Selective reaction hydrolysis

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic reaction sites. Selective reactions of enaiitiotopic groups provide enantiomerically enriched products. Thus, the treatment of an achiral material containing two enantiotopic functional groups is a means of obtaining enantiomerically enriched material. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.11. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

Such esterifications and acetal formations are achieved through enzyme catalyses. However, such reactions are relatively rare in aqueous conditions chemically. This is because the reversed reactions, hydrolysis, are much more favorable entropically. Kobayashi and co-workers found that the same surfactant (DBSA) that can catalyze the ether formation in water (5.2 above) can also catalyze the esterification and acetal formations reactions in water.52 Thus, various alkanecarboxylic acids can be converted to the esters with alcohols under the DBSA-catalyzed conditions in water (Eq. 5.6). Carboxylic acid with a longer alkyl chain afforded the corresponding ester better than one with a shorter chain at equilibrium. Selective esterification between two carboxylic acids with different alkyl chain lengths is therefore possible. 

Selective reaction at the ci.s-2,3-diol grouping of unprotected D-ribonucleosides has occasionally been observed. Treatment of D-ribonucleosides with tris(tetramethylammonium) trimetaphosphate in M sodium hydroxide for 4 days at room temperature led to a mixture of nucleoside 2 - and 3 -phosphates in yields of >70% no 5 -phosphate was detected.213 Reaction of ethyl (trichloromethyl)phos-phonate with nucleosides in N,N-dimethylformamide containing triethylamine, followed by basic hydrolysis of the reaction product, yielded 2 (3 )-phosphates in variable yields.214 The participation of the cis-diol grouping in the reaction was suggested by the failure of thymidine or 2, 3 -0-isopropylideneuridine to undergo reaction. 

The alcoholysis of the cyclic phosphate of catechol by alditols can lead, after acid hydrolysis of intermediate, cyclic phosphates, to the selective formation of phosphoric esters of the primary hydroxyl groups in the alditols. Thus, erythritol and D-mannitol afford, after chromatographic purification of the reaction products, their 1-phosphates in yields of 31 and 38%, respectively.217 The method was used to convert riboflavine into riboflavine 5 -phosphate.218 1-Deoxy-1-fluoro-L-glycerol has been converted into the 3-(dibenzyl phosphate) in 54% yield by selective reaction with dibenzyl phosphorochloridate. 219... 

Skeletal copper has lower activity toward hydrogenation compared with skeletal nickel, but it offers superior selectivity for certain reactions. Hydrolysis of acrylontrile over skeletal copper yields acrylamide, retaining the unsaturated bond [114,135] ... 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione 7. Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group at the 15 position W. Acetal formation with neopentyl glycol affords the protected ketone which consists of a mixture of the A and A isomers (2 ) hindrance at position 17 ensures selective reaction of the 3 ketone. The... 

In keeping with the earlier format we aim to provide the readership with sufficient practical details for the preparation and successful use of the relevant catalyst. Coupled with these specific examples, a selection of the products that may be obtained by a particular technology will be reviewed. In the different volumes of this new series we will feature catalysts for oxidation and reduction reactions, hydrolysis protocols and catalytic systems for carbon-carbon bond formation inter alia. Many of the catalysts featured will be chiral, given the present day interest in the preparation of single-enantiomer fine chemicals. When appropriate, a catalyst type that is capable of a wide range of transformations will be featured. In these volumes the amount of practical data that is described will be proportionately less, and attention will be focused on the past uses of the system and its future potential. 

Electrochemical reduction of TNT led to the formation of TAT-3HC1 selective acidic hydrolysis of this compound led to the formation of 2,6-diamino-4-hydroxytoluene dihydrochloride, which was neutralised to 2,6-diamino-4-hydroxytoluene [38, 40, 46]. The interaction of the last product with perfluorotoluene using aromatic nucleophilic substitution reactions led to the formation of 3,5-diamino-4-methyl-2, 3, 5, 6 -tetrafluoro-4-trifluoromethyldiphenyl ether [38, 47] (Scheme 4.17). 

