Organocatalysts Bronsted acidic

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

Considerable effort has been devoted to the development of enantiocatalytic MBH reactions, either with purely organic catalysts, or with metal complexes. Paradoxically, metal complex-mediated reactions were usually found to be more efficient in terms of enantioselectivity, reaction rates and scope of the substrates, than their organocatalytic counterparts [36, 56]. However, this picture is actually changing, and during the past few years the considerable advances made in organocatalytic MBH reactions have allowed the use of viable alternatives to the metal complex-mediated reactions. Today, most of the organocatalysts developed are bifunctional catalysts in which the chiral N- and P-based Lewis base is tethered with a Bronsted acid, such as (thio)urea and phenol derivatives. Alternatively, these acid co-catalysts can be used as additives with the nucleophile base. 

The most commonly used type of catalyst is a relatively small, bifunctional molecule that contains both a Lewis base and a Bronsted acid center, the catalytic properties being based on the activation of both the donor and the acceptor of the substrates. The majority of organocatalysts are chiral amines, e.g. amino acids or peptides. The acceleration of the reaction is either based on a charge-activated reaction (formation of an imminium ion 4), or involves the generalized enamine catalytic cycle (formation of an enamine 5). In an imminium ion, the electrophilicity compared to a keton or an oxo-Michael system is increased. If the imminium ion is deprotonated to form an enamine species, the nucleophilicity of the a-carbon is increased by the electron-donating properties of the nitrogen. ... 

Recently, Liu has developed a Bronsted acid activated trifunctional organocatalyst, based on the BINAP scaffold, that was used for the first time to catalyze aza MBH reactions between N tosylimines and MVK with fast reaction rates and good enantioselectivity at room temperature. This trifunctional catalyst containing a Lewis base, a Bronsted base and a Bronsted acid, required add activation to confer its enantioselectivity and rate improvement for both electron rich and electron deficient imine substrates. The role of the amino Lewis base of 27 was investigated and found to be the activity switch in response to an acid additive. The counterion of the acid additive was found to influence not only the excess ratio but also the sense of asymmetric induction (Scheme 13.23) [36]. 

Some of the seminal studies of organocatalysts have been described, focusing on chiral Bronsted acid catalysts. Because this review is not comprehensive, there are a number of topics not covered in this chapter, such as carbene catalysts, bifunctional catalysts, and so on. 

The asymmetric reduction of imines and iminium species can be achieved using organocatalysts. The transfer hydrogenation of imines is catalysed by acids and this has led to the development of biomimetic asymmetric reductions using enan-tioselective Bronsted acids in combination with Hantzsch esters as a hydride... 

A number of Bronsted acidic organocatalysts have been applied to the asymmetric hydrophosphonylation of aldimines. Thiourea catalysts related to (6.130) catalyse the asymmetric hydrophosphonylation of a range of aliphatic and aromatic aldimines with high ee and BINOL-derived phosphoric acid derivatives similar in structure to (6.131) are effective catalysts in the asymmetric phosphonylation of cinnamaldehyde-derived aldimines. Asymmetric hydrophosphonylation of aromatic aldimines can also be achieved with high ee using cheap, commercially... 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

The metal-based Lewis acid derived from the camphor-derived Kgands such as (7.159) and La(OTf)3 is effective in the MBH reaction of aromatic aldehydes with a,P-unsaturated aldehydes mediated by l,4-diazabicyclo(2.2.2]octane (DABCO). The best ees (up to 95%) are obtained using sterically bulky acrylates such as a-naphthyl acrylate. More success has been obtained using Bronsted acidic organocatalysts. The partially reduced BINOL (7.160) has been used to effect enantioselective MBH reaction of aliphatic aldehydes such as (7.71) with 2-cyclohexen-l-one (7.161) mediated by triethylphosphine/ while bis(thio)ureas such as (7.163) provide up to 96% ee in the coupling of this ketone with cyclohex-anecarbaldehyde in the presence of DABCO. °... 

A number of BINOL-based bifunctional organocatalysts, for example (7.171-7.173), containing both Bronsted acidic and Lewis basic sites have been used to good effect in the asymmetric MBH reaction. The amine-thiourea (7.171) promotes the MBH reaction of aliphatic aldehydes with 2-cyclohexenone with ees ranging from 80 to 94% while both the (pyridinylaminomethyl)BINOL (7.172) and phosphine (7.173) catalyse the aza-Bayhs-Hilhnan reaction of simple a,p-carbonyls such as MVK and phenyl acrylate with N-tosyl arylaldmines with similar levels of enantioselectivity. 

A new approach to stereoselective transfer hydrogenation of imines was the application of chiral phosphoric acid esters as organocatalysts [50-52]. The mechanism is based on the assumption that the imine is protonated by a chiral Bronsted acid, which acts as the catalyst. The resulting diastereomeric iminium ion pairs, which may be stabilized by hydrogen bonding, react with the Hantzsch dihydropyridine at different rates to give an enantiomerically enriched amine and a pyridine derivative [50-52]. The exact mechanism is still under discussion however computational density functional theory (DFT) studies ]53, 54] suggest a three-point contact model. ... 

Other chiral Bronsted acid organocatalysts developed more recently include chiral binaphthyl-derived disulfonic acids [162] and sulfonimides [163] and SPINOL-derived phosphoric acids [164]. 

The use of chiral Bronsted acids (organocatalyst class) in asymmetric F-C reactions has been extensively reviewed. They can be used instead of oxophilic chiral Lewis acids for the asymmetric coupling of indoles to less reactive ketone substrates such as trihalopyruvates. The use by Mikami (2000) of a chiral phenol cocatalyst in boosting enantioselectivity ( 10%) perhaps provided the first clue to such a possibility. 

Torok (2005) reported the use of chiral cinchona alkaloid Bronsted acid organocatalysts (5 mol %), cinchonidine (102) and cinchonine (103), in the... 

Catalytic chiral Mannich reactions in the next examples are promoted by organocatalysts [35]. Characteristic of the selected organocatalysts is their proton or Bronsted acidity and stabilization of the catalytic complex by hydrogen bonding to enamine. 

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