A-Amino phosphonic acid

The substrate scope is limited, as electron-withdrawing groups (X = p-N02 or p-CF3) on the aromatic substituent are not tolerated. However, this route does provide valuable intermediates to unnatural a-amino phosphonic acid analogues and the sulfimine can readily be oxidized to the corresponding sulfonamide, thereby providing an activated aziridine for further manipulation, or it can easily be removed by treatment with a Grignard reagent. 

Huber, J.W. and Gilmore, W.R, Optically active a-amino-phosphonic acids from ureidophosphonates, Tetrahedron Lett., 3049, 1979. 

Redmore, D., N-Benzyl-a-amino phosphonic acids, J. Org. Chem., 43,996,1978. 

The preparation of resolved species which are chiral at the germanium metal center have been reported (Equation (37), Table 2)44 47 as have species containing biologically important ligands48-52 including derivatives of a-amino-phosphonic acid.48-50... 

The possibility of phosphorus analogues of amino-acids acting as false substrates and so interfering with biological mechanisms led us to consider the a-amino-phosphonous acids 4 as perhaps the closest analogues. 

It was prepared by the ammonolysis of chloromethanephosphonous acid, a method not applicable to other a-amino acid analogues. This paper describes a general synthesis of the a-amino-phosphonous acids and some of their physical, chemical and biological properties. 

Although some reactions of electrophilic animation of phosphorus-stabilized anions had already been reported in the literature [5a,d], the first example of such a stereoselective reaction opening access to optically active a-amino phosphonic acids was described in 1992 by Denmark and co-workers [45] and by Jommi and co-workers [46]. Both of these groups used chiral amino alcohols as auxiliaries for diastereo-selective induction in the animating process. Denmark and co-workers chose trisyl azide (2,4,6-triisopropylbenzenesulfonyl azide) as equivalent of NHJ , whereas Jommi and co-workers performed the reaction with DTBAD. 

These methods have enabled the investigation of a series of chiral oxazaphospho-lanes as precursors of optically active a-amino phosphonic acids. The stereoselectivity of the amination process is dependent on the substituents of the chiral auxiliaiy, and in some cases a good level of asymmetric induction has been achieved (up to 83 % de) unfortunately, no absolute configuration of the final products was determined. 

Another important source of chiral auxiliaries for the synthesis of optically active phosphorus derivates are the C2 symmetric diamines such as 1,2-diaminocyclohex-anes. In 1994, Hanessian and co-workers described the use of A,/V -dimethyl-(R,R)-1,2-diaminocyclohexane 93 as a chiral auxiliary in the synthesis of optically pure or enantiomerically enriched a-alkyl a-amino phosphonic acids [49], Starting from easily accessible optically pure diamine 93, they synthesized in good yield (75 %) enantiomerically pure (R,R)-ethylphosphonamide 94 by condensation with ethyl phosphonic dichloride in benzene in the presence of triethylamine (Scheme 43). 

The major diastereomer 95 could be obtained in optically pure form by silica gel chromatography. The absolute configuration of the amination product was dictated by the choice of the chiral diamine, and correlated with previous results in asymmetric a-alkylation. Furthermore, the major diastereomer 95 was converted to the corresponding (ft)-a-aminoethyl phosphonic acid 96 by sequential treatment with (i) TFA, CH2C12,0 °C (ii) 1 N HC1 and (iii) H2, Pt02,70 psi, followed by Dowex 50 (H+) resin chromatography in 73 % overall yield. Optical rotation of the a-amino phosphonic acid 96 allowed the confirmation of its optical purity (> 98 %) and of its absolute configuration. 

Through a diastereoselective addition of diethyl isothiocyanomethylphosphonate 188 to aldehydes it was possible to obtain differently substituted 2-oxazolidinethiones 190 and 191, which were converted into the corresjwnding a-amino phosphonic acids <03TL4747>. 