These diverse results can be explained either by the variability of the substrates, or by the influence of minor experimental modifications. Particularly, dichloro-methane is the solvent used wherever an alcohol is selectively oxidized, while acetonitrile is the main solvent when a selective dithioacetal hydrolysis is achieved. The presence of water in the reaction media seems to play no role as a selective dithioacetal hydrolysis can be observed under anhydrous reaction conditions after an aqueous work-up.39... 

Enzymes are biocatalysts constructed of a folded chain of amino acids. They may be used under mild conditions for specific and selective reactions. While many enzymes have been found to be catalytically active in both aqueous and organic solutions, it was not until quite recently that enzymes were used to catalyze reactions in carbon dioxide when Randolph et al. (1985) performed the enzyme-catalyzed hydrolysis of disodium p-nitrophenol using alkaline phosphatase and Hammond et al. (1985) used polyphenol oxidase to catalyze the oxidation of p-cresol and p-chlorophenol. Since that time, more than 80 papers have been published concerning reactions in this medium. Enzymes can be 10-15 times more active in carbon dioxide than in organic solvents (Mori and Okahata, 1998). Reactions include hydrolysis, esterification, transesterification, and oxidation. Reactor configurations for these reactions were batch, semibatch, and continuous. 

There are many pharmaceutical applications for the modification of one enantiomer over another, and to this end, many have studied these selective reactions in carbon dioxide. Glowacz et al. (1996) studied the enzymatic hydrolysis of triolein and its partial glycerides and found that stereoselectivity depends on reaction time and enzyme water content. They suggest that the water content varies the local environment of the enzyme in carbon dioxide and changes the local pH value. Rantakyla et al. (1996) also found that the hydrolysis of one stereoisomer over another was water-dependent. They studied the hydrolysis of 3-(4-methoxyphenyl)glycidic acid methylester and found that the 2S,3R enantiomer hydrolyzed more than fivefold faster than the 2R3S form. 

There are a numerous amount of examples for optical resolutions through hydrolytic-enzyme-catalyzed esterifications13 and hydrolysis.14 Only selected reactions are shown in Figure 13-16. For example, in a large scale optical resolution of 1-phenylethanol by lipase (PS) with vinyl acetate, 67.5 Kg of (R)-1-phenylethanol was successfully synthesized with the flow system as shown in Figure 13 (a). 

The reaction of the fused 5,7-dihalopyrimidine (19) to form the 7-methoxy derivative (20) also shows that the more readily displaced chlorine is next to the azole ring (67T675). Hydrazinolysis of the isoquinoline analogue (21) is stepwise with initial 4-substitution (22). The difference in reactivity at C-4 and C-6 in (22) is sufficient for selective acid hydrolysis of the hydrazino group in (22). Reductive cleavage of the hydrazino C—N bond is achieved in the usual manner by the reaction of its tosyl derivative with alkali (75JCS(Pi)2l90). 

Endopeptidases. Our expanding understanding of the relationship between structure and functionality of food proteins presents the opportunity for designing functionality into proteins by selective, specific proteolytic modification. Control of reaction and prevention of autolysis offered by immobilization are essential to establish the conditions for a highly selective modification. Hydrolysis at specific positions in the primary structure of proteins could be coupled with resynthesis of peptide bonds by selection of conditions, for example, as in the plastein reaction. By careful choice of enzymes and conditions according to the characteristics of the substrate proteins, it may be possible to design new structures from known food proteins. 

