Acids achiral

In another example of enantioselective distillation, it was the enantiomeric mixture to resolve itself which contributed to create a chiral environment. Thus, non-racemic mixtures of a-phenylethylamine were enantiomerically enriched by submitting to distillation different salts of this amine with achiral acids [199]. 

Although these enantioselective photoreactions are limited to amide or salt derived from achiral acid and chiral amine, one enantioselective photoisomerization reaction of cobaloxime coordinated with chiral axial ligands such as 1-methylpropylamine, l-(l-naphthyl)ethylamine, and 2-phenylglycinol has been reported. For example, finely powdered (2-cyanoethyl)cobaloxime (60), suspended in liquid paraffin and spread onto a Petri dish, was irradiated to give (S)-(-)-61 of about 80% ee after displacement of the chiral auxiliary of the complex with pyridine [32],... 

Optical Activation via Achiral Acid Hydrolysis ofEnamines Containing Optically Active Secondary Amines... 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

Table 5.1 Derivatization of 1-phenylethylamine into a conglomerate upon salt formation with an achiral acid.

Just how determined you will see. They looked at salts of both amines with about fifty achiral acids of which eight proved to be conglomerates, three for 84 and five for 85 (this is about what would be expected - about 10%). Of these eight, two could not be separated by crystallisation because one salt 86 had crystal facets that acted as seeds for the other enantiomer while the conglomerate of another 87 was unstable and easily reverted to a racemic compound. 

By far the commonest reaction used in kinetic resolution by enzymes is ester formation or hydrolysis. Normally one enantiomer of the ester is formed or hydrolysed leaving the other untouched so one has the easy job of separating an ester from either an acid or an alcohol. There are broadly two kinds of enzymes that do this job. Lipases hydrolyse esters of chiral alcohols with achiral acids such as 119 while esterases hydrolyse esters of chiral acids and achiral alcohols such as 122. Be warned this definition is by no mans hard and fast If the unreacted component (120 or 123) is wanted, the reaction is run to just over 50% completion, to ensure complete destruction of the unwanted enantiomer, while if the reacted component (121 or 124) is wanted it is best to stop short of 50% completion so that little of the unwanted enantiomer reacts. 

Asymmetric protonation of a metal enolate basically proceeds catalytically if a coexisting achiral acid A-H reacts with the deprotonated chiral acid A -M faster than with the metal enolate, a concept first described by Fehr et al. [44]. A hypothesis for the catalytic cycle is illustrated in Scheme 2. Reaction of the metal enolate with the chiral acid A -H produces (R)- or (S)-ketone and the deprotonated chiral acid A -M. The chiral acid A -H is then reproduced by proton transfer from the achiral acid A-H to A -M. Higher reactivity of A -M toward A-H than that of the metal enolate makes the catalytic cycle possible. When the achiral acid A-H protonates the enolate rapidly at low temperature, selective deprotonation of one enantiomer of the resulting ketone by the metallated chiral acid A -M is seen as an alternative possible mechanism. 

Catalytic enantioselective protonations of metal enolates already published can be roughly classified into two methods carried out under basic conditions and acidic conditions. The process under basic conditions is, for example, the protonation of reactive metal enolates such as lithium enolates with a catalytic amount of chiral acid and an excess of achiral acid. The process under acidic conditions employs silyl enol ethers or ketene silyl acetals as substrates. Under the influence... 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

A racemic carbonyl compound may react with an optically active secondary amine to give the corresponding optically active enamine. Subsequent hydrolysis by achiral acids may result in enanriomerically enriched carbonyl compounds. Strong acids (e.g., hydrochloric, sulfuric or 4-methylbenzenesulfonic acid) arc better suited than weak ones (e.g., acetic acid)131, for example, the transformation of racemic 2-phenylpropanal via the enamine to the (R)-enan-tiomer 1. 

In a complementary approach, the stereogenic center is placed in the leaving group of the enol derivative and the proton is introduced by an achiral acid. The first example of this type of reaction is given by the lactone borone enolate 15 prepared in situ from the lithium enolate of 16 (Section 2.1.6.1,3.) and (-)-(l/ )-5-chlorodiisopinocampheylborane. 

The achiral acid needs to be a kinetically slow acid, and is typically a hindered alcohol, an imide or a carbon acid (e.g. malonate). Enantiomerically pure imides (12.30), ° diamine (12.31), amino alcohols, as well as a tetradentate amine have been used to protonate lithium enolates, including enolates (12.32) and... 

Figure 12.1 Catalytic cycle for protonation reactions. Abbreviations AA = achiral acid ERA = enantiomerically pure acid.

In each of these cases, the stoichiometric achiral acid is kinetically slow, and is also added slowly to the reaction mixture. The commercially available amino acid derivative (12.34) has also been used as an effective enantiomerically pure proton source in the protonation of tetralone enolates such as (12.35). Samarium enolates have also been protonated enantioselectively (up to 93% ee) using catalytic amounts of a C2-symmetric diol. ... 

