Application of the Wittig Rearrangement of -Butyl-2-benzyloxybenzamides to Synthesis of Phthalide Natural Products and 3-Aryl-3-benzyloxyisoindolinone Anticancer Agents.

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

Further Studies on the [1,2]-Wittig Rearrangement of 2-(2-Benzyloxy)aryloxazolines.

The behaviour of 14 ortho-functionalised 2-aryloxazolines (11 of them prepared and characterised for the first time) with butyllithium has been examined. Significant limitations to the Wittig rearrangement of such systems are revealed. In terms of asymmetric Wittig rearrangement, good diastereoselectivity is obtained with a valine-derived 4-isopropyl oxazoline, but this is compromised by racemisation upon hydrolysis.

Access to Diarylmethanols by Wittig Rearrangement of , , and Benzyloxy--Butylbenzamides.

The -butyl amide group, CONHBu, has been found to be an effective promoter of the [1,2]-Wittig rearrangement of aryl benzyl ethers and thus allow the two-step synthesis of isomerically pure substituted diarylmethanols starting from simple hydroxybenzoic acid derivatives. The method is compatible with a wide range of functional groups including methyl, methoxy, and fluoro, although not with nitro and, unexpectedly, is applicable to as well as and isomeric series.