Enatioselectivity

In the final part of this chapter, the focus is on the general methods to direct the configurational outcome of enantioselective reactions. This means we can leave out everything connected with auxiliaries. Here, the directing amounts just to the choice of the other enantiomer, and the same is true for large areas of homogeneous catalysis [103]. 

As far as heterogeneous catalysis goes, the chances to mechanistically completely understand and, as a consequence, be able to predict the configurational result are still quite limited. 

This then leaves deficits for the directing of processes. 

Since face selectivity is the decisive challenge in transforming prochiral centers into configurationally well-defined chiral centers, it will be worthwhile to discuss the methods to achieve face selectivity. 

As probably the most important and certainly very powerful approach, one has to mention substrate-directed reactions. There are various properties of a substrate that may influence the steric course of a reaction, and the simplest and obvious 

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Scheme 31 Diastereoselective and enatioselective Cu-catalyzed reaction of keto-unsatur-ated esters...

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Tanaka et al.28 have synthesised a series of (S)-chiral Schiff bases as the highly active (yield 69-99%) and enatioselective (ee 50-96%) catalysts in the reaction of addition of dialkylzinc to aldehydes. The stereochemistry of the asymmetric addition was suggested. In a transition state when S-chiral Schiff base was used as chiral source, the alkyl nucleophile attacked Re face of the activated aldehyde and formed the R-configuration alkylated product [13]. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

An inversion of enantioselectivity was observed experimentally for the hydrosilylation of a series of para-substituted styrenes as shown in Table 1. We intend to examine the nature of the enatioselectivity by studying the catalytic cycle for styrene which reacts to give predominately the S form of the product (64% S ee) and for 4-(dimethylamino)styrene, which gives predominately the stereochemical opposite product (64% R ee). Although we have already examined the hydrosilylation of styrene in Section 3 and 4, in this section we focus on enantioselectivity of the catalytic process for comparison to the hydrosilylation with 4-(dimethylamino)styrene. 

A detailed study of the mechanism of the enantioselective palladium catalyzed hydrosilylation of styrene with trichlorosilane was carried out with combined QM/MM ab initio molecular dynamics simulations. A number of fundamental mechanistic questions have been addressed, including the main features of the catalytic cycle, as well as the specific nature of the regioselectivity and enatioselectivity. 

To examine the nature of the enatioselectivity of the catalysis we have examined the catalytic cycle with two substrates, styrene which leads to predominantly the R form of the product (64% ee) and 4-(dimethylamino)styrene which gives predominantly the S form of the product (67% ee). Our simulations suggest that the t 3-allylic coordination of the styrene substrate plays an important role in defining the enatioselectivity of the hydrosilylation. As a first step, this theoretical study constitutes a valid contribution in rationalizing the enantioselective determining factors and possibly in designing a new catalyst with improved enantioselective properties. We are currently examining nature of the enantioselectivity in more detail as well as the dependence of the enantioselectivity on the electronic nature of the substrates [58]. 

Brussee, J. and van der Gen, A., Biocatalysis in the enatioselective formation of chiral cyanohydrins, valuable building blocks in organic synthesis. In Stereoselective Biocatalysis, Patel, R.N. (ed.). Dekker New York, 2000, pp. 289-320. 

Various polymer-bound (polystyrene-bound) oxazaboroHdine catalysts for the reduction of secondary alcohols were reported [128]. These can simply be prepared by condensation of the resin-bound boronic acid with chiral 1,2-amino alcohols. The best results as far as enatioselectivity is concerned were obtained with oxaza-borohdine (59) (Scheme 4.36). 

The 2//-azirine may be optically active and therefore be regarded as a chiral building block for enatioselective synthesis. This opens a wide field of investigation and recently efforts have been made to produce optically pure azirines. Considering the anionic displacement as the main pathway (and not the nitrene pathway), the Neber reaction may be modified to serve as a synthetic tool for the production of optically active 2//-azirine intermediates. 

Mononuclear oxazolines are among the most effective ligands for enantioselective hydrogenation of nonfunctionalized alkenes." " The styrene substrate 597 is one of the most studied nonfunctionahzed alkenes used to evaluate the efficiency of new chiral ligands (Scheme 8.185). Selected examples of enatioselective hydrogenation of 597 using iridium catalysts are shown in Table g jg 359,425,426,457-459... 

The general affinity of guanidinium cations for oxoanions and the spatial direction of the two NH-protons makes the bicycloguanidinium core presented in the preceding chapters also a useful building block for the design of nucleotide receptors [96]. Besides carboxylates (see Sect. 2), bis(naphthoyl) host 12a binds several phophoesters in chloroform, for example, l,r-binaphthyl-2,2 -diyl phosphate the complex of the (S)-enantiomer is shown in formula 64. Still, despite the chiral nature of 12a, no enatioselectivity was observed [97]. 

Enatioselectivity for the reduction improves as the size differential of the groups on the carbonyl increases. 

Since the seminal work by Tatchell s group, many efforts have been directed to developing a highly enatioselective reduction of ketones.11 One successful... 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

Fehr, C. Enatioselective Rrotonation of Enolates and Enols, Angew. Chem., Int. Ed. Engl. 1996,35,2566-2587. 

Scheme 9 Enzyme-mediated chemical transformations. (A) Enatioselective enzymatic oxidation and lactonization (B) enzyme reduction with baker s yeast and enantioselective rule and (C) enzymatic hydrolytic desymmetrization.

Related results suggest that the catalyst has a rigid stereochemistry throughout the catalytic cycle [19, 20], a conclusion which had already been drawn for enatioselective cyclopropanation [21] (cf. Section 3.1.7). In some cases even yff-lactones could be obtained as major products when using this catalyst [22]. In general, acyclic diazoacetates give higher yields of /9-lactones than cyclic ones [23]. 

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