Cyclic Anhydride Desymmetrization

Alkylative desymmetrization of cyclic anhydrides would be an attractive alternative to this chemistry since the product would be a keto-acid and would allow elaboration of the molecular scaffold. The first catalyzed asymmetric alkylative desymmetrization of a cyclic anhydride was published from our laboratories in early 2002. The phosphinooxazoline ligand t-PrPHOX provided an effective catalyst when bound to nickel, affording keto-acid 179 in 85% yield and 79% ee ... 

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

Scheme 9. Desymmetrization and parallel kinetic resolution of cyclic anhydrides by (DHQD)2AQN...

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. 

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). 

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. 

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. 

Spivey, A. C. Andrews, B. I. Catalysis of the Asymmetric Desymmetrization of Cyclic Anhydrides by Nucleophilic Ring-Opening with Alcohols, Angew. Chem. Int. Ed. 2001, 40, 3131-3134. 

Quite recently, we also observed that quinine-based thiourea derivatives showed dramatic concentration and temperature effects on the enantioselectivity in the alcoholytic desymmetrization ofmeso-cyclic anhydrides, which can also be attributed to the self-association of the catalyst [23]. Of course, the possibility that the variation in... 

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). 

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. 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

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

In a further demonstration of the broad scope of nickel(0) oxidative additions to C-0 bonds, cyclic anhydrides were illustrated to be versatile substrates in crosscoupling processes. For example, enantioselective desymmetrizations with diethylzinc and cyclic anhydrides provide efficient access to functionalized 1,4-dicarbonyl products. The enantioselectivity-detemuning step in this process is the oxidative addition of nickel(O) to anhydride C-0 bond. Several other functionalization processes derived fi-om oxidative addition of nickel(O) to anhydrides were previously described. ... 

A DFT study of the desymmetrization of a cyclic meio-anhydride, 5-norbornene-enr/o-l,2-dicarboxylic anhydride, by MeOH catalysed by a chiral )8-aminoalcohol, (l/ ,2/ )-2-(piperidin-l-yl)cyclohexanol, to form the corresponding chiral monomethyl ester showed that a general base mechanism in which the intermediate oxyanion is stabilized by the hydroxyl group of the catalyst is favoured over a nucleophilic mechanism. ... 

The desymmetrization of prochiral cyclic anhydrides promoted by cinchona alkaloid derivatives is archetypal of this reaction class. First investigated by the groups of Oda and Aitken using cinchonine and quinine respectively, Bolm subsequently showed that cinchona alkaloids could desymmetrize prochiral anhydrides with exquisite enantioselectivities, with the pseudoenantiomeric... 

As well known, desymmetrization reactions of symmetric compoxmds provide step-economical route in organic synthesis. Some approaches on the basis of tire desymmetrization concept have been published. For example, Kitamura et al. achieved Ru-catalyzed desymmetric hydrogenation of a mcso-cyclic acid anhydride 174 to obtain enantiomerically enriched y-lactone 175 (Scheme 71) [119]. In this case, (S,S)-Et-FerroTANA 176 was used as asymmetric phosphine ligand. 

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

Y. Chen, S. Tian, L. Deng, A highly enantioselective catalytic desymmetrization of cyclic anhydrides with modified cinchona alkaloids, J. Am. Chem. Soc. 122 (39) (2000) 9542-9543. 

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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