Desymmetrization

Borysow J, Moraidi M and Frommhoid L 1985 The ooiiision induoed speotrosoopies. Conoerning the desymmetrization of oiassioai iine shape Mol. Phys. 56 913-22... 

Desymmetrization of meso-bis-allylic alcohols is an effective method for the preparation of chiral functionalized intermediates from meso-substrates. Schreiber et al has shown that divinyl carbonyl 58 is epoxidized in good enantioselectivity. However, because the product epoxy alcohols 59 and 60 also contain a reactive allylic alcohol that are diastereomeric in nature, a second epoxidation would occur at different rates and thus affect the observed ee for the first AE reaction and the overall de. Indeed, the major diastereomeric product epoxide 59 resulting from the first AE is less reactive in the second epoxidation. Thus, high de is easily obtainable since the second epoxidation removes the minor diastereomer. 

Enantioselective desymmetrization of achiral or meso compounds with formation of enantiomerically enriched products, among them heterocycles 99JCS(P1)1765. 

NOL-based systems for addition of (substituted) anilines to meso epoxides. Hou found that a ytterbium-BI NO L complex catalyzed desymmetrization of cyclohexene oxide in up to 80% ee [15], Shibasaki demonstrated that a praseodymium-BINOL complex could promote addition of p-anisidine to several epoxides in moderate yields with modest enantioselectivities (Scheme 7.7) [16]. 

Subsequent to the development of the (salen)Cr-catalyzed desymmetrization of meso-epoxides with azide (Scheme 7.3), Jacobsen discovered that the analogous (salen)Co(n) complex 6 promoted the enantioselective addition of benzoic acids to meso-epoxides to afford valuable monoprotected C2-symmetric diols (Scheme 7.15) [26], Under the reaction conditions, complex 6 served as a precatalyst for the (salen) Co(iii)-OBz complex, which was fonned in situ by aerobic oxidation. While the enantioselectivity was moderate for certain substrates, the high crystallinity of the products allowed access to enantiopure materials by simple recrystallization. 

An impressive application of the (salen) Co-catalyzed intramolecular ARO of meso-epoxy alcohols in the context of total synthesis was reported recently by Danishefsky [33], Enantioselective desymmetrization of intermediate 9 by use of the cobalt acetate catalyst 8 at low temperatures afforded compound 10, which was obtained in 86% ee and >86% yield (Scheme 7.18). Straightforward manipulation of 10 eventually produced an intermediate that intersected Danishefsky s previ-... 

The only notable success to date in the use of (salen)metal systems in catalysis of asymmetric cyanide addition to epoxides was achieved by Pietrusiewicz, who reported the aluminium-catalyzed desymmetrization of phospholene meso-epoxide (Scheme 7.23) in moderate ee [47]. Despite these significant efforts, a truly prac-... 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

The principle cost determinant in typical hydrolytic or phenolic resolutions is the cobalt catalyst, despite the relatively low catalyst loadings used in most cases and the demonstrated recyclability with key substrates. From this standpoint, recently developed oligomeric (salen)Co complexes, discussed earlier in this chapter in the context of the hydrolytic desymmetrization of meso-epoxides (Scheme 7.16), offer significant advantages for kinetic resolutions of racemic terminal epoxides (Table 7.3) [29-31]. For the hydrolytic and phenolic kinetic resolutions, the oligo-... 

Andersson also showed that, in addition to meso-desymmetrization, kinetic resolution of some cyclic epoxides by use of the first-generation catalyst was also possible, giving both epoxides and allylic alcohols in good yields (Scheme 7.51) [108], Kozmin reported the effective use of the same catalyst in the desymmetrization of diphenylsilacyclopentene oxide. The resulting products could be used in the ster-eocontrolled syntheses of various acyclic polyols (Scheme 7.52) [109]. 

The epoxidation of divinyl carbinol constitutes a special case of a dienol epoxida-tion, as the starting diene is not conjugated (Scheme 9.10). Desymmetrization by SAE, followed by a Payne rearrangement, furnishes the vinylepoxide in high yield and with excellent enantioselectivity (compare Table 9.2, Entry 1) [43]. 

An area in which catalytic olefin metathesis could have a significant impact on future natural product-directed work would be the desymmetrization of achiral molecules through asymmetric RCM (ARCM) or asymmetric ROM... 

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. ... 

In another signiflcant example published in the same period, Guanti and coworkers described the desymmetrization of the meso cydohexene diester (3) to give the hemiester (4), whose enantiomeric excess increased from 55 to 96% when moving from plain buffer to the same buffer containing 10% v/v t-BuOH (Scheme 1.2 and Table 1.2 [8]). 

However, whatever the mechanism of action is, the effect of solvents on enzyme selectivity is sometimes really dramatic. For example, Hrrose et al. [42] reported that in the Pseudomonas species lipase-catalyzed desymmetrization of prochiral... 

The study concerns the desymmetrization of the prochiral dinitrile (16) with preferential formation of the (Ji)-17, which was known to be a chiral intermediate in the synthesis of the cholesterol-lowering therapeutic drug (18) (Lipitor, Sortis, Torvast, etc.) as shown in Scheme 2.3. 

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. 

The initial results of an early directed evolution study are all the more significant, because no X-ray data or homology models were available then to serve as a possible guide [89]. In a model study using whole E. coU cells containing the CHMO from Adnetohacter sp. NCIM B9871,4-hydroxy-cydohexanone (3 5) was used as the substrate. The WT leads to the preferential formation of the primary product (i )-36, which spontaneously rearranges to the thermodynamically more stable lactone (R)-37. The enantiomeric excess of this desymmetrization is only 9%, and the sense of enantioselectivity (R) is opposite to the usually observed (S)-preference displayed by simple 4-alkyl-substituted cydohexanone derivatives (see Scheme 2.10) [84—87]. 

Table 2.1 Desymmetrization of prochiral ketones by the BV reaction using O2 as the oxidant and the CHMO mutant 1-K2-F5 as the catalyst [90].

Kinetic Resolution, Dynamic Kinetic Resolution, and Desymmetrization... 

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

Figure 6.4 Hydrolase-catalyzed desymmetrization of a prochiral (a), a meso (b), or a centrosymmetric (c) substrate.

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... 

Esterases, proteases, and some lipases are used in stereoselective hydrolysis of esters bearing a chiral or a prochiral acyl moiety. The substrates are racemic esters and prochiral or meso-diesters. Pig liver esterase (PLE) is the most useful enzyme for this type of reaction, especially for the desymmetrization of prochiral or meso substrates. 

A [2 + 2] photoaddition-cycloreversion was applied to the enantioselective synthesis of the natural product byssocMamic add (Figure 6.11). Desymmetrization of a meso-cyclopentene dimethyl ester with PLE in pH 7 buffer-acetone (5 1) provided a monoacid, one of the photopartners. It is noteworthy that both enantiomers of this natural product were synthesized from the same monoacid [58]. 

Figure 6.9 Chemoenzymatic synthesis of amino acids via desymmetrization of malonates.

Several lipases were more efficient than PLE and subtilisin Carlsberg for the desymmetrization of an N-t-butoxycarbonyl (Boc) meso-piperidine diester (Figure 6.13). The (3R)-monoester was converted into optically pure isogalactofagomme, a potent galactosidase inhibitor [60]. 

The first asymmetric synthesis of (—)-Y-jasmolactone, a fruit fiavor constituent, vas achieved via the enantioselective lactonization (desymmetrization) of a prochiral hydroxy diester promoted by porcine pancreas lipase (PPL) (Figure 6.23) [71]. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

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