Two-point binding

Ghosh et al. [70] reviewed a few years ago the utihty of C2-symmetric chiral bis(oxazoline)-metal complexes for catalytic asymmetric synthesis, and they reserved an important place for Diels-Alder and related transformations. Bis(oxazoline) copper(II)triflate derivatives have been indeed described by Evans et al. as effective catalysts for the asymmetric Diels-Alder reaction [71]. The bis(oxazoline) Ugand 54 allowed the Diels-Alder transformation of two-point binding N-acylimide dienophiles with good yields, good diastereos-electivities (in favor of the endo diastereoisomer) and excellent ee values (up to 99%) [72]. These substrates represent the standard test for new catalysts development. To widen the use of Lewis acidic chiral Cu(ll) complexes, Evans et al. prepared and tested bis(oxazoHnyl)pyridine (PyBOx, structure 55, Scheme 26) as ligand [73]. 

A new application of bis(oxazolines) ligands was reported by Reiser et al. who obtained some excellent results, such as that depicted in Scheme 2.14 for the 1,4-addition of ZnEt2 to 2-cyclohexenone. These authors used a bimetallic complex in which the substrate was locked in a two-point binding mode via a zinc atom and a copper atom. 

The utility of bis(oxazoline)-Cu(II) complexes as catalysts for the Diels-Alder reaction has been examined in a number of other systems. Aggarwal et al. (205) demonstrated that a-thioacrylates behave as effective two-point binding substrates for these catalysts. With cyclopentadiene, catalyst 271d induces the reaction at -78°C to provide the cycloadduct in 94 6 diastereoselectivity and >95% ee. Aggarwal proposes that the metal binds to the carbonyl oxygen and to the sulfur atom. The sulfur substituent is placed opposite the ligand substituent thereby shielding the bottom face of the alkene. Considerably lower selectivities are observed with 5-Me substrates. 

With Chiral Bis(oxazoline)/Mg Complexes A chiral bis(oxazoline)/MgI2 complex has been utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and ethyl 2-benzoylacrylate that acts as a two-point binding dienophile [49] (Eq. 8A.27). This reaction proceeds with virtually complete endo/exo selectivity (>99 1). 

Fig. 6.11 Akiyama s two-point binding model for phosphoric acid catalysis.

It is worth mentioning that chiral N,N-dialkylhydrazones (SAMP, RAMP) had been introduced by Enders for asymmetric a-alkylation of carbonyl compounds [29], and addition of organometallic reagents to the C=N bond had also been demonstrated ([30] selected organometallic additions to other chiral hydrazones [31-34]). However, the SAMP and RAMP hydrazones require a multistep preparation, and lacked a carbonyl function for two-point binding, which we regarded as a key design element (see below). 

Although the aforementioned routes provided the desired y-amino acids, it was desirable to develop a synthesis which incorporates the carboxylic acid oxidation state prior to coupling. We hypothesized that manganese-mediated radical addition would accomplish this objective, and therefore initiated a study of manganese-mediated coupling of alkyl iodides with y-hydrazonoesters [104]. We had already shown that the manganese-mediated radical addition conditions offer excellent chemoselectivity, but it remained to be seen whether the stereocontrol model would be disrupted would an additional Lewis basic ester function in the hydra-zone interfere with the role of In(III) in two-point binding and rotamer control ... 

Fig. 2 Representation of the proposed two point binding mode of aspirin (green) inside superbowl 17a. The front wall cavitand of 17a, hydrogen atoms and n-pentyl feet are omitted for clarity...

Related optical and fluorescent sensor systems have been widely used. For instance, the fluorescence of the pyrene unit in species (187) is quenched upon saccharide binding to the boron center. Boronic acid groups were also attached to dendrimers and polymers. The benefit of systems containing at least two boronic acid centers, as shown for the luminescent saccharide sensor (187), is that two-point binding can more effectively control saccharide binding. Similar... 

Much has been published on Lewis acid-catalyzed Diels-Alder reactions between the bidentate dienophile 3-acryloyl-l,3-oxazolidin-2-one and the prototypical diene component cyclopentadiene these afford the endo cycloaddition product with good selectivity. This reaction has become the prototype for two-point binding, Lewis acid catalyzed, asymmetric Diels-Alder reactions. For easier comparison, the data in Sch. 41 include. 

Fig. 2.15. Possible one- and two-point binding of aryldiketones to diol functionalised tem-plated binding sites. From Shea and Sasaki [69].

This difference is also evidenced by the temperature dependence of the number of theoretical plates for the two enantiomers. The template molecule shows hardly any temperature dependence because of increased two-point binding with slow binding rates at higher temperatures, whereas the number of theoretical plates for the second enantiomer increases rapidly, as expected (see Fig. 4.3a) [21]. The effect of concentration on retention is also very different for two enantiomers (see Fig. 4.3b). The wrong enantiomer does not show much effect, whereas retention of the template molecule is greatly increased at lower concentrations, at which only the most selective cavities are occupied by the template molecule. The selectivity therefore increases sharply [49]. It is interesting to notice that this chromatographic... 

With these template monomers very careful investigations on the mechanism of the imprinting procedure have been performed by Shea s group. The influence of the cooperativity of binding sites, of the shape of the cavity, and of the occurrence of one- or two-point binding has been taken into consideration. 

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