Enzymatic desymmetrization

Enantioselective enzymatic desymmetrization is the transformation of a substrate that results in the loss of a symmetry element that precludes chirality (plane of... 

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

Conduritols and inositols are cyclic polyalcohols with significant biological activity. The presence of four stereogenic centers in the stmcture of conduritols allows the existence of 10 stereoisomers. Enzymatic methods have been reported for the resolution of racemic mixtures or the desymmetrization of meso-conduritols. For example, Mucor miehei lipase (MML) showed enantiomeric discrimination between all-(R) and all-(S) stereoisomers ofconduritol E tetraacetate (Figure 6.52). Alcoholysis resulted in the removal of the four acetyl groups ofthe all-(R) enantiomer whereas the all-(S) enantiomer was recovered [141]. 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Few examples of chemical or enzymatic desymmetrizations of centrosymmetric molecules (point group S2 = Q) have been described [150]. The PLE-catalyzed hydrolysis of a centrosymmetric cyclohexanediacetate gave rise to an enantiomeri-cally pure (>99.5% ee) cyclohexanediol monoacetate in high yield [151] (Figure 6.57). 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

The desymmetrization principle was also exploited in the synthesis of (+)-FR900482, an antitumor antibiotic isolated from Streptomyces sandaensis [155]. A prochiral propanediol was enzymatically desymmetrized using PSL to give the corresponding (S)-monoester as illustrated in Figure 6.59. 

Figure 6.59 Application of enzymatic desymmetrization to the synthesis of (+)-FR900482.

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

To outweigh disadvantages of the kinetic resolution presented above, an enzymatic desymmetrization of prochiral sulfinyldiacetates 19 was performed. The use of various enzymes, PLE, a-chymotrypsin (a-CT) ° and PPL," made it... 

Grogan G, GA Roberts, D Bougioukou, NJ Turner, SL Flitsch (2001) The desymmetrization of bicyclic P-diketones by an enzymatic retro-claisen reaction. J Biol Chem 276 12565-12572. 

R,4R)-Supellapyrone (41) is the female sex pheromone of the brown banded cockroach (Supella longipalpa). Scheme 59 summarizes Mori s synthesis of 41 [89].Enzymatic desymmetrization of meso-B to give (2R,4S)-C and Reformatsky-type cyclization of D to furnish E were the key steps. 

Enzyme-catalyzed reactions can provide a rich source of chiral starting materials for organic synthesis.2 Enzymes are capable of differentiating the enantiotopic groups of prochiral and mew-compounds. The theoretical conversion for enzymatic desymmetrization of mew-compounds is 100% therefore enzymatic desymmetrization of mew-compounds has gained much attention and constitutes an effective entry to the synthesis of enantiomerically pure compounds. 

Kinetic resolution reactions on C2-symmetric substrates have important applications. Desymmetrization is just one example of such a kinetic resolution reaction. Enzymatic desymmetrization is outlined in Scheme 8-1.5,6... 

Garcia-Urdiales, E., Alfonso, I. and Gotor, V., Enantioselective enzymatic desymmetrizations in organic synthesis. Chem. Rev., 2005, 105, 313-354. 

The enzymatic hydrolysis of nitriles provides a viable alternative for the generally harsh chemical conditions that are most often used. As a result of the ability of many nitrilehydrolyzing enzymes to give selective monohydrolysis, in the case of dinitriles, additional opportunities such as desymmetrization can be explored. With the previous examples, we have shown that, for several substrate classes, enzymatic desymmetrization of dinitriles is indeed a synthetically viable option. 

The desymmetrization of l-alkylbicyclo[3.3.0]octane-2,8-diones can be achieved in a facile coenzyme-independent enzymatic reaction in buffer. Alkyl chains in the 1 -position of up to at least five carbon atoms are tolerated. The yields of the crude keto-acids are essentially quantitative, and the enantiotopic discrimination by the enzyme is usually excellent." Work remains to be done on the optimization of this biocatalyst with respect to protein stability and reaction engineering, but it remains a unique and intriguing possibility for the generation of interesting intermediates bearing multiple chiral centres. 

The purpose of this review is to cover catalytic enantioselective desymmetriza-tions that have appeared in the literamre from early 1999 to mid-2004. Stoichiometric desymmetrizations will not be considered. Enzymatic desymmetrizations will also not be considered, largely because this method is firmly engrained as a powerful technique and the bulk of the work in this area in recent years has centered on applications of the method to specific substrates rather than developmental advances. This review will also attempt to focus on method development rather than application to synthesis. This field has recently been reviewed, and the purpose of this manuscript is to complement the previous treatises of this subject. 

Zopiclone is a chiral cyclopyrrolone with hypnotic properties, possessing a pharmaceutical profile of high efficacy and low toxicity, similar to that of benzodiazepines. Zopiclone has been commercialized as a racemic mixture however, the (S)-enantiomer is more active and less toxic than the (R)-enantiomer [11]. Although enzymatic hydrolysis of esters or transesteriflcation processes of alcohols have been widely applied for enzymatic resolution or desymmetrization... 

Scheme 7.9. Synthesis of oseltamivir phosphate (1) employing an enzymatic monohydrolysis desymmetrization.

Scheme 7.16 Desymmetrization of 2-substituted 1,3-propanediol to (S)-monoacetate by enzymatic hydrolysis in 80% organic solvent.

Azacycles can also be constructed by C-C bond construction. The enantiomerically-pure amide 8 is easily prepared by photolysis of pyridine followed by acetylation and enzymatic desymmetrization. 

Scheme 14- Synthesis of (-)-paroxetine using an asymmetric desymmetrization of a glutanc ester via enzymatic hydrolysis.

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

With the same protocol, a heterocyclic dibenzoate 86 derived from furan in one step has been efficiently desymmetrized to provide facile entry to either D or L nucleosides (see Scheme 8E.10). As depicted in Scheme 8E.10, the catalyst derived from ligand 71 gave rise to high enantioselectivities in the alkylation with both a purine 83 and a pyrimidine 87 [62], Subsequent allylic alkylations with an achiral ligand introduced the tartronate and aminomalonate moieties to furnish enantiomerically pure Ci s-2,5-disubstituted-2,5-dihydrofurans 89 and 91, respectively. Only six steps from furan were required to synthesize the alio and talo isomers of the nucleoside skeleton of the polyoxin-nikkomycin complexes. It should be noted that the corresponding enzymatic desymmetrization of substrate 86 is impossible because the product is labile. 

Excellent enantioselectivities are observed in the alkylation of various gem-dicarboxylates with both carbon and heteroatom nucleophiles as summarized in Table 8E.2 [71]. Screening various chiral ligands from the DPPBA module revealed that 1,2-diaminocyclohexane derived ligand 5 gives the best results, and the mnemonic of Figure 8E.8 correctly predicts the enantiomer obtained in this reaction. Notably, the corresponding desymmetrization by enzymatic hydrolysis or acylation is not feasible with these 1,1-diol derivatives. 

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