Catalytic asymmetric reactions

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

This asymmetric catalytic reaction has found wide application in converting functionalized ketones to the corresponding secondary alcohols with high ee. A general illustration is given in Scheme 6-32. Five- to seven-membered chelate complexes, formed by the interaction of the Ru atom with carbonyl oxygen and a heteroatom X, Y, or Z may be the key intermediates that cause the high enantioselectivity in the reaction.67... 

The solvent employed in asymmetric catalytic reactions may also have a dramatic influence on the reaction rate as well as the enantioselectivity, possibly because the solvent molecule is also involved in the catalytic cycle. Furthermore, the reaction temperature also has a profound influence on stereoselectivity. The goal of asymmetric hydrogenation or transfer hydrogenation studies is to find an optimal condition with a combination of chiral ligand, counterion, metal, solvent, hydrogen pressure, and reaction temperature under which the reactivity and the stereoselectivity of the reaction will be jointly maximized. 

This article provides a brief overview of several recent total syntheses of natural and unnatural products that have benefited from the use of catalytic asymmetric processes. The article is divided by the type of bond formation that the catalytic enan-tioselective reaction accomplishes (e.g C-C or C-0 bond formation). Emphasis is made on instances where a catalytic asymmetric reaction is utilized at a critical step (or steps) within a total synthesis however, cases where catalytic enantioselective transformations are used to prepare the requisite chiral non-racemic starting materials are also discussed. At the close of the article, two recent total syntheses are examined, where asymmetric catalytic reactions along with a number of other catalyzed processes are the significant driving force behind the successful completion of these efforts (Catalysis-Based Total Syntheses). 

Although the number of enantiopure ionic liquids as successful asymmetric catalytic reaction media is still very limited, the research field has attracted considerable attention. Due to the large number of possible applications in combination with the advantages of easy recoverability, the further development of the field is very important. However, it shall be mentioned here that some reported examples of catalytic activities of ionic liquids have to be investigated in more detail. In particular, ionic liquids incorporating [BF ] and [PF ] have to be very pure and normally should not be used with water for a prolonged time, since the anions could decompose and release HF, which could be itself the cause of the observed activity [164]. 

Asymmetric catalytic reactions under solvent-free conditions have also been reported. Contrary to the previous result, a neutral rhodium(I) complex provided comparable enantioselectivity with high chemical yield [24c], Eor certain cases, benzaldehyde gave improved enantioselectivity over cirmamaldehyde (Tab. 11.6), although the rationale behind choosing this particular CO source is not entirely clear. Additionally it should be noted that when the reaction was carried out using a stoichiometric amount of an aldehyde as the CO source in xylene, the reaction takes much longer and the enantioselectivity decreases substantially. 

Selected derivatives of the ligands and complexes described above have been tested in catalytic applications. Early tests with bidentate P,P or P,N ligands such as 4, 6, and 8 in Rh-catalyzed asymmetric hydrogenation were disappointing, with ee values below 20%. However, as was demonstrated mainly by the Fu group, phosphaferrocene derivatives do have the potential for successful applications in asymmetric catalytic reactions, provided the phosphaferrocene is endowed with sufficient steric bulk. Examples are depicted in Eig. 1.5.8 the Cp derivative 32,... 

Recently. Frunza et al.[15] have investigated the embedding of enantioselective homogeneous chiral Mn(III) cationic salen complexes into the pore of mesoporous MCM-41 materials. Very few asymmetric catalytic reactions have been examined using chiral salen complexes immobilized on MCM-41. 

Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided.166 The paradigm followed in many asymmetric catalytic reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here,166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known. Enantioselective additions of pyrroles and indoles to ,/9-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex have been accomplished.167... 

The coordination chemistry of optically pure, chiral phosphetanes has been studied with special attention to the preparation and characterization of complexes since they are suitable for asymmetric catalytic reactions. The optically active P-menthylphosphetanes showed similar reactivities with usual trivalent phosphines to afford stable palladium(n) and ruthenium complexes, under usual reaction conditions. Similarly, the Pd-allyl complex 28 <1997JOM(529)465> has been prepared from [(allyl)PdCl]2 and was characterized by X-ray crystallography. Reaction of the P(R),C(3 )-2-benzyl-3,3,4,4-tetramethyl-l-menthylphosphetane 64 with Ru3(C0)12/HC02H proceeds normally to give the formato bridged dimer 65 (Figure 11) <1998S1539>. 

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

The second part of the chapter deals with several kinds of asymmetric reactions catalyzed by unique heterobimetallic complexes. These reagents are lanthanoid-alkali metal hybrids which form BINOL derivative complexes (LnMB, where Ln = lanthanoid, M = alkali metal, and B = BINOL derivative). These complexes efficiently promote asymmetric aldol-type reactions as well as asymmetric hydrophosphonylations of aldehydes (catalyzed by LnLB, where L = lithium), asymmetric Michael reactions (catalyzed by LnSB, where S = sodium), and asymmetric hydrophosphonylations of imines (catalyzed by LnPB, where P = potassium) to give the corresponding desired products in up to 98% ee. Spectroscopic analysis and computer simulations of these asymmetric reactions have revealed the synergistic cooperation of the two different metals in the complexes. These complexes are believed to function as both Brpnsted bases and as Lewis acids may prove to be applicable to a variety of new asymmetric catalytic reactions.1,2... 

Although a large number of asymmetric catalytic reactions with impressive catalytic activities and enantioselectivities have been reported, the mechanistic details at a molecular level have been firmly established for only a few. Asymmetric isomerization, hydrogenation, epoxidation, and alkene dihydroxylation are some of the reactions where the proposed catalytic cycles could be backed with kinetic, spectroscopic, and other evidence. In all these systems kinetic factors are responsible for the observed enantioselectivities. In other words, the rate of formation of one of the enantiomers of the organic product is much faster than that of its mirror image. 

A recent discovery that has significantly extended the scope of asymmetric catalytic reactions for practical applications is the metal-complex-catalyzed hydrolysis of a racemic mixture of epoxides. The basic principle behind this is kinetic resolution. In practice this means that under a given set of conditions the two enantiomers of the racemic mixture undergo hydrolysis at different rates. The different rates of reactions are presumably caused by the diastereo-meric interaction between the chiral metal catalyst and the two enantiomers of the epoxide. Diastereomeric intermediates and/or transition states that differ in the energies of activation are presumably generated. The result is the formation of the product, a diol, with high enantioselectivity. One of the enantiomers of... 

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