Desymmetrization reactions, kinetic

If the 3-position is a quaternary stereocenter, then Rh(I)/Tol-BINAP is the catalyst of choice for the hydroacylation process. With this catalyst, both kinetic resolutions (Eq. 20) and desymmetrization reactions (Eq. 21) may be accomplished. 

This chapter covers the kinetic resolution of racemic alcohols by formation of esters and the kinetic resolution of racemic amines by formation of amides [1]. The desymmetrization of meso diols is discussed in Section 13.3. The acyl donors employed are usually either acid chlorides or acid anhydrides. In principle, acylation reactions of this type are equally suitable for resolving or desymmetrizing the acyl donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes. 

The most powerful approaches, which can be used with several different enzyme systems, lead to a single enantiomer as the product in high yield and do not rely on a classic resolution approach in which the unwanted enantiomer is discarded. These approaches include dynamic kinetic resolutions, der-acemizations, and asymmetric and desymmetrization reactions (49, 50). In some cases, a chemical catalyst may be available to recycle the unwanted isomer in the same reactor vide infra). It is sometimes possible to racemize the unwanted isomer of the substrate and then to perform the reaction again (51). 

On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [66] can be recognized as an intermolecular version of desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative [64] asymmetric induction. The reaction of allylic ethers catalyzed by the (f )-BINOL-derived complex (1) provides the 2R,5S)-syn products with > 99 % diastereoselectivity and > 95 % ee (Sch. 18). The high diastereoselectivity, coupled with the high ee, strongly suggests that the cata-lyst/glyoxylate complex efficiently discriminates between the two enantiomeric substrates to accomplish the effective kinetic resolution. In fact, the relative rates of the reactions of the enantiomers, calculated by use of the equation ... 

On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [42a, 42b] might be recognized as an intermolecular version of the desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides an efficient access to remote but relative... 

C-H bonds. This strategy has been used in an intramolecular fashion for the oxidation of hydrocarbons (eq 49) and steroids. Fructose-derived ketone 5 has also been used for this purpose in an intermolecular reaction for the desymmetrization and kinetic resolution of 1,2-diols to a-hydroxy ketones (eq 50). There has also been a report of the direct oxidation of hydrocarbons to ketones and lactones by Mn-porph)rin complexes with Oxone. ... 

The most striking difference from the above-mentioned types of desymmetrization reactions, which show a theoretical yield of 100%, is that in kinetic resolution each of the enantiomers can be obtained in only 50% yield. 

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. 

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. 

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... 

The kinetic resolution by etherification has also been conducted through the cyclization of epoxy aliphatic alcohols.274 In these reactions catalyzed by monomeric complex 51, the ring closure of acyclic substrates occurred with exclusive / -selectivity (Equation (74)), whereas m -openings were observed in the desymmetrization of... 

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... 

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic di-methylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf)2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cydohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a y/a ratio of 98 2 (Scheme 8.28). The other substrates investigated produced sigmficantly lower ees of between 66% and 85%. 

Hence, when enantiopure compounds are needed, desymmetrization constitutes a useful alternative to kinetic resolution of racemates. Hydrolases are useful for such transformations, in both hydrolytic and acylation reactions [6]. Meso-compounds have been used extensively in such reactions. The success of such a reaction depends on one of the pro-R or pro-S groups reacting much faster than the other. If the monoderivatized product reacts further, the second step of course gives the doubly reacted meso-product. If the second step favors the minor one of... 

A similar sequence was reported where the asymmetry was introduced by the reaction of weio-3-substituted glutanc anhydrides and (S)-methylbenzylamines to give diastereomeric hemiamides that could be separated by recrystallization The asymmetnc desymmetrization of certain 4-aryl substituted glutanmides has also been accomplished with high levels of selectivity (up to 97% ee) by enolization with a chiral bis-lithium amide base. The selectivity of the reaction was shown to be the result of asymmetric enolization, followed by a kinetic resolution." ... 

The second MS-based approach does not require any derivatization reaction and has in fact been applied several times in the area of directed evolution [20,33-36]. It makes use of deuterium-labeled pseudo enantiomers or pseudo meso compounds. This practical method is restricted to studies involving kinetic resolution of race-mates and desymmetrization of prochiral compounds bearing reactive enantiotopic groups (Figure 9.2) [20]. 

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