Enantioselective Protonation of Enolates in Natural Product Synthesis


  • Charles Fehr




Since their discovery in 1967, the damascones with their typical fruity flowery scent and exceptional odor strength, have become important perfume components. Our interest originated in the synthesis of (E)-prop-1-enyl ketones starting from appropriate carboxylic-acid derivatives by Grignard mono-addition. In the presence of LDA, nonenolizable or slowly enolizable esters or carboxamides are converted into ketones which are protected from further reaction by their in situ conversion into enolates. The predominant formation of (E)-enolates is of synthetic interest, and this point is discussed in the last section. Alternatively, regioisomeric enolates of defined configuration could be obtained by first converting esters into their Li-enolates which react with organometallic reagents to afford directly ketone- and aldehyde enolates. This sequence is applied to the synthesis of γ-damascone. Likewise, such enolates can be protonated enantioselectively (up to 84% ee) by use of a judiciously chosen chiral proton donor. This has allowed the synthesis of enantiomerically pure (R)- and (S)-α-damascone. The outcome of this reaction critically depends on the presence of lithium alkoxide ligands. Enantioselective protonation is presently being applied to a planned synthesis of α-irisfuran, a recently isolated iris oil constituent. In the last section, a novel access to trimethyl-trans-decalins is discussed. The success of this synthetic approach critically depends on the diastereocontrolled formation of a trienolate and its corresponding silyl ether, the latter being submitted to a thermal electrocyclic reaction. This novel reactive sequence has allowed the synthesis of bicyclic damascone analogs which exhibit interesting organoleptic properties and opens a new route for the direct construction of biologically active C(6)-functionalized drimanes such as cinnamodial and forskolin.




How to Cite

C. Fehr, Chimia 1991, 45, 253, DOI: 10.2533/chimia.1991.253.