Vinylcyclopropane (5+2) cycloaddition explained

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. 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,[1] other reaction protocols have been developed with transition metal complexes of rhodium,[2] ruthenium, iron,[3] nickel,[4] iridium[5] and other metals.

Mechanism

Thermal reactions

Vinylcyclopropanes can undergo formal [5+2] cycloadditions with highly activated dienophiles such as tetracyanoethylene (TCNE).[6] 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, 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, 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

Notes and References

  1. Wender. Paul A.. Takahashi. Hisashi. Witulski. Bernhard . vanc . 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. en. 117. 16. 4720–4721. 10.1021/ja00121a036. 0002-7863.
  2. Ylijoki KE, Stryker JM . [5 + 2] cycloaddition reactions in organic and natural product synthesis . Chemical Reviews . 113 . 3 . 2244–66 . March 2013 . 23153111 . 10.1021/cr300087g .
  3. Fürstner A, Majima K, Martín R, Krause H, Kattnig E, Goddard R, Lehmann CW . 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 . February 2008 . 18197669 . 10.1021/ja0777180 . 11858/00-001M-0000-0024-C2BF-2 . free .
  4. Zuo G, Louie J . Selectivity in nickel-catalyzed rearrangements of cyclopropylen-ynes . Journal of the American Chemical Society . 127 . 16 . 5798–9 . April 2005 . 15839672 . 10.1021/ja043253r .
  5. Melcher MC, von Wachenfeldt H, Sundin A, Strand D . Iridium catalyzed carbocyclizations: efficient (5+2) cycloadditions of vinylcyclopropanes and alkynes . Chemistry: A European Journal . 21 . 2 . 531–5 . January 2015 . 25413863 . 10.1002/chem.201405729 .
  6. Sarel. Shalorn. Felzenstein. Abraham. Yovell. Joseph. vanc . 1973. Alternative modes of addition of dienophiles to vinylcyclopropane systems. Journal of the Chemical Society, Chemical Communications. en. 22. 859–860. 10.1039/c39730000859. 0022-4936.
  7. Felzenstein. Avraham. Sarel. Shalom. Yovell. Joseph. vanc . 1975. Uncatalysed olefin metathesis reaction. Journal of the Chemical Society, Chemical Communications. en. 22. 918–919. 10.1039/c39750000918. 0022-4936.
  8. Herges. Rainer. Ugi. Ivar. vanc . 1985. Synthesis of Seven-Membered Rings by [(?2+?2)+?2] Cycloaddition to Homodienes. Angewandte Chemie International Edition in English. en. 24. 7. 594–596. 10.1002/anie.198505941. 0570-0833.
  9. Yu ZX, Wender PA, Houk KN . 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 . August 2004 . 15281784 . 10.1021/ja048739m .
  10. Yu ZX, Cheong PH, Liu P, Legault CY, Wender PA, Houk KN . 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 . February 2008 . 18251468 . 10.1021/ja076444d .
  11. Liu P, Cheong PH, Yu ZX, Wender PA, Houk KN . 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 . 2008-05-13 . 18412215 . 10.1002/anie.200800420 . free .
  12. Trost. Barry M.. Toste. F. Dean. Shen. Hong. vanc . 2000. Ruthenium-Catalyzed Intramolecular [5 + 2] Cycloadditions. Journal of the American Chemical Society. en. 122. 10. 2379–2380. 10.1021/ja993400z. 0002-7863.
  13. Wender. Paul A.. Husfeld. Craig O.. Langkopf. Elke. Love. Jennifer A.. vanc . 1998. First Studies of the Transition Metal-Catalyzed [5+2] Cycloadditions of Alkenes and Vinylcyclopropanes: Scope and Stereochemistry. Journal of the American Chemical Society. en. 120. 8. 1940–1941. 10.1021/ja973650k. 0002-7863.
  14. Wender. Paul A.. Glorius. Frank. Husfeld. Craig O.. Langkopf. Elke. Love. Jennifer A.. vanc . 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. en. 121. 22. 5348–5349. 10.1021/ja9903072. 0002-7863.
  15. Wender. Paul A.. Rieck. Heiko. Fuji. Masahiro. vanc . 1998. The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels−Alder Reaction. Journal of the American Chemical Society. en. 120. 42. 10976–10977. 10.1021/ja982196x. 0002-7863.
  16. Wender. Paul A.. Barzilay. Claudia M.. Dyckman. Alaric J.. vanc . 2001. The First Intermolecular Transition Metal-Catalyzed [5+2] Cycloadditions with Simple, Unactivated, Vinylcyclopropanes. Journal of the American Chemical Society. en. 123. 1. 179–180. 10.1021/ja0021159. 11273617. 0002-7863.
  17. Wender PA, Haustedt LO, Lim J, Love JA, Williams TJ, Yoon JY . Asymmetric catalysis of the [5 + 2] cycloaddition reaction of vinylcyclopropanes and pi-systems . Journal of the American Chemical Society . 128 . 19 . 6302–3 . May 2006 . 16683779 . 10.1021/ja058590u . 197039161 .
  18. Liu CH, Yu ZX . 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 . July 2017 . 28643412 . 10.1002/anie.201702288 .
  19. Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF . [Rh(CO)2Cl]2-catalyzed domino reactions involving allylic substitution and subsequent carbocyclization reactions . Organic Letters . 7 . 8 . 1661–3 . April 2005 . 15816777 . 10.1021/ol0504300 .
  20. Ashfeld BL, Miller KA, Smith AJ, Tran K, Martin SF . Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates . The Journal of Organic Chemistry . 72 . 24 . 9018–31 . November 2007 . 17973524 . 10.1021/jo701290b . 22154209 .
  21. Wender. Paul A.. Fuji. Masahiro. Husfeld. Craig O.. Love. Jennifer A.. vanc . 1999. Rhodium-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: Asymmetric Total Synthesis of (+)-Dictamnol. Organic Letters. en. 1. 1. 137–140. 10.1021/ol990599b. 1523-7060.
  22. Wender. Paul A.. Zhang. Lei. vanc . 2000. Asymmetric Total Synthesis of (+)-Aphanamol I Based on the Transition Metal Catalyzed [5 + 2] Cycloaddition of Allenes and Vinylcyclopropanes. Organic Letters. en. 2. 15. 2323–2326. 10.1021/ol006085q. 10930274. 1523-7060.
  23. Wender. Paul A.. Bi. F. Christopher. Brodney. Michael A.. Gosselin. Francis. vanc . 2001. Asymmetric Synthesis of the Tricyclic Core of NGF-Inducing Cyathane Diterpenes via a Transition-Metal-Catalyzed [5 + 2] Cycloaddition. Organic Letters. en. 3. 13. 2105–2108. 10.1021/ol0160699. 11418060. 1523-7060.
  24. Trost BM, Waser J, Meyer A . Total synthesis of (-)-pseudolaric acid B . Journal of the American Chemical Society . 129 . 47 . 14556–7 . November 2007 . 17985906 . 2535803 . 10.1021/ja076165q .
  25. Trost BM, Waser J, Meyer A . Total synthesis of (-)-pseudolaric acid B . Journal of the American Chemical Society . 130 . 48 . 16424–34 . December 2008 . 18998641 . 2698933 . 10.1021/ja806724x .
  26. Trost BM, Hu Y, Horne DB . Total synthesis of (+)-frondosin A. Application of the Ru-catalyzed [5+2] cycloaddition . Journal of the American Chemical Society . 129 . 38 . 11781–90 . September 2007 . 17760442 . 10.1021/ja073272b .

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