Chiral phosphonic acids

Highly enantioselective Mannich-type reactions of A-(2-hydroxyphenyl) aldi-mines with ketene trimethylsilyl acetals and of A-Boc-aldimines with acetyl acetone or furan are catalyzed by chiral phosphonic acids 9 derived from 3,3 -diaryl-(l )-BlNOL and POCI3 (Scheme 12.7). ... 

The asymmetric synthesis of chiral phosphonic acids has been accomplished starting from alkyl phosphonamides 5 derived from MiV -dimethyl-diaminocyclohexane, which are easily prepared by condensation with alkyl phosphonic dichlorides (eq 7). Upon... 

Schaper derived equations to describe the nonlinear dependence of the biological activities of racemates at different concentrations on the activities of the pure enantiomers [875]. Not only quantitative but also qualitative differences were observed for the QSARs of different enantiomers of chiral phosphonic acids a linear dependence of butyrylcholinesterase inhibition on chain length resulted for the ( + ) enantiomers, while a clear bilinear dependence was observed for the (—) isomers [876]. 

Freire and coworkers described the intercalation of a chiral phosphonic acid derivatised [Mn (sa/e )Cl] complex within KlO-Montmorillonite layers by ion-exchange with the interlayer potassium cations. The catalytic performance of the heterogeneous catalyst (denoted as [Mn (sa/en)Cl] K10) was evaluated in the enantioselective epoxidation of styrene, a-methylstyrene and 6-cyano-2,2-dimethylchromene, at 0 °C in dichloromethane or acetonitrile, using three different oxidant systems m-CPBA/NMO, PhIO and NaOCl the results are summarised in Table 11.1. 

Chiral phosphonous acid diester induces the kinetic resolution of racemic a-substituted y-unsaturated carboxylic acids through asymmetric protolac-tonization (Scheme 53) (130L2838). Dinamic kinetic resolution with Candida antartica lipase B and the ruthenium catalyst [RuCl(CO)2(T -C5Ph5)] of several homoallylic alcohols is applied in the key step to the synthesis of enantiomericaUy pure 5,6-dihydro-2ff-pyran-2-ones ( [13CEJ13859]). 

In recent years, several papers have been published on the combination of an organometaUic catalyst with a chiral phosphonic acid in order to achieve enantioselective reduction of an imine. This obviates the requirement for a Hantzsch base by replacing it with the combination of an organometaUic complex and hydrogen gas. However, since these involve the use of hydrogen gas, they are technically outside the scope of this review, although a recent overview is highlighted [152] and one example is illustrated (Fig. 45) [153]. 

Two chiral phosphonic acid derivatives 19a,b, containing a stereogenic phosphorus atom connected to a mercaptoisoborneol moiety, were prepared as a mixture, and were then chromatographically separated. Their ability in asymmetric carbonyl olefination was examined in the reaction with 4-tert-butylcyclohexanone la [56). The two lithium carbanions reacted with the carbonyl group of the substrate to give opposite enantiomers 90a, although no remarkable degree of asymmetric induction was observed (up to 16% ee). 

Chiral cyclic esters of phosphonic acid in the synthesis of coordination compounds and homogeneous asymmetric catalysis 99KK83. 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Hoppe, I., Schollkopf, U., Nieger, M., and Egert, E., Asymmetric addition of a chiral cyclic phosphite to a cyclic imine — synthesis of phosphonic acid analogues of d- and L-penicillamine, Angew. Chem., Int. Ed. Engl., 24, 1067, 1985. 

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... 

More recently, the chiral phosphonate 85 has been used as a CDA with chiral amines to form diastereomeric phosphonic amides (86)79 which are analyzed by 31P-NMR spectroscopy for the determination of enantiomeric ratios. The reagent is readily prepared from (5)-2-butanol and phosphorous trichloride, and all a-amino acids and amines thus far examined react quantitatively in a few hours at room temperature in aqueous ethanol79. 

Evans has reported that the cationic C2-symmetric chiral Lewis acid Cu(ll)bis(oxazoline) complex promotes the hetero-Diels-Alder reaction of 0 ,/3-unsaturated acyl phosphonates with enol ethers to give the cycloadducts with excellent ee (Scheme 52). As well as simple dihydropyrans, various fused bis-dihydropyrans are also reported <1998JA4895, 2000JA1635>. 

The reaction of phosphonic acid chloride (254) with (S)-proline ethyl ester afforded a mixture of diasteromeric amides (255) in high diastereoselectivity. The diastereomers (255) can easily be purified by chromatography. The chiral, practically optical pure organophosphorus compound (256) was obtained from purified (255) by acid alcoholysis. 

The synthesis of chiral w-amino phosphonic acids (analogues of natural amino acids) may be accomplished from imines. The key step in this synthesis is the formation of an aziridine by reaction of a phosphonamide with an imine (equation 153)555. The reaction occurs in very good yield in THF, at —78 °C with BuLi. 

By the alkylation of N-benzoyl uracil with the chiral 2-trityloxy-oxirane was obtained glycoside-like derivative N-[l-(2-hydroxy-3-trityloxy-propyl)-2-oxo-l,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide as a single isomer. From N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-l,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide and toluene-(4-sulfomethyl)phosphonic acid diethyl ester was prepared [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-l-yl]-l-trityloxymethylethoxymethyljphosphonic acid diethyl ester. As a result of... 

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. 

Akiyama T, Morita H, Itoh J, Fuchibe K (2005a) Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of alpha-amino phosphonates. Qrg Lett 7 2583-2585 Akiyama T, Saitoh Y, Morita H, Fuchibe K (2005b) Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid derived from TADDOL. Adv Synth Catal 347 1523-1526... 

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