Catalysis, asymmetric

Asymmetric catalysis is an important technique for the synthesis of chiral compounds. The introduction of supported IL catalyst into the field of asymmetric catalysis might offer new approaches to improve the catalytic performance and also the reusabiUty of chiral catalysts. The first example of a supported IL asymmetric catalyst is the proUne-catalyzed aldol reaction [116]. In this work, the IL molecule covalently attached to modified silica gel was used as the support for IL-phase containing L-proUne. The modification of the silica gel surface by the IL molecule is crucial to gain high enantioselectivity. In the model reaction of acetone and benzaldehyde, the yield to 4-hydroxy-4-phenylbutan-2-one was 51% with 64% ee. Otherwise, the yield was only 38% with 12% ee without the silica gel modification. 

10 Asymmetric Catalysis 19.2.10.1 Asymmetric Diels-Alder Reactions 

Efficient asymmetric Diels-Alder reactions catalyzed by chiral Lewis acids have recently been reported [34]. Although rare earth compounds were expected to be promising Lewis acid reagents, few asymmetric reactions catalyzed by chiral rare earth Lewis acids were reported [35], although rare earth triflates, especially Yb(OTf)3 and Sc(OTf)3, are good catalysts in the Diels-Alder reactions of a variety of dienophiles with cyclic and acyclic dienes (as mentioned in Section 19.2.6). 

It was first found that a chiral Yb catalyst, prepared in situ from Yb(OTf)3, (R)-(+)-l,T-bi-2-naphthol [(l )-BINOL], and a tertiary amine, in dichloromethane, was quite effective in enantioselective Diels-Alder reactions [36]. Some additives were also found to be effective not only in stabilizing the catalyst but also in controlling enantiofacial selectivity in the Diels-Alder reaction. When 3-acetyl-l,3-oxazolidin-2-one was combined with the chiral catalyst as an additive, the (2S,3R) form of the endo adduct was obtained in 93 % ee. When, on the other hand, 3-phenylacetylacetone was mixed with the catalyst as an additive, the (2R,3S) form of the endo adduct was obtained in 81 % ee [37]. 

The chiral Sc catalyst could be prepared similarly from Sc(OTf)3, (R)-BINOL, and a tertiary amine in dichloromethane (Eq. 14) [38]. The catalyst was also found to be effective in Diels-Alder reactions of an acrylic acid derivative with dienes (Table 3). The amines employed in the preparation of the catalyst had a large influence on enan-tioselectivity. The highest enantioselectivity was observed when ds-l,2,6-trimethylpi-peridine was employed as the amine. It should be noted that even 3 mol % of the catalyst was enough to complete the reaction yielding the endo adduct with 92 % ee. 

It was found that 3-acetyl-l, 3-oxazolin-2-one or 3-benzoyI-l,3-oxazolin-2-one was a good additive for stabilization of the chiral Sc catalyst, but that enantioselectivity could not be reversed by use of additives, behaviour different from that of the chiral Yb catalyst. This can be explained by the coordination number of Sc(III) and Yb(III)—whereas Sc(III) has up to seven ligands, specific coordination numbers of Yb(III) enable up to twelve [39], 

Furthermore, he showed that these considerations apply to catalytic asymmetric syntheses and decompositions alike, though in the former the stability of the optically active state (measured by the ratio of the time required for racemate formation to the time required for attainment of maximum optical activity) will be considerably greater than in the latter. 

The application of NHC ligands in this reaction has naturally been extended to asymmetric processes. In general, the chiral induction of NHCs was low, probably due to the rapid internal rotation of the chiral substituents around the C-N axis. Also, metalation procedures involving deprotonation of a chiral azolium precursor with strong bases may cause loss of chirality in the desired complex. In contrast, the silver transmetalation route generally yields the optically active target complex. Since the first reports by Herrmann et al., and shortly after by Enders et al. in 1996-1997 on the synthesis and applications of chiral NHC-Rh complexes in the hydrosilylation of carbonyl compounds, increased efforts were made in this area.  

