A-amino-phosphonate

Fee et al. have investigated the Fewis acid-catalyzed three-component synthesis of a-amino phosphonates [73]. This was carried out in the ionic liquids [BMIM][PFg],... 

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. 

The discussion of the activation of bonds containing a group 15 element is continued in chapter five. D.K. Wicht and D.S. Glueck discuss the addition of phosphines, R2P-H, phosphites, (R0)2P(=0)H, and phosphine oxides R2P(=0)H to unsaturated substrates. Although the addition of P-H bonds can be sometimes achieved directly, the transition metal-catalyzed reaction is usually faster and may proceed with a different stereochemistry. As in hydrosilylations, palladium and platinum complexes are frequently employed as catalyst precursors for P-H additions to unsaturated hydrocarbons, but (chiral) lanthanide complexes were used with great success for the (enantioselective) addition to heteropolar double bond systems, such as aldehydes and imines whereby pharmaceutically valuable a-hydroxy or a-amino phosphonates were obtained efficiently. 

There is a wide variety of commercially available chiral stationary phases and mobile phase additives.32 34 Preparative scale separations have been performed on the gram scale.32 Many stationary phases are based on chiral polymers such as cellulose or methacrylate, proteins such as human serum albumin or acid glycoprotein, Pirkle-type phases (often based on amino acids), or cyclodextrins. A typical application of a Pirkle phase column was the use of a N-(3,5-dinitrobenzyl)-a-amino phosphonate to synthesize several functionalized chiral stationary phases to separate enantiomers of... 

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. 

Groger, H., Saida, Y., Sasai, H., Yamaguchi, K., Martens, J., and Shibasaki, M., A new and highly efficient asymmetric route to cyclic a-amino phosphonates the first catalytic enantioselective hydrophosphonylation of cyclic imines catalyzed by chiral heterobimetallic lanthanoid complexes, /. Am. Chem. Soc., 120, 3089, 1998. 

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2-63). 

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 reactions of dimethyl phenylphosphonite with acid chlorides, a-halogeno-ketones, and iV-(bromomethyl)phthalimide have been used to prepare acyl phos-phinates, /3-keto-alkylphosphinates, and phthalimidomethylphosphinates as intermediates in the synthesis of a-diazophosphinic esters.39 a-Amino-phosphonates have also been prepared by the addition of secondary phosphites to nitriles40 and to isocyanides.41... 

Based on prior results where Ricci used Cinchona alkaloids as phase-transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48], Employing the chiral tertiary amine as a Brpnsted base, a-amino phosphonates products were synthesized in high yields and good selectivities. 

Akiyama et al. disclosed an asymmetric hydrophosphonylation in 2005 (Scheme 32) [55], Addition of diisopropyl phosphite (85a) to A-arylated aldimines 86 in the presence of BINOL phosphate (R)-M (10 mol%, R = 3,5-(CF3)j-C Hj) afforded a-amino phosphonates 87 in good yields (72-97%). The enantioselectivities were satisfactory (81-90% ee) in the case of imines derived from a,(3-unsaturated aldehydes and moderate (52-77% ee) for aromatic substrates. 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Yadav and co-workers have described a general method for the reaction between benzaldehyde, benzylamine and diethyl phosphite. In the presence of KSF clay, a-amino phosphonates were formed in a few minutes under microwave irradiation, Scheme 5.35. 

Kaboudin, B. and Nazari, R., Microwave-assisted synthesis of 1-aminoalkyl phosponates under solvent-free conditions, Tetrahedron Lett., 2001, 42, 8211-8213 Yadav, J.S., Subba Reddy, B.V. and Madan, Ch., Montmorillonite clay-catalyzed one-pot synthesis of a-amino phosphonates, Synlett, 2001, 1131-1133. 

Keywords aldehyde, ketone, primary amine, diethyl phosphite, montmorillonite KSF, microwave irradiation, a-amino phosphonate... 

Aldehyde/ketone (5 mmol), amine (5 mmol), diethyl phosphite (5 mmol) and montmorillonite (1.5 g, Aldrich, montmorillonite, KSF) were admixed in a Pyrex test tube and exposed to microwave irradiation at 450 W using a (BPL, BMO, 700T, indicates the commercial name of microwave oven) focused microwave oven for an appropriate time (pulsed irradiation 1 min with 20 s interval). After complete conversion of the reaction, as indicated by TLC, the reaction mixture was directly charged on a small silica gel column and eluted with a mixture of ethyl acetate-hexane (3 7) to afford corresponding pure a-amino phosphonate. 

Addition of phosphates to chiral sulfinimines derived from aromatic aldehydes has been used to prepare a-amino phosphonate esters asymmetrically.35 The sulfinimines employed, p- Me Ph S (= O) N=C H A r. have sufficiently bulky substituents to prevent inversion, as shown by 1H-NMR over a wide range of temperatures. 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

For a review of asymmetric catalytic approaches to a-hydroxy and a-amino phosphonates, see H. Grocer,... 

A BINOL-derived phosphoric acid derivative has been used as a catalyst in the enantioselective synthesis of a-amino phosphonates via hydrophosphonylation of imines with diisopropyl phosphite.82... 

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. 

The phosphonic amino acids are also an important class of compounds with applications as antibiotics, antiviral agents, and enzyme inhibitors. The first example of electrophilic amination of a-cuprophosphonates 14 was reported by Genet and co-workers [5a]. This route has opened new access to N-protected a-amino phosphonic derivates 15 from the corresponding phosphonates 13 (Scheme 5). 

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. 

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