Regioselectivity aldol cyclization

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

A similar regioselectivity under different conditions for aldol cyclization of 1,5-diketones obtained by the Michael addition of substituted acetoacetic esters to methyl vinyl ketones has been reported by another laboratory (equation IV),5... 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

In the cyclization step (the aldol reaction) there is chemoselectivity in the formation of an e-niii from the ketone and not from the aldehyde and regioselectivity in the formation from the en- - -.W 3... 

Nakane and Hutchinson have further shown that the aldol step in this cyclization is stereoselective as well as regioselective. Treatment of (39) with Hunig s base, acetic anhydride and 4-(A, A -dimethyl-amino)pyridine (DMAP), followed by sodium borohydride reduction of the intermediate P-hydroxy aldehyde, gives diol (40) in 48% yield no diastereomeric diols were detected (equation 102). 2i... 

An exception to the generalization that the enamine of the more hindered aldehyde acts as the nucleophilic arm in intramolecular aldol reactions of unsymmetrical dialdehydes is seen in equation (103). -2 The regioselectivity of this cyclization is apparently very high none of the other isomer was detectable by HPLC or NMR the 57% yield quoted is the overall yield of the alcohol obtained by sodium borohy-... 

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