Wipf et al.22 reported thiol additions to the highly
functionalized core structures of aranorosin and manumycin-type antibiotics reveal
the general reactivity patterns of epoxyketone natural products. Rapid
hemiacetal and hydrate formations decrease the reactivity of the epoxyketone
moiety in aqueous media toward the cellular scavenger glutathione and secondary
1,2-shift, elimination, aromatization and intramolecular aldol reactions
provide novel reaction pathways. In a hydrophobic environment, the thiol capture
function of the ketone moiety facilitates electrophilic attack. Aranorosin core
(10)23 with thiophenol
immediately revealed an unexpected and novel reaction pathway. In the presence
of 5 equiv. of thiophenol in THF, a complex mixture of products was rapidly
formed and was converted upon addition of solid sodium carbonate into a major
compound, bicyclo[3.3.1]nonane (11)
in 71% yield. A hypothesis for the reaction pathway is shown in Scheme 3.
Sequential opening of the epoxide rings and aldol dehydration provided 12, which underwent a base-catalyzed
intramolecular aldol reaction to the lactol/aldehyde function. The new C-C bond
was formed stereoselectively and only the thermodynamically more favored
diastereomer (11) was isolated. Due
to enolate chemistry of aranorosin- and manumycin-type epoxyquinols include
elimination, aromatization, and intramolecular aldol reactions that ultimately
provide new scaffolds with very stable carbon-sulfur linkages.
 |
___________
22. P. Wipf, P. Jeger, Y. Kim, Bioorg. Med. Chem. Lett., 1998, 8, 351.
23. P. Wipf, and Y. Kim, J. Org. Chem., 1993, 58, 1649.
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