Desymmetrization reactions examples

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). 

Major advances were also made in the field of ARCM. Notable examples of this process are shown in Scheme 2 and include AROM <02JA10779>, and the desymmetrization reactions of acetals <00TL9553> and ethers <02JA2868>. Especially noteworthy are the ARCM to yield medium-sized, cyclic amines that occur in high yield and enantiomeric excess in the absence of solvent <01JA6991> [—m indicates the site of RCM]. 

On the basis of this strategy, a conceptually related desymmetrization reaction of enone-diones was introduced by the same group [26aj. An initial enone carbometalation furnished a rhodium enolate, which efficiently differentiated between the two carbonyl groups of the neighboring dione. Compound 55 as a representative example could be converted into the aldol product 57 in 87% yield and excellent selectivities. Only a single diastereomer out of 16 potential stereoisomers was formed selectively (Scheme 8.16). 

As well known, desymmetrization reactions of symmetric compoxmds provide step-economical route in organic synthesis. Some approaches on the basis of tire desymmetrization concept have been published. For example, Kitamura et al. achieved Ru-catalyzed desymmetric hydrogenation of a mcso-cyclic acid anhydride 174 to obtain enantiomerically enriched y-lactone 175 (Scheme 71) [119]. In this case, (S,S)-Et-FerroTANA 176 was used as asymmetric phosphine ligand. 

Extension of these processes to provide enantio-enriched products was successfully applied after desymmetrization of the starting materials. An example is shown below (Reaction 76), where silane-mediated xanthate deoxygenation-rearrangement-electrophile trapping afforded the conversion of (+)-94 to (+)-95 in 56% yield. ... 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

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... 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

The arena in which catalytic asymmetric olefin metathesis can have the largest impact on organic synthesis is the desymmetrization of readily accessible achiral molecules. Two examples are illustrated in Scheme 4. Treatment of achiral triene 18 with 2 mol % 4a leads to the formation of (R)-19 in 99% ee and 93% yield [ 12]. The reaction is complete within 5 min at 22 °C and, importantly, does not require a solvent. Another example is illustrated in Scheme 4 as well here, BINOL complex 11a is used to promote the formation of optically pure (R)-21 from siloxy triene 20 in nearly quantitative yield. Once again, solvent is not needed [15]. Readily accessible substrates are rapidly transformed to non-ra-cemic optically enriched molecules that are otherwise significantly more difficult to access without generating solvent waste. 

The intramolecular aldol reaction of triketones with asymmetric desymmetrization has been known for a long time. When Eder, Sauer, and Wiechert [97, 98], and in parallel Hajos and Parrish [99-101] reported this reaction in the early 1970s it was the first example of an asymmetric catalytic aldol reaction, and one of the first examples of an organocatalytic asymmetric synthesis [104]. 

It should finally be mentioned that chiral base methodology is not limited to the desymmetrization of meso-epoxides but also enables kinetic resolution of racemic epoxides [57, 63, 65], This (organocatalytic) type of reaction seems, however, to be less prominent than the desymmetrization of meso-epoxides. Some examples of kinetic resolution of chiral epoxides are summarized in Scheme 13.35. 

Olefin metathesis does not generate stereogenic centers, however, the reaction may be employed in the desymmetrization of prochiral (poly)olefins of the kinetic resolution of racemates. In the example depicted in Scheme 17, a trialkene is desymmetrized, and the preference for the cyclization reaction with one of the two symmetry-equivalent C = C double bonds leads to the enantioselective formation of the reaction product, a chiral dihydrofuran. The following principal conclusions can be drawn from this study ... 

Reactions with Nitrogen Nucleophiles. The palladium(O)-catalyzed asymmetric desymmetrization of cw-3,5-dibenzoyloxy-1-cyclopentene, with 6-chloropurine and 2-amino-6-chloropurine as nucleophiles, has been utilized in the synthesis of (-)-carbovir and (—)-neplanocin. In these examples, the diphenylethanediamine and the anthracenyldiamine based ligands were found to be superior to the standard ligand. 

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