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Monday, August 22, 2005
Douglass Taber
University of Delaware

Enantioselective Ring Construction by Intramolecular C-H Insertion and by Cycloaddition

The prochiral aziridine 1 is easily prepared from cyclooctene. Paul Müller of the University of Geneva has shown (Helv. Chim. Acta 2004, 87, 227. ) that metalation of 1 in the presence of the chiral amine sparteine leads to the bicyclic amine 3 in 75% ee, by way of intramolecular C-H insertion by the intermediate chiral carbene 2. The sparteine can be recovered and recycled.

As exemplified by the recent synthesis of (+)-trehazolin (7) by Susumu Ohira of Okayama University of Science (Tetrahedron Lett. 2004, 45, 7133. ), carbenes can also be conveniently generated by exposure of ketones such as 4 to lithiated TMS diazomethane. Intramolecular C-H insertion then proceeds with high diastereoselectivity, to give 6, a key intermediate on the way to 7.

The central role of the Diels-Alder reaction as a workhorse for carbocyclic construction has driven the development of effective chiral catalysts. The state of the art is represented by the catalyst 9, developed (J. Am. Chem. Soc. 2004, 126, 13708. ) by E.J. Corey of Harvard University. This catalyst is effective with a range of dienes and dienophiles, as illustrated by the combination of 8 and 10 to give the endo adduct 11 in high de and ee. The acid corresponding to 11 was a key starting material for the Aubé synthesis of 12, the Dentrobatid alkaloid 251F.

Cyclopentadiene Diels-Alder adducts such as 11 are highly strained. Huw M.L. Davies of the State University of New York, Buffalo, has established (J. Am. Chem. Soc. 2004, 126, 2692. ) an important strategic connection between Diels-Alder adducts such as 13 and the enantiomerically-enriched cyclohexane derivative 14. Oxidative cleavage of the alkene of 14 would lead to a cyclohexane derivative that would be difficult to access by other means. The same adduct 14 (albeit in racemic form) is also available directly by AlCl3-mediated addition of methacrolein 15 to cyclopentadiene.

D. F. Taber, Org. Chem. Highlights 2005, August 22.