Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 30, 2010
Douglass F. Taber
University of Delaware

Tethered Diels-Alder Cycloaddition: ()-Neovibsanin B (Imagawa, Nishizawa), Valerenic Acid (Mulzer), (-)-Himandrine (Movassaghi), ()-Pallavicinolide A (Wong), (+)-Phomopsidin (Nakada)

It has generally been observed that prospective intramolecular Diels-Alder cycloadditions that would form a γ-lactone are reluctant to proceed. In the course of a synthesis of ()-Neovibsanin B (4), Hiroshi Imagawa and Mugio Nishizawa of Tokushima Bunri University reversed (Org. Lett. 2009, 11, 1253. DOI: 10.1021/ol802973f) the usual connectivity, and found that the dienyl ester 1 could be induced to cyclize to 3. The solvent 2 improved both the yield and the diastereoselectivity of the cycloaddition.

It was not surprising that Johann Mulzer of the University of Vienna could see (Org. Lett. 2009, 11, 1151. DOI: 10.1021/ol9000137) no evidence of cyclization on heating the acrylate 5. In contrast, following the lead of Barriault, they found that MgBr2-tethered cycloaddition of methyl acrylate (7) with the alcohol 6 proceeded smoothly, to give 8, that they carried on to Valerenic Acid (9).

Intramolecular Diels-Alder reactions to form 6,6-systems are often facile. Mohammad Movassaghi of MIT, en route to (-)-Himandrine (12), showed (J. Am. Chem. Soc. 2009, 131, 9648. DOI: 10.1021/ja903790y) that the tetraene 10 cyclized to 11 at 95C with 5:1 dr. In this case the solvent was the more typical acetonitrile with 10% diethyl aniline.

The intramolecular Diels-Alder reaction is concerted but non-synchronous (Tetrahedron Lett. 1981, 22, 5141. DOI: 10.1016/S0040-4039(01)92442-6), with β-bond formation preceding α-bond formation. This contributes to the reluctance of 8 to cyclize. In contrast, Henry N. C. Wong of the Chinese University of Hong Kong observed (Angew. Chem. Int. Ed. 2009, 48, 2351. DOI: 10.1002/anie.200806335) that the tetraene 13, that is polarity matched, cyclized to 14 spontaneously as soon as it was formed. Functional group conversion completed the synthesis of ()-Pallavicinolide A (15).

The transannular Diels-Alder (TADA) reaction can proceed with high diastereocontrol, but the factors directing these cyclizations are not completely understood. In the course of a synthesis of (+)-Phomopsidin (18), Masahisa Nakada of Waseda University found (Tetrahedron 2009, 65, 888. DOI: 10.1016/j.tet.2008.11.030) that 16 led to 17 with 16:1 dr. In contrast, the triene epimeric to 16 at the silyloxy group cyclized with only 2:1 dr.

D. F. Taber, Org. Chem. Highlights 2010, August 30.