Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

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

The Shen/Yang/Hao Synthesis of Perforanoid A

Yuemao Shen of Shandong University, Zhen Yang of the Peking University Shenzhen Graduate School and Xiaojiang Hao of the Kunming Institute of Botany isolated (Angew. Chem. Int. Ed. 2016, 55, 7539. DOI: 10.1002/anie.201602783) the cytotoxic limonoid perforanoid A (3) from the shrub Harrisonia perforata. To confirm the structure, and to assign the relative configuration of the acyclic stereogenic center (C-10), they envisioned a total synthesis, centered on the Rh-catalyzed cyclocarbonylation of 1 to 2.

The assembly of the pendant lactone began with the conjugate addition of the crotyl Grignard reagent 5 to the lactone 4, to give 6 as a mixture of diastereomers. After ozonolysis and TBDPS protection, the lactone 7 was opened with dimethyl amine. At this point, the diastereomers could be separated by chromatography. The alcohol 8 was oxidized, and methyl magnesium chloride was added to the resulting methyl ketone to give the lactone 9. Deprotection followed by oxidation with DMP completed the preparation of 10.

The construction of 1 began with the enantioselective addition of 2-butyne to 3-furfural (11). Pd-catalyzed cyclization of the alcohol 12 with the enol ether 13 led to 14 as the expected mixture of diasteromers. After the sidechain was extended, oxidation gave the lactone 15. Methoxycarbonylation followed by coupling with the reagent 16 led through the alkynyl ester (not illustrated), that on heating with LiCl in DMF was converted to the desired allene 9. The modified Pauson-Khand cyclocarbonylation required some optimization, but eventually delivered 2 in good yield and as a single dominant diastereomer.

The coupling of 2 with 10 presumably gave the alcohol 17 as a mixture of diastereromers. Nevertheless, dehydration of that mixture delivered perforanoid A (3) as the desired E geometric isomer.

Remarkably, while 3 is cytotoxic at 4-25 µM, 10-epi 3 shows no cytotoxicity at >50 µM. If 10-epi 3 maintains the antibacterial and antimalarial activity associated with these limonoids, that lack of cytotoxicity could be advantageous.

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