Ketones hemiketal formation

Circiunstantial support for this mechanism was supplied by the fact that A-tosyl-Phe-CMK, a specific inhibitor of chymotrypsin, did not react with anhydrochymotrypsin [104]. Although both X-ray crystallographic and NMR studies supported the alkylated hemiketal as the structure of the inhibited enzyme, those studies did not prove whether alkylation or hemiketal formation oecurred first [105, 98]. Carbon-13 NMR studies were also used to determine the pKa (7.88-8.1) of the hemiketal hydroxyl and this finding provided the first evidence that serine proteinases could stabilize the ionized form of the alkylated hemiketal, via hydrogen bonds in the oxyanion hole [106,107]. A series of more recent papers has confirmed that hemiketal formation precedes the alkylation step and has shown that the initial, reversible part of the interaction is made up of two discrete stages (a) formation of a Michaelis complex, followed by (b) hemiketal formation [102, 108]. The requirement of an intermediate hemiketal may mean that chloromethyl ketone (CMK) inhibitors should be considered as transition-state [109] analogue inhibitors (see diseussion in seetion on Aldehydes). 

Lead tetraacetate oxidation (63) of oxodelcosine (LXXXV) gave LXXXVII, presumably arising from the expected diketone LXXXVI. Evidence favoring structure LXXXVII was the further oxidation of one of the two hydroxyls to a five-membered ketone (LXXXVIII) with Sarett s reagent. Thus, the unreacted hydroxyl of LXXXVII must be tertiary this can be explained if the C-1 hydroxyl reacted with the C-8 ketone to form a hemiketal. Furthermore, the hemiketal formation as... 

The preference for the /3-silyl isomer product complements methods available for hydrostannation of alkynes, for which the a-stannyl regioisomer is formed preferentially.70 7011 70c In addition, the /3-silyl products serve as the platform for a tertiary alcohol synthesis (Scheme 15). Upon treatment of vinylsilanes such as B with tetrabutylam-monium fluoride (TBAF) in DMF at 0 °C, a 1,2 carbon-to-silicon migration occurs, affording the tertiary heterosilane E. Oxidation of the C-Si bond then provides the tertiary alcohol. Good 1,2-diastereocontrol has been demonstrated for y-alkoxy substrates, as in the example shown. The studies suggest that the oxidation of the sterically demanding silane intermediate is facilitated by the intramolecular formation of a silyl hemiketal or silyllactone for ketone or ester substrates, respectively.71... 

Second reaction. Air is not required for formation of the keto-enol. The C1-C6 and 07-08 bonds are broken, and a new Cl-0 bond is made. It makes sense that the driving force for breaking the C1-C6 bond should be provided by migrating Cl from C6 to 07 (note a 1,2-shift) and expelling 08. Then 08 can add back to C6 to give a hemiketal which can open up to the ketone. 

Hemiacetal Acetal FIGURE 7-5 Formation of hemiacetals and hemiketals. An aldehyde or ketone can react with an alcohol in a 1 1 ratio to yield a hemiacetal or hemiketal, respectively,... 

Although the spectral properties of cyclopropanones and the easy formation of hydrates and hemiketals are inconsistent with the dipolar form, some reactions of cyclopropanones do indicate that the ring carbons are much more electrophilic than in other cyclic or acyclic ketones. For example, nucleophilic ring opening often occurs easily ... 

In accord with the above, substituent effects in 2-arylcyclopropanone hemiketals indicate that initial conversion to the parent ketone takes place prior to a C2—C3 ring opening. 16> Although hemiketal-ketone equilibration is slow under neutral conditions, ketone formation and hence cleavage through 130 is accelerated in acid. 

Ketones react with alcohols to form hemiketals and then ketals. This pair of reactions is exactly analogous to the formation of hemiacetals and acetals. In the... 

The intermediate formed from this first nucleophilic addition is known as hemiacetal. When ketone is the starting material, the structure obtained is a hemiketal. Once the hemiacetal is formed, it is protonated and water is eliminated by the same mechanism described in the formation of imines with the only difference that oxygen donates a lone pair of electrons to force the removal of water rather than nitrogen (Following fig.). The resulting oxonium ion is extremely electrophilic and a second nucleophilic addition of alcohol to forms the acetal. 

Figure 11.5. Furanose Formation. The open-chain form of fructose cyclizes to a five-membered ring when the C-5 hydroxyl group attacks the C-2 ketone to form an intramolecular hemiketal. Two anomers are possible, but only the a anomer is shown.

These extended-chain ketones are believed to interact with HLE similarity to the aldehyde and TFMK series of inhibitors. Although studies showing that they are true transition-state analogue inhibitors have not been reported, the formation of the covalent hemiketal adduct was documented in an X-ray crystallographic study of a DFK bound to PPE [150]. One notable finding is that the acidic N-terminal substituents first used by Trainor and co-workers to produce TFMKs with good in vivo profiles... 

Cyclopropanones readily take up water, alcohols and carboxylic acids to form the corresponding hydrate, hemiketal or 1-acetoxy carbinols. The hydrates are relatively stable, but the hemiketals appear to be in equilibrium with the parent ketone, as evidenced by the fact that one hemiketal may be converted to another on standing with the appropriate alcohoF . The formation and reactions of these cyclopropanone hemiacetals is reviewed in the chapter by Salaun (cf. Chapter 13) and will not be covered extensively here. 

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