Hemiketal formation from

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...

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... 

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... 

For the stereoselective synthesis of C-glycosides, deoxygenation of hemiketals, obtained from Wacker oxidation of sngar-derived olefin alcohols, was envisaged as an easy and efficient protocol. In our earlier study on the synthesis of 4-epiethisolide, attempted PdCV mediated conversion of the terminal olefin (1), obtained from sugar chiron into a methyl ketone (2) resulted in the exclnsive formation of an anti-Markovnikov product (3), which happened to be the first report in the literature (Scheme 22.1). 

The reaction mechanism is the same for both aldehydes and ketones. If acetone (6) reacts with ethanol in the presence of a catalytic amount of j5-tol-uenesulfonic acid, 53 is formed but not isolated. This compound is formally analogous to the hemiacetal derived from an aldehyde, but it is derived from a ketone. Therefore, it is called a hemiketal. The isolated product is 54 (2,2-diethoxypropane)—again, analogous to the acetal however, the starting material is a ketone rather than an aldehyde, so the final product is called a ketal. A ketal is a compound derived from a ketone that contains two OR groups connected to the same carbon. The mechanism for ketal formation from ketones is identical to that for acetal formation, and every step in this sequence is reversible. The same methods used to remove water from the reaction that was used to drive the equilibrium toward the acetal in that reaction (see Section 18.6.3) can be used here for conversion of the ketone to the ketal. 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

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. 

A vast range of natural sugars exempMly these cyclic addition products. A typical sugar exists predominantly in the form of a hemiacetal or hemiketal in solution, although this is an equilibrium reaction, and the open chain carbonyl form is always present to a small extent (<1%). The formation of a six-membered cyclic hemiacetal from glucose is achieved by attack of the C-5 hydroxyl onto the protonated carbonyl (conjugate acid). 

Theoretical studies have been done in order to understand this behavior difference. Semiempirical calculations (AMI, MNDO) of formation energy (of the hemithio-ketal-hemiketal interconversion) have shown that hemithioketals are less stable than the corresponding hemiketal (from 10 to 15 kcal/mol). This difference can be due to steric factors, connected to the respective sizes of sulfur and oxygen. Stereoelectronic factors can also be evoked stabilization that is brought about by the anomeric effect is a priori more important for a gem-dihydroxylated compound than for the hemi-thioketal. Moreover, at the kinetic level, displacement of the water molecule of the inhibitor (under aqueous conditions, the inhibitor is hydrated) by the thiol of the enzyme is a slow and disfavored reaction. In contrast, the same reaction is favored with the hydroxyl of a serine. Experimentally, equilibrium occurs very slowly with the enzyme as well as with model molecules. ... 

The stereochemical consequences of the cyclization of some 3-(2,5-dihydroxyphenyl)pro-pan-l-ols (247) have been investigated, with a view to optimizing the chiral economy of a tocopherol synthesis from (S)-chroman-2-carboxylic acid (81JOC2445). It was observed that acid-catalyzed dehydration occurred with retention of configuration and it was proposed (79JA6710) that the process involved the formation of a hemiketal through nucleophilic attack by the side-chain hydroxy group on the keto tautomer. 

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