Desymmetrization reactions, kinetic resolutions

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. 

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. ... 

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%. 

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. 

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]. 

Desymmetrization of a seven-membered cyclic meso compound, followed by a metallo-ene reaction, provides ready access to the trans-hydroazulene skeleton (Scheme 8E.15) [69]. By using BINAP in preference to BINAPO ligand, which gave a lower enantioselectivity (70% ee), two alkylation products were obtained in differential enantioselectivities. The high enantiopurity of the major product 106 may be the consequence of a subsequent kinetic resolution because the second ionization, followed by proton loss from enf-106, involved a matched event. 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

The desymmetrization of meso diols requires selective chemical transformation of one of the two enantiotopic hydroxyl functions. Among other possibilities this transformation can consist in acylation or - less commonly - oxidation to a ketone (Scheme 13.19). It should be noted that the enantiomeric purity of the initial reaction products can be upgraded by subsequent conversion of the unwanted enantiomer into the diacylated compound (or diketone), i.e. by subsequent kinetic resolution. 

High enantiomeric excess in organocatalytic desymmetrization of meso-diols using chiral phosphines as nucleophilic catalysts was achieved for the first time by Vedejs et al. (Scheme 13.21) [36a], In this approach selectivity factors up to 5.5 were achieved when the C2-symmetric phospholane 42a was employed (application of chiral phosphines in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). A later study compared the performance of the phos-pholanes 42b-d with that of the phosphabicyclooctanes 43a-c in the desymmetrization of meso-hydrobenzoin (Scheme 13.21) [36b], Improved enantioselectivity was observed for phospholanes 42b-d (86% for 42c) but reactions were usually slow. Currently the bicyclic compound 43a seems to be the best compromise between catalyst accessibility, reactivity, and enantioselectivity - the monobenzoate of hydrobenzoin has been obtained with a yield of 97% and up to 94% ee [36b]. 

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. 

Enantioselective RCM is achieved using the chiral Mo complex 79 [30]. Kinetic resolution occurred in the reaction of the racemic diene 80 catalysed by 79, and the cyclized product 81 with 93% ee was obtained, and the unreacted diene 80 (19%) of 99% ee was recovered. Also the optically active dihydrofuran 83 with 93% ee was obtained in 85% yield by enantioselective desymmetrization through RCM of triene 82 using the Mo complex 79 [30a]. 

The preparation of stereochemically enriched compounds by asymmetric acyl transfer in a stoichiometric sense can be divided into two broad classes [1] (1) those in which a racemic or achiral /weso nucleophile reacts diastereoselectively with an enantiomerically highly enriched acyl donor (Type I, see below) and (2) those in which an enantiomerically highly enriched nucleophile reacts diastereoselectively with a racemic or achiral/meso acyl donor (Type II, see below). When a racemic component is involved, the process constitutes a kinetic resolution (KR) and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoeselectivity - is 50%. When an achiral/meso component is involved, the process can constitute a site-selective asymmetric desymmetrization (ASD) or, in the case of 7r-nucleophiles and reactions involving ketenes, a face-selective addition process and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoselectivity - is 100% (Scheme 8.1). 

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