Regioselective hydrolysis

Regioselective hydrolysis of diesters is a challenging problem ia synthetic chemistry because the side reactions always reduce the yield of desired product. Some Upases are well suited to perform this task. Lipase OF-360 (Meito Sangyo) hydrolyzes diester (55) ia 74% theoretical yield and 93% ee (70). Lipase from Pseudomonas cepacia suspended ia diisopropyl ether saturated with water hydrolyzes triester (56) with a remarkable efficiency and regio- and stereoselectivity (71). 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

The highly regioselective hydrolysis of tryptophan-containing peptides with the [Pd(en)]2+ (en = H2NC2H4NH2) complex has been reported by Kostic and co-workers.436 The hydrolysis does not proceed without the palladium(II) complex. However, when equimolar amounts of a... 

Regioselective hydrolysis of the diester 27 gave the 1,3-thiazetidine 28 where the thiazetidine ring is fused to a quinolone nucleus <99CPB1765>. Derivatives of the tricyclic system, e.g. 29, showed activity against gram-positive bacteria including quinolone-resistant MRS A <99H(51)2915>. 

A full paper containing all these data (previously published as short communications), as well as some mechanistic proposals concerning the regioselective hydrolysis of the diesters and the unexpected formation under certain conditions of the products not related to the cycloadditions, was published later [88]. 

Figure 19.4. Enantioselective hydrolysis of methyl [i-acetylthioisobutyratc (a) and regioselective hydrolysis of methyl cetraxate (b) catalyzed by DHase. The numbers in parentheses are the maximum yields of individual products in reactions with E. coli transformant cells overexpressing the DHase gene. Source Honda et al., 2002.

The most prominent green example, the regioselective hydrolysis of an amide on an industrial scale, is the production of penicillin. PenG acylase selectively hydrolyses the more stable amide bond, leaving the /Mactam ring intact [75, 76]. For a full discussion of this example see Chapter 1 (Fig. 1.37) and Chapter 8. Since the starting material is already enantiopure the enzyme induces no stereoinformation. In other industrial processes the enantioselectivity of the enzymes is used. This is, in particular, the case in the production of natural and unnatural amino acids. 

Meth-Cohm, O. and Wang, M.X. 1997a. Rationalisation of the regioselective hydrolysis of aliphatic dinitriles with Rhodococcus rhodochrous AJ270. Chemical Communications, 1041-2. 

In the synthesis of highly phosphorylated phosphoinositide derivatives regioselective hydrolysis of one out of three butyrates by a lipase in pH 7.8 buffer containing... 

Hot (80 °C) O.IM hydrochloric acid effects rapid (20 min) regioselective hydrolysis of 4-cyano-imino-3-(methoxymethyl)perhydro-l,3,5-oxadiazine (30) (see Section 6.18.10.1.1) to 4-cyano-iminoperhydro-l,3,5-oxadiazine in 72% yield <83BCJ3319>. 

The chemistry of complex lipids is dominated by regioselective hydrolysis reactions of (1) the glyceryl fatty acid esters and (2) phosphate diesters. Both types of reactions are routinely performed with the corresponding esterases. A large variety of lipid active transferase enzymes is also commercially available. Phospholipases Aj, A, C, and D, for example, split any of the four ester bonds of a phospholipid regioselectively. The product without a fatty acid side chain at C2 of glycerol is called a lysophospholipid. Lecithin-cholesterol-acyltransferase transfers the fatty acid at C2, often linoleic acid, to the OH group at C3 of cho-... 

The attachment and use of enzymes on hydrophilic supports covered with a dense layer of highly hydrophobic groups has been shown by Vita-Invest in recent years [78]. Various lipases were immobilized on Octyl-Sepharose CL-4B, and in certain cases an increase of activity of more than 100 times could be observed. The usefulness of these supported enzymes was demonstrated in first experiments by the regioselective hydrolysis of glucose pentaacetate (57) to glucose tetraacetate with Candida rugosa lipase (Scheme 18). The regioselectivity was found to be pH dependent, and the 2-0-deacylated derivative 58 could be obtained at pH 5, whereas the 6-0-deacylated product 59 was formed at pH 7. 

Conversely (Scheme 6), another approach for the synthesis of (SR)-fluoroepimer 28 involved the fluorobromination of the C(8)-C(9) olefinic bond of common intermediate 22 and formation of the C(9)-C(13) epoxide 27. This compound, after regioselective hydrolysis and oxidation of the re-... 

Scheme 2.24 Regioselective hydrolysis of /Z-diastereotopic diesters by porcine liver esterase...

Scheme 2.51 Regioselective hydrolysis of carbohydrate esters by porcine panceatic lipase...

For instance, 1,3- and 1,4-dicyanobenzenes were selectively hydrolyzed by Rhodococcus rhodochrous to give the corresponding monoacids [672, 673]. In the aliphatic series, tranexamic acid (iratw-4-aminomethyl-cyclohexane-l-carboxylic acid), which is a hemostatic agent, is synthesized fi om trans-, 4-dicyanocyclohexane. Complete regioselective hydrolysis was achieved by using an Acremonium sp. [674]. The outcome of regioselective nitrile hydrolysis is believed to depend on the distance of the nitrile moieties and the presence of other polar groups within the substrate [675, 676]. 

Xu, Y., Jia, X., Panke, S., and Li, Z. (2009) Asymmetric dihydroxylation of aryl olefins by sequential enantiose-lective epoxidation and regioselective hydrolysis with tandem biocatalysts. Chem. Commun., 1481-1483. 

Crosby, J., Moilliet, J., Parratt, J.S., and Turner, NJ. (1994) Regioselective hydrolysis of aromatic dinitriles using a whole cell catalyst. J. Chem. Soc., Perkin Trans. 1, 1679-1687. 

Figure 15.4 Regioselective hydrolysis using hydrolase enzymes.

Dicarbonyl Compounds.— 2,3-Dihydroxy-l,4-dioxan functions as a stable synthetic equivalent to glyoxal, particularly in the synthesis of a variety of heterocycles. The dioxan overcomes the prerequisite preparation of pure glyoxal immediately prior to its use (because of its tendency to polymerize) and offers an alternative available for reaction under non-aqueous conditions. Monoprotected a-keto-aldehydes are seldom available by selective derivatization of the parent dicarbonyl compound. However, 1,1,2,2-tetramethoxy-alkanes, readily prepared from a,a-dichloro-aldehydes, undergo regioselective hydrolysis to give l,l-dimethoxyalkan-2-ones. The sequence from the dichloro-aldehyde may be carried out without isolation of the tetramethoxylated intermediate. a,a-Bis(phenylseleneno)-aldehydes may be prepared from aldehydes or the intermediate a-(phenylseleno)-aldehyde by treatment with morpholinophenyl-selenenamide. a-(Arylseleno)-ap-unsaturated aldehydes result from the electrochemical oxidation of 3-hydroxyalkynes in the presence of a diaryl diselenide [equation (42)]. Treatment of a,a -dibromo-ketones with primary... 

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