Catalysts, design primary amines

The first designed catalyst where there was some understanding of the relationship between structure and function was oxaldie 1, a 14-residue peptide that folds in solution to form helical bundles [11] (Fig. 12). Oxaldie 1 was designed to catalyze the decarboxylation of oxaloacetate, the a-keto acid of aspartic acid, via a mechanism where a primary amine reacts with the ketone carbonyl group to form a carbinolamine that is decarboxylated to form pyruvate. The reaction is piCj dependent and proceeds faster the lower the piC of the primary amine if the reaction is carried out at a pH that is lower than the piCj, of the reactive amine. The sequence contains five lysine residues that in the folded state form... 

Reductive alkylation is an efficient method to synthesize secondary amines from primary amines. The aim of this study is to optimize sulfur-promoted platinum catalysts for the reductive alkylation of p-aminodiphenylamine (ADPA) with methyl isobutyl ketone (MIBK) to improve the productivity of N-(l,3-dimethylbutyl)-N-phenyl-p-phenylenediamine (6-PPD). In this study, we focus on Pt loading, the amount of sulfur, and the pH as the variables. The reaction was conducted in the liquid phase under kinetically limited conditions in a continuously stirred tank reactor at a constant hydrogen pressure. Use of the two-factorial design minimized the number of experiments needed to arrive at the optimal solution. The activity and selectivity of the reaction was followed using the hydrogen-uptake and chromatographic analysis of products. The most optimal catalyst was identified to be l%Pt-0.1%S/C prepared at a pH of 6. 

The formation of such bridged metallaziridine species rationalizes the selectivity for primary amines and suggests that dimeric species may be key catalytic intermediates. This is further supported by experiments that illustrated that increasing catalyst concentration results in an increase in hydroaminoalkylation product versus hydroamination product. [72] Therefore, we proposed that catalyst-controlled chemoselectivity for hydroaminoalkylation (C—C bond formation) versus hydroamination (C—N bond formation), could be achieved by designing catalyst systems that promote the formation of bridged species. 

N-primary-amine-terminal p-turn tetrapeptides were designed and applied by Da and coworkers for the asymmetric aldol reaction. The con-formationally restricted p-turn, due to the u-Pro-Gly-unit, was indicated by CD and NOESY spectra, contributes to the high enantioselectivity in the aldol reaction of aldehydes with acetone in methanol, assisted by benzoic acid as additive. When employing hydroxyacetone instead of acetone, (5 )-BINOL was used as additive. In every case, tetrapeptide 48 was the best performing catalyst, giving the desired products in enantiomeric excesses of more than 99% (Scheme 13.28a). ... 

Lately, Maruoka, et al. reported an organocatalytic Diels-Alder reaction of a-substimted a,p-unsaturated aldehydes with cyclopentadiene, Scheme 3.16 [29], Usually, the organocatalytic Diels-Alder reactions were not applicable to a-substi-tuted acroleins due to serious steric repulsion between the substituent of aldehyde and the secondary amine catalyst. A binaphthyl-based primary amine, catalyst 49, was designed for the reaction, and a plausible mechanism for the stereoselectivity reaction was presented. 

Ishihara has designed dipeptide-derived triamine catalyst 20 and elegantly demonstrated its value in a Diels-Alder reaction [57]. The primary amine group, in combination with an acid co-catalyst, facilitated the activation of a-acyloxyacrolein in the Diels-Alder reactions, and the adducts were obtained in good yields and with good to excellent enantioselectivities (Scheme 3.21). 

A wide range of small organic molecules, mainly secondary amines such as proline derivatives, promote asymmetric aldol reactions through enamine catalysis [6]. List, Reymond, Gong, and others reported the first examples of peptidic catalysts for aldol reactions [7]. In their report, Reymond and coworkers [7a] developed two classes of peptides, following two different designs. In the first peptide class a primary amine is present as a side chain residue (similar to the natural type I aldolase) or as free N-terminus in the second a secondary amine or a proHne residue is present at the N-terminus of the peptide, which incorporated at least one free carboxyhc function (Figure 5.3). 

Anti-selective Mannich reactions have been developed using (R)-3-pyrrolidine-carboxylic acid (75) or primary amine-containing amino acid 21 these catalysts were designed through consideration of mechanism and transition state models. 

In comparison with the widespread application of chiral secondary amines in organocatalytic Diels-Alder reactions, only a few successful examples have been reported with the use of chiral primary amines. In the case of a-substituted acroleins, it is difficult for chiral secondary amines to activate this type of substrates, probably because of poor generation of the corresponding iminium ions. To solve this problem, Ishihara and Nakano designed and synthesized a novel class of primary amine catalysts (55) [24]. Indeed, this type of less bulky ligand proved to be effective for enantioselective Diels-Alder reactions of a-acyloxyacroleins 51 or a-phthalimidoacroleins 53 to produce the desired cycloadducts 52 or 54 with quaternary stereocenters (Scheme 38.16). 

Gong group designed chiral primary amine-amide type catalyst for the aldoliza-tion of hydroxyacetone [24] with excellent iyn-aldol selectivity (up to >20 1 dr.) and stereoselectivity (up to 98% ee) (Scheme 5.12). Recently, Zhao and Da have further explored this type of primary amine catalysts [25]. Feng developed bispidine-derived chiral primary amine catalyst 45 for the aldolization of activated ketone acceptors with excellent enantioselectivity (Scheme 5.12) [26]. 

Zhao and co workers [54] developed simply primary-secondary diamine catalysts derived from primary amino acids. This type of catalysts such as 105 was found to catalyze the asymmetric Michael addition of malonates to acyclic a,p-unsaturated ketones with good activity and excellent enantioselectivity (Scheme 5.27). Liang and coworkers designed a new primary amine catalyst combining two privileged skeletons, cinchona and cylohexanediamine [55], The obtained optimal catalysts 107 and 110 were applicable to the Michael additions reactions of malonate or nitroalkanes to a,p-unsaturated ketones. The reactions worked well with both cyclic and acyclic enones (Scheme 5.28). 

The asymmetric catalytic reduction of ketones (R2C=0) and imines (R2C=NR) with certain organohydrosilanes and transition-metal catalysts is named hydrosilylation and has been recognized as a versatile method providing optically active secondary alcohols and primary or secondary amines (Scheme 1) [1]. In this decade, high enantioselectivity over 90% has been realized by several catalytic systems [2,3]. Therefore the hydrosilylation can achieve a sufficient level to be a preparative method for the asymmetric reduction of double bond substrates. In addition, the manipulative feasibility of the catalytic hydrosilylation has played a major role as a probe reaction of asymmetric catalysis, so that the potential of newly designed chiral ligands and catalysts can be continuously scrutinized. 

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