Lewis acids aldehydes activated

LA represents Lewis acid in the catalyst, and M represents Bren sled base. In Scheme 8-49, Bronsted base functionality in the hetero-bimetalic chiral catalyst I can deprotonate a ketone to produce the corresponding enolate II, while at the same time the Lewis acid functionality activates an aldehyde to give intermediate III. Intramolecular aldol reaction then proceeds in a chelation-controlled manner to give //-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an a-proton of a ketone leads to the production of an optically active aldol product and the regeneration of the catalyst I, thus finishing the catalytic cycle. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

Lewis acid catalysts activate the aldehyde by coordination to the carbonyl oxygen. Shibasaki et al. [13] were able to demon,strate that the activation of the enol ether is possible too. The reaction of the aldehyde 37 with the silyl enol ether 38 in the presence of the catalyst 39 proceeds with good, but still not excellent enantioselectivity to yield the aldol adduct 40. Only 5 mol % of the chiral palladium(II) complex 39 was used (Scheme 6a). Activation of the Pd(lI)-BINAP complex 39 by AgOTf is necessary. Therefore, addition of a small amount of water is important. 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

The exact course of the mechanism of the allylation is not fully understood. The chiral Lewis acid presumably activates the aldehyde toward nucleophilic attack by the allyltributyltin. After loss of the tributyltin group, the... 

Aldehydes that contain a heteroatom substituent at the a-carbon often display high stereoselectivity in reactions with ally lie stannanes. This behavior is particularly the case for heteroatom substituents permitting effective chelation with a Lewis acid. Internal activation of the carbonyl oxygen provides a five-membered chelation complex with Lewis acids, which minimally offer two coordination sites. The stability of the metallocycle may account for high diastereoselection, as nucleophilic approach of the stannane occurs to the less hindered face of the carbonyl. 

A second bicyclization is initiated by Lewis acid induced activation of an aldehyde. Only one diastereomer is formed after a sequence of two b-endo reactions59. 

The actual catalyst is believed to be a complex (A) of the three components since it is soluble in CH2CI2 even though none of the components is. The amine-coordinated tin(ll) triflatc acts as a lewis acid to activate the aldehyde, and the tin(IV) fluoride or acetate interacts with the silyl enol ether. 

An alternative use of copper(II) catalysts has been reported by Carreira. Using a fluoride counterion, they reason that the reaction proceeds via formation of a copper enolate rather than through Lewis acid-mediated activation of the aldehyde. Using TolBlNAP as the hgand, the catalyst affords high enantioselectivities. The reaction worked well with most of the aldehydes that were reported (65—95% ee), including the reaction of benzaldehyde (7.17). 

Trost has described very efficient and versatile bimetallic zinc catalyst 10 generated in situ from diethyl zinc and a chiral Ugand derived from proline and p-cresol (Scheme 10) [46], For example, this complex can promote catalytic aldol reactions with high enantiomeric excess. The role of two proximal zinc species is for one of them to form the enolate and for the second one to function as a Lewis acid to activate the aldehyde. 

The most common electron-withdrawing group used for acceptor activation has been alkoxycarbonyl. As would be expected, addition of Lewis acid further activates the acceptor [8]. At elevated temperatures, ene adducts can be equihbrated [9]. In this case, equilibration may be taking place by enoh-zation, rather than by retro-ene followed by recyclization. Aldehydes and ketones can also be used to activate acceptors [10]. In the case shown, further activation with Lewis acids gave largely non-ene products. 

Subsequently, Kim and Song reported the enantioselective cyanosilylation of aldehydes catalysed by (/ ,/ )-(salen)Al 3/triphenylphosphine oxide (Scheme 19.2). The (salen)Al 3 alone induced no enantioselectivity and reactivity, which indicated a double activation process occurring within the catalysis. The complex functioned as a Lewis acid to activate the aldehyde, while triphenylphosphine oxide acted as a Lewis base for the activation of trimethylsilyl cyanide. 

A catalytic amount of Sc(OTf)3 was found to promote the reaction of less reactive N-acylhydrazones (aromatic aldehyde- or ketone-derived substrates) with trimethylsilylcyanide (TMSCN) to give a-hydrazinonitriles in the presence of an amine (Scheme 12.10) [18]. A mechanistic study indicated that the amine worked as a Bronsted base, which initiated the reaction by abstraction of the amide hydrogen of the substrate. Sc(OTf)3 might act as a Lewis acid to activate the stable intermediate O-Si-(l). This is a rare example of cyanation of C=N bonds promoted by a Bronsted base and a Lewis acid. 

Kobayashi etal. found that aldimines were preferentially activatedby Yb(OTf)3 in the comparative reaction of aldehydes and aldimines with enol silyl ethers in sharp contrast to conventional Lewis acids, which activated aldehyde and promoted aldol reactionexclusively (Table 13.6) [10]. NMR-analyses revealed selective formation... 

An effective synthesis of 1,2-dihydroquinolines has been devised using a Lewis acid-mediated bicyclization reaction between alkynylanilines and aldehydes (Scheme 3.14 and Example 3.3) [14]. The authors screened a range of Lewis acids for activity toward the reaction, and scandium(III) triflate was the most effective under the reaction conditions. The reaction proceeded under mild conditions and afforded moderate to good yields of the polycyclic compounds when electron-neutral or electron-rich aldehydes were used. Electron-deficient aldehydes were sluggish under the standard conditions however, the authors discovered that the use of benzoic acid as a cocatalyst enabled the use of these substrates in the bicyclization reaction. 

Recently, hydrocyanation and cyanosilylation reactions with other type of chiral aluminum complexes were reported. In 1999, Shibasaki and Kanai reported enantioselective cyanosilylation of aldehydes catalyzed by Lewis acid-Lewis base bifunctional catalyst (64a) [56, 57]. In this catalyst, aluminum center works as a Lewis acid to activate the carbonyl group, and the oxygen atom of the phosphine oxide works as a Lewis base to activate TMSCN. Asymmetric induction was explained by the proposed transition state model having the external phosphine oxide coordination to aluminum center, thus giving rise to pentavalent aluminum... 

Catalysis with BINAP-CuFz, Carreira and co-workers have recently reported a novel aldol addition reaction using a putative Cu(I) fluoride complex as catalyst [32]. The cmiqilex is readily assembled in situ upon dissolving BINAP and CufOTflj, in THF followed by addition of Bu4NPh3SiF2, as an anhydrous fluoride source. Dienolate 105 undergoes addition to a wide range of aldehyde substrates at -78°C with 5 mol % catalyst, giving the protected acetoacetate adducts with up to 94% ee. The reaction has been mechanistically examined in some detail, leading to the postulation that the addition process includes a metalloenolate in the catalytic cycle as relevant reactive intermediate (Scheme 8B2.11) [33]. This perspective contrasts the more traditional role of transition-metal catalysis of the Mukaiyama aldol addition reaction wherein the metal functions as a Lewis acid and activates the electrophilic aldehyde partner. 

Inspired by the work of Burk and Feaster ) we attempted to use (2-pyridyl)hydrazine (4.36) as a coordinating auxiliary (Scheme 4.10). Hydrazines generally react effidently with ketones and aldehydes. Hence, if satisfactory activation of the dienophile can be achieved through coordination of a Lewis acid to the (2-pyridyl)hydrazone moiety in water. Lewis-add catalysis of a large class of ketone- and aldehyde-activated dienophiles is antidpated Subsequent conversion of the hydrazone group into an amine functionality has been reported previously by Burk and Feaster ... 

---