Enantioselective alcoholysis

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. 

K. Naemura, K. Kittaka, M. Murata, H. Ida, K. Hirose, Y. Tobe, Lipase-Catalyzed Enantioselective Alcoholysis of Enol Acetates Optical Resolution of Ketones and Aldehydes Using Lipases in Organic Solvents , Enantiomer 1996, 1, 219-222. 

Based on the very different behaviors of lipases A (CAL-A) and B (CAL-B) from Candida antarctica towards polyfunctional compounds in non-aqueous media, Liljeblad et al82 reported a novel lipase-catalyzed method for the resolution of A -heterocyclic amino esters using methyl pipecolinate 69 as a model compound. For this purpose, the chemo-and enantioselective alcoholysis and transesterification reaction of 69 in the presence of CAL-B and the A-acylations using CAL-A were studied, (cf. fig. 37 and 38). 

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]. 

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.

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. 

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]. 

In some cases, the use of a large excess of alcohol is an option to drive the reaction to completion. Alcoholysis of glutamic acid dimethyl ester derivatives with acylase I was regio- and enantioselective (Figure 6.15). An excess of butanol was used as nucleophile and solvent [62]. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

Optically pure a, . (R)-3-hydroxybutanoates can be obtained by alcoholysis of poly-(R)-3-hydroxybutanoate, a fermentation product of fructose by Alcaligones eutrophus.4 (S)-Ethyl 3-hydroxybutanoate in 84-87% ee can be synthesized in 57-67% yield on a decagram-scale by an Organic Syntheses procedure6 using bakers yeast reduction of ethyl 3-oxobutanoate with the aid of sucrose.7 In order to obtain enantioselectivity as high as 95-97% ee, the substrate concentration should be kept below 1 g/L.6... 

Enantioselective epoxidation of aUylic alcohols with tantalum surface species prepared by alcoholysis of [(=SiO)Ta(=CH Bu)(CH2 Bu)2j strongly suggests that other transition metals from group 5 and 6 might be used. 

The syn addition of the adducts suggests a mechanism different from that observed in rhodium-catalyzed alcoholysis and aminolysis reactions. Mechanistic investigations from the Tautens laboratory have revealed that the most likely mechanism involves an enantioselective carbopalladation followed by a (3-alkoxide elimination to afford the ring-opened product." ... 

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. 

In addition, the use of an enantioselective or diastereoselective hydrolysis of racemic oxazolones offers another possibility to obtain new synthetic amino acids. Similarly, alcoholysis of 5(4H)-oxazolones gives the corresponding A -acylamino acid esters. 

Chiral titanium complexes with a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(477)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand. Selected examples of the alcoholysis of saturated 5(477)-oxazolones are shown in Table 7.21 (Fig. 7.23). 

To test the feasibility of enzyme-catalyzed enantiosective reactions in solid/gas reactors and to evaluate the efficiency of the resolution obtained in the gas phase compared to liquid systems, resolution of racemic 2-pentanol, catalyzed by CALB, through alcoholysis with methyl propanoate as acyl donor has been investigated in both liquid media and the gas phase [24]. As CALB has an enantiopreference for R enantiomers of secondary alcohols, this last reaction leads to S-2-Pentanol. This compound is a chiral intermediate in the synthesis of several potential anti-Alzheimer s drugs that inhibit 3-amyloid peptide release and/or its synthesis [25]. The degree of enantioselectivity was measured by using the enantiomeric ratio E, which is defined as the ratio of the specificity constants kcat/KM for the enantiomers (R/S in this case). E can be determined from the enantiomeric excess of... 

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. 

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