Herrmann et al. studied a number of monodentate NHC ligands bearing chiral groups on the backbone derived from 2,2 -bipiperidine or partially reduced bis-isoquinoline. The NHC complexes of Rh and Ir were used for the hydrogenation of methyl 2-acetamidoacrylate and all complexes exhibited 

The catalytic synthesis of an enantioselective product from a prochiral reactant is said to involve asymmetric catalysis and the catalyst is called an asymmetric catalyst. Asymmetric catalysis is found in homogeneous, heterogeneous and phase-transfer reactions. - ° This area of research gained a significant momentum after the award of a 2001 Nobel Prize to the researchers working on asymmetric catalytic chemical processes. - In the case of phase transfer catalysis, the quantitative assessment of rate enhancement is not carried out in any such catalytic reaction simply because the reaction system is just too complex for such effort. Almost all reported asymmetric catalytic reactions are involved with synthesis in which the main aim has been focused on the yield of enantioselective -zso 

Physical Chemistry, 4th ed. Orient Longmans Ltd., New Delhi, New Impression reprinted in India 1969, pp. 300-301. 

Atkins, P.W. Physical Chemistry, Oxford University Press, Oxford, UK, 1978, p. 

Effects of cetytrimethylammonium bromide (CTABr) micelles on the rate of the cleavage of phthahmide in the presence of piperidine. Colloids Surf. A 2001,181, 99-114. 

(a) Khan, M.N. The kinetics and mechanism of a highly efficient intramolecular nucleophilic reaction the cyclization of ethyl N-[o-(N-hydroxycarbamoyl)ben-zoyl]carbamate to N-hydroxyphthalimide. J. Chem. Soc. Perkin Trans. 2. 1988, 213-219. (b) Khan, M.N. Effect of hydroxy lamine buffers on apparent equilibrium constant for reversible conversion of N-hydroxyphthalimide to o-(N-hydroxycar-bamoyl)benzohydroxamic acid evidence for occurrence of general acid-hase catalysis. Indian J. Chem. 1991, 30A, in 7S3. 

Synthesis of optically pure compounds via transition metal mediated chiral catalysis is very useful from an industrial point of view. There can be produced large amounts of chiral compounds with the use of very small quantities of a chiral source. Compared to the substrate to be refined, the chiral catalyst is present in substoichiometric quantities. Therefore, asymmetric catalysis results in an economical multiplication of the chiral information contained in a small amount of catalysts. Multiplication factors up to millions are possible. 

pharmaceuticals and vitamins, agrochemicals, flavors and fragrances, but also functional materials are increasingly produced as enantiomerically pure compounds. The reason for this is the often superior performance of the pure enantiomers. For some purposes the production and application of pure enantiomers are required by law. The enantioselectivity (expressed as e.e. %) of a catalyst should be 99% for pharmaceuticals if no purification is possible e.e. 80% are often acceptable for agrochemicals or if further enrichment is easy. 

Also useful for synthetic apphcation are heterogeneous metallic catalysts, modified with chiral auxiliaries and finally chiral soluble organic bases or acids. Less easy to apply are chiral polymeric and gel-type materials, phase-transfer catalysts or immobilized complexes. 

The essential feature for a selective synthesis of one optical isomer of a chiral substance is an asymmetric site that will bind a prochiral olefin preferentially in one conformation. The recognition of the preferred conformation can be accomplished 

In principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

The other approach, resolution of a racemic mixture, is also used in many industrial processes. Here physical resolution (i.e., resolution by crystallization of a diastereomeric derivative) is in general the favored method. However, kinetic resolution in principle can also be used for separating out two enantiomers. Although kinetic resolution involving a soluble metal complex catalyst has yet to be widely practiced, the potential importance of such an approach is significant (see Section 9.3.5). 

