Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 26, 2007
Douglass F. Taber
University of Delaware

Synthesis of (-)-Blepharocalyxin D, (-)-Lasonolide A, and Attenol A

Blepharocalyxin D (3), isolated from the seeds of Alpinia blepharocalyx, shows antiproliferative activity against murine colon 36-L5 carcinoma in cell culture. A key step in the first synthesis of 3, reported (Org. Lett. 2007, 9, 141. DOI: 10.1021/ol0627956) by Eun Lee of Seoul National University, was the Prins-pinacol rearrangement of 1 to 2. Remarkably, the axial aldehyde was the dominant kinetic product from the cyclization. This could be equilibrated to the equatorial aldehyde, which was then carried on to 3.

Lasonolide A (8), isolated from the Caribbean marine sponge Forcepia sp., showed potent antineoplastic activity, with IC50 values of 8.6 nM and 89 nM against A-549 human lung carcinoma and Panc-1 human pancreatic cancer. Arun K. Ghosh of Purdue University recently described (Org. Lett. 2007, 9, 1437. DOI: 10.1021/ol0701013) a concise synthesis of 8. The first stage was a clever assembly of the doubly chiral ether of 4. The key reaction was the selective opening at the distal position of a Sharpless-derived epoxide. The preference for the two anomeric alkyl substituents on the incipient tetrahydropyran ring to be equatorial then set the transition state for the cyclization to 5. It is particulary impressive that the alkyated quaternary center of 5 was formed with high diastereocontrol. Further elaboration set the stage for the intramolecular Horner-Emmons cyclization that established the macrocyclic ring of 8.

Attenol A (14), isolated from the Chinese bivalve Pinna attenuata, shows moderate cytotoxic activity against P388 leukemia. Usually, spiro ketals such as 13 are formed under equilibrating conditions. As the anomeric oxygen prefers to be axial on the six-membered ring and the anomeric alkyl group prefers to be equatorial, that diastereomer is usually heavily favored. Scott D. Rychnovsky of the University of California, Irvine has described (J. Org. Chem. 2007, 72, 2602. DOI: 10.1021/jo0626459) a concise convergent synthesis of 14, combining the protected triol 9 and the vinyl ether 10.

There were two tasks to be acccomplished as 9 and 10 were combined and carried forward, establishment of the carbon connectivity of 14, and control of the relative configuration of the spiro ether. First, 9 and 10 were coupled to form the crossed cyanohydrin ether 11. There was no need for stereocontrol at the incipient spiro center, as that center was destroyed in the next transformation. Reductive cyclization then proceeded with selective axial bond formation, to give the kinetically-preferred spiroketal 12. On brief exposure to acid, the spiroketal equilibrated to the more stable 13, that was carried on to Attenol A (14).

This reductive cyclization to kinetically form the less stable spiro ketal, first developed in the Rychnovsky group, is a powerful strategy for the construction of spiroketal natural products, as it opens access selectively to either diastereomer of the spiroketal.

D. F. Taber, Org. Chem. Highlights 2007, November 26.