Cyclic meso-anhydrides

Enantioselective alcoholysis of racemic, prochiral, or meso cyclic anhydrides can be catalyzed by hydrolases, yielding the corresponding monoesters (Eigure 6.25). In most cases, the enantioselectivity was moderate ]75-77]. Organometallic catalysts or organocatalysts such as cinchona alkaloids are often more efficient than enzymes for the stereoselective ring opening of cyclic anhydrides. 

Nagao has disclosed bifunctional chiral sulfonamide 69 as being effective for the thiolytic ASD of meso-cyclic anhydrides in up to 98% ee when employed at the 5 mol% level for 20 h at room temperature in ether [228], Catalyst 69 is a 1,2-diamine derivative in which one of the nitrogens presents as an acidic NH group (part of an electron deficient aryl sulfonamide) and the other as a nucleophihc/basic teri-amine group with the intention to act synergistically in activation of the substrate carbonyl function and thiol nucleophile respectively (Fig. 16) [228],... 

Desymmetrization of prochiral cyclic anhydrides In the presence of the chiral nucleophilic catalyst (e.g. A, Scheme 13.1, top) one of the enantiotopic carbonyl groups of the prochiral (usually meso) cyclic anhydride substrate is selectively converted into an ester. Application of catalyst B (usually the enantiomer or a pseudoenantiomer of A) results in generation of the enantiomeric product ester. Ideally, 100% of one enantiomerically pure product can be generated from the starting anhydride. No reports of desymmetrizing alcoholyses of acyclic meso anhydrides appear to exist in the literature. 

Type II Alcoholative ASD of Achiral/meso-Cyclic Anhydrides... 

In 2000, Deng reported that commercially available Sharpless ligands also catalyze the highly enantioselective alcoholysis of meso-cyclic anhydrides [179]. 

Surprisingly few studies have been directed towards the development of noncinchona alkaloid-based catalysts for the alcoholative ASD of meso-anhydrides, or indeed any of the enantioselective alcoholysis processes. Uozumi has reported a series of (2S, 4R)-4-hydroxyproline-derived 2-aryl-6-hydroxyhexahydro-lfi-pyr-rolo[l,2-c] imidazolones which mediate the methanolytic ASD of ds-hexa-hydrophthalic anhydride in up to 89% ee when employed at the 10 mol% level for 20 h at —25 °C in toluene [186]. Additionally, Nagao has described the use of a bifunctional chiral sulfonamide for the thiolytic ASD of meso-cyclic anhydrides in up to 98% ee when employed at the 5 mol% level for 20 h at rt in ether [187]. 

There has been considerable interest in the stereoselective ring opening of meso-cyclic anhydrides. The stereoselective alcoholysis of these anhydrides is particularly attractive as the resulting hemiesters are used as versatile intermediates in the construction of many bioactive compounds [1], Much effort has, therefore, been devoted to the development of efficient enzymatic and nonenzymatic catalytic systems for this reaction [2], Among the stereoselective catalysts developed to date,... 

However, highly interestingly, unusual concentration and temperature effects on the enantioselectivity were observed by Song and coworkers [11a]. As shown in Figure 11.2, the enantioselectivity in the methanolytic desymmetrization reaction of the meso-cyclic anhydride IS increases with increasing dilution of the reaction mixture and on raising the reaction temperature from —20 to 20 °C. 

When an anhydride such as succinic anhydride is reacted with a racemic alcohol in organic solvent with a lipase, an enantioselective resolution can be achieved [89]. The enantioselective opening of racemic or meso cyclic anhydrides can constitute a good method for the preparation of nearly optically pure esters [90-93]. Examples of these reactions are depicted in Scheme 13. 

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. 

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). 

Deng reported the cinchona alkaloid-catalyzed desymmetrization of meso and achiral cyclic anhydrides by alcoholysis [26]. 

HIGHLY EFFICIENT ASYMMETRIC ESTERIFICATION OF CYCLIC MESO-DICARBOXYLIC ANHYDRIDES CATALYZED BY DIPHENYLBORYL TRIFLATE. 

SCHEME 71 Desymmetric hydrogenation of a meso-cyclic acid anhydride. 

Procedure for ASD of a cyclic meso-anhydride using quinidine ASD of bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid endo cis-anhydride [204]... 

Fig. 15. Connon/Song s and Fujimoto s catalysts for alcoholative ASD of cyclic meso-anhydrides and mono benzoylation of meso-diols respectively [220-225]...

Scheme 6.145 Chiral hemiesters obtained from the 121-catalyzed methanolic desymmetrization of cyclic meso-anhydrides.

In the presence of a cinchona alkaloid, certain cyclic carboxylic anhydrides with meso structures are converted to the chiral diacid monoesters in up to 76% ee (Scheme 10) 31). Quinine or cinchonidine and quinidine or cinchonine show opposite asymmetric induction. 

In the mid-1980s Oda et al. reported that of a series of alkaloids screened for catalytic desymmetrization of cyclic meso-anhydrides with methanol, (+)-cinchonine (1) performed best [4-6]. As shown in Scheme 13.2, 10 mol% of this catalyst was... 

The non-alkaloid derived organocatalysts 13a-e - readily accessible from proline and hydroxyproline, respectively - were reported by Uozomi et al. (Scheme 13.7) [17]. Of the five compounds, 13b and 13e performed best. In the presence of 100 mol% 13e, the methanolytic desymmetrization of cyclic meso anhydrides was found to proceed with up to 89% ee. 

Procedure for ASD of a Cyclic meso-Anhydride Using (DHQD AQN as Catalyst ... 

Cw-Disubstituted butyrolactones (50) have been investigated less extensively than their /ra/i -counterparts. One attractive route to such compounds involves the diastereoselective opening of a cyclic meso-anhydride (49) (scheme 15) [67]. The required anhydride was prepared by a route involving two consecutive Stobbe condensations, leading to the doubly unsaturated anhydride (48). Differentiation of the two acyl groups of (49) was achieved by reaction with an enantiomerically pure primary amine. The monoacid monoamide was then converted into the required lactone (50). 

C. Bolm, I. Schiffers, C.L Dinter, A. Gerlach, Practical and highly enantioselective ring opening of cyclic meso-anhydrides mediated by cinchona alkaloids, J. Org. Chem. 65 (21) (2000) 6984-6991. 

W.-M. Dai, K.K.Y. Yeung, C.W. Chow, I.D. Williams, Study on enantiomerically pure 2-substituted N,N-dialkyl-l-naphthamides resolution, absolute stereochemistry, and application to desymmetrization of cyclic meso anhydrides. Tetrahedron Asymmetry 12 (11) (2001) 1603-1613. 

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