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Organic Chemistry Highlights

Total Synthesis

Monday, July 1, 2013
Douglass F. Taber
University of Delaware

The Kuwahara Synthesis of Paspalinine

The hexacyclic indole diterpenoid Papalinine (3), produced by the ergot Claviceps paspali, induces tremors in domestic animals that graze on pasture grass infected by that fungus. Shigefumi Kuwahara of Tohoku University envisioned (Angew. Chem. Int. Ed. 2012, 51, 12833. DOI: 10.1002/anie.201206299) assembly of the tetracylic nucleus of 3 by the oxidative cyclization of 1 to 2. The challenge, then, was the assembly of the angularly-substituted trans-anti-trans 6-6-5 alicyclic nucleus of 1.

The synthesis began with the Wieland-Miescher ketone (4), which is available commercially in enantiomerically-pure form. Exposure to ethylene glycol under acidic conditions converted 4 to the known monoketal 5. The alkylation with 6 followed by selective hydrolysis gave 7 as an inconsequential mixture of diastereomers. Exposure to base effected both equilibration to the more stable equatorial diastereomer and cyclization, to give the enone 8.

There was still the problem of the introduction of the axial angular methyl group. This was solved by selective reduction of 8 to the endo alcohol. Hydroxyl-directed Simmons-Smith cyclopropopanation followed by oxidation gave 9. The enolate resulting from the dissolving metal reduction of 9 was trapped with Comins reagent to generate the enol triflate 10.

Acetanilide 11 was converted to the stannane 12 by ortho metalation, following the literature protocol. Pd-mediated coupling of 12 with 10 proceeded efficiently, to give 1. Oxidation with stoichiometric Pd trifluoroacetate then induced Type 5 indole formation (Tetrahedron 2011, 67, 7195. DOI: 10.1016/j.tet.2011.06.040). Hydrolysis and conjugation completed the synthesis of 2.

To introduce the side chain, the enone was converted to the allyl enol carbonate. Pd-mediated rearrangement converted that to the α-allyl enone, which participated in Ru-catalyzed metathesis with 14 to give 15. Asymmetric dihydroxylation proceeded with only modest diastereoselectivity, but only the desired diastereomer cyclized onto the ketone, to give 16.

The ketone 16 was an intermediate in Smith’s earlier synthesis. Professor Kuwahara devised an alternate end game, selenylation followed by oxidation and sigmatropic rearrangement, to install the axial OH and complete the synthesis of Paspalinine (3).

D. F. Taber, Org. Chem. Highlights 2013, July 1.