Vinylcyclopropane (5+2) cycloaddition

Vinylcyclopropane (5+2) cycloaddition is a type of cycloaddition between a vinylcyclopropane (VCP) and an olefin or alkyne to form a seven-membered ring.

Examples of thermal VCP (5+2) cycloaddition are relatively rare, but still feasible in certain cases.^[1] However, vinylcyclopropanes readily undergo formal (5+2) processes catalyzed by transition metal complexes. Since the initial report of a rhodium-catalyzed VCP (5+2) cycloaddition from Paul A. Wender's research group,^[2] other reaction protocols have been developed with transition metal complexes of rhodium,^[3] ruthenium,^[3] iron,^[4] nickel,^[5] iridium^[6] and other metals.

Mechanism

Thermal reactions

Vinylcyclopropanes can undergo formal (5+2) cycloadditions with highly activated dienophiles such as tetracyanoethylene (TCNE).^[1] The proposed reaction mechanism involves an initial [2+2] cycloaddition between the vinylcyclopropane and TCNE, followed by rearrangement to furnish the seven-membered ring in the product. Evidences have shown that depending on the reaction conditions, the rearrangement step can occur via either radical or ionic intermediates.^[7]

Facile (5+2) cycloaddition is also observed when the vinylcyclopropane moiety is part of a strained heterobicyclic system. A zwitterionic intermediate is proposed for this reaction.^[8]

Metal-Catalyzed reactions

Rhodium-catalyzed reactions

In his initial disclosure, Paul Wender proposed a cyclometalation mechanism for Rh-catalyzed VCP (5+2) cycloaddition,^[2] which is similar to Trost's mechanistic proposal for Ru-catalyzed reactions (see next section). However, DFT calculation studies by Kendall Houk and co-workers suggested a different mode of action in intermolecular cases.^[9][10][11] The Rh-VCP complex first undergoes a C-C bond activation event to form a rhodium π-allyl complex, a process that can be best visualized as the conceptual equivalent of cyclometalation with a diene. Subsequent alkyne coordination followed by 1,2-migratory insertion and reductive elimination affords the heptadiene product.

Ruthenium-catalyzed reactions

Barry M. Trost and co-workers proposed a mechanism for Ru-catalyzed VCP (5+2) cycloaddition that is slightly different from its rhodium counterpart.^[12] Cyclometalation of the ruthenium complex with the enyne takes place first to form a ruthenacyclopentene intermediate with a pendant cyclopropane ring. Subsequent C-C bond activation, which can be viewed as conceptually analogous to tautomerization of metal π-allyl complexes, and reductive elimination afford the final product.

Reaction scope

Intramolecular (5+2) cycloaddition of VCP with a tethered alkyne,^[2] alkene,^[13] or allene^[14] have been reported.

Examples of intermolecular VCP cycloaddition with alkynes were also reported. However, a heteroatom substituent (e.g. a siloxy group)^[15] or a sterically bulky group^[16] on the vinylcyclopropane is usually required.

Other variants

Asymmetric (5+2) cycloaddition

An enantioselective version of the reaction was reported by Wender et al in 2005, featuring a Rh-BINAP catalyst that induces up to >99% enantiomeric excess.^[17]

Bridged (5+2) cycloaddition

Yu and co-workers reported a unique variant of the reaction that preferentially forms bridged bicyclic compounds.^[18]

Tandem allylic alkylation/(5+2) cycloaddition

Martin and co-workers developed an allylic alkylation/(5+2) cycloaddition sequence that forms the enyne precursor in situ with Tsuji-Trost allylic substitution chemistry.^[19][20]

Applications in total syntheses

Metal-catalyzed VCP (5+2) cycloaddition has found applications in the total syntheses of a variety of molecules such as (+)-dictamnol,^[21] (+)-aphanamol I,^[22] (+)-allocyathin B₂^[23] (–)-pseudolaric acid B,^[24][25] and (+)-frondosin A.^[26]

See also

• Cycloaddition
• Cyclopropane
• Vinylcyclopropane rearrangement