Achiral catalysts

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

A combination of the Lewis acid zinc triflate and the bases NEt, or pyridine acted as an achiral catalyst for this reaction. Instead, using a chiral base which incorporates a bipy ligand to bind zinc gave 26% ee of the product (Scheme 5-42a). Alternatively, diethylzinc was an active precatalyst, but attempts to use chiral amino alcohols as ligands in this system gave low ees (Scheme 5-42b) [31]. 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

Fig. 12.22 CH2- and CH3-resonances observed in the -PHIP-NMR spectrum of the intermediate attached to an achiral catalyst during the hydrogenation of styrene.

C=C reduction. The achiral catalysts are relatively cheap, easy to prepare/handle, and sufficiently active to set SCRs near the threshold for Ru content in pharma products. This suggests that these catalysts could certainly be competitive, easy to operate in hydrogenations in which heterogeneous catalysts are less effective, and thereby also worthy of investigation in other cases. 

Marks and coworkers developed a series of cyclopentadienyl-lanthanide complexes. In the initial investigations on achiral catalysts 36a and 36b (Fig. 29.21), TOFs greater than 100000 IT1 were observed in the hydrogenation of 1,2-disub-stituted unfunctionalized alkenes [48]. 

TADDOL ligand over the competing (achiral) catalyst [Ti(OPr1)4]. The rate enhancement by the TADDOL ligands is due to an increase in the rate of ligand exchange in the TADDOL complex over the Ao-propoxyl complex because of the steric bulk of the TADDOL compared with two Ao-propoxides. 

Specific control of the stereochemistry of the chemical reaction is better achieved using chiral phase-transfer catalysts. These catalysts interact specifically with the substrate and sterically hinder the approach of nucleophile to one face of the reactive site. Experimental procedures are essentially the same as those employed in reactions using achiral catalysts where there is no stereochemical control and, in subsequent sections, reference is made back to the appropriate Chapter unless variations in the procedure differ significantly. 

Above we mentioned the results reported by Ewen [13] who found that Cp2TiPh2/alumoxane gives a polypropene with isotactic stereoblocks. Naturally, this achiral catalyst can only give chain-end control as it lacks the necessary chiral centre for site control. In the 13C NMR the stereoblocks can be clearly observed as they lead to the typical 1 1 ratio of mmmr and mmrm absorptions in addition to the main peak of mmmm pentads. These are two simple examples showing how the analysis of the 13C NMR spectra can be used for the determination of the most likely mechanism of control of the stereochemistry. Obviously, further details can be obtained from the statistical analysis of the spectra and very neat examples are known [18],... 

So far we have looked at chain-end control and site control if they were independent. As already mentioned, a site-control-o /y mechanism does not exist. Since we are, by definition, making a chiral chain-end and since chain-end control does occur as found in achiral catalyst systems, site control must be accompanied by chain-end influences, or a(n) (a)symmetric site may amplify specific chain end influences. Recent results have shown that this is indeed the case [18,19,21,26], The simple explanation given above has to be modified. We limit ourselves to two issues, (a) the stereochemistry of the coordinating propene and (b) reinforcement of the two mechanisms. 

The following general features were found for Ir-catalyzed allylic substitutions with achiral catalysts [6, 11]. Points (b)-(e) are illustrated by Scheme 9.2. 

Analysis of the results presented in Figure 6.20 (conversion versus time) and Table 6.14 indicates that for both the monometallic and the achiral catalysts the reaction rate was lower than the corresponding values observed in the hydrogenation of acetophenone. This fact has been explained in terms of the mesomeric effect due to the -OCH3 in para position, which causes a higher repulsion between... 

Roles that are normally associated with metals as Lewis acids and as redox agents [4,5], can be emulated by organic compounds. This review will introduce the reader to the research field of Lewis acid organocatalysts. This field, compared to other types of organocatalysts, which are highlighted in the other chapters of this volume, is still limited. The number of asymmetric catalyzed examples is small, and the obtained enantiomeric excess is sometimes low. Therefore, this review will also cover a number of reactions promoted by achiral catalysts. Nevertheless, due to the broad variety of possible reactions, which are catalyzed by Lewis acids, this research field possesses a large potential. 

The present procedure involving homogeneous catalysis is operationally simple and takes advantage of the easy availability of 2-(l -hydroxyalkyl )-acrylic esters. A two-step procedure Involving kinetic resolution of the racemic starting material with an optically active hydrogenation catalyst, followed by a further reduction with an achiral catalyst, leads to diastereomerically pure products in 4. 97t ee. 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

Katsuki has extended his earlier work on asymmetric induction using achiral catalysts such as 13. In these systems, the stereochemical bias is imbued by a chiral non-racemic axial ligand, such as (+)-3,3 -dimethyl-2,2 -bipyridine A2,A -dioxide (14), which was purified by crystallization with (5)-binaphthol. Epoxidation using these conditions resulted in good ee s and fair yields, as exemplified by the preparation of chromene epoxide 16 <99SL783>. 

