Meso-anhydride

Although, from a historical standpoint the cinchona alkaloids also occupy a central position in the field owing to their use as catalysts for the alcoholative ASD of meso anhydrides (a Type II process, see Schane 2), the past few years have witnessed an explosion of interest in the development of other classes of iert-amine-based catalysts primarily for Type I processes. 

Table 8 Bolm s quinidine/quinine promoted ASD of meso-anhydrides...

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]... 

Table 9 Bolm s quinidine catalyzed ASD of meso-anhydrides [203]...

Table 10 Deng s (DHQD) AQN catalyzed ASD of achiral/meso-anhydrides [208, 210]...

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.

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... 

Hydrolysis cinchona alkaloid meso- anhydrides deer. to 60 Woltinger, 2002... 

Continuous reactors are not always beneficial to achievement of good reactor performance (Woltinger, 2002) in the asymmetric opening of meso-anhydrides, due to product inhibition of the cinchona alkaloid catalyst the conversion and enantiomeric excess decreased rapidly during a continuous reaction. Even optimization of reaction parameters to decrease residence time to a very low value (1 h) did not improve the situation sufficiently. In contrast, performing the reaction in repetitive batch mode allowed a modest 60% e.e. to be sustained over 18 cycles. 

J. Woltinger, H.-P. Krimmer and K. Drauz, The potential of membrane reactors in the asymmetric opening of meso-anhydrides, Tetrahedr. Lett. 2002,43, 8531-8533. 

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 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]. 

As exemplified in Scheme 13.4, attack of the nucleophile methanol occurs uniformly at one or the other of the two enantiotopic carbonyl groups of the meso-anhydride (affording the hemi-esters 10 and mt-10, respectively), depending on whether (—)-quinine (2) or (+)-quinidine (3) is employed as catalyst. 

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. 

Type II catalytic asymmetric acyl transfer processes have been most extensively developed for the case of ASD of meso-anhydrides by nucleophilic ring-opening with alcohols, and so these processes will be the first type II processes considered here. 

A variant of this procedure that employs a substoichiometric quantity of cinchona alkaloid has also been developed by Bolm [176]. In this method, 10 mol% quinidine was used in conjunction with a stoichiometric amount of 1,2,2,6,6-pentamethylpiperidine (pempidine) to prevent sequestration of the cinchona alkaloid by the acidic hemiester product. The chiral hemiester products derived from various meso-anhydrides were obtained with >74% ee and >94% yields (Table 8.8). 

Fig. 8.8 Mnemonic for prediction of stereoselection in Deng s ASD of achiral/meso-anhydrides [179].

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