Racemic cyclic anhydrides

With respect to diastereoselectivity, the reaction of the imine of l-ferrocenyl-2-methyl-propylamine and piperonal with a racemic cyclic anhydride gave a much better result (diastereomer ratio 81 10 of the isoindole derivatives, total yield 91%) the major isomer crystallized from the reaction mixture. This reaction was the key step in an enantioselective synthesis of the alkaloid (+ )-corynoline (Fig. 4-31 c). The l-ferrocenyl-2-methyl-propyl auxiliary could be cleaved by the 2-mercaptoacetic acid technique. The final elaboration of the intermediate to (+ )-corynoline needed only five steps [166]. 

Dynamic) Kinetic Resolution of Racemic Cyclic Anhydrides... 

Dynamic) kinetic resolution of racemic cyclic anhydrides... 

Although at first impression parallel kinetic resolution of racemic cyclic anhydrides is not very attractive (a mixture of two, usually difficult to separate diastereomers is formed), there are still a few reports where Cinchona alkaloids have been used for that purpose (Scheme 15.17). ... 

Despite its widespread application [31,32], the kinetic resolution has two major drawbacks (i) the maximum theoretical yield is 50% owing to the consumption of only one enantiomer, (ii) the separation of the product and the remaining starting material may be laborious. The separation is usually carried out by chromatography, which is inefficient on a large scale, and several alternative methods have been developed (Figure 6.2). For example, when a cyclic anhydride is the acyl donor in an esterification reaction, the water-soluble monoester monoacid is separable by extraction with an aqueous alkaline solution [33,34]. Also, fiuorous phase separation techniques have been combined with enzymatic kinetic resolutions [35]. To overcome the 50% yield limitation, one of the enantiomers may, in some cases, be racemized and resubmitted to the resolution procedure. 

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. 

The acid esters of 1,2-dicarboxylic acids are conveniently prepared by heating the corresponding cyclic anhydride with one molar proportion of the alcohol (see the preparation of alkyl hydrogen phthalates from phthalic anhydride and their use in the resolution of racemic alcohols, Section 5.19). 

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). 

Quite remarkable progress has also been achieved in enantioselective transformation of cyclic anhydrides derived from a-hydroxy and a-amino carboxylic acids. By careful choice of the reaction conditions, dynamic kinetic resolution by alcoholysis has become reality for a broad range of substrates. Again, the above mentioned dimeric cinchona alkaloids were the catalysts of choice. In other words, organoca-talytic methods are now available for high-yielding conversion of racemic a-hydroxy and a-amino acids to their enantiomerically pure esters. If desired, the latter esters can be converted back to the parent - but enantiomerically pure - acids by subsequent ester cleavage. 

It might be anticipated that, if a racemic unsymmetrically substituted cyclic anhydride were to be used as a substrate for asymmetric alcoholysis, a KR would ensue. In fact, Deng has shown that for monosubstituted succinic anhydrides, because both carbonyl groups have comparable reactivity, what actually occurs on subjection to his (DHQD)2AQN-catalyzed asymmetric alcoholysis conditions, is a PKR [188]. Thus, the reaction of 2-methyl succinic anhydride (39a) with 2,2,2-trifluoroethanol (10 equiv.) in ether at —24 °C in the presence of (DHQD)2AQN (15 mol%) provided a mixture of two regioisomeric hemiesters... 

Type II Alcoholative ASD of Achiral/weso-Cyclic Anhydrides 312 Type II Alcoholative KR of Racemic Anhydrides, Azlactones, N-Carboxyanhydrides, Dioxolanediones and N-Acyloxazolodin-... 

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). 

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... 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

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. 

N-Methylmorpholine [1, 690]. In the mixed anhydride synthesis of peptides, N-methylmorpholine was found to give little or no racemization in cases where triethylamine, the commonly used base, caused extensive racemization.1 Trimethyl-amine, a potent racemizer, can be used successfully if an excess is avoided. N-Methylmorpholine was used by Wieland2 in the synthesis of antamanide, a cyclic decapeptide of Amanita phalloides, which counteracts the lethal action of Amanita toxins. 

The intermediate (a) can also be arrived at directly from the unprotected linear peptide by applying the mixed anhydride method. After addition of one equivalent of acid, e.g. trifluoroacetic acid, the amino group will be protonated and the (still deprotonated) carboxyl anion will react with alkyl chloroformate to form (a), X = CO—O—Aik. Very conveniently, carbodiimides can be reacted with linear peptides unprotected at both ends to form cyclic peptides in satisfactory yields [26]. Since the carbodiimide method, particularly in the presence of V-hydroxybenzotriazole, is causing little racemization (see p. 93) this system is preferred in most laboratories. 

Racemic Malolactonate. The first cyclic monomer prepared was the benzyl ester of the 3-lactone of malic acid. Initial attempts to make the lactone directly from malic acid itself were unsuccessful, so bromosuccinic acid was chosen as the starting material. This compound was converted to its anhydride by refluxing in acetyl chloride, and the anhydride was reacted with benzyl alcohol to yield a mixture of the two bromosuccinic acid monobenzyl ester isomers. Only one of these esters, IIIB, is capable of being converted to the lactone by... 

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