A Comparison Between the Homogeneous and the Anchored Rhodium Skewphos 

Nagendranath Mahata, Setrak Tanielyan and Robert Augustine 

Center for Applied Catalysis, Seton Hall University, South Orange, NJ 07079 

Previous studies on the use of Anchored Homogeneous Catalysts (AHC s) have been concerned with studying the effect which different reaction variables had on the activity, selectivity and stability of these catalysts (1-9). These reactions were typically ran at relatively low substrate/catalyst ratios (turnover numbers-TON s), usually between 50 and 100. While these low TON reactions made it possible to obtain a great deal of information concerning the AHC s, in order to establish that these catalysts could be used in commercial applications it was necessary to apply them to reactions at much higher TON S and, also, to make direct comparisons with the corresponding homogeneous catalyst under the same reaction conditions. 

The standard method used to prepare these AHC s was by anchoring a preformed complex onto an alumina support which had been treated with a heteropoly acid such as phosphotungstic acid (PTA). Alternately, the AHC can be prepared by treating an anchored Rh(COD)2 precursor with an appropriate ligand (8). We report here the use of AHC s which have been prepared by this 

The importance of producing pharmaceuticals in enantiomerically pure forms was brought to the public s attention with the thalidomide (Formula 4.2) tragedy in the early 1960s. Thalidomide, as a racemic mixture, was originally produced in 1953 as a sedative and a non-addictive alternative to barbiturates. It was later found that it alleviated many of the unpleasant symptoms of early pregnancy but by 1961 its use had been linked with an increase in the number of severe birth deformities and it was withdrawn. It 

Since then our knowledge of the mode of action of drugs has greatly improved and even more stringent testing of all new drugs takes place 

The synthetic utility of this reaction has been extended by the finding 

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

Finally, Finke has argued that kinetic measurements provide the most definitive data to distinguish between homogeneous and heterogeneous catalysts when particulate material is observed visually, with light scattering, or with First, if ttie observed 

Sigmoidal profile of the cyclohexene concentration vs. time for hydrogenation starting with [Bu,N] Na3[(1,5-C0D)lr-P3-W,Nb30J. This profile is characteristic of a reaction in which a nanocluster that catalyzes the reaction forms in an induction period. Adapted with permission from Widegren, J. A.  

Many of the molecules that constitute living organisms, such as amino acids, enzymes, proteins, and DNA, are chiral and present in only one of the two enantiomeric forms. When small, chiral organic molecules interact with the homochiral molecules of biological 

Compared to studies of enantioselective Diels-Alder reactions in organic solvents, there are few reports in water. The first reported enantioselective Diels-Alder reaction in water used 

The pyridine and the carbonyl moieties of the substrate are crucial for chiral induction. It was assumed that the copper cation coordinates strongly to the metal in a bidentate fashion. 

Arene-arene interactions between the pyridine part of the substrate and L-abrine, which are enforced in water through the hydrophobic effect, also havebenefidal effects on reaction rate and enantioselectivity (Table 3.2). 

As noted in Table 3.1, various cations were screened in an aqueous aldol reaction, and it was found that some cations such as Fe +, Cu +, Zn , Cd +, Pb + as well as rare earth metal cations were water-compatible and worked as Lewis acid catalysts in water. On the other hand, even if metal cations are water-compatible, chiral Kgand-coordinated metal complexes are decomposed in water, and this decomposition must be suppressed to realize asymmetric reactions successfully in aqueous media. An effective strategy to utilize multicoordination systems was demonstrated in order to address this issue. Combinations of metal cations and 

This study, based on the size-fitting strategy, showed that a slight change of ionic diameters of lanthanide cations greatly affected the diastereoselectivity as well as enantioselectivity of the reaction. 

Not surprisingly, this approach has been used for reactions where large amounts of data exist. Heck, metathesis, hydroformylation, and hydrocyanation are reactions where QSAR-type approaches have been attempted. In metathesis reactions based on such an analysis a number of bulky NHC-carbene Ugands have been suggested for further development. 

In the earlier chapters, selected chiral molecules and chiral ligands were mentioned (see Sections 1.3 and 2.1.7). In this section we discuss the basic principles behind asymmetric catalysis. In other words, we discuss the structural requirements and the physical principles behind enantioselective catalysis. 

