Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, September 2, 2019
Douglass F. Taber
University of Delaware

The Hsieh Synthesis of Palhinine A

Palhinine A (3) is a Lycopodium alkaloid isolated from the club moss Palhinhaea cernua. Hsing-Pang Hsieh of National Health Research Institutes, Taiwan envisioned assembling the tetracyclic skeleton of 3 by the acyl radical cyclization of 1 to 2 (Angew. Chem. Int. Ed. 2018, 57, 15572. DOI: 10.1002/anie.201809130).

The synthesis began with isovanillin (4). Allylation followed by Claisen rearrangement led to 5, that was silylated, then reacted with acetonitrile to give 6. Reduction of the nitrile followed by Boc protection delivered 7, that was converted to 8 by hydroboration followed by mesylation.

The cyclization to form the nine-membered ring of 9 was carried out with NaH. Careful methanol quench of the cyclization mixture allowed selective deprotection of the phenol. Oxidation gave the diene 10, to which acrolein 11 was added to give 12. Selective Wittig reaction protected the aldehyde, allowing deoxygenation and reduction. Hydrolysis then led to 1, setting the stage for cyclization to 2.

Oxidation of 2 gave the diketone 13, that was deprotected and N-methylated to complete the synthesis of palhinine A (3). It is instructive to compare this synthesis of 3 with those previously reported, including that by Fan (The Fan Synthesis of Palhinine A 2017, November 6).

D. F. Taber, Org. Chem. Highlights 2019, September 2.