Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 29, 2011
Douglass F. Taber
University of Delaware

Intramolecular Diels-Alder Cycloaddition: Brombyin II (Lygo), Ptilocaulin (Livinghouse), Bistellettadine A (Snider), (-)-Pycnanthuquinone C (Trauner), (+)-Caribenol A (Li/Yang)

The biosynthesis of Brombyin III (2) and Brombyin II (3), racemic in their natural form, might logically be expected to proceed by thermal cyclization of 1. Barry Lygo of the University of Nottingham observed (Synlett 2010, 618. DOI: 10.1055/s-0029-1219158) that the cyclization of 1 in toluene required 165C. It is intriguing that on water in the presence of the detergent SDS, the cyclization proceeded smoothly at only slightly above ambient temperature.

Intramolecular Diels-Alder cycloaddition can also be promoted by transition metal catalysis. Tom Livinghouse of Montana State University optimized (Synlett 2010, 247. DOI: 10.1055/s-0029-1218572) a Rh catalyst for the diastereoselective cyclization of the highly-substituted Z-triene 4 to 5, setting the stage for the synthesis of Ptilocaulin (6).

It seemed plausible that the biosynthesis of Bistellettadine A (9) was proceeding by intermolecular dimerization of the monomeric carboxylic acid corresponding to 7. Barry B. Snider of Brandeis University found (Org. Lett. 2010, 12, 828. DOI: 10.1021/ol902895e) that that intermolecular dimerization did proceed efficiently, but to give a 5:4 mixture of diastereomers. In contrast, the linked diester 7 cyclized with exclusive diastereocontrol. The product 8 was readily carried on to Bistellettadine A 9. This raises the possibility that a chiral template, attached either covalently or through salt formation, could be designed that would direct the absolute configuration of the cycloaddition.

It also seemed plausible that (-)-Pycnanthuquinone (13) could be derived biosynthetically by cycloaddition of a triene (12), with one of the alkenes of the diene incorporated in a quinone. Dirk Trauner of the University of Munich prepared (Angew. Chem. Int. Ed. 2010, 49, 6199. DOI: 10.1002/anie.201001862) 12 by Heck coupling of the bromide 10 with commercial linalool (11). In mixed water/toluene, the cyclization was followed by the addition of water and reoxidation, to directly deliver (-)-Pycnanthuquinone (13). Related quinone cycloadditions have been reported (Org. Lett. 2010, 12, 5554, DOI: 10.1021/ol102438r; Tetrahedron Lett. 2010, 51, 5116, DOI: 10.1016/j.tetlet.2010.07.109).

Chuang-Chuang Li of the Shenzhen Graduate School and Zhen Yang of Peking University anticipated (J. Am. Chem. Soc. 2010, 132, 13608. DOI: 10.1021/ja106585n) that it would be possible to prepare (+)-Caribenol A (16) by the cyclization of the alkyne 14. Direct thermal cyclization of 14 was not effective, nor were Lewis acid catalysts. Thermal cyclization in the presence of BHT, in contrast, proceeded smoothly to give the desired 15. In other contexts, methylene blue and solvent diethylaniline have successfully promoted such cyclizations.

D. F. Taber, Org. Chem. Highlights 2011, August 29.