Asymmetric decarboxylative

Thus, if we can apply the type of asymmetric decarboxylation reactions mentioned above to synthetic substrates, unique asymmetric reactions and C—C bond-forming reactions will be realized which are otherwise difficult to be realized. 

Although there were some trials to prepare optically active carboxylic acids via asymmetric decarboxylation, the optical yields of the products were not high enough for practical use. Thus, it is strongly desirable to find an enzyme which catalyzes asymmetric decarboxylation of arylmethylmalonates to give optically pure arylpropionates. 

Aiming at the feasibility study of such type of asymmetric decarboxylation, we screened microorganisms which are able to grow on the medium containing tropic acid as the sole source of carbon. It is expected that at least one of the major metabolic pathway of tropic acid is the oxidation of the hydroxyl group followed by decarboxylation and further oxidation of the resulting aldehyde (Fig. 20). If... 

Biocatalytk decarboxylation is a imique reaction, in the sense that it can be considered to be a protonation reaction to a carbanion equivalent intermediate in aqueous medimn. Thus, if optically active compoimds can be prepared via this type of reaction, it would be a very characteristic biotransformation, as compared to ordinary organic reactions. An enzyme isolated from a specific strain of Alcaligenes bronchisepticus catalyzes the asymmetric decarboxylation of a-aryl-a-methyhnalonic acid to give optically active a-arylpropionic acids. The effect of additives revealed that this enzyme requires no biotin, no co-enzyme A, and no ATP, as ordinary decarboxylases and transcarboxylases do. Studies on inhibitors of this enzyme and spectroscopic analysis made it clear that the Cys residue plays an essential role in the present reaction. The imique reaction mechanism based on these results and kinetic data in its support are presented. 

Keywoids Asymmetric decarboxylation. Enzyme, Reaction mechanism, a-Arylpropionic acid. 

At the start of this project, we chose a-arylpropionic acids as the target molecules, because their S-isomers are well established anti-inflammatory agents. When one plans to prepare this class of compounds via an asymmetric decarboxylation reaction, taking advantage of the hydrophobic reaction site of an enzyme, the starting material should be a disubstituted malonic acid having an aryl group on its a-position. 

In the previous studies using inhibitors and additives, it became clear that AMDase requires no cofactors, such as biotin, coenzyme A and ATP. It is also suggested that at least one of four cysteine residues plays an essential role in asymmetric decarboxylation. One possibility is that the free SH group of a cysteine residue activates the substrate in place of coenzyme A. Aiming at an approach to the mechanism of the new reaction, an active site-directed inhibitor was screened and its mode of interaction was studied. Also, site-directed mutagenesis of the gene coding the enzyme was performed in order to determine which Cys is located in the active site. 

So far, it has become clear that Cys plays an essential role in the asymmetric decarboxylation of disubstituted malonic acids. It follows that studies of reaction kinetics and stereochemistry will serve to disclose the role of the specific cysteine residue and the reaction intermediate. 

Novel asymmetric conjugate-type reactions have been accomplished with Cinchona alkaloid-derived chiral thioureas, including less traditional reactions such as asymmetric decarboxylation [71]. In the following discussion, asymmetric reactions involving nitro-olefms, aldehydes and enones, and imines will be highlighted (Fig. 5). 

The Rouden group utilized 121 and 124 as organic bases for the asymmetric decarboxylative protonation of cyclic, acyclic, and bicyclic N-acylated a-amino hemimalonates [290]. The introduced protocol suffered from high catalyst loading... 

Scheme 6.135 Typical products obtained from the 121- and 124-catalyzed asymmetric decarboxylative protonation of N-acylated a-amino hemimalonates.

Scheme 7 Alternative mechanism for asymmetric decarboxylation of 2-cyano-2-(6-methoxy-naphth-2-yl)propionic acid in the synthesis of Naproxen involving a pre-association mechanism.

Asymmetric decarboxylative rearrangement (Carroll rearrangement) of allyl a-acetamido-/3-ketocarboxylates, catalysed by a palladium complex modified with a chiral phosphine ligand, has been reported to give optically active /,5-unsaturated a-amino ketones with up to 90% ee (Scheme 92).135 The mechanism for the Carroll rearrangement is shown in Scheme 93. 

The epi-quinine urea 81b was also found by Wennemers to promote an asymmetric decarboxylation/Michael addition between thioester 143 and 124 to afford the product 144 in good yield and high enantioselectivity (up to 90% ee) (Scheme 9.49). Here, malonic acid half-thioesters serve as a thioester enolate (i.e., enolate Michael donors). This reaction mimics the polyketide synthase-catalyzed decarboxylative acylation reactions of CoA-bound malonic acid half-thiesters in the biosynthesis of fatty adds and polyketides. The authors suggested, analogously with the enzyme system, that the urea moiety is responsible for activating the deprotonated malonic add half-thioesters that, upon decarboxylation, read with the nitroolefin electrophile simultaneously activated by the protonated quinuclidine moiety (Figure 9.5) [42]. 

Novelization of the alkaloids is easy using the methods known in synthetic production, such as catalytic asymmetric reactions and inductions. Organo-catalytic cascade, asymmetric photocycloaddition, cyclization, and asymmetric decarboxylative allylation are used in total synthesis, as well as catalytic asymmetric induction reactions and condensation of alkaloid molecules (two or more). Novelization of alkaloids by total synthesis is generally used by the pharmacological industry around the globe. 

Following the previous successful application of the asymmetric decarboxylative protonation reaction in the catalytic asymmetric synthesis of isoflavanones we hoped to expand the scope of this work to the catalytic asymmetric synthesis of tertiary a-aryl cyclohexanones and, in particular, cyclopentanones given the dearth of reported methods for their direct asymmetric synthesis to date (see Sect. 4.6). 

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