Synthesis of sanshools and related compounds

Abstract

Sanshools are naturally occurring aliphatic acid amide compounds found within plants from Zanthoxylum genus, the prickly ash genus of the rue family (Rutaceae). Sichuan pepper is produced by a widely distributed aromatic spiny shrub member of Zanthoxylum Piperitum, and is a very commonly used spice in Asian cuisine and traditional folk medicine. Sanshool compounds have been known to cause a tingling or numbing sensation when consumed. These unique qualities have stimulated interest in a wide range of research from their underlying mode of action to their applications in food flavoring, analgesic drugs to insecticides, etc. Sanshools, together with their close relatives, the bungeanools, have been obtained from plants for characterization and research purposes. However, their isolation is expensive, tedious and low yielding. Thus, their chemical synthesis has become essential. In this thesis, we have designed synthetic routes towards the sanshools and the related bungeanools, and the analogs IBA and hydroxy-IBA. Firstly, hydroxy-γ-sanshool and dihydrobungeanool were synthesized from a key common phosphonium salt intermediate using Wittig reactions involving appropriate aldehydes. Hydroxy-γ-sanshool was synthesized via this route using sorbaldehyde. The intermediate (2E,4E,8Z,10E,12E)-tetradeca-2,4,8,10,12-pentaenoic acid of was crucial because it could be recrystallized to high level of stereochemistry before the final amidation step. However, (2E,4E,8Z)-tetradeca-2,4,8-trienoic acid could not be recrystallized to purity , and the dihydrobungeanool obtained was a mixture of isomers. Secondly, the synthesis of sanshool analogues IBA and hydroxy-IBA was accomplished. The synthesis started with the Wittig reaction between two commercially available starting materials, an aldehyde and an ylide. This was followed by hydrolysis of an ester group to yield (2E,4E,8Z)-undeca- 2,4,8-trienoic acid intermediate that could be converted to both IBA and hydroxy-IBA. However, the IBA and hydroxy-IBA prepared were mixtures of isomers due to an inability of the carboxylic acid intermediate to recrystallized to purity. Thirdly, considering the issues regarding the impure intermediates due to the inability of the corresponding carboxylic acids to be recrystallized to highest purity, we successfully designed an alternative route for synthesizing IBA, hydroxy-IBA and dihydrobungeanool in high stereochemical purity. The synthesis of IBA and hydroxyIBA started with using a commercially available aldehyde in a Corey-Fuchs reaction. On the other hand, the required starting aldehyde for dihydrobungeanool was synthesized via catalytic hydrogenation to reduce an alkyne to a Z-alkene in order to ensure unambiguous stereochemistry. Overall in this project, we have successfully synthesized hydroxy-γ-sanshool, dihydrobungeanool, IBA and hydroxy-IBA, all with high levels of stereochemical purity. This research should greatly increase their availability, and it is our hope that this will facilitate future studies of such compounds.