A second way (method ) uses a chiral auxiliary by converting the propenoic acid into an amide. Catalytic hydrogenation with the achiral catalyst 5 shows a modest diastereoface selection, 6/7 1.9 1. Both methods lead to the (5) configuration at C-2 and combining the effects, i.e., chiral auxiliary with ( + )-3 ( matched combination ), increases the (5) selectivity from 11 1 to 16 1 (calculated value 11 x 1.9 = 21 1). In contrast, the use of the chiral auxiliary with (—)-3 counteracts the inherent (S) induction in the starting amide ( mismatched combination ) and favors (R) induction, 6/7 1 4.5 (calculated value 1.9 11 = 1 6). 

If an asymmetric hydrogenation of C=C bonds is desired in the presence of achiral catalysts, chiral information is required to be present in the substrate. Peptides and cyclopeptides containing dehydroaminos acid units are very good substrates achieving quite high stereoselectivities upon asymmetric hydogenation on 10% Pd-C or other achiral catalysts 49 841. 

In the asymmetric hydrogenation of the (R)-phenylglycine derivative (54) in the presence of an achiral catalyst the stereoselectivity was reported 89) to be low. The lactone (55) could subsequently be converted into (S)-aspartic acid 89). This reaction sequence is an example of the intramolecular transfer of chirality with subsequent disappearance of the original chiral center. 

Optically inactive reactants with achiral catalysts or solvents yield optically inactive products. With a chiral catalyst, e.g., an enzyme, any chiral product will be optically active. 

As discussed in this chapter, the fundamental host-guest chemistry of 1 has been elaborated to include both stoichiometric and catalytic reactions. The constrained interior and chirality of 1 allows for both size- and stereo-selectivity [31-35]. Additionally, 1 itself has been used as a catalyst for the sigmatropic rearrangement of enammonium cations [36,37] and the hydrolysis of acid-labile orthoformates and acetals [38,39]. Our approach to using 1 to mediate chemical reactivity has been twofold First, the chiral environment of 1 is explored as a source of asymmetry for encapsulated achiral catalysts. Second, the assembly itself is used to catalyze reactions that either require preorganization of the substrate or contain high energy intermediates or transition states that can be stabilized in 1. 

Amplification of Chirality. Perhaps the most striking of the nonclas-sical aspects that emerge from the enantioselective alkylation is the phenomenon illustrated in Scheme 22 (3, 14, 16, 20k, 40). A prominent nonlinear relation that allows for catalytic chiral amplification exists between the enantiomeric purity of the chiral auxiliary and the enantiomeric purity of the methylation or ethylation product (Scheme 23). Typically, when benzaldehyde and diethylzinc react in the presence of 8 mol % of (-)-DAIB of only 15% ee [(-) (+) = 57.5 42.5], the S ethylation product is obtained in 95% ee. This enantiomeric excess is close to that obtained with enantiomerically pure (—)-DAIB (98%). Evidently, chiral and achiral catalyst systems compete in the same reaction. The extent of the chiral amplification is influenced by many factors including the concentration of dialkylzincs, benzaldehyde, and chiral... 

With an amino ester as nucleophile, the example shown in Equation 8E.5 demonstrates that the catalyst rather than the substrates can dominate in determining the diastereoselectivity. The 3 1 selectivity exhibited in the alkylation with the achiral catalyst was increased to 19 1 with (/ ,/ )-5 whereas the (S,5)-5, under identical conditions, gave a 1 3 ratio. 

The chiral hydrogenation of ketimines can be performed either by the hydrogenation of compounds containing a chiral auxiliary group on achiral catalysts, or by hydrogenating achiral ketimines on chiral catalysts. Some examples for diastereoselective hydrogenation of ketimines can be seen in equations 51-53. 

Diazoacetamides are also exceptional substrates for dirhodium carboxamidate-catalyzed reactions, although with these substrates a mixture of /3-lactam and y-lactam products are formed [8]. The rhodium carboxamidate catalyst can have a major effect on the ratio of products formed. A good synthetic example is the Rh2(4S-MPPIM)4)-catalyzed synthesis of (-)-hcliotridanc 11 (Scheme 5) [9]. The key C-H insertion step of 9 generated the indolizidine 10 in 86 % yield and 96 % de, whereas reaction of 9 with achiral catalysts tended to favor the opposite diaster-eomer. 

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