Claisen rearrangement, dimethylacetamide dimethylacetal

The allylic alcohol was subjected to an Eschenmoser-Claisen rearrangement with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereoselective manner. Reduction of the amide to the corresponding aldehyde with phenyl silane in the presence of Ti(0/Pr)4 was followed by an acid-promoted closure of the C-ring of codeine. In order to prevent N-oxidation, the amine was converted to the corresponding tosylamide, via debenzylation and treatment with tosyl chloride, before the allylic alcohol was introduced by the reaction of the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy functionality was corrected by applying the well-known oxidation/reduction protocol [46, 60] before the benzylic double bond was reductively removed under Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of approximately 0.6%. 

Condensation of the sodium enolate of acetylacetone 194 with carbethoxy-cyclopropyltriphenyl tetrafluoborate 195 led in high yield to acetylcyclopen-tenyl ester 196 and thence to ketal aldehyde 197. The latter with m-methoxy-phenethyl magnesium chloride 198 yielded allylic alcohol 199, which on Claisen rearrangement with dimethylacetamide dimethylacetal afforded amide 200. Conversion to amine, amine oxide, and Cope elimination then led to the desired... 

An interesting method of indole C-4 substitution has been developed from a Claisen rearrangement. Reaction of 3-hydroxy-2-methoxyindoline (349) with W,A(-dimethylacetamide dimethylacetal gives the intermediate (350), which undergoes a Claisen rearrangement to yield a mixture of the 4-substituted indoline (351) and indole (352). The indoline can be converted into the indole by a sequence of methanol ehmination and base hydrolysis (Scheme 111) <(90CC78i). 

The synthesis of the branched-chain conduritol 103 by treating the alcohol 104 with N,N-dimethylacetamide dimethylacetal to effect a [3,3]-sigmatropic Claisen rearrangement has been described. 

---