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Organic Chemistry Highlights

Total Synthesis

Monday, April 5, 2021
Douglass F. Taber
University of Delaware

The Shenvi Synthesis of Picrotoxinin

Picrotoxinin (3), isolated from the fruit of the Southeast Asian climbing plant Anamirta cocculus, exhibits useful therapeutic properties - chronic dosing of Down syndrome model mice at sublethal concentrations normalizes memory performance. Ryan A. Shenvi of Scripps/La Jolla began with dimethyl carvone 1, requiring the removal of the extra methyl group from 2 to arrive at 3 (J. Am. Chem. Soc. 2020, 142, 11376. DOI: 10.1021/jacs.0c05042).

The ketone 1 was prepared from commercial carvone (4) by sequential methylation. With the two methyl groups in place, aldol reaction with 5 followed by dehydration led predominantly to the desired diastereomer 6. On exposure to base, the ester 6 cyclized to the crystalline triene 7. In the derived bromoether 8 the axial methyl group blocked one face of the cyclopentene, so epoxidation led to 9.

Even with stoichimetric OsO4, osmylation of the congested alkene of 9, leading to the lactone 2, required seven days at room temperature. A series of oxidation steps ensued, to remove the superfluous methyl group. Iodination led to the cyclic ether 10, that was oxidized with trifluoromethyl methyl dioxirane to the lactol 11. Suarez fragmentation led to the iodide 12, that on free radical reduction followed by transesterification gave the des-methyl alcohol 13. More vigorous oxidation of 13 gave the lactone, that was reduced with zinc to picrotoxinin (3).

The approach outlined here opens ready access to structural variation. Mukaiyama hydration of 3 delivered picrotin (14). Direct oxidation of 2 followed by reduction led to the methylated analogue 15 of picrotoxinin, that also showed antagonism of the GABAA receptor.

Jeffrey I. Seeman of the University of Richmond ( has devoted much of his career to gathering the history of organic chemistry. He has assembled many interesting stories, as did D. Stanley Tarbell and Ann Tracy Tarbell of Vanderbilt University (J. Chem. Educ. 1977, 54, 26. DOI: 10.1021/ed054p26) before him.

D. F. Taber, Org. Chem. Highlights 2021, April 5.