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Organic Chemistry Highlights

Total Synthesis

Monday, January 4, 2016
Douglass F. Taber
University of Delaware

The Tang Synthesis of Schilancitrilactone C

Schilancitrilactone C (5), isolated from the traditional Chinese medicinal plant Schisandra lancifolia, was shown to have activity against HIV. Pingping Tang of Nankai University envisioned (Angew. Chem. Int. Ed. 2015, 54, 5732. DOI: 10.1002/anie.201501169) that 5 could be assembled by the triply convergent coupling of the lactone 1 with the aldehyde 2, followed later by the alkenyl stannane 3.

Following a literature procedure, the combination of citraconic anhydride (6) with 7 followed by exposure to acid gave the carboxylic acid 8. Decarboxylative bromination led to 9 with retention of alkene geometry. Pd-mediated coupling then delivered 3.

The preparation of 1 began with epoxidation of carvone followed by oxidative cleavage, to give the keto acid 11. Iodolactonization followed by reduction of the aldehyde to the alcohol and reduction of the iodide led to the alcohol 12, that was carried on to the iodide 1.

The preparation of 2 began with the condensation of the prochiral 13 with Meldrum’s acid (14), following the Trost protocol, to give 15. Methylation followed by decarbomethoxylation by a modified Krapcho protocol led to the volatile lactone 16. Alkylation of 16 with the bromoacetate 17 followed by exposure to acid gave the free acid, that on addition of ethyl magnesium bromide cyclized to the lactone 18. Ozonolysis to the dialdehyde 19 followed by intramolecular aldol condensation completed the assembly of 2.

A ketone related to 1 cyclized smoothly to the cyclobutane on exposure to base (J. Org. Chem. 2005, 70, 6417. DOI: 10.1021/jo0508752). Nevertheless, 1 could be deprotonated at low temperature, then added to the aldehyde 2, to give, after dehydration, the diene 20. Reductive cyclization then led to the deconjugated dilactone 21. The angular hydroxyl group of 4 was installed by epoxidation, followed by β-elimination and reduction of the resulting conjugated alkene. The ketal of 4 could open with acid to the enol ether, so iodine monochloride effected iodination, leading to 22 as an inconsequential mixture of diastereomers. Coupling with 3 then delivered predominantly the diastereomer 5, Schilancitrilactone C.

D. F. Taber, Org. Chem. Highlights 2016, January 4.