Methenylation, ketone

S.J. Danishefsky and co-workers identified an exo-methylene hydroazulenone as a versatile intermediate in efforts directed toward the total synthesis of guanacastepene. The exo-methylene group was introduced on the hydroazulene by the two-step Eschenmoser methenylation procedure. The substrate was deprotonated with LiHMDS followed by the addition of 3 equivalents of Eschenmoser s salt. The resulting a-(dimethylamino)methyl ketone was treated with mCPBA to form the A/-oxide, which spontaneously underwent a Cope elimination to afford the desired exo-methylene hydroazulenone. 

In the laboratory of J.L. Wood, an expeditious approach to the densely functionalized isotwistane core of CP-263,114 was developed. For the proposed radical cyclization, an exo-methylene group was installed on a five-membered lactone ring. It was discovered that both the formation of the lactone ring and the Eschenmoser methenylation could be conducted in a one-pot operation by simply treating the a-acetoxy ketone with excess amounts of LiTMP and then with Eschenmoser s salt. 

During the early stages of the total synthesis of (+)-gelsemine, S.J. Danishefsky et al. wanted to install a key oxetane ring on a bicyclic ketone intermediate. The Eschenmoser methenylation was chosen to prepare the required bicyclic a-methylene ketone which was later converted to the oxetane in a few steps. 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

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