Opposite enantiopreference

An interesting case is the resolution of a heterohelicenediol. The very bulky racemic substrate roc-15 is resolved by lipase-catalyzed acylation with vinyl acetate in dichloromethane. Oddly enough, Candida antarctica lipase (CAL) and Pseudomonas cepacia lipase (PCL) display opposite enantiopreferences [54]. In Scheme 4.13, only the remaining substrates are shown and not the other products, the mono- and diacetates. 

The lipase-catalysed access to enantiomerically pure compounds remains a versatile method for the separation of enantiomers. The selected examples shown in this survey demonstrate the broad applicability of lipases in terms of substrate structures and enantioselectivity. More recently, modem molecular biology methods such as rational protein design and especially directed evolution103 will further boost the development of tailor-made lipases for future applications in the synthesis of optically pure compounds. It has been already shown that a virtually non-enantioselective lipase (E=l.l in the resolution of 2-methyldecanoate) could be evolved to become an effective biocatalyst (E>50). Furthermore, variants were identified which showed opposite enantiopreference. 

Interestingly, the bacterial epoxide hydrolase from Agrobacterium radiobacter ADI seems to hydrolyze para-substituted styrene oxides with opposite enantiopreference when compared to EHs from fungi or yeast[n8]. Although initial selectivities were... 

Iwabuchi with coworkers designed a series of 4-silylo)yproline derivatives with a view to confer lipophilic properties to the proline motif and thereby secure a basis for the catalytic activity growth. They found that (2S,4R)- and (2R,4R)-4-silylo yprolines 30 or their BU4N salts 31 (Figure 10.3) exhibit enhanced catalytic potencies to enantioselectively convert a-sym-metric keto-aldehyde 36 to bicyclo[3.3.1]-type products 37 or ent-37 with opposite enantiopreferences and different enantiocontrolling proficiencies (Scheme 10.8). Unexpectedly, the use of carbojylate (2S,4R)-31 (5 mol%) markedly enhanced the aldolisation rate to complete the reaction in 3 h at room temperature and furnish 77% 37 with 98% diastereomeric excess and... 

Another vanadium-dependent haloperoxidase from the marine alga Corallina officinalis was shown to possess a matching opposite enantiopreference by forming (5)-sulfoxides [1343, 1344]. Although simple open-chain thioethers were not well transformed, cyclic analogs bearing a carboxylic acid moiety in a suitable position within the substrate were ideal candidates [1345]. 

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

The product of a NHase/amidase cascade reaction is an acid, which is the same as the single enzymatic reaction performed by a nitrilase. However, the NHases usually have different substrate specificities than nitrilases, making them more suitable for the production of certain compounds. Although most organisms have both NHase and amidase activity (see earlier text), it is sometimes preferable, in a synthetic application, to combine enzymes from different organisms. The reasons for this are the enantioselectivity of the amidase or specific activity or substrate specificity of either of the enzymes. In this way, products with different enantiomeric purity can be obtained. Recently, a coupling of a NHase with two different amidases with opposite enantiopreference together with an -amino-a-caprolactam racemase that allows the formation of small aliphatic almost enantiopure (R)- or (S)-amino acids via dynamic kinetic resolution processes has been described [52]. 

Thus, compounds 5 and 6, two lead molecules within the class of hPPAR 2-aryloxy-3-phenyl propionic acid agonists, exhibit opposite enantiopreference for compound 1, the main object of our consideration in this chapter, which is also an 2-aryloxy-propionic acid derivative. Since, no details of the structure of the complex of 1 and the LBD of hPPARs were reported, it can be assumed that the absence of a phenyl group at position C(3) in 1 somehow results in inverse steric requirements for this agonist at LBD, when compared with its 3-phenyl congeners, 5 and 6. Since, the route to enantiomerically pure (R)-l includes a number of original synthetic solutions, a detailed discussion of these is presented in later sections. 

An alternative for the transformation of a racemate into one single enantiomer in >99% yield and with high enantiomeric excess is the stereoinversion. In the case of racemic alcohols, this approach relies on the formation of prochiral ketones through an enantioselective oxidation process and subsequent opposite stereoselective reduction of these prochiral intermediates (Scheme 4.12). Therefore, an ideal system to carry out this type of transformation is composed of a pair of (bio) catalysts with opposite enantiopreference and different cofactor selectivity to avoid undesired interferences. 

Tetrahydroisoquinolines bearing a chiral center at the Cl position constitute a structural motif found in many biologically active compounds. For instance, (5)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 114 is a precursor of the natural product (5)-calycotomine (Scheme 57.31). Kanerva, Fiilbp, et al. have described the preparation of both enantiomers of 114 by enzymatic hydrolysis of the ethyl ester derivative rac-113. Considering this substrate undergoes spontaneous racemization in an aqueous medium, these authors carried out an exhaustive study of the reaction variables in order to find the optimal conditions and thus achieve the DKR of this substrate. Two enzymes with opposite enantiopreferences were used CAL-B and... 

Another approach for the coupled racemization step has been used for compounds having an acidic hydrogen on the stereocenter. Examples of such compounds are chiral acyl donors such as a-substituted esters which are prone to base-catalyzed racemization via an enolate intermediate. This approach has been frequently used and a few examples will be given here to illustrate the utility (Scheme 11). The first examples involve oxa-zolinones where it was found that porcine pancreatic lipase and lipase from Aspergillus sp. exhibited opposite enantiopreferences [106,107]. The remaining oxazolinone was spontaneously racemized via the enolate intermediate and both (l)- and (D)-iV-benzoyl amino acids could be produced this way in high chemical and optical yields. The p Ka values of thio esters are lower than those of oxo esters [108]. This has been used in the lipase-... 

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