The last 15 years have witnessed significant developments in the efficiency and scope of the application of DKR. These now offer a serious alternative to conventional methods for asymmetric synthesis. Indeed, impressive examples using new enzymes and major progress in the DKR of racemates have taken place over the past few years. The powerful combination of enzymes and metals has also been the subject of spectacular development. In addition, a new type of DKR, involving organocatalysts, has recently appeared. Although asymmetric catalysis has undergone development during the last two decades, the most common industrial process used to obtain enantiomerically pure compounds is still via resolution of racemic mixtures. This is despite the major disadvantage that only a maximum of 50% product yield can be obtained. It is not surprising that DKR, which solves the problem of the limitation in yield, has attracted an increasing amount of interest from both the industrial and the academic perspective. This book provides an up-date on the principle methods employed to obtain dynamic kinetic resolution (DKR) by either enzymatic or non-enzymatic methods. It also illustrates the diversity of useful chiral products that can be obtained through this powerful concept. Divided into three sections, the book deals successively with non-enzymatic methods, enzymatic methods, and the use of transition metals and enzymes in tandem.
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About the Author
Hélène Pellissier was born in Gap, France. She carried out her PhD under the supervision of Dr G. Gil in Marseille and then entered the Centre National de la Recherche Scientifique in 1988. After a postdoctoral position in Professor K. P. C. Vollhardt's group at Berkeley, she joined the group of Professor M. Santelli in Marseille in 1992. Here she focused on the chemistry of BISTRO and its large application in organic synthesis.
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Chirality from Dynamic Kinetic Resolution
By Hélène Pellissier
The Royal Society of ChemistryCopyright © 2011 Hélène Pellissier
All rights reserved.
There are numerous ways of obtaining resolutions of chiral compounds by chemical means. The combination of these chemical kinetic resolutions with racemisation is, however, less obvious. Nevertheless, DKR processes can be exploited just as successfully for non-enzymatic reactions. Typically, chiral auxiliaries or chiral organometallic complexes are employed to achieve the desired resolution. Hence, besides metal complexes bearing chiral ligands, such as ruthenium catalysts together with a chiral ligand such as 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl (BINAP), there is also the possibility of using chiral auxiliaries for the asymmetric induction through a dynamic kinetic process. One of the first clear examples of DKR was reported by Weygand et al. (1966), dealing with the reaction of azlactones with chiral auxiliaries such as chiral amino esters to form dipeptides.
1.2 Configurationally Labile Alkyl Halides
Nucleophilic substitution on configurationally labile halides has been involved in compounds with a bromo or iodo atom in the α-position with respect to a carboxylic acid derivative, in which the SN2 reaction is governed by a chiral auxiliary placed in the carboxylic moiety. Racemisation takes place by consecutive inversions at the labile centre induced by additives such as polar solvents, bases or halide salts (Scheme 1.1).
Extensive studies have been carried out on nucleophilic substitution of α-halocarboxylic acid derivatives containing a chiral auxiliary in the carboxylic moiety. Racemisation of the labile chiral centre in the α-position to the carbonyl — induced by additives such as polar solvents, bases or halide salts — allows a high asymmetric induction through a DKR process to be obtained. This methodology has been recently recognised as a powerful synthetic method for asymmetric syntheses of α-heteroatom-substituted carboxylic acid derivatives. As an example, tert-butyl (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate was used by Nunami and colleagues as a chiral auxiliary for DKR of α-bromo-carboxylic acids. In this case, the nucleophile was a malonic ester enolate and the role of the polarity of the solvent (hexamethylphosphoramide, HMPA) was demonstrated (Scheme 1.2).3 The alkylated products were further easily converted to chiral α-alkylsuccinic acid derivatives and chiral β-amino acid derivatives. Moreover, these authors showed that this methodology could be extended to other nucleophiles such as amines. Therefore, the reaction of a diastereomeric mixture of tert-butyl (4S)-1-methyl-2-oxoimidazolidine-4carb-oxylate with potassium phthalimide predominantly afforded tert-butyl (4S)-1methyl-3-((2S)-2-(phthaloylamino)propionyl)-2 -oxoimidazolidine-4-carboxylate in 90% yield and 94% diastereomeric excess (de). The successive removal of the chiral auxiliary afforded N-phthaloyl-L-alanine.