The BOP- or PyBOP-mediated SPPS of phosphinot or phosphono peptides can be carried out without protecting the phosphinic or phosphonic acid group. Indeed, phosphinic acids are activated, but the P—N bond is not formed. Phosphonic acids are also acti-vatedt and in fact an amide of methyl phenylphosphonic acid has been obtained, however, in the case of protected a-amino phosphonic acids, phosphonamides are only obtained by using AT-phthalyl protection. Side-chain unprotected phosphorylated tyrosine [Tyr(P03H2)] can be coupled by solid-phase synthesis using BOP (PyBOP), but pyrophosphate formation is also observed and some particular Tyr(P)-peptide syntheses are prone to total failure. ... 

The first highly diastereoselective hydrophosphonylation of heterocyclic imines, 3-thiazolines (330) by a chiral phosphorus reagent BINOL, has been performed. The relative configuration of BINOL and the newly formed stereogenic centre in the a-amino phosphonic acid derivatives (331) have been elucidated by X-ray analysis. 

Thiourea-catalysed enantioselective hydrophosphonylation of imines (370) using phosphite (371) provides a general and convenient route to a wide range of highly enantiomerically enriched a-amino phosphonates (372). The deprotection of these products yields the corresponding a-amino phosphonic acids (373) (Scheme 95). ... 

Several addition reactions to C=N groups have been developed in recent years with a high synthetic potential but with no commercial use so far [12 zb]. The addition reaction of (MeO)2PHO to cyclic imines (58-60), an interesting method for the preparation of a-amino phosphonic acids, seems to be an exception [46]. While ee values of the heterobimetallic catalyst (cf. Section 3.1.5) are very high, TON and TOP values are relatively low. 

Kitamura, M., Yoshimura, M., Tsukamoto, M., Noyori, R. Synthesis of a-amino phosphonic acids by asymmetric hydrogenation. Enantiomer 1996, 1, 281-303. 

Camphor and camphor-derived analogs are used frequently as chiral auxiliaries in asymmetric synthesis. There have been numerous reports in the use of camphor imine as templates to direct enantioselective alkylation for the synthesis of a-amino acids, a-amino phosphonic acids, a-substituted benzylamines, and a-amino alcohols (e.g.. Scheme 9) [43-47]. Enantiomeric excesses of the products range from poor to excellent, depending on the type of alkyl halides used. 

The Kabachnik Fields reaction, which involves the hydrophosphonylation of phos phites with imines generated in situ from carbonyl compounds and amines, is an attractive method for the preparation of a amino phosphonates. Optically active a amino phosphonic acids and their phosphonate esters are an attractive class of compounds due to their potent biological activities as nonproteinogenic analogues of a amino acids. Therefore, considerable attention has been given to their enantio selective synthesis by hydrophosphonylation of preformed imines, using either metal based catalysts or organocatalysis [107]. 

Several reports have appeared - of reactions of phosphites with acid chlorides to give acyl phosphonates (37), and in one case this reaction has been used as a new route to a-amino-phosphonic acids through the oxime (38) and... 

An easy approach to optically active a-amino phosphonic acid derivatives was achieved in high yields and with up to 98% ee by enantioselective amination of P-keto phosphonates with azodicarboxylates, catalyzed by chiral bis(oxazolines) and Zn(OTf)2 <05JA5772>. 

The application of the heterobimetallic lanthanoid complexes of the LnMB type led to a breakthrough in establishing a highly efficient asymmetric catalytic route to a-hydroxy as well as a-amino phosphonic acid esters, which have attracted much attention due to their wide ranging biological activity [57-64]. The heterobimetallic catalysis described below represents the first and until now the only highly efficient asymmetric catalytic approach to both a-hydroxy and a-amino phosphonates by the attractive way of asymmetric catalytic hydrophos-phonylation. 

