Hydrolysis dynamic mixtures

Another example where aggregation of a library member drives its synthesis was recently reported by Ulijn ct al. [24, 25]. They used reversible amide bond formation, mediated by thermolysin, which is an enzyme that can catalyze both amide bond hydrolysis and formation, and is only moderately peptide-sequence-dependent. The authors reported that starting from dipeptides and fluorenyl-protected amino acids, the action of thermolysin gives rise to a dynamic mixture of peptides of different lengths (containing typically one to five amino acid residues). When using phenylalanine or leucine as the starting amino acids the... 

Because hydrolytic reactions are reversible, they are seldom carried out in batch wise processes [26,28,36,70]. The reactor is usually a double jacket cylindrical flask fitted with a reflux condenser, magnetic stirrer, and thermometer connected with an ultrathermostat. The catalyst is added to the reaction mixture when the desired temperature has been reached [71,72]. A nitrogen atmosphere is used when the reactants are sensitive to atmospheric oxygen [36]. Dynamic methods require more complicated, but they have been widely used in preparative work as well as in kinetic studies of hydrolysis [72-74]. The reaction usually consists of a column packed with a layer of the resin and carrying a continuous flow of the reaction mixture. The equilibrium can... 

In the early 1960s, seminal work by Jencks and coworkers demonstrated that formation and hydrolysis of C=N bonds were proceeding via a carbinolamine intermediate, thus leading to a more general mechanism of addition reactions on carbonyl groups [17-19]. The dynamic nature of the reaction of imine formation can be exploited to drive the equilibrium either forward or backwards. Since the reaction involves the loss of a molecule of water, adding or removing water from the reaction mixture proved an efficient way to shift the equilibrium in either direction. The responsive behavior of imines to external stimuli makes the reversible reaction of imine formation perfectly suited for DCC experiments [20], Thermodynamically controlled reactions based on imine chemistry include (1) imine condensation/hydrolysis, (2) transiminations, and (3) imine-metathesis reactions... 

Rhodium and ruthenium complexes of CHIRAPHOS are also useful for the asymmetric hydrogenation of p-keto esters. Dynamic kinetic resolution of racemic 2-acylamino-3-oxobutyrates was performed by hydrogenation using ((5,5)-CHIRAPHOS)RuBr2 (eq 3). The product yields and enantiomeric excesses were dependent upon solvent, ligand, and the ratio of substrate to catalyst. Under optimum conditions a 97 3 mixture of syn and anti p-hydroxy esters was formed, which was converted to o-threonine (85% ee) and D-allothreonine (99% ee) by hydrolysis and reaction with propylene oxide. 

The reactor is warmed to 0° while the mixture is stirred. Warming should continue so that over a 1-hr period the reaction mixture reaches 25°. The vessel is then cooled to -23° (50/50 ethanol water, v/v, and liquid N2), and all substances that are volatile at this temperature should be transferred out under dynamic vacuum into a U-trap that can be removed subsequently to the fume hood. The contents of the U-trap are destroyed by hydrolysis in aqueous base. An off-white crystalline solid, S(CN)2, remains in the reaction vessel. The pure white crystalline sulfur dicyanide is obtained by subliming under vacuum (1-5 X 10 torr) (0.42 g, 80-85% yield). Sulfur dicyanide is stored in a glass vessel equipped with a Teflon stopcock at 0-10°. 

There are stUl other opportunities in using elegant enzymatic synthesis methods, for instance, the hydrolysis ofN-acetyl-(D)-amino acids from racemic mixtures by (L)-acylase cleavage, by dynamic kinetic resolution, or by employing a race-mase and a hydantoinase. 

These reactions were investigated mainly for alkaline halides and their mixtures. Hanf and Sole studied the hydrolysis of solid and molten NaCl in the temperature range 600-950 C by so-called dynamic method which consisted of passing inert gas (Nj) containing water vapor through a layer of solid or fused NaCl. The developed routine determined the equilibrium constant of the following reaction ... 

The full transformation of a racemic mixture into a chiral product is possible by the combination of formation of a chiral product and a fast racemization of the residual substrate. Dynamic KR is detailed in Chapter 5. There is another strategy for transforming the two enantiomers of a racemic substrate into the same enantiomer of the product (enantioconvergent reactions). Two different types of reactions must concern the two enantiomers. For example, hydrolysis of rac-l-phenyloxirane fuUy converted it into (R)-l-phenyl-l,2-dihydroxyethane in the presence of a biocatalyst [87,88]. The regioselectivity of the reaction is not the same for both enantiomers moreover, hydrolysis at the asymmetric centre occurs with inversion (Scheme 2.8). 

The ability of chiral CTV derivatives to racemize can be manipulated to resolve the enantiomers by dynamic thermodynamic resolution as recently illustrated by Xu and Warmuth. " Their approach is outlined in Scheme 10. A racemic mixture of the tris-aldehyde 5 is reacted with (/ ,R)-diaminocyclohexane to give an enantiomerically pure anft -cryptophane. Only the (P,P,R,R,R) isomer of the cryptophane is formed from reaction of (P)-S with the amine the (M)-5 isomer is completely inverted. Hydrolysis of the cryptophane then gives (P)-5 at >99% ee. 

Based on the estimated solubility of trimethylsilanol in water (42.56 mg/mL) (32), the concentration of trimethylsilanol ( 160 mg/mL) saturated the aqueous medium and created a two-phase reaction mixture. Since proteases will only interact with water-soluble substrates (31), the trypsin-catalyzed condensation of trimethylsilanol was postulated to occur in the aqueous phase. Although the condensation reaction was conducted in water, the enzyme-catalyzed reaction was promoted by the phase separation of the product. The immiscibility of the product, hexamethyldisiloxane, changed the equilibrium (37) and promoted the condensation reaction in the presence of water. Since the aqueous medium was saturated with trimethylsilanol, the reactant would continue to enter the aqueous phase due to the dynamic equilibrium of the condensation reaction. In addition, the hydrolysis or reverse reaction would be severely hindered due to the immiscibility of the disiloxane product in the aqueous phase. 

The first goal was, therefore, a SD-flavin preparation, which would yield direct evidence for 8a-substitution. This was first achieved by drastic acid hydrolysis of a flavin peptide preparation and subsequent direct inspection of the radical cation obtained by reduction of the hydrolysate with TiCb in 6 N HCl. At pH < 1 flavin photolysis is negligible because of dynamic proton quenching of the photoexcited flavo-quinone cation 107) and the semiquinoid state is highly stable. This allows hyperfine analysis of SD-flavin even in the presence of large amounts of non-flavin peptides and of mixtures of flavin peptides if the attachment of the peptides to the flavin nucleus is the same. The ESR spectra obtained pointed conclusively to 8a as the position of substitution 67). 

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