There are many examples where organic molecules with carbon to carbon or carbon to oxygen double bonds are converted to chiral products. These molecules, represented by the general formula (RjXR ) C=X (X=CH2 or CHR, or O), are achiral because of the presence of a symmetry plane. In all the alkenes and ketones represented by 3.41-3.47, this symmetry plane is coincident with the plane of the paper. However, these molecules have two nonidentical faces that are called enantiofaces because of their handedness. Thus in 3.41, R, is to the right of X if viewed from the front, but to the left if viewed from the back of the paper. 

Alkenes and ketones of this type are called prochiral. The two different enantiofaces are called the re and si face according to well-established nomenclature protocols of organic chemistry. The two enantiofaces of 

In all these molecules, the carbon atom where the potential handedness resides is labeled with an asterisk. Asymmetric catalj4ic transformations of most of these prochiral substrates will be discussed later. In particular, we will see the basic mechanisms of hydrogenation of 3.42 and 3.43, asymmetric epoxidation of 3.44, stereoselective polymerization of propylene, and asymmetric dihydroxylation of 3.46. Asymmetric isomerization of 3.47 is one of the critical steps in a homogeneous catalyst-based industrial manufacturing process for L-menthol. 

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Catalytic Asymmetric Synthesis, VCH publishers New York, 1993 (d Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley New York, 1994... 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Chiral heterocycles as ligands in asymmetric catalysis 99JHC1437. 

Derivatives of pyridine, azoles and macroheterocycles with C3 symmetry in asymmetric catalysis and chiral recognition 98AG(E)248. 

Asymmetric catalysis using chiral ligands, including cyclic phosphine or pyra-zole fragments covalent-bonded with ferrocene system 98PAC1477. 

Borane complexes of P-heterocycles as versatile precursors for the synthesis of chiral phosphine ligands used for asymmetric catalysis 98S1391. 

Complexes with chiral heterocycles possessing P-containing substituents as P-mono- andP,N-bidentate ligands and their use in homogeneous asymmetric catalysis 98KK883. 

Pyridines and pyridine A -oxides as additives in asymmetric catalysis 99AG(E)1570. 

Macroheterocyclic systems with 1,1 -binaphthyl fragments in molecular recognition and asymmetric catalysis 98CRV2405. 

Chiral cyclic esters of phosphonic acid in the synthesis of coordination compounds and homogeneous asymmetric catalysis 99KK83. 

Catalytic, enantioselective cyclopropanation enjoys the unique distinction of being the first example of asymmetric catalysis with a transition metal complex. The landmark 1966 report by Nozaki et al. [1] of decomposition of ethyl diazoacetate 3 with a chiral copper (II) salicylamine complex 1 (Scheme 3.1) in the presence of styrene gave birth to a field of endeavor which still today represents one of the major enterprises in chemistry. In view of the enormous growth in the field of asymmetric catalysis over the past four decades, it is somewhat ironic that significant advances in cyclopropanation have only emerged in the past ten years. 

The ethers clearly do not interfere with the selective reaction by providing an alternative site for reagent coordination, a problem that will be addressed again later in the section on asymmetric catalysis. Cyclic allylic alcohols are cyclopropa-nated with high selectivity as well (Table 3.8, entry 8). 

Although is it possible to delineate the requirements for a suitable catalytic system, reducing this to practice is a daunting prospect. As is the case in many examples of asymmetric catalysis, empirical survey provides the initial leads which, aided by an understanding of the process, allows for accelerated development. 

For some excellent monographs and reviews that deal with catalytic asymmetric synthesis, see (a) Asymmetric Synthesis, Morrison, J. D., Ed., Academic Press New York, 1985, Vol. 5 (b) Bosnich, B. Asymmetric Catalysis, Martinus Nijhoff Dordrecht, 1986 ... 

The Sharpless-Katsuki asymmetric epoxidation (AE) procedure for the enantiose-lective formation of epoxides from allylic alcohols is a milestone in asymmetric catalysis [9]. This classical asymmetric transformation uses TBHP as the terminal oxidant, and the reaction has been widely used in various synthetic applications. There are several excellent reviews covering the scope and utility of the AE reaction... 

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