Anhydrides, alcoholysis enantioselectivity

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. 

Alcoholysis of meso-cycYic anhydrides offers a versatile route to succinate and glu-tarate half-esters. Although a number of stoichiometric approaches to this problem have been investigated, a successful catalytic version of this reaction appeared as recently as 2003. ° Bolm and coworkers have developed a protocol for the metha-nolysis of a variety of succinic anhydrides using cinchona alkaloids [Eq. (10.50)]. The reaction may be made catalytic in alkaloid when pentamethylpiperidine is used as a stoichiometric additive. A moderate decrease in enantioselectivity is observed in a number of cases, although excellent selectivities are still attainable. More problematic is the reaction time (6 days under catalytic conditions) ... 

Deng also showed that (DHQD)2AQN could catalyze the parallel KR (PKR) of a variety of monosubstituted succinic anhydrides via asymmetric alcoholysis [215]. The nature of the solvent was found to have a significant influence on the selectivity. Hence, increasing the size of the alcohol from methanol to ethanol resulted in increased levels of enantioselectivity, albeit with reduced reaction rates. In this context, 2,2,2-trifluoroethanol appeared to be the alcohol of choice as it allowed the ASD of 2-methyl succinic anhydride (58a) with a remarkable level of selectivity. Indeed, the use of (DHQD)2AQN (15 mol%) provided a mixture of two regioiso-meric hemiesters 59a and 60a in a 1 1 ratio with 93 and 80% ee respectively. 

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. 

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]. 

During alcoholysis of racemic substituted glutaric acid anhydride one is faced with regio- and enantioselectivity. These two processes may not cooperate in a matching sense. Despite this fact, the monoalkyl glutarates 19-21 have been obtained with moderate to good enantiomeric excess by lipase-catalyzed alcoholysis of the corresponding anhydrides in the presence of Candida antarctica B lipase with 2-methyl-propanol. 

Asymmetric synthesis of unnatural j8-amino acids derivatives based on azide chemistry is known. Enantioselective desymmetrization of mera-anhydride 293 mediated by cinchona alkaloids gives optically active monomethylester 294. This compound was converted into the acyl azide, which underwent Curtius degradation followed by alcoholysis of the intermediate isocyanate affording 8-amino acid derivative 295 in high enantiomeric excess. The authors observed that Grubbs catalyst was able to polymerize norbomene-type monomer 295 affording the corresponding polymer 296 in quantitative yield (Scheme 3.45). 

In addition to enantioselective alcoholysis of meso anhydrides [84, 85], a series of sulfonamide derivatives of quinidine was prepared and shown to elFec-tively catalyze the conjugate addition of bicyclic a-substituted [l-ketoesters to P-nitroalkenes (Scheme 6.38) [86]. 

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. 

Scheme 10.36 Enantioselective alcoholysis of meso-succinic anhydride 36.

At Bristol-Myers Squibb, the quinine-catalyzed alcoholysis of the anhydride 25 initially provided kilogram quantities of the (lS,2k)-monoester 24a with 90.8% ee. To improve the enantioselectivity of desired 24a, alternative enzymatic processes were evaluated [75]. Screening of various enzymes was carried out to prepare (lS,2k)-monoester 24a from dimethyl ester 26. After evaluating yield and optical purity of desired product, reaction rate, and cost of enzyme, the immobilized lipase from C. antarcUca (Novozym 435) was chosen for further development. After optimizing the reaction parameters such as pH, temperature, substrate and enzyme input, a small scale reaction of 50 mL (57.2 g) of dimethyl ester 26 afforded (lS,2k)-monoester 24a in 96% yield and >99.9% ee after 24 h reaction. 

The Song group has also developed monobasic cinchona alkaloid catalysts [24] such as the bulky sulfonamide 77 that do not display self-aggregation behavior. These catalysts are highly useful for the enantioselective alcoholysis of meso anhydrides [25], as demonstrated in Scheme 6.11. 

It should be noted that the presence of a hydrogen bond donor/ Brpnsted acid is not required for high enantioselectivities in alcoholysis of meso anhydrides. For leading references to other cinchona- alka loid based catalysts for this transformation, see Li H, Liu X, Wu F, Tang L, Deng L (2010) Proc Nat Acad Sci, doi 10.1073/pnas.l004439107... 

Table 7.4 Enantioselective alcoholysis of anhydrides catalyzed by p-amino alcohols 80a-c O...

Later, Bohn et al. presented ordinary p-amino alcohols 80 for the enantioselective alcoholysis of various anhydrides. Up to 82% ee was obtained (Table 7.4) [62, 85]. 

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