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]

References

^ ^a ^b Sarel S, Felzenstein A, Yovell J (1973). "Alternative modes of addition of dienophiles to vinylcyclopropane systems". Journal of the Chemical Society, Chemical Communications (22): 859–860. doi:10.1039/c39730000859. ISSN 0022-4936.
^ ^a ^b ^c Wender PA, Takahashi H, Witulski B (1995). "Transition Metal Catalyzed [5 + 2] Cycloadditions of Vinylcyclopropanes and Alkynes: A Homolog of the Diels-Alder Reaction for the Synthesis of Seven-Membered Rings". Journal of the American Chemical Society. 117 (16): 4720–4721. doi:10.1021/ja00121a036. ISSN 0002-7863.
^ ^a ^b Ylijoki KE, Stryker JM (March 2013). "[5 + 2] cycloaddition reactions in organic and natural product synthesis". Chemical Reviews. 113 (3): 2244–66. doi:10.1021/cr300087g. PMID 23153111.
^ Fürstner A, Majima K, Martín R, Krause H, Kattnig E, Goddard R, Lehmann CW (February 2008). "A cheap metal for a "noble" task: preparative and mechanistic aspects of cycloisomerization and cycloaddition reactions catalyzed by low-valent iron complexes". Journal of the American Chemical Society. 130 (6): 1992–2004. doi:10.1021/ja0777180. hdl:11858/00-001M-0000-0024-C2BF-2. PMID 18197669.
^ Zuo G, Louie J (April 2005). "Selectivity in nickel-catalyzed rearrangements of cyclopropylen-ynes". Journal of the American Chemical Society. 127 (16): 5798–9. doi:10.1021/ja043253r. PMID 15839672.
^ Melcher MC, von Wachenfeldt H, Sundin A, Strand D (January 2015). "Iridium catalyzed carbocyclizations: efficient (5+2) cycloadditions of vinylcyclopropanes and alkynes". Chemistry: A European Journal. 21 (2): 531–5. doi:10.1002/chem.201405729. PMID 25413863.
^ Felzenstein A, Sarel S, Yovell J (1975). "Uncatalysed olefin metathesis reaction". Journal of the Chemical Society, Chemical Communications (22): 918–919. doi:10.1039/c39750000918. ISSN 0022-4936.
^ Herges R, Ugi I (1985). "Synthesis of Seven-Membered Rings by [(?2+?2)+?2] Cycloaddition to Homodienes". Angewandte Chemie International Edition in English. 24 (7): 594–596. doi:10.1002/anie.198505941. ISSN 0570-0833.
^ Yu ZX, Wender PA, Houk KN (August 2004). "On the mechanism of [Rh(CO)2Cl]2-catalyzed intermolecular (5 + 2) reactions between vinylcyclopropanes and alkynes". Journal of the American Chemical Society. 126 (30): 9154–5. doi:10.1021/ja048739m. PMID 15281784.
^ Yu ZX, Cheong PH, Liu P, Legault CY, Wender PA, Houk KN (February 2008). "Origins of differences in reactivities of alkenes, alkynes, and allenes in [Rh(CO)2Cl]2-catalyzed (5 + 2) cycloaddition reactions with vinylcyclopropanes". Journal of the American Chemical Society. 130 (8): 2378–9. doi:10.1021/ja076444d. PMID 18251468.
^ Liu P, Cheong PH, Yu ZX, Wender PA, Houk KN (2008-05-13). "Substituent effects, reactant preorganization, and ligand exchange control the reactivity in Rh(I)-catalyzed (5+2) cycloadditions between vinylcyclopropanes and alkynes". Angewandte Chemie. 47 (21): 3939–41. doi:10.1002/anie.200800420. PMID 18412215.
^ Trost BM, Toste FD, Shen H (2000). "Ruthenium-Catalyzed Intramolecular [5 + 2] Cycloadditions". Journal of the American Chemical Society. 122 (10): 2379–2380. doi:10.1021/ja993400z. ISSN 0002-7863.
^ Wender PA, Husfeld CO, Langkopf E, Love JA (1998). "First Studies of the Transition Metal-Catalyzed [5+2] Cycloadditions of Alkenes and Vinylcyclopropanes: Scope and Stereochemistry". Journal of the American Chemical Society. 120 (8): 1940–1941. doi:10.1021/ja973650k. ISSN 0002-7863.
