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Organic Chemistry Highlights

Total Synthesis

Monday, December 7, 2015
Douglass F. Taber
University of Delaware

The Ding Synthesis of Steenkrotin A

Steenkrotin A (3) was isolated from Croton steenkampianus Gerstner, widely used in folk medicine for the treatment of coughs, fever, malaria and rheumatism. Hanfeng Ding of Zhejiang University envisioned (Angew. Chem. Int. Ed. 2015, 54, 6905. DOI: 10.1002/anie.201502034) that the intriguingly compact core of 3 could be assembled by reductive cyclization of the aldehyde 1 to 2, followed by intramolecular aldol condensation.

The diastereoselective assembly of 1 from the cycloheptenone core 4 depended on the conformational preferences of the seven-membered ring. Enol ether formation followed by Rubottom oxidation led to the silyl ether 5. Oxidative rearrangement of the tertiary alcohol generated by 1,2-addition to 5 of in situ-generated allyl lithium established the enone 6. Again taking advantage of the conformational preference of the seven-membered ring, cyclopropanation of the silyl enol ether derived from 6 proceeded across the open face of the electron-rich alkene to give 7.

The other oxygenated quaternary center of 1 was constructed by O-alkylation of 7 with diazo malonate followed by methylation and reduction. Acetylation of the diol 8 proceeded with 10:1 diastereoselectivity, to give, after oxidation, the aldehyde 9.

In the first of a sequence of three intramolecular bond-forming reactions, cyclized the aldehyde onto the endocyclic alkene, and also freed the alcohol, that was alkylated with the dibromide 10 to give 11 as a 1.5:1 mixture of diastereomers. On exposure to SmI2, the major diastereomer cyclized to give a intermediate that was carried on to 1. The minor diastereomer was merely reduced, to a product that could be recycled to 11.

With 1 in hand, the stage was set for the second intramolecular cyclization. Even though 1 was predominantly in the lactol form, there was enough of an equilibrium concentration of aldehyde present for the SmI2-mediated cyclization to proceed smoothly to 2.

With 2 in hand, in addition to the last intramolecular cyclization, the two stereogenic centers marked by (*) had to be inverted. The methyl group adjacent to the ketone was readily equilibrated. The secondary alcohol could be inverted by late-stage oxidation and reduction, and the authors did do that. However, they also observed a small amount of the desired epimeric alcohol 14 from the intramolecular aldol reaction of 12. Reasoning that the epimerization arose from the intermediacy of the aldehyde 13, the authors carefully optimized conditions to maximize the formation of 14. LiOH-mediated elimination then completed the synthesis of Steenkrotin A (3).

For convenience, this synthesis was carried out beginning with racemic 4, but the individual enantiomers of 4 are readily available (Tetrahedron Lett. 1999, 40, 4199. DOI: 10.1016/S0040-4039(99)00711-X).

D. F. Taber, Org. Chem. Highlights 2015, December 7.