Substrates, reactions of prochiral

The asymmetric synthesis of allenes by stereoselective manipulations of enantio-merically pure or enriched substrates relies on the availability of such optically active substrates. In contrast, a direct synthesis of allenes by the reaction of prochiral substrates in the presence of an external asymmetric catalyst is an almost ideal process [102]. Most of the catalytic asymmetric syntheses in organic chemistry involve the creation of chiral tetrahedral carbon centers [103], whereas the asymmetric synthesis of allenes requires the construction of an axis of chirality. 

In ordinary reagent- or catalyst-based enantioselective reactions of prochiral substrates (equations 4 and 5, respectively), 100% enantiomeric purity of the chiral source is assumed, and the major concern is the efficiency of the chirality transfer from the chiral source to the substrate, namely, optical yield. In some special cases, however, a chiral metal complex can even amplify chirality (equation 6). A catalyst that is itself only partially resolved may form a chiral product with very high enantiomeric purity (24) (Chapter 5). 

Many of the copper-mediated transformations summarized in the previous sections of this chapter can also be performed efficiently with catalytic amounts of copper salts or reagents. Indeed, some of the copper-catalyzed reactions have been discovered before the development of stoichiometric organocopper reagents. The focus of the last decade has been put on new copper-catalyzed transformations (e.g., conjugate reductions) and in particular on the discovery of chiral copper catalysts for highly enantioselective 1,4-addition and S -substitution reactions of prochiral substrates. 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

Reetz and coworkers developed a highly efficient method for screening of enantioselectivity of asymmetrically catalyzed reactions of chiral or prochiral substrates using ESI-MS [60]. This method is based on the use of isotopically labeled substrates in the form of pseudo-enantiomers or pseudo-prochiral compounds. Pseudo-enantiomers are chiral compounds which are characterized by different absolute configurations and one of them is isotopically labeled. With these labeled compounds two different stereochemical processes are possible. The first is a kinetic separation of a racemic mixture, the second the asymmetric conversion of prochiral substrates with enantiotopic groups. The conversion can be monitored by measuring the relative amounts of substrates or products by electrospray mass spectrometry. Since only small amounts of sample are required for this method, reactions are easily carried out in microtiter plates. The combination of MS and the use of pseudo-enantiomers can be used for the investigation of different kinds of asymmetric conversion as shown in Fig. 3 [60]. 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

In summary, the 1,3-dipolar cycloaddition allows the production of various 5-membered heterocycles. Many reactions can be performed with high regioselectivity and even enantioselective transformations of prochiral substrates. 

Similar to the conjugate addition, the focus of the last decade has been put on the development of chiral copper catalysts for enantioselective S -substitutions of prochiral substrates.197,197a,197b 271,285 These represent a useful alternative for the preparation of those substitution products which cannot be obtained by anti-stereoselective copper-promoted or -catalyzed SN2 -substitution of chiral substrates (see Section 9.12.2.1.2). The first reported example for such a transformation is the reaction of the allyl acetate 333 with //-butylmagnesium bromide in the presence of 15 mol.% of the copper arenethiolate 334 which gave the substitution product 335 with exclusive y-selectivity and 50% ee (Equation (18)),286 286a... 

The efficiency of these chiral host compounds has been shown in highly enantioselective photocyclization and photocycloaddition reactions of prochiral lactams. These substrates, for example 2-quinolone derivatives, are expected to coordinate to lactam 44 with its NH-group as the hydrogen donor and the carbonyl group as the hydrogen acceptor, as depicted in Scheme 15. In this complex, any... 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

Figure 2.1 Difference in the Gibbs free energy change (4AC ) for the R and S transition states as a function of product enantioselectivity for the reaction ofa prochiral substrate for the R and S enantiomers. A subtle difference (1.78 kcal mol ) in the energy for the R and 5 transition states makes a big difference in the enantioselectivity (98% ee) at-78°C.

Optimization of the enantioselective catalytic key steps calls for careful experimental investigation of many reaction parameters. Besides temperature, concentration of substrate, solvent effects, pressure, and conversion rate, a defined robustness of the process towards impurities, for example contained in reagents, as well as its sensitivity towards air (oxygen) or moisture at various temperatures are important aspects. In particular, the purity of prochiral substrates is of utmost importance for the success of asymmetric hydrogenation experiments. As a consequence, considerable attention had to be paid to even the smallest differences in the impurity profile of substrates, which may be due to different preparation and/or purification procedures at lab, pilot, or production scale. 

Substituting a phosphine with a polyether chain may also make the phosphine water-soluble. However, diphosphines of the type 15 (Structures 15-17) are only soluble in water when n > 15 [24]. This type of materials can also be used to prepare thermally responsive catalysts [58]. Other examples related to 15 are the class of compounds 16 (cf. Section 3.2.2.3 n = 12, 16, 110) and 17 (n= 18) [12, 25]. The number n gives the average value of the degree of polycondensation . So far, these polyether-based diphosphines have mainly been used in asymmetric hydrogenation of prochiral substrates such as a-acetamidocinnamic acid where ee values vary from 11 to 91% depending on the reaction medium and ligand used (cf. Section 4.6.3). 

While effective bimetallic catalyst design has the potential to lead to an enhancement of the reaction rate, the use of chiral bimetallic catalysts has also been explored to enhance the enantioselectivity of a reaction. Such bimetallic chiral induction is excellently demonstrated by the use of digold catalysts for the hydroamination of prochiral substrates such as allenes and alkenes [59]. The bimetallic Au catalyst 66, for example, was shown to be an effective catalyst for the hydroamination of amino-allenes in the presence of a silver salt activator (Scheme 24) [106]. The highest enantioselective induction for this reaction was achieved with a 1 1 ratio of AgBp4 to 66 (51 % ee) suggesting that the monocationic... 

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