title: Synthesis of Cembranoid Analogues through Ring-Closing Metathesis of Terpenoid Precursors: A Challenge Regarding Ring-Size Selectivity.
abstract: A systematic study on ring-closing metathesis with Grubbs II catalyst to cembranoid macrocycles is described. Acyclic terpenoids with a functional group X in the homoallylic position relative to an RCM active terminus and substituents R, R(1) directly attached to the other terminal double bond were prepared from geraniol derived trienes and fragments that are based on bromoalkenes and dimethyl malonate. Such terpenoids were suitable precursors, despite the presence of competing double bonds in their framework. The size of R and R(1) is crucial for successful macrocyclization. Whereas small alkyl substituents at the double bond directed the RCM towards six-membered ring formation, cross metathesis leading to dimers dominated for bulkier alkyl groups. A similar result was obtained for precursors without functional group X. In the case of unsymmetrically substituted terpenoid precursor (R = Et, R(1) = Me) with homoallylic OTBS or OMe group, the RCM could be controlled towards formation of macrocyclic cembranoids, which were isolated with excellent E-selectivity. The role of the substituents was further studied by quantum chemical calculations of simplified model substrates. Based on these results a mechanistic rationale is proposed.
authors.affiliation: Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart (Germany).
authors.forename: Tanja
authors.initials: T
authors.lastname: Heidt
authors.affiliation: Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart (Germany).
authors.forename: Angelika
authors.initials: A
authors.lastname: Baro
authors.affiliation: Institut für Theoretische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart (Germany).
authors.forename: Andreas
authors.initials: A
authors.lastname: Köhn
authors.affiliation: Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart (Germany). sabine.laschat@oc.uni-stuttgart.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Laschat
keywords: macrocycles; metathesis; regioselectivity; substituent effects; terpenoids