Hydroformylation-acetalization intramolecular

The hydroformylation of allylic and homoallylic alcohols has been widely studied in this process because hydroxy-aldehydes can easily lead to hemiacetals with five- or six- member rings. Likewise, the hydroformylation of allyhc alcohol to give 4-hydroxybutanol and 1,4-dihydroxybutanoI is an important industrial process [63]. 

The general trend is that reactivity is low when double bond substitution is high, and the formyl group is also introduced into the less substituted carbon in this case. 

Aldehyde 99 spontaneously cycles to give the hemiacetal 100. This leads to the acetal 102 if the reaction takes place in the presence of an alcohol and the catalytic system [Rh(CO)2-zeohte]/PEt3 [64], or in the presence of a carboxylic acid and a rhodium catalyst [65]. Lactone 101 is easily obtained from hemiacetal 100 by oxidation. 

An enantioselective version of this reaction has been reported [66]. The hydroformylation of 97 (R=Ph) with the catalytic system [Rh(acac)(CO)2]/ 4 BINAPHOS gives the hemiacetal 100 (R=Ph) with a yield up to 99%, which after oxidation provides the lactone 102 (R=Ph) with 88% ee. 

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The nature of the products in the intramolecular hydroformylation-acetalization of isopulegol depends on the reaction conditions (Scheme 5.81). At low temperature, the reaction is stopped at the level of the hemiacetal, whereas higher temperatures force the elimination of water in a final step [73]. 

In the presence of alcohols or amines, the aldehydes generated in the hydroformylaton reaction give acetals or imines. Depending on the hydroformylation catalyst used an additional acid catalyst is required. When the process is intramolecular, (i.e. when alcohols, amines or amides are present in the starting material), it is spontaneous and gives hemiacetals or imines, especially if five or six member rings can be formed [4b]. Moreover the presence... 

Figure 29. Hydroformylation-intramolecular acetalization of allylic alcohols...

Figure 30. Different allylic alcohols studied in hydroformylation-intramolecular acetalization...

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. 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

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