Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, May 4, 2015
Douglass F. Taber
University of Delaware

The Snyder Synthesis of Psylloborine A

In addition to the monomeric coccinellid alkaloids produced by the ladybug, some dimeric alkaloids, exemplified by Psylloborine A (3), have been isolated. Scott A. Snyder of Scripps/Florida initially attempted a direct dimerization strategy for the assembly of 3, but when that failed, he devised (J. Am. Chem. Soc. 2014, 136, 9743. DOI: 10.1021/ja5045852) a route to the tethered dimer 1, that could indeed be cyclized to 2, the immediate precursor to 3.

The starting material for both 9, the lower half of 1, and 13, the upper half of 1, was the commerical enantiomerically-pure piperidine 4. Metalation followed by allylation gave the desired trans diastereomer 5. Oxidative cleavage followed by condensation with 6 gave the ester 7, that was hydrogenated, then converted with 8 to the desired phosphonate 9.

To prepare 13, 4 was metalated and alkylated with methallyl bromide. The product 10 was carried on to the enone 12 by oxidative cleavage followed by the addition of 11, oxidative cleavage, and dehydration. Reduction to the desired diastereomer was achieved by conjugate addition of hydride in the presence of the sterically very demanding Yamamoto Lewis acid ATPH. Deprotection followed by oxidation then gave 13, that was condensed with 9 and deprotected to give 14. Selective deprotection followed by Swern oxidation and condensation with 15 then led to 1.

A key element in the design of this synthesis was the ability to easily tune the sulfone activating group, to direct the proper order of bond formation. The vision was that regeneration of the enone and deprotection, with tetramethylguanidine, would lead to 16. The free amine would add to the saturated ketone to give an enamine, that would in turn add in a conjugate sense to the enone to give 17. Further deprotection of 17 under acid conditions would again generate an enamine, that, it was hoped, would, after further cyclization, add to the unsaturated sulfone to give 2. As illustrated, the 3,5-bis(trifluoromethyl)phenyl sulfone gave the best results. Desulfurization of 2 completed the synthesis of the complex dimeric alkaloid Psylloborine A (3).

D. F. Taber, Org. Chem. Highlights 2015, May 4.