In spite of the high level of interest in the asymmetric synthesis of a-amino phosphonic acids, less is known in the case of cyclic a-amino phosphonates. Although in recent years descriptions of promising pharmaceutical applications for cyclic compounds (and acylated derivatives thereof) have been published [61-64], until now no efficient general asymmetric route has been available to prepare this class of a-amino phosphonates. Several attempts at a diastereose-lective synthetic route which were made by the addition of a stoichiometric amount of chiral phosphites to cyclic imines, namely thiazolines, gave only limited diastereoselection ratios of dr=2 1 or below [75,76]. 

Attack on Unsaturated Carbon. - A new method to obtain a-amino phosphonic acids (7) in high enantiomeric excess involves the selective addition of trimethyl phosphite to chiral oxazolidines (8). The reaction probably occurs by... 

Joly, G.D. and Jacobsen, E.N. (2004) Thiourea-catalyzed enantioselective hydrophosphonyla-tion of imines practical access to enantiomerically enriched a-amino phosphonic acids. Journal of the American Chemical Society, 126, 4102-4103. 

A simple, inexpensive, and efficient approach to enantiopure a-amino-phosphonic acids (297) based on the reaction of chiral benzylidenes (296) derived from R)- or (5)-l-(a-aminobenzyl)-2-naphthol (Betti bases, 295) with trialkyl phosphites in the presence of trifluoroacetic acid (TEA), have been demonstrated by Alfonsov et al. (Scheme 68). °" ... 

Hydrophosphonylation, Nitroaldol Reaction (Kaneka Co., Hokko Chemical Industry). First industrial applications of the heterobimetallic catalysts developed by Shibasaki were realized for the synthesis of several chiral-building blocks. The catalysts are aluminum or lanthanoid cations coordinated to two and three binol ligands, respectively. In addition, one or several alkali metals are coordinated to the binol as well. The asymmetric hydrophosphonylation methodology (85) is now being applied to the preparation of several a-amino phosphonic acids... 

Halogenoalkyl and halogenocycloalkyl acids. a-Trifluoromethylphospho-nate (140) is a newly prepared synthon for making fluorinated a-hydroxy and a-amino phosphonic acid derivatives (141) and (142) (Scheme 50). ... 

A wide range of a-amino phosphonic acid derivatives (213) have been synthesized with good enantioselectivities, in reactions of enamides or enecarbamates with iminophosphonates catalyzed (with a high turnover frequency) by a copper(ii) complex (214) (Scheme 82). ... 

A -Phosphinoyl and A -thiophosphinoyl ketimines, Ph-C(Me)=N-P(=X)Ph2 (X = O and S), have been hydrophosphonylated in high yield and ee using a copper(I) catalyst liganded with a chiral diphosphino ethane. In the case of the sulfur substrates, facile differentiated removal of the t/imphosphinoyl group affords a-amino phosphonic acid derivatives, Ph- C(Me)(NH2)-P(=0)(0Et)2, that is, phosphonic acid analogues of enantio-enriched a,a-disubstituted a-amino acids. The reaction also accommodates alkyl, cycloalkyl and alkenyl substituents in place of the phenyl. 

A direct approach to a-amino phosphonic acids derivatives (594) has been developed by McDonald and Wang. Thus, copper-catalysed electrophilic amination of a-phosphonate zincates (592) with O-acyl hydro-xylamines (593) (Scheme 172) provided the first example of C-N bond formation which directly introduced acyclic and cyclic amines (592) to the a-position of phosphonates (591) in one step. ° ... 

Lavielle G, Hautefaye P, Schaeffer C et al (1991) New a-amino phosphonic acid derivatives of vinblastine chemistry and antitumor activity. J Med Chem 34 1998-2003... 

Yokomatsu T, Shibuya S (1992) Enantioselective synthesis of a-amino phosphonic acids by an application of stereoselective opening of homochiral dioxane acetals with triethyl phosphite. Tetrahedron Asym 3 377-378... 

---