Diols, desymmetrization kinetic resolution

The groups of Sigman and Stoltz have concurrently published the palladium-catalyzed oxidative kinetic resolution of secondary alcohols using molecular oxygen as the stoichiometric oxidant. Both communications also described a single example of a diol desymmetrization using a palladium catalyst in the presence of (—(-sparteine [Eqs. (10.42) ° and (10.43) ] ... 

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. 

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]. 

Fu et al. used the planar chiral DMAP derivative 46 (Scheme 13.24) [39]. Although this catalyst has been employed successfully for kinetic resolution of a large variety of racemic secondary alcohols (Section 12.1), substrate 47 seems to be the only meso-diol that has been desymmetrized by use of the acylation catalyst... 

The peptide catalysts 53a-e incorporating a 4-pyrrolidinopyridine moiety were tested in the desymmetrization of cyclohexane meso-1,2- and meso-1,3-diols by Ka-wabata et al. (Scheme 13.26) [42]. As summarized in Scheme 13.26, enantiomeric excesses were up to 65% and chemical yields were in the range 40-77%. (Application of the Kawabata catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Dynamic kinetic resolution of azlactones rearrangement of O-acyl azlactones, O-acyl oxindoles, O-acyl benzofuranones [13.6]... 

KINETIC RESOLUTION OF DIOLS 5.5.1. Desymmetrization of racemic diols... 

Enantioselective C-H insertion is still a virgin area in dioxirane chemistry, but its feasibility has been demonstrated in the kinetic resolution of racemates and in the desymmetrization of meso 1,2-diols and their acetals. Moderately good enan-tioselectivity has been achieved by use of Shi s ketone 9 as the precursor to the dioxirane (Scheme4) [27, 28],... 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

In chiral organotin dibromide- and bistriflate-catalyzed desymmetrization of 2-substituted 1,3-propandiols with phenyl isocyanate the enantiomeric excess of the product was uniquely dependent on the reaction temperature. The chirality of the product was inverted from one enantiomer to anofher upon changing the reaction temperature from 0 to -78 °C (Scheme 12.170) [308]. When, on the ofher hand, this nonracemic organotin dihalide was employed as a catalyst for benzoylation of racemic 1,2-diols, nonenzymatic kinetic resolution was achieved under sophisticated reaction conditions (Scheme 12.171) [309]. 

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. ... 

Hu and Vasella explored the use of chiral, proUne-derived diamine catalyst 10 -previously employed by Oriyama for kinetic resolutions and enantioselective desymmetrizations of 1,2-diols - for regioselective benzoylations of hexopyranosides [36]. Scheme 8 depicts one of several instances in which some level of regiochemical complementarity was achieved using the two enantiomers of... 

As a rule of thumb, oxidation of the (S)- or pro-(S ) hydroxyl group occurs selectively with HLADH (Scheme 2.143). In the case of 1,4- and 1,5-diols, the intermediate y- and 8-hydroxyaldehydes spontaneously cyclize to form the more stable five- and six-membered hemiacetals (lactols). The latter are further oxidized in a subsequent step by HLADH to form y- or 5-lactones following the same (S)-or pro-(5) specificity [1035]. Both steps - desymmetrization of the prochiral or meso-diol and kinetic resolution of the intermediate lactol - are often highly selective. By using this technique, enantiopure lactones were derived from... 

Kinetic resolution of secondary alcohols and desymmetrization of diols were reported by asymmetric oxidation using chiral (nitrosyl)Ru(salen) chloride (31) (Eq. (7.42)) [97] in addition to the aerobic oxidation reaction [97d]. 

Aerobic Alcohol Oxidations. The combination of PdCl2(CH3CN)2 (5-10 mol%) with (—(-sparteine (20 mol%) constitutes an effective catalyst system for the oxidative kinetic resolution of secondary alcohols with molecular oxygen as the terminal oxidant, with enantiomeric excesses t)q)ically above 90% ee (eq 45). This enantioselective aerobic oxidation has been successfully extended to the desymmetrization of meso-1,3-diols. 

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. 

This chapter illustrates the application of lipases and esterases as user-friendly biocatalysts in (i) desymmetrization of prochiral or meso-diols and diacetates, (ii) kinetic resolution of racemic alcohols, and (iii) preparation of enantiopure intermediate(s) from a mixture of stereoisomers by enzymatic differentiation. All the examples were taken from our own works in natural products synthesis. 

The most important technical applications of catalytic hydrolysis and acylation involve technical enzymes, as used in food processing, washing powders, or derace-misations. Especially the latter application has also found significant application in chemical synthesis. The kinetic resolution of chiral, racemic esters, anhydrides, or alcohols relies on the faster conversion of only one substrate enantiomer by the chiral catalyst, whereas the other enantiomer ideally remains unchanged. A special case within kinetic resolutions is the desymmetrization of prochiral mexo-compounds like mera-anhydrides (2) or meso-diols, (5) that requires a selective conversion of one of the two enantiotopic functional groups (carbonyl or OH-group, Scheme 7.1). 

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

In the previous chapters, achiral substrates or substrates with a chiral acid moiety have been considered. But the kinetic resolution of racemic alcohols and the desymmetrization of meyo-diols are equally important for the synthesis of pharmaceutical and natural substances [87], Enantioselective acylation of racemic... 

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