Hemiacetal transition state

Models were built (Figs. 3 and 4) of the Michaelis complex (3b), the hemiacetal transition state (3c), the acyl enzyme (3d) and the deacylation step. All of these models could nicely be accommodated in the crystal structure without changing any protein coordinates except for those of the catal)dic serine. 

The second step in acetal and ketal hydrolysis is conversion of the hemiacetal or hemiketal to the carbonyl compound. The mechanism of this step is similar to that of the first step. Usually, the second step is faster than the initial one. Hammett a p plots and solvent isotope effects both indicate that the transition state has less cationic character than... 

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

The mechanism of the acid-catalysed breakdown of hemiorthoesters Electron releasing substituents when attached to the pro-acyl carbon have a smaller effect on fcH+ for the breakdown of hemiorthoesters than of orthoesters (see p. 67 above) which suggest that these two classes of compounds react by different mechanisms and that the transition state for breakdown of the hemiorthoesters has less carbocationic character. Jencks and his coworkers (Funderburk et al., 1978) proposed mechanism (5) for the breakdown of hemiacetals and a similar mechanism (6) can be written for the breakdown of hemiorthoesters. This would explain (i) the general acid catalysis observed... 

The much greater value of kHO- for the breakdown of the hemiorthoester compared to the hemiacetals may be attributed partly to the more favourable pKa of the former, but must be mainly due to conjugation of the additional alkoxy group with the developing carbonyl group in the transition state. 

McClelland et al.221 have suggested that the general acid-catalyzed decomposition of a hemiacetal anion, Equation (63), proceeds through an imbalanced transition state where sp3 to sp2... 

The formation of a tetrahedral hemiacetal adduct was analyzed for the interaction between the inhibitor aldehyde and the catalytic serine residue (18)35>. The overall dissociation constants for an enzyme and an interacting transition state analog may be given by ... 

The overall reaction gives the ester 165 and not, as we might expect, a diol or an acetal. The alcohol 164 reacts with acetaldehyde to form a hemiacetal 166. It is the hydrogen on this hemiacetal that is delivered as a hydride to reduce the neighbouring carbonyl but only after a Sm chelate 167 is formed. Compare this transition state 167 with 162 where trisacetoxyborohydride donated the hydride ion. They are very similar both transfer a hydride via a six-membered cyclic transition state. In 162 the boron holds the two oxygens in a ring while in 167 it is samarium.41... 

The 2, 3 -dideoxy-3 -C-(phosphonomethyl)nucleosides (38) of the five common nucleotide bases have been prepared by a condensation of the nucleobases with 1,2-di-O-acetyl-S-O-benzoyl-3-deoxy-3-(methoxyphosphorylmethyl)-6-D-ribofuranose (39). Conversion to the deoxyribose derivative was accomplished by reduction of the 2 -thionocarlKHUite and hydrolysis of the phosphonic ester groups using bromotrimethylsilane. 9-(l-Deoxy-l-phosphono-B-D-p(5CO-furanosyl)-l,9-dihydro-67f-purin-6-one (40, Scheme 4) has been prepared as a potential transition state inhibitor of purine nucleoside phosphorylase. The crucial step in the synthesis involved the carixm-phosphorus bond formation by reaction of the hemiacetal (41) with triethyl-phosphite. Nucleotide (40) proved to be very susceptible to hydrolysis of the glycosidic bond (half-life of thirty-nine minutes, pH 7), but showed weak inhibitory activity (K- = 26 /iM) against purine nucleoside phosphorylase. 

Aldehydes can react with one molecule of an alcohol to form a hemiacetal (see Chapter 11). Because the catalytic site of elastase contains an active serine hydroxyl group, it is reasonable that an aldehyde derivative of a peptide substrate of elastase would react with the serine -OH group to form a hemiacetal, which is a tetrahedral analogue of the transition state of the peptide hydrolysis reaction. (See also Robert C. Thompson and Carl A. Bauer. [1979]. Biochemistry 18, 1552-1558.)... 

Attack on the hydroxy hemiacetal should be favored by stabilizing the developing carbonyl group in the transition state through electron release from the ring-oxygen atom, and also by steric factors. 

The proposed transition state TS-1 to explain the role of the catalyst is depicted in Figure 6.5. The first reaction step between trifluoroacetaldehyde methyl hemiacetal 118 and the aniline 120 provides the corresponding V,0-acetal in the presence of catalyst 121 and molecular sieves. The V,0-acetal is expected to be in equilibrium with the imine 124, which would be protonated and activated by the chiral phosphoric acid to shield the ii-face of the imine. Contemporaneously,... 

Let s begin with the preparation of a 113, the precursor of 107. Known aldehyde 109 was treated with fm -crotyltributylstannane in the presence of a Lewis acid to provide 110. The relative stereochemistry between Cis and Ci9 was chelation controlled. The relative stereochemistry between C17 and C18 resulted from presumed addition of the stannane to the aldehyde via a chair-like transition state with Sn coordinated to the carbonyl oxygen. An interesting procedure was used to convert 110 to the homologous aldehyde, which cyclized to a mixture of anomeric hemiacetals 111. Dehydration of the mixture provided 112. Metallation of 112 using Schlosser s base, followed by stannylation of the resulting vinyl anion, provided 113. ... 

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