Templates, enantioselective synthesis

Wulff and his collaborators reported, in 1989, the preparation of imprinted polymers able to perform enantioselective synthesis [11, 12]. The imprinting complex was prepared by reacting 3,4-di-hydroxy-phenyl-alanine methyl-ester (l-DOPA methyl ester) (16) with the 4-vinyl-salicylaldehyde (17) to form the corresponding Schiff s base (18), which was further reacted with the 4-vinyl-phenyl-boronic acid (19) to afford to the corresponding ester (20) (Scheme 4). The imprinting complex obtained was then polymerised and the template removed. The resulting polymers were incubated with sodium glycinate to allow formation... 

Giovenzana, G.B., Pagliarin, R., Palmisano, G., Pilati, T., and Sisti, M., Camphor-based oxazaphos-pholanes as chiral templates for the enantioselective synthesis of a-chlorophosphonic acids. Tetrahedron Asymmetry, 10, 4277, 1999. 

Scheme 10-130 Methyl 7-deoxycholate provides a chiral template for the enantioselective synthesis of the binaphthyl compound 401.

The interaction of artificial metal ions/complexes with peptides/proteins [11], nucleic acids/DNA [12,13], enzymes [14], steroids [15] and carbohydrates [16] forms a bridge between natural and artificial macromolecular metal complexes. Biometal-organie chemistry concentrates on such complexes [17]. The reason for the increasing interest in this field lies in medical applications of metal complexes (cancer, photodynamic therapy of cancer, immunoassays, fluorescence markers, enantioselective catalysis, template orientated synthesis of peptides, etc.). Figure 2-4 presents an overview of metals in medicine [18]. Some examples are given below. 

Wulff, G. Vietmeier, J. Enzyme-analogue built polymers, 26. Enantioselective synthesis of amino adds using polymers possessing chiral cavities obtained by an imprinting procedure with template molecules. Makromol. Chem. 1989,190, 1727-1735. 

A conceptually diHerent, convergent route was developed in 2006 by Nicolaou and Harrison [35, 146] for the enantioselective synthesis of 290 and 291. On the basis of an enantioselective Mg(II)-templated Diels-Alder reaction between chiral dienol 292 and methyl acrylate and on previous model studies to build the spirotetronic core [143c], Nicolaou prepared a ring-closing metathesis (RCM) precursor (296) that smoothly afforded atropoisomer 290 after oxidation and deprotection (Scheme 1.45). Nicolaou also observed that 290 and 291 participate in an acid-catalyzed intercorversion leading to equilibrium mixtures of various ratios depending on the acidic media. 

Swango JH, Bhatti BS, Qureshi MM, Crooks PA. A novel enantioselective synthesis of (5)-(—)-and (R)-(+)-nornico-tine via alkylation of a chiral 2-hydroxy-3-pinanone keti-mine template. Chirality 1999 11(4) 316-318. 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

J. D. Elliott, V. M. F. Choi, and W. S. Johnson, Asymmetric synthesis via acetal templates. 5. Reactions with cyanotrimethylsilane. Enantioselective preparation of cyanohydrins and derivatives, J. Org. Chem. 78 2294 (1983). 

Similar features may be achieved with organic polymeric materials. Template imprinting of complementary cavities containing appropriate functional groups yields models of enzyme active sites [7.34, 7.35, 7.75]. They perform the synthesis of amino acids with enantioselectivity [7.76] or the esterolysis of activated esters by TSA imprinting [7.77]. 

Diols such as the optically active 1,1 -binaphthyl-2-2 -diol (BINOL) have been used as versatile templates and chiral auxiliaries in catalysts employed successfully in asymmetric synthesis. The application of enzymes in the enantioselective access to axially dissymmetric compounds was first reported by Fujimoto and coworkers.83 In aqueous media, the asymmetric hydrolysis of the racemic binaphthyl dibutyrate (the ester) using whole cells from bacteria species afforded the (A)-diol with 96%ee and the unreacted substrate (A)-ester with 94% ee at 50 % conversion. Recently, in non-aqueous media, lipases from Pseudomonas cepacia and Ps. fluorescens have been employed in the enantioselective resolution and desymmetrization of racemic 6,6 -disubstituted BINOL derivatives using vinyl acetate.84 The monoacetate (K)-73 (product) was obtained in 32-44 % chemical yields and 78-96% ee depending on the derivatives used. The unreacted BINOL (S)-72 was obtained in 30-52 % chemical yield and 55-80% ee. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

Camphor and camphor-derived analogues are used frequently as chiral auxiliaries in asymmetric synthesis (cf Chapter 23). 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 phos-phonic acids, a-substituted benzylamines, and a-amino alcohols (e.g., Scheme 5.9).43 47 Enantiomeric excesses of the products range from poor to excellent depending on the type of alkyl halides used. 

Fig. 25 Enantioselective non covalent synthesis of double rosettes exploiting the chiral memory effect. Pyridyl residues on the dimelamine units bind chiral dicarboxylic acids leading mainly to one diastereoisomer. Once the chiral templating carboxylic acid is removed by precipitation, the enantioenriched double rosette persists for several hours...

In this work, the synthesis of high surface densities of chlororopropyl groups covalently grafted on mesoporous micelle templated aluminosilicates (Al-MTS) of various initial pore diameters is presented. The hybrid chiral materials resulting from halogen substitution are applied in the enantioselective addition of diethylzinc to benzaldehyde. 

Angew. Chem. Int. Ed. Engl. 44, 3668-3688, 2005 Kent, M. and Tepe, J.J., One-pot Friedel-Crafts/ Robinson-Gabriel synthesis of oxazoles using oxazolone templates, J. Org. Chem. 70, 4211 213, 2005 Movassaghi, M. and Ondrus, A.E., Enantioselective total synthesis of tricyclic myrmicarin alkaloids, Org. Lett. 7, 4423 426, 2005 Paizs, C., Katona, A., and Retey, J., The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase form parsley. Chemistry 12, 2739-2744, 2006. Cuprous ions have been observed to promote a Friedel-Crafts acylation reaction (Kozikowski, A.P. and Ames, A., Copper(l) promoted acylation reactions. A transition metal-mediated version of the Friedel-Crafts reaction, J. Am. Chem. Soc. 102, 860-862, 1980). 

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