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Organic Chemistry Highlights

Total Synthesis

Monday, November 7, 2016
Douglass F. Taber
University of Delaware

The Yokoshima/Fukuyama Synthesis of Lycopalhine A

Lycopalhine A (3) was isolated from the staghorn clubmoss Palhinhaea cernua, used in traditional Chinese herbal medicine for the treatment of contusions, scald, and rheumatism. Satoshi Yokoshima and Tohru Fukuyama of Nagoya University envisioned (Org. Lett. 2016, 18, 1494. DOI: 10.1021/acs.orglett.6b00338) the assembly of the central framework of 3 by the rearrangement of 1 to 2.

The starting point for 1 was the triol 4. Following the published procedure (Tetrahedron Asymmetry 2000, 11, 4171. DOI: 10.1016/S0957-4166(00)00368-2), monosilylation followed by lipase-mediated acetylation with 5 led to 6 in high ee. The enone 7 was iodinated, and the resulting α-iodoenone was coupled with the alkyl borane 8 to give 9. Reduction followed by the Johnson modification of the Claisen rearrangement gave 10, that was carried on to the α-diazo β-keto ester 11.

Cu-mediated cyclization of 11 to 12 established the second carbocyclic ring of 3, including the all-carbon quaternary center. Saponification of the ester followed by coupling with the arenesulfonamide and then desilylation gave 13, that was oxidized to 1. In situ, β-elimination of the dicarbonyl-stablized anion followed by proton transfer and intramolecular conjugate addition gave 2.

The N-sulfonyl amide 2 was still lacking three of the carbon atoms of 3. The first was attached by global reduction, followed by protection of one of the alcohols along with the hemiaminal as the acetonide. Mesylation of the other alcohol followed by displacement with cyanide delivered the nitrile 14. The next stereogenic center was established by the addition of the allyl silane 15 to the open face, leading to 16.

In the course of the transformation of 16 to 17, the aldehyde from the reduction of the nitrile underwent epimerization followed by intramolecular aldol reaction. Deprotection of 17 led to a diamine that condensed with the aldehyde to give the desired aminal 18. Deprotective transesterification then completed the synthesis of lycopahline A (3).

It is instructive to compare this synthesis of lycopalhine A (3) to the complementary approach described in Alkaloid Synthesis: Coccoline (Kurkin), Decrusivine (Xia), Grandilodine C (Nishida), Lycopalhine A (Trauner), Daphenylline (Yokoshima/Fukuyama), Communesin F (Movassaghi) 2016, October 31.

D. F. Taber, Org. Chem. Highlights 2016, November 7.