Durst and colleagues applied the same methodology to benzylamine as the nucleophile and obtained the expected aminoimides in good yields and excellent enantiomeric purities (R1 = Et: 92%, de = 98%). They also described in same paper the successful condensation of dibenzylamine on racemic α-bromoesters of (R)-pantolactone (Scheme 1.3).
In 2004, Ben and colleagues reported the first example of a DKR using immobilised amine nucleophiles. This novel approach involved a nucleophilic amine attached to a solid phase resin via an organic spacer, providing optical purities of the N-substituted α-amino ester products superior to the solution phase DKR process with diastereoselectivities ranging from 84 to 90% and yields between 66% and 95% (Scheme 1.4).
In the course of preparing α-amino acids and their N,N-dibenzyl derivatives, Camps et al. involved (R)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as the chiral auxiliary (Scheme 1.5).8 In this way, the corresponding α-dibenzylamino acids were obtained through a DKR process followed by a non-epimerisable hydrolysis.
The use of alkoxides as nucleophiles is not common in the area of DKR. In 1997, Camps et al. reported, however, the asymmetric synthesis of ahydroxyacids based on the DKR of a diastereomeric mixture of abromoesters derived from (R)- or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone with p-methoxyphenoxide in the presence of tetra-n-hexylammonium iodide (Scheme 1.6).
The synthesis of (R)-α-aryloxypropanoic acid herbicides was achieved by involving the same chiral auxiliary with the corresponding trisubstituted phenoxides. The DKR, which gave in this case moderate diastereoselectivities, was followed by mild acid hydrolysis, as shown in Scheme 1.7.
In 1999, Bettoni and colleagues developed a DKR in order to prepare 2-aryloxyacid analogues of clofibrate, which show markedly different biological activities depending on the nature of the enantiomer. The key step of the synthesis was the condensation of sodium 4-chlorophenoxide on diastereomeric 2-bromoimides. (4S)-4-Isopropyl-1,3-oxazolidin-2-one was used as the chiral auxiliary, as shown in Scheme 1.8.
Chiral imidazolidinones have been widely employed as chiral auxiliaries for more than 20 years due to their low flexibility. In this context, Caddick and colleagues studied the DKR of α-haloacylimidazolidinones with a large variety of nitrogen, sulfur and carbon nucleophiles. An unusual dichotomy of diastereoselection has been observed whereby the metallated nucleophiles preferentially reacted via the (5S, 2'R) diastereomer (Scheme 1.9) while the amine nucleophiles reacted via the (5S, 2'S) diastereomer (Scheme 1.10).
In order to explain the stereochemical outcome of their DKR processes, extensive molecular modelling experiments were carried out by Caddick and colleages. It seems that a non-bifurcated H-bond model which minimises the bromine–phenyl interaction is probably the most accurate. The stereoselectivity of the reaction therefore arises from the interaction between the leaving group and the stereo-differentiating substituent of the chiral auxiliary (Figure 1.1).
As the amine undergoes substitution, a twisting of the C1–C2 bond is required which potentiates these interactions in the 2'R isomer but not in the 2'S isomer, thereby explaining its greater reactivity with H-bonding nucleophiles. For the DKRs with metallated nucleophiles, a different result was observed. In fact, considering that the counterion of these nucleophiles can only be weakly complexed to the carbonyl group of the chiral auxiliary, direct attack of the anion should be more relevant and should take place preferentially from the less hindered side of the substrates in the anti-parallel carbonyls conformation. Therefore, the most reactive diastereomer was the 2'R and the selectivity depends mainly on the ability of the chiral auxiliary's substituent to generate steric/electrostatic repulsions with the nucleophile. In addition, the final outcome of the DKR reactions with metallated nucleophiles was the result of a competition between direct attack and complexed attack (through the sodium ion). In 2005, Caddick's group demonstrated that diastereoselective substitution reactions of α-bromoacyl-imidazolidinones with nitrogen nucleophiles could be promoted with either retention or inversion of configuration by carrying out reactions under epimerising or non-epimerising conditions. Hence, an alternative general strategy was sought in which the substitution of the (2'R)-bromide (depicted in Scheme 1.11) with a nucleophile under epimerising conditions led to the corresponding (2'R)product with overall retention of configuration via DKR, in which the (2'S)-isomer was the most reactive. This process was complemented by classical inversion, providing access to the (2'S)-product under non-epimerising conditions and in the presence of tetramethylguanidinium azide (TMGA). Substitution of the diaster-eomerically pure bromides with benzylamine under DKR conditions was shown to proceed with a high level of stereocontrol and with retention of configuration (Scheme 1.11). This was consistent with a reaction involving the initial conversion of the (2'R)-bromide into a mixture of (2'S)/(2'R)-halides and then selective reaction of the (2'S)-product with inversion of configuration.
