Chiral dicarboxylic acid

The topical homochirality problem is presently being investigated in several research laboratories across the world. One new object of study is systems with eutectic mixtures. The addition of chiral dicarboxylic acids that co-crystallise with chiral amino acids to aqueous mixtures of d- and L-amino acids allows tuning of the eutectic composition of the amino acids in several cases, these systems yield new eutectic compositions of 98% ee or higher. Thus, solid mixed crystals with a ratio... 

In 2007, Maruoka et al. introduced chiral dicarboxylic acids consisting of two carboxylic acid functionalities and an axially chiral binaphthyl moiety. They applied this new class of chiral Brpnsted acid catalyst to the asymmetric alkylation of diazo compounds withA-Boc imines [91]. The preparation of the dicarboxylic acid catalysts bearing aryl groups at the 3,3 -positions of the binaphthyl scaffold follows a synthetic route, which has been developed earlier in the Maruoka laboratory [92]. 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

Chiral dicarboxylic acid (R)-5g (5 mol%, R = Mes) bearing simpler mesityl-substituents at the 3,3 -positions was found to catalyze efficiently the trans-selective asymmetric aziridination of iV-aryl-monosubstituted diazoacetamides 177 and aromatic (V-Boc imines 11 (Scheme 75) [94], In sharp contrast to previous reports on this generally dx-selective sort of aziridination, this method exhibited unique fran -selectivity and afforded exclusively the fran -aziridines 178 in moderate to good yields along with excellent enantioselectivities (<20-71%, 89-99% ee). The 1,2-aryl shift products 179 were observed as side products in varying ratios (178 179= 56 44-90 10). Diazoacetamides were chosen instead of diazoesters. Due... 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

Fig. 25 Enantioselective non covalent synthesis of double rosettes exploiting the chiral memory effect. Pyridyl residues on the dimelamine units bind chiral dicarboxylic acids leading mainly to one diastereoisomer. Once the chiral templating carboxylic acid is removed by precipitation, the enantioenriched double rosette persists for several hours...

Asymmetric hydrocarboxylation has also been applied to heterofunctionalized alkenes, such as vinyl imides, giving chiral amino acids. Similarly, methacrylic esters give chiral dicarboxylic acids and allylic alcohols give chiral y-butyrolactones. The results of these conversions are compiled in Tabic 12. 

Scheme 24.21 Asymmetric addition to imines catalysed by axially chiral dicarboxylic acids.

In the same year, chiral dicarboxylic acids 63 were applied to the asymmetric addition of weak nucleophiles to acyclic azomethine imines in this case the protonated acyclic azomethine imine I was generated in situ from aldehyde and N-benzylbenzoylhydrazide thanks to the presence of the chiral Bronsted acid 63f the following addition of a mild nucleophile such as allq l diazoacetate gave 77 with good yields and ee values that ranged from 93% to 99% (Scheme 24.24). 

Finally, a direct Mannich-type approach has been developed for the enantioselective synthesis of hydrazines and amines (Scheme 16.40). Thus, by trapping with alkyl diazoacetates some in s/iw-generated acyclic azomethine imines, in the presence of axially chiral dicarboxylic acids, a series of a-diazo-(3-hydrazino esters were obtained with excellent enantioselectivities [86]. 

Other supermolecules that have been studied by DFT calculations of VCD spectra are as follows the assignment of the helicity of a quinoline-derived foldamer with a single chiral center 19 as left handed by the calculation of its simphfied model 19, " the absolute configuration determination of a cryptophane 20, the determination of the predominant conformation in the cyclic tetramer of a chiral dicarboxylic acid 21," and the assignment of the conformations of a polyguanidine 22 by the VCD calculation of a dimeric model 22 (Figure 12b)." ... 

For example, as discussed in Chapter 7, Walden carried out studies involving the chiral dicarboxyUc acid, 2-hydroxybutane-l,4-dioic acid (2-hydroxysuccinic acid maUc acid), which, as noted there, he was able to obtain from the chiral dicarboxylic acid, 2-aminobutane-l,4-dioic acid (2-aminosuccinic acid aspartic acid). These dioic acids were readily available to Walden because they are naturally occurring. The first occurs as a species found in the citric acid cycle (also called the tricarboxylic acid cycle or the Krebs cycle ) and will be discussed in more detail in Chapter 11. The second, an amino acid, will be discussed with other members of the same family in Chapter 12. 

In 2012, Maruoka and coworkers developed a new catalytic asymmetric Ugi-3CR through the use of an axially chiral dicarboxylic acid 27 [28], In the approach, a variety of aldehydes, 2-benzoyloxyphenyl isocyanide (26), and an acyclic azomethine imine 25 were initially reacted, yielding heterocyclic compounds 28 in excellent yields and good enantiomeric excesses (Scheme 7.11). Upon acid hydrolysis of the heterocyclic compound 28a, the corresponding a-hydrazino amide 29 was obtained without loss of enantioselectivity (bottom-left. Scheme 7.11). 

Scheme 2.5 Domino Michael-aldol-dehydration reaction catalysed by a combination of a chiral diamine and a chiral dicarboxylic acid.

Maruoka and co-workers reported the first catalytic asymmetric three-component 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using CuOAc/Ph-pybox and axially chiral dicarboxylic acid cocatalysts (Scheme 27) [48]. This transformation has abroad tolerance with regard to the substrates, affording diverse chiral 3,4-disubstituted pyrazolines with high enantioselectivities. The role of the axially chiral dicarboxylic acid is to generate the protonated acyclic azomethine imine, which then reacts with chiral Cu-acetylide. 

Scheme 7.47 Chiral dicarboxylic acid-catalyzed Mannich-type reactions.

The axially chiral dicarboxylic acid 27b was also uniquely reactive in achieving the highly enantioselective addition of aldehyde N,N-diaIkylhydrazones, a readily... 

Recently, Maruoka and coworkers have also developed an asymmetric inverse electron demand 1,3-dipolar cycloaddition of C,A -cyclic azomethine imines with fort-butyl vinyl ether catalyzed by a newly developed axially chiral dicarboxylic acid having diarylmethyl groups at the 3,3 -positions (Scheme 7.7) [18]. Based on this finding, the concept of the inverse electron demand umpolung 1,3-dipolar cycloaddition was introduced as a strategy for switching the regioselectivity of the cycloaddition from that of the titanium BINOLate-catalyzed normal electron demand 1,3-dipolar cycloaddition with enals (Table 7.3) by... 

Axially chiral dicarboxylic acids were introduced by Maruoka and coworkers as a new class of Bronsted acid catalysts in 2007 [176]. The enantioselective Mannich... 

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