A highly enantioselective hydrogenation of enamides (152) to afford amines (153), catalyzed by a dual chiral-achiral acid system has been developed by Antilla and Liu (Scheme 41). By employing a substoichio-metric amount of the chiral phosphoric acid (154) and acetic acid, the catalyst loading as low as 1 mol %, excellent chemical yields and enan-tioselectivities of the reduction products (153) were obtained. 

When a prochiral ( )-enolate is selectively (Si)-facially protonated, the result is the (H)-enantiomer. (Jle)-Facial protonation leads to the (S)-enantiomer. From the (Z)-enolate, the direct opposite is obtained. If it is not possible to control the ( )/(Z)-configuration of the enolate, in order to obtain good selectivity, one needs then an enantiomericaUy pure acid, whose protonation preference is dependent on the enolate configuration, i.e. for example, it transfers a proton (Si)-facially to the ( )-enolate, but (Re)-fadally to the (Z)-enolate. In many successful cases the enantiomericaUy pure acid is bonded to the metal of the enolate therefore, at the same time it acts also as a Lewis base. In addition, at least from a theoretical point ofview, enantioselective inter- and intra-molecular protonations with achiral acids are conceivable, in which another ligand of the enolate complex is enantionmericaUypure. 

A similar achiral, acid-labile protecting group has been employed in oligonucleotide synthesis this is the 3-methoxy-1,5-dicarbo-methoxypentanyl (MDMP) group (51), which when present at the 2 -... 

Subsequently, Romo et al. studied an intramolecular nucleophile (O-acetyl quinidine, O-Ac-QD) catalysed aldol-lactonisation (NCAL) process of achiral acid-aldehydes (R = R ) promoted by a modified Mukaiyama reagent (Scheme 15.10) and EtsN, providing p-oxoketenes in situ, leading to a variety of novel p-lactone-fused bicyclic systems. This process was then extended to keto-acid substrates and more recently to racemic substrates (R t R ) demonstrating the utility of the Cinchona alkaloid catalysts O-TMS quinidine (O-TMS-QD) and O-TMS quinine (O-TMS-Q), in doubly diastereoseleetive NCAL reactions. ... 

One important breakthrough in the field was achieved by Li and AntUla in 2009 [61], when they reported the asymmetric hydrogenation of enamides with high enantioselectivity through the employment of chiral phosphoric acid catalysis (Scheme 15.28). Starting from the assumption that a reactive iminium was the intermediate of this reaction, the authors followed the catalytic strategy to pair the phosphoric acid with a suitable achiral acid, to facilitate iminium formation while... 

One set of reactions deserves special mention the conversion of a chiral carbonyl derivative to an achiral enolate that is then protonated enantioselectively. This is clearly a synthetic method that achieves enantiopurity from a racemate but it is clear (because the intermediate is typically isolated) that the separation is achieved not by a separation of enantiomers but rather by their destruction and recreation. The enantioselective step of interest is more akin to a regular synthetic asymmetric step on a prochiral species, and it is for this reason that such techniques in general have not been covered in this book in detail, for fear of mission creep into asymmetric catalysis proper. Nonetheless, the achievements of enantioselective protonations in particular have been striking [138, 139], given the extent to which the pfC s ofaU the compounds involved must be understood for the processes to be effective. An early example serves to illustrate the potential [140]. Amide 23 (Scheme 7.5) was converted to its lithium enolate that could be enantioselectively protonated with chiral acid 24 furthermore, the process could be catalytic in 24 when an achiral acid 25 was added slowly during the reaction. The overall process was only effective when the pKa of the chiral acid was finely tuned. 

In 2008, we reported the use of chiral IV-trifyl thiophosphoimide to catalyze enantioselective protmiation of silyl enol ethers with various achiral proton sources (Fig. 13) [56]. It was found that neither the achiral acids nor stoichiometric amount of chiral catalyst alone can protonate the silyl enol ether substrate under such reaction conditions. We believe the combined BBA catalyst, which is an oxonium cation with chiral thiophosphoimide counteranion, is the reactive species for this protonation reaction. On the other hand, since the extremely bulky chiral counter anion cannot accomplish the desilylation step, presence of achiral proton source for catalyst regeneration turns out to be essential. 

In 2010, the Jacobsen group further advanced this chemistry to the combined use of strong achiral acid components with chiral urea and thiourea catalysts for Povarov reaction (Fig. 21) [77]. Different types of electron-rich alkenes, such as 2,3-dihydrofuran, various enamides and enecarbamates, can be used for the Povarov reaction with imine substrates. Detailed kinetic, as well as computational studies, led to the picture of inducing high enantioselectivity with protio-iminium... 

A fluorous chiral organocatalyst (18) promotes the formation of the anti-Mol product (with up to 96% ee) on reaction between aromatic aldehydes with ketones in brine. The enantioselectivity achieved on promotion of aldol and Mannich reactions by another di-diamine-based catalyst (19) can be reversed by the addition of an achiral acid and is to be the subject of further mechanistic investigation. ... 

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