zn(ll) 1 ppm, Pb(ll) 5 ppm, Cd ll) 2.5 ppm, Mn(ll) 1.5 ppm, and Cu(ll) 5 ppm on the aminophosphonic acid functionalized silica column, 250 mm x 4.6 mm. Eluent ImolT KNO3, 5 mmol 1 HNO3. Detection, PAR/ZnEDTA postcolumn reaction at 495 nm. (Reprinted with permission from Nesterenko PN, Shaw MJ, Hill S, and Jones P (1999) Aminophosphonate-functionalised silica A versatile chromatographic stationary phase for high performance chelation ion chromatography. Microchemical Journal 62-. 58-69 Elsevier.)...

Entries 1-9 show that several Rh/P-stereogenic diphosphine ligands are able to hydrogenate a,p-unsaturated phosphonates in very high enantioselectivities. The t-butoxy analogue of DiPAMP and Trichickenfootphos (entries 1,4 and 7) lead to the best results. ot,p-Unsaturated phosphonates are interesting because they are precursors of ot-hydroxy- and a-aminophosphonic acids, compounds with a broad spectrum of biological activity. ... 

For other protonation values of aminophosphonic acids see Volume 1, p. 396. 2. Amino-dihydrogenphosphates ... 

Addition of diethyl lithiodifluoromethylphosphonate to enantiomerically pure aromatic, heteroaromatic and aliphatic aldehyde-derived sulfinimines afforded diastereomerically pure N-sulfinyl oc,a-difluoro-P-aminophosphonates (200) which were used to prepare a,a-difluoro-P-aminophosphonic adds (201) and the sodium salt of difluorophosphonamidic acid (7 )-(202) (Scheme 73). ... 

The catalytic activity of polystyrene-supported p-toluenesulfonic acid (PS/PTSA) has been studied in an efficient, green synthesis of a new class of a-aminophosphonates (363). Under solvent-free and microwave irradiation conditions of the Kabachnik-Fields reaction, a series of... 

Very recently, Gangireddy et al. elaborated the synthetic scope for the 2-aminofluorene-substituted phosphonate derivatives (58) using a variety of aliphatic/alicyclic/aromatic aldehydes via three-component one-pot Kabachnik-Fields reactions under solvent-free microwave irradiation, just replacing the catalyst with polystyrene-supported p-toluenesulfonic acid (PS/PTSA). This procedure is also a simple, high yielding, straightforward, environmentally-friendly method for the synthesis of biologically relevant a-aminophosphonate scaffolds (Scheme 27). ... 

Huber R, Knierzinger A, Obrecht J-P, Vasella A. Nucleophilic additions to A-glycosylnitrones. Asymmetric synthesis of a-aminophosphonic acids. Helv. Chim. Acta 1985 68 1730-1747. 

Kafarski P, Lejczak B (1991) Biological activity of aminophosphonic acids. Phosphorus, Sulfur, Silicon Relat Elem 63 193-215... 

Aminophosphonic and Aminophosphinic Acids, Chemistry and Biological Activity, Kukhar, V.P. and Hudson, H.R., Eds., John Wiley Sons, Chichester, England, 2000 — Contributed chapters deal with syntheses and biological activity of compounds in the title categories. 

Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonate derivatives. The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(0Et)2 and P(OEt)3 in ionic liquids. TaCb-Si02 has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-... 

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