Enantioselective Ring Construction by Intramolecular C-H Insertion

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

The prochiral aziridine 1 is easily prepared from cyclooctene. Paul Muller 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 15% 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 (-r)-trehazolin 7 by Susumu Ohira of Okayama University of Science Tetrahedron Lett. 2004, 45, 7133), cai-benes 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 Aube 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 cycloheptane 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 AlCl,-mediated addition of methacrolein 15 to cyclopentadiene. 

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Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, /26,8664) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbenc or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol. 

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