However, disappointingly poor selectivities were observed with sulfur nucleophiles. The high reactivity of the sulfur nucleophiles resulted in rapid nucleophilic displacement reactions relative to the epimerisation process and this may explain the lack of selectivity (Scheme 1.12). Moreover, the results of DKR reactions using sulfur nucleophiles are in agreement with the observed dichotomy: methyl thioglycollate and benzyl mercaptan behaved similarly to amines, whereas thiophenol (which should be in the form of the thiophenolate anion under the reaction conditions used) showed the same preferential reactivity as the metallated nucleophiles.
In 2004, Bettoni and colleagues applied DKR methodology to α-bromo esters containing lactamides as chiral auxiliaries, allowing the synthesis of chiral analogues of antilipidemic clofibrate. Hence, the displacement of the bromine with 4-chlorophenoxide was found to proceed with good to high diastereoselectivity to give the corresponding 4-(chlorophenoxy)butanoyl esters (Scheme 1.13). After hydrolysis, the (R)-enantiomer of antilipidemic 2-(4-chlorophenoxy)butanoic acid was obtained. In 2006, the same group improved the stereoselectivity up to 98% de by using other chiral auxiliaries such as piperidine-, morpholine-, pyrrolidineand 4-methylpiperazine-derived lactamides (Scheme 1.13). In addition, these authors have developed an asymmetric synthesis of the non-steroidal anti-inflammatory (S)-ibuprofen on the basis of the DKR methodology. The racemic ibuprofen was converted into the corresponding diastereomeric mixtures of esters with amides of (S)-lactic acid as chiral auxiliaries, using dicyclohexylcarbodiimide and 4-dimethylaminopyridine as condensation agents. The reactions afforded predominantly one of the two diastereomers with moderate diastereoselectivities of up to 70% de.
This methodology was extended by Cardillo et al. to the synthesis of chiral α-benzylamino-β,γ-unsaturated acids, starting from α-bromo-α,β-unsaturated chlorides. The treatment of these latter compounds with (R)-pantolactone in the presence of triethylamine (TEA) allowed the in situ formation of the deconjugated ketenes and their direct transformation into the corresponding chiral esters. The substitution of bromine with benzylamine, followed by acid hydrolysis, produced enantiomerically enriched α-benzylamino-β,γ-unsaturated acids (Scheme 1.14). The displacement of the bromine with other nitrogen nucleophiles, such as p-methoxybenzylamine and allylamine, also occurred with good yields with complete diastereoselectivity.
The incorporation of unnatural amino acids into peptides to enhance their metabolic stability and activity is an area of major interest in peptidomimetic chemistry. In order to accomplish this goal, Park and colleagues have developed nucleophilic substitutions of α-bromo amides derived from L-amino acids in the presence of amine nucleophiles on the basis of DKR processes. Whereas moderate stereoselectivities were obtained when using benzylamine as the nucleophile, the nucleophilic substitution reactions of various α-bromo amides with the more sterically demanding secondary amine nucleophile, dibenzylamine, allowed the stereoselectivity of the reactions to be increased remarkably. This methodology provided, in the presence of tetra-n butyl-ammonium iodide (TBAI) and TEA, the corresponding dipeptide analogues in up to 98% yield and 98% de (Scheme 1.15).