The Leukart reaction has also been used in the conversion of dehydroepiandro-sterone into 17/3-formylamino-3/3-formyloxyandrost-5-ene, which on reduction with lithium aluminium hydride afforded 3/3-hydroxy-17/3-me thylaminoandrost-5-ene. Acylation with isocaproyl chloride then furnished the N-methyl-N-isocaproyl steroid (197), after selective ester hydrolysis of the initially formed ON-diacyl derivative. The amide (197) was further converted into its 3,5-cyclo-6-ketone via the 3,5-cyclo-6/3-alcohol and thence by reaction with hydrogen bromide into the corresponding 3/3-bromo-5a-6-ketone which upon dehydrobromination furnished a A2-5a-6-ketone and ultimately the 2-monoacetate of the 2/3,3/3-diol (198) after reaction with silver acetate and iodine. Hydrolysis to the 2/3,3/3-diol (198) gave a separable mixture of the 2/3,3/8-dihydroxy-5a- and -5/3-ketones.88... 

Understanding the degradation chemistry of drug with excipients is essential to select proper excipients in the formulation stages [16, pp 101-151]. Drug-excipient compatibility studies are crucial to decide optimal tablet formulation and to understand the possible mechanism in many cases [10,12,14], Drug instability occurs by three types of reactions hydrolysis, oxidation, and aldehyde-amine addition. Table 11 gives reaction types of chemical and physical instability. 

The plant bufadienolide scillarenin (500) has been synthesized. The starting material was 15a-hydroxycortexone (501), which was converted into the diketone ketal (502) by cupric acetate oxidation at C(21), followed by selective ketalization and tosylate elimination. Protection at C(3) as the dienol ether, oxiran formation at C(20) with dimethylsulphonium methylide, and regeneration of the C(3)- and C(21)-oxo-groups by acid hydrolysis then provided (503). Selective reaction at C(21) with the sodium salt of diethyl methoxycarbonyl-methylphosphonate, and boron trifluoride rearrangement of the epoxide ring to the aldehydo-unsaturated ester (504), was followed by enol lactonization to the bufadienolide (505). This was converted, in turn, to scillarenin (500) via the 14,15-bromohydrin, by standard reactions. Unsubstituted bufadienolides have also been prepared by the same method. 

Alkaline hydrolysis of 2-cyano-l-hydroxyimidazole 3-oxide affords the 2-carboxamide with barium hydroxide the corresponding carboxylic add salt is formed." Selective reaction at each of the two different cyano groups of 1,2-disubstituted 4,5-dicyanoimidazole allows the synthesis of purine derivatives of unequivocal structure. ... 

Two syntheses of this alkaloid (119) have been reported. In one of them (120), starting from conessine (XCVI), the more reactive 3/3-nitrogen was protected by a selective reaction with 1 mole of hydrogen peroxide to form the 3-mono-IV-oxide CXX subsequent treatment with cyanogen bromide yielded iV-cyanoconessimine-3-IV -oxide (CXXI) which on reduction of the A -oxide grouping with sodium borohydride and aluminum chloride followed by alkaline hydrolysis yielded conessimine. 

In the second step, the concentration of pyridine as ligand must be low because it has an inhibitory effect on the hydroalkoxycarbonylation. In situ isomerization to the 4-pentenoic acid ester is a prerequisite for the subsequent carbonylation which provides dimethyl adipate. To ensure internal double-bond rearrangement, the temperature of the reaction is increased to 160-200 °C to give dimethyl adipate with 80 % selectivity. After hydrolysis of the ester, adipic acid is obtained with an overall selectivity of about 70% [1]. So far, this process has been performed on pilot-plant scale. 

SSR182289A 363 is a selective and potent orally-active thrombin inhibitor [127]. The central non-natural amino acid residue 362 was constructed using a Sonogashira reaction. Hydrolysis of the methyl ester followed the cross-couphng reaction of 360 with 361 to produce 362. 

Evidence exists that at least three reactions, hydrolysis, oxidation, and cross-linking, contribute to the deterioration of paper (4, 5, 6). The magnitude and rate of change of a specific physical property will depend on the extent one reaction proceeds relative to the others. It must also be recognized that each degradatlve reaction is affected differently by environmental variables and the results obtained from an accelerated aging test will depend on the selection of the environmental variables. It is therefore necessary to establish the relative importance of each environmental variable. 

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