Meso-Anhydrides, desymmetrization

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

Narasaka et al. demonstrated the utility of titanium-ligand complexes in the resolution of chiral a-aryl esters [52]. Ti(Oi-Pr)4-ligand 56 complex resolves 2-pyridine thioesters with high selectivities (fcrei=26-42, see Scheme 13). Seebach and co-workers have examined titanium-TADDOLate complexes as reagents for the ring opening of meso anhydrides, dioxolanones, and azalactones [53]. Addition of an achiral isopropoxide source renders the desymmetrization of meso... 

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. 

Desymmetrization and Kinetic Resolution of Anhydrides Desymmetrization of meso-Epoxides and other Prochiral Substrates... 

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... 

A very efficient and practical process for desymmetrization of meso-anhydrides was reported by Bolm et al. in 1999 and in subsequent publications (Scheme 13.3) [9, 10]. In their approach, which is a further development and improvement in the use of alkaloids as catalysts, (—)-quinine (2) or (+)-quinidine (3) in this case, low reaction temperature and solvent optimization proved crucial to achieving optimum enantioselectivity. Under their conditions methanolysis of several meso anhydrides (8a-g, 9a-g, Scheme 13.3) can be achieved in good yields and with excellent enantiomeric excesses in the presence of equimolar amounts of the inexpensive and readily available alkaloids 2 and 3 [9, 10]. 

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. 

The field of organocatalytic enantioselective anhydride transformations has seen tremendous progress during recent years. For example, the alcoholytic desymmetrization of meso anhydrides, effected by stoichiometric quantities of inexpensive and readily available cinchona alkaloids, has been developed to a very practical level, and several applications, e.g. for the synthesis of enantiomerically pure... 

For a recent summary of developments in the metal-based and metal-free catalytic desymmetrization of meso anhydrides with alcohols, see A. P. Spivey, B. I. Andrews, Angew. Chem. 2001, 113, 3227-3230 Angew. Chem. Int. Ed. 2001, 40, 3131-3134. 

Scheme 11.13 Applications of alcoholytic desymmetrization of meso-anhydrides.

Desymmetrization of /neso-compounds is a challenging but rewarding task. Deng et al. have established a method to desymmetrize the meso-anhydride 580 in the presence of catalytic amoimts of the modified Cinchona alkaloid catalyst 581 to yield the hemiester 582 quantitatively and with very high enantiopurity (486). Further transformatirHi into lactone 583 represents a short and efficient formal synthesis of (+)-biotin (584) (Scheme 121). 

Scheme 121 Desymmetrization of meso-anhydrides using Cinchona alkaloid catalysts...

SCHEME 6.44 Organocatalytic desymmetrization of the meso-anhydride 276 in the syntheses of the monoterpenoid indole alkaloids ( )- and (Z)-alstoscholarine (275). 

Cinchona alkaloid derivatives are rarely applied in large-scale preparations of enantioenriched compounds. One example, though, is the large-scale enantiose-lective desymmetrization of meso-anhydrides (Scheme 6.16) as catalyzed by the C9 O-propargyl ethers of 1 and 4 [38]. 

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. 

Enantioselective desymmetrization of meso-succinic anhydrides with diphenylzinc is catalyzed by Pd(OAc)2/chiral diphosphine 209 (Equation (113)).470... 

The synthetic utility of this methodology was further demonstrated in a formal synthesis of (+)-biotin by the same authors [211], Following this work, various reusable immobilised analogues of (DHQD) AQN were reported to catalyze the desymmetrization of a number of meso-cyc ic anhydrides with good selectivities [212-214],... 

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). 

Shortly thereafter, Aiken and coworkers also reported that quinine (4) could be used as a catalyst (50mol%) to promote the methanolytic desymmetrization of the meso-epoxy anhydride 8a to give the lactone 9a in 57% yield and 76% ee (Scheme 11.6) [4]. Lowering the reaction temperature to 0 or —30 °C did not result in any increase in selectivity. meso-Aziridine anhydride 8b was also tested under similar reaction conditions, but a lower enantioselectivity (40% ee) was obtained (Scheme 11.6). 

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. 

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

Seebach and coworker have reported the enantioselective desymmetrization of meso esters, anhydrides and sulfonylimides using TADDOL-Ti reagents [334]. In the desymmetrization of anhydrides, a catalytic amount of the chiral TADDOL-Ti... 

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

Scheme 10.35 Desymmetrization of meso-glutaric anhydrides catalyzed by squaramide 33.

Chen and coworkers have developed a bifunctional quinine-derived squaramide-promoted enantioselective alcoholysis of meso-succinic anhydride 36 [116]. Whereas modest enantioselectivity can be obtained in the presence of a catalytic amount of squaramide 22, high enantioselectivity was realized when more than 1 equivalent of squaramide was utQized (Scheme 10.36). The utility of the squaramide-catalyzed desymmetrization was nicely illustrated by carrying out an efficient synthesis of (-f)-biotin from the enantioenriched hemiester 37, which, in turn, was obtained by desymmetrization of 36. 

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). 

Schone 7.1 Desymmetrization of meio-anhydrides 2 emd meso-diols 5... 

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