Hemiketal formation

The mechanism involves hemiketal formation followed by reduction of the oxocarbonium group ... 

Since the carbonyl group is planar and may be attacked from either side, two epimeric structures (anomers) are possible in each case, and in solution the two forms are frequently in equilibrium, because hemiacetal or hemiketal formation is reversible (see Section 7.2). The two anomers are designated a or P by comparison of the chiralities at the anomeric centre and at the highest numbered chiral centre. If these are the same (RS convention), the anomer is termed P, or a if they are different. In... 

Pretazettine (242) has a trans B-D ring juncture and seems a fairly strained molecule whereas tazettine (240) bears a cis B-D fusion allowing more flexibility, and the driving force for the B-ring opening is attributed to the relief of this internal strain. The reaction would be completed by an intramolecular crossed Cannizzaro reaction followed by hemiketal formation yielding the cis B-D fusion present in 242. 

Fig. 9.7. Stereochemistry of the hemiketal formation from D-fructose in aqueous solution at 25°C (in the formulas for the six-membered ring hemiketal the carbon skeleton of 5-valerolactol is black, which emphasizes the relationship to the reaction from Figure 9.5, whereas the extra substituents as well as the bonds leading to them are red).

Figure 2 NMR study of the hemiketal formation from 5. The spectra correspond to the pure reactant (5), or the product(s) formed by the interaction of 5 with 2-propanol or CD...

Monosaccharides Form Rings as a Consequence of Internal Hemiacetal or Hemiketal Formation. 

Establish the orientation of the asymmetric carbon created by hemiacetal or hemiketal formation. By definition, an a-anomeric OF is on the same side of the Fischer projection as the... 

Nakamura, S., Inagaki, J., Kudo, M., Sugimoto, T, Ohara, K., Nakajima, M. and Hashimoto, S., 2002. Studies directed toward the total synthesis of pinnatoxin A synthesis of the 6,5,6-dispiroketal (BCD ring) system by double hemiketal formation/hetero-Michael addition strategy. Tetrahedron 58, 10353-10374. 

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). 

Gracias, V., Milligan, G. L., Aube, J. Efficient Nitrogen Ring-Expansion Process Facilitated by in Situ Hemiketal Formation. An Asymmetric Schmidt Reaction. J. Am. Chem. Soc. 1995, 117, 8047-8048. 

Studies of Equilibria, Configuration and Conformation. - Alcoholic solutions of acylphosphonates have been shown to contain considerable amounts of hemiketals by examination by P NMR spectroscopy. Because of the great difference between the P chemical shifts of acylphosphonates (831 0) and their hemiketals (63ip= 17-21), P NMR spectroscopy was shown to be a suitable method for studying the rates and equilibrium of hemiketal formation of acylphosphonates with different alcohols. 

FIGURE 2.2 An example of fine-tuning of pharmacologically active chemicals Erythromycin 2 -ethylsuccinate and clarithromycin are semisynthetic derivatives of the macroUde antiinfective erythromycin. The small molecular change in the former leads to the elimination of bitterness which is important as this class of drugs is often used in pediatrics and administered as a syrup. In the latter, because hemiketal formation is no longer possible (arrow), clarithromycin is stable in the acidic milieu of the stomach (pH 2). 

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... 

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