Brpnsted acid catalysis

Figure 11.4. Hydrogen-bonding and Br0nsted acid complexation modes for the LUMO-lowering activation of substrates inherent to the field of Brpnsted acid catalysis.

Hydrogen would be the simplest center element. Indeed, chiral Brpnsted acids have emerged as a new class of organocatalysis over the last few years [3-13]. The field of asymmetric Brpnsted acid catalysis can be divided into general acid catalysis and specific acid catalysis. A general acid activates its substrate (1) via hydrogen bonding (Scheme 2, a), whereas the substrate (1) of a specific acid is activated via protonation (Scheme 2, b). 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

Two years later, Terada and coworkers described an asymmetric organocatalytic aza-ene-type reaction (Scheme 28) [50], BINOL phosphate (7 )-3m (0.1 mol%, R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of A-benzoylated aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent hydrolysis led to the formation of P-amino ketones 77 in good yields (53-97%) and excellent enantioselectivities (92-98% ee). A substrate/catalyst ratio of 1,000 1 has rarely been achieved in asymmetric Brpnsted acid catalysis before. 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

Until 2006, a severe limitation in the field of chiral Brpnsted acid catalysis was the restriction to reactive substrates. The acidity of BINOL-derived chiral phosphoric acids is appropriate to activate various imine compounds through protonation and a broad range of efficient and highly enantioselective, phosphoric acid-catalyzed transformations involving imines have been developed. However, the activation of simple carbonyl compounds by means of Brpnsted acid catalysis proved to be rather challenging since the acid ity of the known BINOL-derived phosphoric acids is mostly insufficient. Carbonyl compounds and other less reactive substrates often require a stronger Brpnsted acid catalyst. 

Specific Brpnsted acid catalysis is a popular field within the domain of asymmetric organocatalysis. Since the introduction of stronger chiral Brpnsted acids as powerful catalysts for enantioselective synthesis in 2004, numerous asymmetric Brpnsted acid-catalyzed transformations have been developed. 

An enantioselective Strecker reaction involving Brpnsted acid catalysis uses a BINOL-phosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at -40 °C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-l-amino-2-hydroxycyclohexane-l -carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl (g)... 

The formation of imidazo[l,2-c]pyrimidines (171) via a ring closure of 2-(2-sulfon-ylimino-1,2-dihydro-l-pyrimidinyl)acetamides (170) has been studied using DFT methods, which revealed the requirement for Brpnsted acid catalysis.220... 

Most chemical reactions proceed via charged intermediates or transition states. In asymmetric Brpnsted acid catalysis the substrate is protonated by the catalyst and a chiral H-bond-assisted ion pair is generated. We reasoned that, in principle, any reaction that proceeds via cationic in-... 

Selected recent developments in the area of asymmetric organocatalysis in our laboratory have been briefly summarized. Enamine catalysis, Brpnsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. Using Hantzsch ester as the hydride source, highly enantioselective transfer hydrogenantion reactions have been developed. We have also developed an additional new con-... 

Acidic activation of the epoxide can be achieved either by Brpnsted-acidic catalysis via addition of a proton to the epoxide oxygen or by Lewis-acidic catalysis via coordination of the epoxide oxygen to a multivalent cation. In basic catalysis one of the epoxide carbons is attacked by a nucleophile. Only acid-catalyzed ringopening leads to an intermediate carbocation (3) which can easily result in the mi-... 

Step 4 in the route to LA fi om cellulose deals with the dehydration of the triose sugars, according to a retro-Michael mechanism, forming the imstable intermediate pyruvic aldehyde (or methyl glyoxal). This reaction is typically performed by Brpnsted acid catalysis, although Lewis acids are also capable of this water... 

The use of chiral Brpnsted acid catalysis as a mode of asymmetric activation burgeoned dramatically in the early part of the twenty first century [35]. The role of hydrogen in this process is, in essence, similar to that of Lewis acid catalysts - i.e. activation of the C=X bond (X=0, NR, CR ) by decreasing the LUMO energy and ultimately leading to promotion of nucleophilic addition to the C=X bond (Fig. 1.5). 

Fig. 1.5 Mode of action of Brpnsted acid catalysis and some examples...

A different organocatalytic approach to isoquinuclidine molecules has been described based on a cooperative double Brpnsted acid catalysis (Scheme 11.46) [127]. Thus, a proton transfer from the chiral Brpnsted acid to the aromatic imine would occur forming the chiral ion pair A ready to react with the dienol derived from... 

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