Tetrahedral intermediate stable

We have approached this problem by studying the interactions between pepsin and ketones with structures based on that of pepstatin. Our strategy was to design ketones which would serve as pseudosubstrates, that is, be subject to the catalytic action of the enzyme, but only to the point of formation of a tetrahedral intermediate which, because of the increased stability of a C-C vs a C-N bond, would not break down to products. Such a stable tetrahedral intermediate would then, in principle, be amenable to study by the appropriate physical methods. appeared to be an ideal method since changes... 

These hemiketalic adducts are very good mimics of the tetrahedral transition state involved in the enzymatic hydrolysis of an ester bond or a peptidic bond [71,72], The nucleophilic entity of the enzyme active site (e.g. the hydroxyl of hydrolytic serine enzymes) can easily add onto the activated carbonyl of a fluor-oketone leading to a very stable tetrahedral intermediate. The enzyme is not regenerated and is thus inhibited (Fig. 21) [73],... 

The 1,2,5-oxadiazine (62) is reported to be in tautomeric equilibrium with the ring opened nitrone (63). The nitrone is the only species observed in aqueous solution (69ZOR355). The 1,3,4-thiadiazine (64), which can be regarded as a stable tetrahedral intermediate, readily ring opens to (65), which is favoured in ethanol solution (77ACH(94)391). 

Kaloustian and Khouri (74) have also observed that the sodium salts 174 (n = 2 and 3) of the hemi-orthothiol esters 156 and 157 are stable tetrahedral intermediates. These insoluble salts were produced by reacting the... 

SN Reactions at the Carboxyl Carbon via a Stable Tetrahedral Intermediate... 

Fig. 6.4. Mechanism of SN reactions at the carboxyl carbon via a stable tetrahedral intermediate.

The Weinreb amide syntheses in Figure 6.50 proceeding via the stable tetrahedral intermediates B and F are chemoselective SN reactions at the carboxyl carbon atom of carbon acid derivatives that are based on strategy 1 of the chemistry of carboxylic acid derivatives outlined in Figure 6.41. Strategy 2 of the chemistry of carboxylic acid derivatives in Figure 6.41 also has a counterpart in carbon acid derivatives, as is demonstrated by a chemoselective acylation of an organolithium compound with chloroformic acid methyl ester in this chapter s final example ... 

The alkoxide formed by addition of a Grignard reagent to an aldehyde or ketone is stable. Tetrahedral intermediates are similarly formed by addition of a nucleophile to a carbonyl group, so why are they unstable . The answer is to do with leaving group ability. 

A stable tetrahedral intermediate is more likely in the reduction of lactones, and DIBAL is most reliable in the reduction of lactones to lactols (cyclic hemiacetals), as in E.J. Corey s synthesis of the prostaglandins. The key step, the hydride transfer from Al, is shown in the green frame. 

Figure 2 Intermediate in the EPSP synthase pathway, (a) The mechanism of the reaction catalyzed by EPSP synthase is shown. The reaction proceeds by an addition-elimination mechanism via a stable tetrahedral intermediate, (b) A single turnover reaction is shown in which 10- xM enzyme was mixed with 1 OO-m-M S3P and 3.5-riM radiolabeled PEP. Analysis by rapid-quench kinetic methods showed the reaction of PEP to form the intermediate, which then decayed to form EPSP in a single turnover. The smooth lines were computed from a complete model by numerical integration of the equations based on a global fit to all available data. Reproduced with permission from Reference 7.

Diisobutylaluminum hydride (DIBAL) is a reliable reagent for the reduction of lactone 29 to the corresponding lactol 67. This is due to the formation of stable tetrahedral intermediate 66, which prevents further reduction (via hydroxyaldehyde 68 to the diol) and decomposes during aqueous workup to provide the desired lactol 67. 

Organometallic addition to the /V-methoxy-A -methylamide (15) also affords an exceptionally stable tetrahedral intermediate (16) and carbonyl-protecting group, first used in the synthesis of X-206. Deprotonation of the hydrazone in intermediate (16) was subsequently carried out with lithium diisopropylamide. The resulting dianion initiated a novel attack upon epoxide (17) and in the ensuing transformation was followed by tetrahydrofuran ring formation as depicted, in 71% yield, all in one pot (Scheme 4). 

Figure 1.24 Mechanism of peptide hydrolysis by a serine protease and enzyme inhibition by forming stable tetrahedral intermediate.

The only stationary point at the 4-3IG level is the ion-molecule complex, 17.2 kcal moP below the reactant level, with an S... C = 0 distance of 3.38 A. Subsequently, the energy steadily increases, and no stable tetrahedral intermediate can be located all attempts to find a corresponding stationary point ended in convergence to the ion-molecule complex minimum. 

A stable tetrahedral Intermediate Is more likely In the reduction of lactones, for the same reasons that cyclic hemiacetals are more stable than acyclic ones. DIBAL Is most reliable In the reduction of lactones to cyclic hemiacetals (also known as lactols), as In this reaction from E. J. Corey s synthesis of the prostaglandins. 

Acetals, as aheady pointed out, are stable tetrahedral intermediates and so they can be used as protective groups in organic synthesis. Acetals are stable under basic conditions, so they can be used to protect ketones from a base. An acetal group is hydrolyzed under acidic conditions. Scheme 7.73 gives an example with a dioxolane protecting group. 

Bredt s amides are very reactive Twisted amides display enhanced sensitivity to hydrolysis and a host of other interesting chemical peccadillos. For example, Kirby reported the formation of stable tetrahedral intermediates from l-aza-2-adamantanone (Figure 11.56). This compound combines amine reactivity (it can be rapidly protonated) with ketone reactivity (it undergoes Wittig olefination). ... 

Figure 11.56 1 -aza-2-adamantanone can be converted into stable tetrahedral intermediates. 

Thus, it is possible to form the very reactive, aldehyde-functionalized polymers by functionalization of polymeric organolithium compounds with 4-morpholinecarboxaldehyde. The key to the success of this procedure is due to the formation of a stable, tetrahedral intermediate that does not decompose to form the aldehyde group until work-up with alcohol. Work-up with acidic methanol is the preferred procedure to prevent dimer formation from base-catalyzed aldol condensation, primarily for functionalizations of poly(dienyl)lithiums. 

Nucleophilic addition of methyl anion to the carbonyl group generates a stable tetrahedral intermediate, which gives a ketal after acid treatment. 

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