Enantiodivergence

This suite of BVMOs is available via whole-cell expression systems and represents a complementary platform of biocatalysts for diverse applications in chiral synthesis. Representatives of this collection were utilized in the enantiodivergent synthesis of the indole alkaloids alloyohimbane and antirhine from a fused bicyclic precursor (Scheme 9.19) [151]. 

Table 9.4 Mutagenesis of CHMOAcineto toward enantiodivergent Baeyer-Villiger oxidations.

Parallel to the modification of the catalytic performance in Baeyer-Villiger oxidations, random mutagenesis was successfully applied to improve the stereoselectivity of CHMOAcineto hi cascs of essentially racemic sulfoxide formation. In addition, enantiodivergent clones with >98% ee for both antipodal products were identified (Table 9.5) [205]. However, improvement in stereoselectivity of mutant enzymes was often accompanied by increased formation of sulfone. This effect can also be utilized to resolve racemic sulfoxides. 

Table 9.5 Random mutagenesis of CHMO, 6to toward enantiodivergent sulfoxidations. ...

Feske, B.D., Kaluzna, I.A. and Stewart, J.D. (2005) Enantiodivergent, biocatalytic routes to both taxol side chain antipodes. The Journal of Organic Chemistry, 70 (23), 9654-9657. 

The diacetoxylation works well with a number of cyclic and acyclic conjugated dienes and has been applied to the synthesis of natural products33,34. For example, the meso diacetate from 2,4-hexadiene was used for the enantiodivergent synthesis of the carpenter bee pheromone343. 

Xenovinine 195, a natural alkaloid, was obtained by catalytic hydrogenolysis of carbamate 194 and subsequent intramolecular reductive amination of the in /-////-generated A-deprotected ketopyrrolidine <1999T8915>. Enantiodivergent synthesis of 195 with the same reductive amination as final step was also reported (Scheme 45) <1998EJO 955>. 

The required (R)- and (S)-P-hydroxysulfides were easily obtained from the same (/ )-epichlorhydrin through enantiodivergent synthesis (R = n-Bu in the scheme). 

To a first approximation, the chiral discrimination should be independent of the nucleophile. The palladium-catalyzed desymmetrization protocol utilizing a heterocyclic nucleophile provides enantio- and diastereoselective entries to diverse carbo-nucleosides. As shown in Scheme 8E.9, introduction of purine bases rather than the hydroxymethyl synthon also affords high enantioselectivities [61]. A variety of natural and unnatural nucleosides can be flexibly prepared because the simple change of ligand chirality or, alternatively, switching the alkylation sequence leads to opposite enantiomers. The palladium-catalyzed approach sharply contrasts with the chiral-pool method, whose enantiodivergency is limited by the availability of the starting material. 

T. Hudlicky, H. Luna, J. D. Price, and F. Rulin, An enantiodivergent approach to d- and L-erythrose via microbial oxidation of chlorobenzene, Tetrahedron Lett. 1989,... 

F. Rulin, Microbial oxidation of chloro-aromatics in the enantiodivergent synthesis of pyrrolizidine alkaloids trihydroxyhelio-tridanes,/. Org. Chem. 1990, 55, 4683-4687. 

The resulting stereoisomeric (6R, 8.S )-cyclohcptcnone 31 is used for the synthesis of (+)-scopadulcic acid A 32 as an enantiodivergent approach. 

The above described total synthesis features the first enantiodivergent approach to (+)- and (—)-scopadulcic acid A. The central transformations are the stereoselective carbonyl group reduction with (S)-Alpine Borane , the use of enolization stereoselection to dictate which enantiomer is produced, and the palladium-catalyzed bis-Heck cyclization which occurs with complete stereo- and regiocontrol to establish the scopadulan scaffold. 

The latter reaction was further described by Koizumi et al. [86b] with slightly different results (lower facial selectivity for the exo-approach), in connection with the enantiodivergent synthesis of fused bycyclo [2,2,1] heptane lactones 91 (see Scheme 47). The key step of this transformation was the regioselective DIBAL reduction of only one of the two ester groups in the adducts, followed by... 

An enantiodivergent route to 2-arylpiperidines was described starting from bicyclic lactam 222 with different reducing agents <02CC256>. 

The sulfite method is an ideal diastereoselective route to o.p. sulfoxides, especially when group permutation is possible. Thus, a single intermediate is used in an enantiodivergent approach to both, sulfoxides. 

The pseudosymmetric acetate of Scheme 8-17 was employed in combination with the palladium-catalyzed reaction for the enantiodivergent synthesis of cis- and trans- 4-aminocyclohex-2-enol [72]. 

Scheme 8-17 Enantiodivergent synthesis of (2,4-cycloalkadien-l-yl)acetic acid.

Kornienko s group reported the formal synthesis of cydophelitoi (1) via RCM to the diene derived from D-xylose [50]. Their s)mthetic strategy was interestingly focused on the latent plane of chirality present in D-xylose as shown in O Fig. 1, and the enantiodivergent s)mthesis of (-1-)- and (-)-cyclophelitol from D-xylose was achieved (O Fig. 1). 

An efficient enantiodivergent synthesis of levorotatory (lS,2/ ,8aS>l,2-dihydroxyindolia e (62a) and its antipode (62b) has been developed starting from commercially available o-isoascoibic acid (61 Scheme 27). This strategy illustrates the complementary use of iminium and IV-acyliminium ion inter-... 

Khiar, N., Singh, K., Garcia, M., Martin-Lomas, M. A short enantiodivergent synthesis of D-erythro and L-threo sphingosine. Tetrahedron Lett. 1999, 40, 5779-5782. 

Scheme4.19 Enantiodivergent enzymatic reduction of butinones using LBADH.

Strategic disconnections illustrated for the total syntheses in Scheme 14, Section III. Although some of the approaches are quite creative and some offer a synthesis of the appropriate enantiomer or an unnatural derivative, few compete with the very first and simplest route to the alkaloid—that of Weinreb. Future improvements in this area should address the asymmetric version of the Weinreb synthesis, or else offer a completely new strategy (hopefully an asymmetric one), which would deliver the title alkaloid in fewer than six steps and in an enantiodivergent manner. 

Apparently, the reaction proceeds in an enantiodivergent manner, i.e., the re-gioisomeric lactones 8a and 8b emanate from opposite enantiomeric ketones and show different ee values. Transformations of this kind are rare, and the most significant examples of these have been summarized by Kagan [27]. 

The first natural product in this family to be synthesized with this methodology was (+)-erogorgiaene (201) [142], and provided an excellent proof of concept for the more complex structures to follow (Scheme 50). Importantly, this synthesis began with racemic dihydronaphthalene precursor 205, and included a powerful enantiodivergent carbenoid transformation. In this key step, one enantiomer of the substrate was poised to react with the rhodium carbenoid to form the desired C-H... 

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