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Organic Chemistry Highlights

Total Synthesis

Monday, November 6, 2017
Douglass F. Taber
University of Delaware

The Fan Synthesis of Palhinine A

Palhinine A (3), a tetracyclic Lycopodium alkaloid isolated from Palhinhaea cernua, the nodding clubmoss of the American Southeast, contains a strained nine-membered ring. Chun-An Fan and co-workers of Lanzhou University observed (J. Am. Chem. Soc. 2017, 139, 4282. DOI: 10.1021/jacs.6b13401) that the transannular interactions of this ring prohibited direct construction either by SN2 displacement or by ring-forming metathesis. As an alternative, they relied on a temporary additional connection, cyclizing the nitrone 1 to the pentacyclic 2.

The preparation of 1 followed their earlier report (Org. Lett. 2012, 14, 3696. DOI: 10.1021/ol301534r). Alkylation of 4 with 5 followed by oxidation gave the enone 6. Sakurai addition of 7 followed by oxidative cleavage of the alkene led to the aldehyde 8, that was coupled with 9 to give 10. Intramolecular Diels-Alder cycloaddition of the derived triene 11 led, after silyl group removal, selective ketalization and oxidation, to the aldehyde 12.

Debenzylation of 12 followed by methylenation and oxidation led to 13, that was carried on to the nitrone 1. The cyclization of 1 to 2 was best carried out in o-dichlorobenzene under microwave irradiation. The structure of the crystalline product 2 was established by x-ray crystallography.

The dipolar cycloaddition proceeded with high diastereoselectivity, but led to the relative configuration opposite to that of the natural product. Methylation of 2 followed by reductive cleavage gave 14. Oxidation followed by regio- and diastereoselective reduction led, after deprotection, to palhinine A (3).

The synthesis reported here was of racemic 3. The absolute configuration of the final product was established in the conjugate allylation of 6. It is noteworthy that the catalytic enantioselective allylation of 6 has already been described (J. Org. Chem. 2011, 76, 7614. DOI: 10.1021/jo2013753).

D. F. Taber, Org. Chem. Highlights 2017, November 6.