Syntheses of Seven‐Membered Rings: Ruthenium‐Catalyzed Intramolecular [5+2] Cycloadditions

Abstract

The Ru-catalyzed intramolecular [5+2] cycloaddition of cyclopropylenynes is investigated with respect to the regio- and diastereoselectivity as well as the functional group compatibility of the reaction. Evidence for the mechanism as occurring through a ruthenacyclopentene intermediate is elucidated from 1) the study of the diastereoselectivity of the cycloaddition; 2) the effect of variation of substituents on the regioselectivity of cyclopropyl bond cleavage in 1,2-trans- and 1,2-cis-disubstituted cyclopropanes and 3) examples that clearly do not involve ruthenacyclohexene as intermediates as products still incorporate the cyclopropyl moiety. The scope and limitations of the Ru-catalyzed cycloaddition are discussed and compared with the Rh-catalyzed reaction. The potential power of this methodology towards natural product total synthesis is demonstrated by the formation of several polycyclic systems with the chosen reaction conditions and readily available cyclopropylenyne substrates.

Transition metals in organic synthesis: Highlights for the year 2005

“…Seven-membered rings were prepared by ruthenium-catalyzed [5 + 2]cycloisomerization of 1-cyclopropyl-6-yne-1-enes (Eq. (285)) [1368]. In contrast nickel catalyzed the formation of five-membered rings from 1-cyclopropyl-6-yne-1-enes (Eq.…”

Recent Developments in the [5+2] Cycloaddition

“…The comparison with the noncatalyzed cycloaddition allowed one to see how the rhodium catalyst transformed a two-step process with high barriers into a multi-step process with lower activation energies. [ 35] This methodology was more recently applied by these authors to the [5 + 2] cycloaddition of cyclopropylenynes such as 45a-l. [36] This study reported the scope of these reactions regarding the functional group tolerance of the reaction, and the length and nature of the tether between alkyne and VCP. A broad range of vinylcyclopropyl-alkyne substrates 45a-l reacted under ambient conditions (room temperature in acetone, DMF or DCE), providing, in the presence of 5-10 mol% of the Ru catalyst, the corresponding cycloadducts 46a-l in high yields.…”

“…[36] As shown in Scheme 25, a series of variously functionalized tricyclic products 54a-i could be synthesized with up to 90% de. These authors have reported another extension of this methodology applied to the development of the first total synthesis of the natural biologically active product, (+)-frondosin A.…”

“…[36] For 1,2-trans-disubstituted cyclopropylenynes or 1,2-cis-disubstituted ones, either the more or the less substituted C À C bond of the cyclopropane could be cleaved to form two possible regioisomeric products. The regioselectivity of the cycloaddition was explored with a variety of trans-and cis-1,2-disubstituted cyclopropylenynes.…”

“…[36] To shed light on this issue, they prepared a range of cycloaddition precursors 47a-g bearing one or more substituents on the carbon tether and subjected them to the Ru-catalyzed [5 + 2] cycloaddition conditions. As shown in Scheme 22, in all cases, good to excellent yields of the desired hydroazulene products 48a-g were obtained despite the presence, in all the substrates, of an ionizable functional group at the allylic position.…”