As an extension of the preceding methodology, Park's group reported the stereoselective syntheses of triand tetrapeptide analogues starting from achloro as well as α-bromo amides (Scheme 1.16). Mechanistic investigations suggested that α-iodo acetamides were real intermediates for the nucleophilic substitutions of both α-chloro and α-bromo amides in the presence of TBAI. The methodology was also successful for the N-terminal functionalisation of peptides, affording a generalised and practical method for the asymmetric syntheses of N-carboxyalkyl, N-aminoalkyl and N-hydroxyalkyl peptide analogues.
In 2006, the same group reported the synthesis of other chiral N-aminoethyl prolinol derivatives on the basis of a DKR of N-(α-bromo-α-phenylacetyl)-proline methyl ester in asymmetric nucleophilic substitution and subsequent reduction (Scheme 1.17). These peptide-derived prolinols were tested as chiral ligands in the asymmetric addition of a Reformatsky reagent to aromatic aldehydes, providing enantioselectivities of up to 98% enantiomeric excess (ee).
Carbohydrates are readily available inexpensive natural products in which numerous functional groups and stereogenic centres are present in a molecule. A number of carbohydrate-based templates have been used as chiral auxiliaries for various stereoselective reactions. In 2005, Park's group described the first successful example of a carbohydrate-mediated DKR of α-halo esters in nucleophilic substitution for asymmetric syntheses of α-amino acid derivatives. Thus, use of diacetone-D-glucose as a chiral auxiliary allowed the substitution products to be obtained in up to 99% yield and 94% de. The procedure was generalised to various amine nucleophiles, as depicted in Scheme 1.18. In addition, the application of this mild and simple method to highly stereoselective preparations of 1,1'-iminodicarboxylic acid derivatives was also demonstrated on the basis of substitution with various amino ester nucleophiles (Scheme 1.18). In 2007, this methodology was also applied to the synthesis of N-carboxyalkylated 6- and 7-aminoflavones by using 6- and 7-aminoflavones as amine nucleophiles providing diastereoselectivities of up to 98% de. In addition, diastereoselectivities of up to 96% de were obtained by these authors in the synthesis of dihydroquinoxalinones by using various phenylenediamine nucleophiles in the same methodology.
In 2009, Park's group applied the DKR methodology to the nucleophilic substitution reaction of α-bromo esters containing methyl (S)-mandelate as chiral auxiliaries. Hence, the displacement of the bromine with various aryl amine nucleophiles was found to proceed with high diastereoselectivities of up to 92% de combined with high yields to give the corresponding chiral amines, as shown in Scheme 1.19. The DKR was performed in the presence of TBAI combined with diidopropylethylamine (DIEA) in dichloromethane or acetonitrile as the solvent at room temperature.
The scope of this methodology was extended to the reaction of these α-bromo esters with 1,2-diaminobenzene and 2-aminohydroxybenzene nucleophiles, allowing the asymmetric syntheses of the corresponding (R)-dihydroquinoxalinones and (R)-dihydrobenzoxazinones, the structural cores of which are of great interest as important pharmacophores in many biologically active compounds. As shown in Scheme 1.20, the substitution reaction of methyl (S)-mandelate-derived α-bromo esters with variously substituted 1,2-phenylenediamines was spontaneously followed by cyclisation, yielding the corresponding chiral substituted dihydroquinoxalinones in both high yields and diastereoselectivities of up to 94% de. Similarly, the reaction between the α-bromo-α-phenyl ester and variously substituted 2-aminophenols afforded the corresponding chiral dihydrobenzoxazinones in good yields and good diastereoselectivities of up to 82% de (Scheme 1.20). Since both enantiomers of mandelic acid are readily available, this simple and easy methodology enables the preparation of the corresponding (S)dihydro-quinoxalinones and (S)-dihydrobenzoxazinones.
Excerpted from Chirality from Dynamic Kinetic Resolution by Hélène Pellissier. Copyright © 2011 Hélène Pellissier. Excerpted by permission of The Royal Society of Chemistry.
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Table of Contents
Introduction; Non-enzymatic methods; Enzymatic methods; Use of transition metals and enzymes in tandem; Conclusions