Lactols alcohols, cyclic

Horse liver alcohol dehydrogenase (HLADH (E.C. 1.1.1.1), commercially available) is a well-documented enzyme capable of catalyzing the enantioselective oxidation of acyclic and cyclic meso-configurated dimethanol derivatives to chiral lactols and further to the corresponding chiral lactones with high enantioselectivity and in high yield (Table 11) 162 ,69. Incases where the two enantiomeric lactols are formed, a kinetic enantiomer separation can occur in the second oxidation step166. 

In the first step the free hydroxy group is protected as a ten-butyl dimethyl si lyl ether Then the lactone is reduced to a lactol, which is the cyclic herniacetal of an aldehyde. Overreduction to an alcohol can be prevented by stoichiometric addition of the reducing reagent at low temperature. Selectivity here depends on the relative stability of intermediate 19, which decomposes only in the course of workups (see Chapter 3). 

As can be seen from Figure 9.1, carbonyl compounds without electron-withdrawing a-sub-stituents do not react intermolecularly with alcohols to form hemiacetals to any significant extent. However, while for such carbonyl compounds there is too little driving force for hemi-acetalization to occur, the reaction is not drastically disfavored. This explains why this type of compound undergoes almost complete hemiacetal formation provided it takes place intramolecularly and leads to a nearly strain-free five- or six-membered cyclic hemiacetal— a so-called lactol (Figure 9.4). What makes the difference is that only in the intramolecular hemiacetal formation is no translational entropy lost (because the number of molecules moving about independently of each other does not decrease). 

Reminder, Cyclic hemlacetals are more stable than acyclic ones. Note how the product stays as a lactol—an acyclic hemiacetal would revert to alcohol plus aldehyde. 

Several types of scc-alcohols bearing a leaving group (Nu) attached to the carbinol moiety are chemically unstable and therefore prone to decomposition via a reversible elimination-addition process of a nucleophile (HNu) onto an aldehyde or ketone, respectively. This applies to cyanohydrins (Nu = C=N), and hemi(thio)acetals (Nu = OR, SR ) or hemiaminals (Nu = NHR ), respectively. It is obvious that the corresponding cyclic structures - (thio)lactols, etc. - behave in the same way [215-217]. 

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

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