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Organic Chemistry Highlights

Total Synthesis

Monday, November 2, 2015
Douglass F. Taber
University of Delaware

The Johnson Synthesis of Paspaline

Paspaline (3), isolated from the ergot fungus Claviceps paspali, is a Maxi-K channel antagonist, and so a potential lead for the treatment of Alzheimer's disease. The selective C-H functionalization that converted 1 to 2 was a key step in the synthesis of 3 reported (J. Am. Chem. Soc. 2015, 137, 4968, DOI: 10.1021/jacs.5b02631; J. Org. Chem. 2015, 80, 9740, DOI: 10.1021/acs.joc.5b01844) by Jeffrey S. Johnson of the University of North Carolina.

The prochiral diketone 4 was the starting point for the assembly of 1. Selective reduction with a commercial strain of yeast set both the relative and the absolute configuration of 5. The ketone interfered with the subsequent acid catalyzed cyclization of the epoxy alcohol, so it was protected as the tosylhydrazone. This set the stage for the direct Bamford-Stevens conversion to the fully-substituted alkene 7.

Ireland-Claisen rearrangement of the isobutyrate derived from 7 proceeded with substantial preference for the equatorial diastereomer 8. This was carried on to the methyl ketone 9. Hydroboration of 9 showed substantial axial preference, to deliver, after oxidation, the equatorial aldehyde 10. Intramolecular aldol condensation followed by hydrogenation and benzyl oxime formation then completed the preparation of 1.

Intramolecular Pd-catalyzed acetoxylation has been extensively studied by Sanford (Org. Lett. 2010, 12, 532. DOI: 10.1021/ol902720d) The Sanford conditions, carried out on a gram scale, converted 1 into the equatorial diastereomer 2 with remarkable diastereoselectivity. The final carbocyclic ring was then added by vinyl Grignard addition to the derived keto aldehyde 12. Grubbs cyclization gave 13, that on exposure to acid rearranged to the enone 14. Reduction of the ketone occurred from the open face to give an alcohol that then directed hydrogenation from the opposite face, leading to the desired trans-fused ketone. Sulfenylation then completed the synthesis of the ketone 15.

At this point, the authors followed Smith (J. Am. Chem. Soc. 1985, 107, 1769. DOI: 10.1021/ja00292a058) in using the Gassman protocol (J. Am. Chem. Soc. 1974, 96, 5495. DOI: 10.1021/ja00824a028) to construct the indole. Amination of the sulfur of 15 with N-chloroaniline gave the sulfonium salt, that on exposure to Et3N rearranged to 16. Reductive desulfurization followed by cyclization completed the synthesis of Paspaline (3).

D. F. Taber, Org. Chem. Highlights 2015, November 2.