Primary Amino Acid-Derived Diamine Catalysts

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

Very recently, You and co-workers [21] have developed an elegant cascade FCA-Mannich process of indolyl enones to afford enantioenriched polycyclic indolines with the use of quinine-derived primary amine 6c as the catalyst (Scheme 9.7). Moreover, a-amino acid-derived 1,2-vicinal diamine 7 was proved to be efficient to catalyze the reaction of 4,7-dihydromdoles with a,p-unsaturated ketones [22]. 

Chiral diamines derived from natural primary amino acids give up to 99% ee in i yn-selective aldols of linear ketones with aromatic aldehydes, using TFA and 2,4-dinitrophenol as co-catalysts. ... 

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). 

In the previous section, chiral secondary amines are shown to be efficient catalysts for the AFC reaction of 4,7-dihydroindoles with a,p-unsaturated aldehydes by Wang and co-workers. Subsequently, the same group extended the AFC reaction to a,p-unsaturated ketones by using a new chiral primary/ secondary diamine catalyst derived from an amino acid. They found that chalcones, particularly challenging substrates for iminium catalysis, could afford the AFC products 122 in high yields (69-97%) with moderate to excellent enantioselectivity (66-97% ee). Note that the substitution on the 4,7-dihydroindolic nitrogen had a detrimental effect on the reactivity (<10% yield for Al-methyl indole) (Scheme 6.50). 

Other catalysts besides proline have also been investigated. A particularly large amount of data has been collected for the aldol reaction of acetone tvith p-nitrobenzaldehyde (Scheme 4.32). Simple primary a-amino acids and acyclic N-methylated a-amino acids are not catalytically active under standard reaction conditions. Of the simple cyclic amino acids studied, azeti-dine, pyrrolidine, and piperidine 2-carboxylate, proline is clearly the best catalyst, a-, a -, and, in particular, N-methylation reduce the efficiency and vhereas substitution of the 3- and 4-positions are tolerated vithout dramatic effects. Proline amide is essentially catalytically inactive under the standard reaction conditions (DMSO, room temperature, 2 h) but after three days, the aldol could be isolated in good yields, albeit vith very low enantiose-lectivity. Clearly, the carboxylic acid plays an important role in the catalysis and in determining enantioselectivity. That the enantioselectivity can be improved vas sho vn vith penicillamine derivative 168, proline derived diamine salt 169, and amide 170 [129-132]. 

The simple primary-tertiary diamine salts can be successfully applied in the aldol reactions of a-hydroxyketones with good activity and excellent stereoselectivity. Notably, the catalyst enabled the reaction of dihydroxyacetone (DHA), a versatile C3-building block in the chemical and enzymatic synthesis of carbonhydrates. By employing either free or protected DHA, syn- or anh-diols could be selectively formed with excellent enantioselectivity (Scheme 5.7). Since enantiomers of diamine 26 and 29 are readily available, this class of chiral primary amine catalysts thus functionally mimics four types of DHA aldolases in nature [17b]. Later, simple chiral primary-tertiary diamine 27 derived from amino acid was also found to be a viable catalyst for the iyn-selective aldol reactions of hydroxyacetone and free DHA (Scheme 5.7) [18]. 

The iminium activation strategy with the trifunctional chiral primary amine 28, which was used in the y-selective conjugate addition of y-butenolides (Scheme 28), also proved highly effective for promoting reaction with the y-butyrolactam (Scheme 32, first line) [52]. Although various chiral diamines, amino thioureas, and amino sulfonamides were evaluated during the optimization study, none of these catalysts gave rise to impressive levels of diastereoselectivity. Eventually, a bulky acid additive, such as the protected tryptophan derivative (V-Boc-L-Trp-OH),... 

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