Desymmetrization of meso-diols

The enantioselective discrimination of one of the hydroxyl groups of meso-diols can give chiral monoprotected diols, which serve as versatile intermediates for asymmetric organic synthesis. In addition to the enzymatic methods, a number of chemical approaches have been reported using chiral 1,2-diamine catalysts, chiral phospholane-based catalysts, planar chiral DMAP derivatives, and oligopeptide-based catalysts [2,28], Surprisingly, however, relatively a few publications are devoted to this reaction with cinchona-based organocatalysts. 

The first cinchona-mediated desymmetrization of meso-diols was reported by Duhamel and coworker. Using an excess amount of O-benzoylquinidine (19,2 equiv) 

Kiindig and coworkers extended the substrate scope of catalysts 24 and 25 from weso-l,4-diol complexes such as 26 to simple meso- 1,2-diols 28 [31c], In the presence of 2 mol% of the catalyst, all of the tested cyclic and acyclic 1,2-meso-diols, except for substrates incorporating phenyl groups, were efficiently desymmetrized to 

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Various biocatalytic options have been presented for the desymmetrization of meso-diols to chiral hydroxyl-ketones. A particularly facile system is represented by... 

Hydrolase-catalyzed desymmetrizations of meso-diols have also been exploited (Scheme 4.16). Thus, the monoacetate 23 is produced in excellent yield and by acylation with vinyl acetate of the corresponding meso-diol catalyzed by CRL in hexane [62]. In a similar way the monoacetate 24 is produced from the meso-tetrol by acylation in vinyl acetate catalyzed by PPL [63]. The meso-piperidine derivative... 

Scheme 4.33 Some examples of products obtained by hydrolase-catalyzed desymmetrizations of meso-diols (products shown).

E.3.1, Enantioselective Ionization Desymmetrization of meso-Diol Derivatives... 

Catalytic oxidation is a possible means of kinetic resolution of racemic mixtures of alcohols (Scheme 10.19, Eq. 1) or of desymmetrization of meso-diols (Scheme 10.19, Eq. 2). 

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. 

As summarized in Schemes 12.9 and 12.10, kinetic resolution of propargylic [21] and allylic [22] alcohols work equally well. The DMAP-ferrocene hybrid 21c was also used for kinetic resolution of racemic diols and for the desymmetrization of meso diols [20]. These two applications are discussed in Section 13.3. 

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. 

In an early example of the desymmetrization of meso-diols by acylation Duhamel... 

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]. 

Cycloadditions [8.2] Desymmetrization of meso-diols [13.3] Desymmetrization of meso-epoxides [13.4]... 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

Desymmetrization of meso-Diols. BTM-catalyzed de-symmetrization of meso-diol lobelanidine has been employed as the key step in an asymmetric synthesis of alkaloid lobeline (eq 6).5... 

Shimizu, H., Onitsuka, S., Egami, H., et al. (2005). Ruthenium(Salen)-Catalyzed Aerobic Oxidative Desymmetrization of Meso-Diols and its Kinetics, J. Am. Chem. Soc., 127, pp. 5396-5413. 

Other examples include OKR of racemic secondary alcohols (Scheme 25A), oxidative desymmetrizations of meso-diols, etc. The kinetic resolution is generally defined as a process where two enantiomers of a racemic mixture are transformed to products at different rates. Thus, one of the enantiomers of the racemate is selectively transformed to product, whereas the other is left behind. This method allows to reach a maximum of 50% yield of the enantiopure remaining sec-alcohol. To overcome this fim-itation, a modification of the method, namely dynamic kinetic resolution (DKR), was introduced. In this case, the kinetic resolution method is combined with a racemization process, where enantiomers are interconverted while one of them is consumed (e.g., by esterification. Scheme 25B). Therefore, a 100% theoretical yield of one enantiomer can be reached due to the constant equifibrium shift. In most of the proposed DKR processes, several catalytic systems, e.g., enzymes and transition-metal catalysts, work together. Both reactions (transfer hydrogenation of ketones and the reverse oxidation of secondary alcohols using ketone as a hydrogen acceptor) can be promoted by a catalyst. The process can involve a temporary oxidation of a substrate with hydrogen transfer to a transition-metal complex. 

Suzuki T, Morita K, Matsuo Y, Hiroi K. Catalytic asymmetric oxidative lactonizations of meso-diols using a chiral iridium complex. Tetrahedron Lett. 2003 44 2003—2006. Moritani J, Hasegawa Y, Kayaki Y, Ikariya T. Aerobic oxidative desymmetrization of meso-diols with bifunctional amidoiridium catalysts bearing chiral N-sulfonyldiamine ligands. Tetrahedron Lett. 2014 55 1188-1191. 

Kinetic Resolution of Racemic Alcohols/Desymmetrization of Meso-Diols... 

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