^ Wender PA, Glorius F, Husfeld CO, Langkopf E, Love JA (1999). "Transition Metal-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: First Studies of Endo−Exo Selectivity, Chemoselectivity, Relative Stereochemistry, and Chirality Transfer". Journal of the American Chemical Society. 121 (22): 5348–5349. doi:10.1021/ja9903072. ISSN 0002-7863.
^ Wender PA, Rieck H, Fuji M (1998). "The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels−Alder Reaction". Journal of the American Chemical Society. 120 (42): 10976–10977. doi:10.1021/ja982196x. ISSN 0002-7863.
^ Wender PA, Barzilay CM, Dyckman AJ (2001). "The First Intermolecular Transition Metal-Catalyzed [5+2] Cycloadditions with Simple, Unactivated, Vinylcyclopropanes". Journal of the American Chemical Society. 123 (1): 179–180. doi:10.1021/ja0021159. ISSN 0002-7863. PMID 11273617.
^ Wender PA, Haustedt LO, Lim J, Love JA, Williams TJ, Yoon JY (May 2006). "Asymmetric catalysis of the [5 + 2] cycloaddition reaction of vinylcyclopropanes and pi-systems". Journal of the American Chemical Society. 128 (19): 6302–3. doi:10.1021/ja058590u. PMID 16683779. S2CID 197039161.
^ Liu CH, Yu ZX (July 2017). "Rhodium(I)-Catalyzed Bridged [5+2] Cycloaddition of cis-Allene-vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton". Angewandte Chemie. 56 (30): 8667–8671. doi:10.1002/anie.201702288. PMID 28643412.
^ Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF (April 2005). "[Rh(CO)2Cl]2-catalyzed domino reactions involving allylic substitution and subsequent carbocyclization reactions". Organic Letters. 7 (8): 1661–3. doi:10.1021/ol0504300. PMID 15816777.
^ Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF (November 2007). "Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates". The Journal of Organic Chemistry. 72 (24): 9018–31. doi:10.1021/jo701290b. PMID 17973524. S2CID 22154209.
^ Wender PA, Fuji M, Husfeld CO, Love JA (1999). "Rhodium-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: Asymmetric Total Synthesis of (+)-Dictamnol". Organic Letters. 1 (1): 137–140. doi:10.1021/ol990599b. ISSN 1523-7060.
^ Wender PA, Zhang L (2000). "Asymmetric Total Synthesis of (+)-Aphanamol I Based on the Transition Metal Catalyzed [5 + 2] Cycloaddition of Allenes and Vinylcyclopropanes". Organic Letters. 2 (15): 2323–2326. doi:10.1021/ol006085q. ISSN 1523-7060. PMID 10930274.
^ Wender PA, Bi FC, Brodney MA, Gosselin F (2001). "Asymmetric Synthesis of the Tricyclic Core of NGF-Inducing Cyathane Diterpenes via a Transition-Metal-Catalyzed [5 + 2] Cycloaddition". Organic Letters. 3 (13): 2105–2108. doi:10.1021/ol0160699. ISSN 1523-7060. PMID 11418060.
^ Trost BM, Waser J, Meyer A (November 2007). "Total synthesis of (-)-pseudolaric acid B". Journal of the American Chemical Society. 129 (47): 14556–7. doi:10.1021/ja076165q. PMC 2535803. PMID 17985906.
^ Trost BM, Waser J, Meyer A (December 2008). "Total synthesis of (-)-pseudolaric acid B". Journal of the American Chemical Society. 130 (48): 16424–34. doi:10.1021/ja806724x. PMC 2698933. PMID 18998641.
^ Trost BM, Hu Y, Horne DB (September 2007). "Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition". Journal of the American Chemical Society. 129 (38): 11781–90. doi:10.1021/ja073272b. PMID 17760442.

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