Aldol Transition-metal Lewis acid

The advances that have taken place over the past five years in catalytic, enantioselective aldol addition reactions is evident in a number of important respects. The types of transition metals and their complexes that function competently as catalysts have been expanded considerably. Thus, in addition to B(III), Ag(I), Au(I), Sn(II), and La(III), chiral catalysts prepared from Cu(II), Ti(IV), Ln(III), Si(IV), Pt(II) and Pd(II) have been introduced. The expansion in the use of transition metals has taken place hand-in-hand with the design and synthesis of new bidentate and tridentate organic ligands based on nitrogen, oxygen, and phosphorus donors. Additionally, whereas the older methods primarily relied on the use of Lewis-acids for the activation of... 

The mechanisms for metal-catalyzed and organocatalyzed direct aldol addition reactions differ one from another, and resemble the mode of action of the type 11 and type I aldolases, respectively. Some metal-ligand complexes, for example, 1-4 and 9 are considered to have a bifunctional character [22], embodying within the same molecular frame a Lewis acidic site and a Bronsted basic site. Whereas base would be required to form the transient enolate species as an active form of the carbonyl donor, the Lewis acid site would coordinate the acceptor aldehyde carbonyl, increasing its electrophilicity. By this means, both transition state stabilization and substrates preorganization would be provided (see Scheme 5 for a proposal). 

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

Since the middle of the 198O s remarkable progress has been achieved in the development of asymmetric aldol reactions of silyl enolates. In the beginning of this evolution, chiral auxiliary-controlled reactions were extensively studied for this challenging subject [106]. As new efficient catalysts and catalytic systems for the aldol reactions were developed, much attention focused on catalytic enantiocontrol using chiral Lewis acids and transition metal complexes. Thus, a number of chiral catalysts realizing high levels of enantioselectivity have been reported in the last decade. 

In 1986, Reetz et al. reported that chiral Lewis acids (B, Al, and ll) promoted the aldol reaction of KSA with low to good enantioselectivity [115]. The following year they also introduced asymmetric aldol reaction under catalysis by a chiral rhodium complex [116]. Since these pioneering works asymmetric aldol reactions of silyl enolates using chiral Lewis acids and transition metal complexes have been recognized as one of the most important subjects in modern organic synthesis and intensively studied by many synthetic organic chemists. 

Advances in the development of metal-catalyzed Mukaiyama aldol addition reactions have primarily relied on a mechanistic construct in which the role of the Lewis acidic metal complex is to activate the electrophilic partner towards addition by the enol silane. Alternate mechanisms that rely on metallation of enol silane to generate reactive enolates also serve as an important construct for the design of new catalytic aldol addition processes. In pioneering studies, Bergman and Heathcock documented that transition-metal enolates add to aldehydes and that the resulting metallated adducts undergo silylation by the enol silane leading to catalyst turnover. 

The aldol reactions of titanium enolates have been the best studied of all the transition metal enol-ates."- In many cases they show higher stereoselectivity and chemoselectivity in their reactions than lithium enolates and are easily prepared using inexpensive reagents. They also promote high levels of diastereofacial selectivity in reactions of chiral reactants. The Lewis acidity of the titanium metal center can be easily manipulated by variation of the ligands (chloro, alkoxy, amino, cyclopentadienyl, etc.) attached to titanium, which leads to enhanced selectivity in appropriate cases. Moreover, the incorporation of chiral ligands on titanium makes possible efficient enantioselective aldol reactions. 

Even more efficient catalysis of the Mukaiyama aldol reaction is possible with complexes of transition metals. A number of titanium-based Lewis acids with binaphthyl hgands have been reported to give high enantioselectivities. For example, only 2 mol% of the Lewis acid 80 is required to effect the aldol reaction of... 

Transition metal enolate complexes have been prepared with most or all transition metals, and the enolate ligands have been shown to adopt a variety of bonding modes. Bofli early and late transition metal enolate complexes are intermediates in a number of important catalytic processes. Early transition metal enolates are important intermediates in asymmetric aldol reactions that exploit the Lewis acidic character of early metals. Late transition metal enolates are intermediates in aldol and Michael addition processes, -Saegusa oxidations,Heck-type processes, catalytic asymmetric conjugate additions, - and cross coupling of enolate nucleophiles. - ... 

The fundamental mechanistic concept around which the course of aldol reactions under conditions of kinetic control has been interpreted involves the postulation of a cyclic transition state in which both the carbonyl and the enolate oxygen are coordinated to a Lewis acid. We will use the Li cation in our discussion, but another metal cation or electron-deficient atom may play the same role. 

It is difficult to summarize all the progress of the homogeneous catalytic aldol reaction due to the space limitations. With representative or selected examples, this article focuses on those efforts in homogeneous catalysis and will be discussed with selected examples according to the different types of catalysts il) transition metals based Lewis acids, such as palladium, copper, iron, etc (2)... 

As the S=0 bond is an acceptor site for the Lewis acids [109], the conformation of the sulfinylimine moiety in the transition state influenced the stereochemical outcome of this reaction by intramolecular chelation with metal salts [108]. The potential of diastereo- and enantioselective reactions that form multiple carbon-carbon bonds in acyclic systems, including the formation of all-carbon quaternary stereocenters in a one-pot operation from easily accessible starting materials, has been further extended and has led to a unique approach to aldol products bearing all-carbon quaternary stereocenters in acyclic systems (Scheme 10.129) [110]. 

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