Chemistry:Vinylcyclopropane (5+2) cycloaddition

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

VCP 5+2 TOC.png

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]

Bicyclic thermal 5+2.png

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.

Rh cycle.png

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.

Ru VCP cycle.png

Reaction scope

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

5+2 Reaction scope.png

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.

Intermolecular reaction scope.png

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]

Asymmetric 5+2.png

Bridged [5+2] cycloaddition

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

Bridged VCP 5+2.png

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]

Tandem allylation 5+2.png

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]

VCP 5+2 Total Synthesis Application.png

See also

References

  1. ↑ 1.0 1.1 Sarel, Shalorn; Felzenstein, Abraham; Yovell, Joseph (1973). "Alternative modes of addition of dienophiles to vinylcyclopropane systems" (in en). Journal of the Chemical Society, Chemical Communications (22): 859–860. doi:10.1039/c39730000859. ISSN 0022-4936. http://xlink.rsc.org/?DOI=c39730000859. 
  2. ↑ 2.0 2.1 2.2 Wender, Paul A.; Takahashi, Hisashi; Witulski, Bernhard (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" (in en). Journal of the American Chemical Society 117 (16): 4720–4721. doi:10.1021/ja00121a036. ISSN 0002-7863. 
  3. ↑ 3.0 3.1 "[5 + 2] cycloaddition reactions in organic and natural product synthesis". Chemical Reviews 113 (3): 2244–66. March 2013. doi:10.1021/cr300087g. PMID 23153111. 
  4. ↑ "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. doi:10.1021/ja0777180. PMID 18197669. 
  5. ↑ "Selectivity in nickel-catalyzed rearrangements of cyclopropylen-ynes". Journal of the American Chemical Society 127 (16): 5798–9. April 2005. doi:10.1021/ja043253r. PMID 15839672. 
  6. ↑ "Iridium catalyzed carbocyclizations: efficient (5+2) cycloadditions of vinylcyclopropanes and alkynes". Chemistry: A European Journal 21 (2): 531–5. January 2015. doi:10.1002/chem.201405729. PMID 25413863. 
  7. ↑ Felzenstein, Avraham; Sarel, Shalom; Yovell, Joseph (1975). "Uncatalysed olefin metathesis reaction" (in en). Journal of the Chemical Society, Chemical Communications (22): 918–919. doi:10.1039/c39750000918. ISSN 0022-4936. http://xlink.rsc.org/?DOI=c39750000918. 
  8. ↑ Herges, Rainer; Ugi, Ivar (1985). "Synthesis of Seven-Membered Rings by [(?2+?2)+?2] Cycloaddition to Homodienes" (in en). Angewandte Chemie International Edition in English 24 (7): 594–596. doi:10.1002/anie.198505941. ISSN 0570-0833. 
  9. ↑ "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. doi:10.1021/ja048739m. PMID 15281784. 
  10. ↑ "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. doi:10.1021/ja076444d. PMID 18251468. 
  11. ↑ "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. doi:10.1002/anie.200800420. PMID 18412215. 
  12. ↑ Trost, Barry M.; Toste, F. Dean; Shen, Hong (2000). "Ruthenium-Catalyzed Intramolecular [5 + 2] Cycloadditions" (in en). Journal of the American Chemical Society 122 (10): 2379–2380. doi:10.1021/ja993400z. ISSN 0002-7863. 
  13. ↑ Wender, Paul A.; Husfeld, Craig O.; Langkopf, Elke; Love, Jennifer A. (1998). "First Studies of the Transition Metal-Catalyzed [5+2] Cycloadditions of Alkenes and Vinylcyclopropanes: Scope and Stereochemistry" (in en). Journal of the American Chemical Society 120 (8): 1940–1941. doi:10.1021/ja973650k. ISSN 0002-7863. 
  14. ↑ Wender, Paul A.; Glorius, Frank; Husfeld, Craig O.; Langkopf, Elke; Love, Jennifer A. (1999). "Transition Metal-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: First Studies of Endo−Exo Selectivity, Chemoselectivity, Relative Stereochemistry, and Chirality Transfer" (in en). Journal of the American Chemical Society 121 (22): 5348–5349. doi:10.1021/ja9903072. ISSN 0002-7863. 
  15. ↑ Wender, Paul A.; Rieck, Heiko; Fuji, Masahiro (1998). "The Transition Metal-Catalyzed Intermolecular [5+2] Cycloaddition: The Homologous Diels−Alder Reaction" (in en). Journal of the American Chemical Society 120 (42): 10976–10977. doi:10.1021/ja982196x. ISSN 0002-7863. 
  16. ↑ Wender, Paul A.; Barzilay, Claudia M.; Dyckman, Alaric J. (2001). "The First Intermolecular Transition Metal-Catalyzed [5+2] Cycloadditions with Simple, Unactivated, Vinylcyclopropanes" (in en). Journal of the American Chemical Society 123 (1): 179–180. doi:10.1021/ja0021159. ISSN 0002-7863. PMID 11273617. 
  17. ↑ "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. doi:10.1021/ja058590u. PMID 16683779. 
  18. ↑ "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. doi:10.1002/anie.201702288. PMID 28643412. 
  19. ↑ "[Rh(CO)2Cl]2-catalyzed domino reactions involving allylic substitution and subsequent carbocyclization reactions". Organic Letters 7 (8): 1661–3. April 2005. doi:10.1021/ol0504300. PMID 15816777. 
  20. ↑ "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. doi:10.1021/jo701290b. PMID 17973524. 
  21. ↑ Wender, Paul A.; Fuji, Masahiro; Husfeld, Craig O.; Love, Jennifer A. (1999). "Rhodium-Catalyzed [5 + 2] Cycloadditions of Allenes and Vinylcyclopropanes: Asymmetric Total Synthesis of (+)-Dictamnol" (in en). Organic Letters 1 (1): 137–140. doi:10.1021/ol990599b. ISSN 1523-7060. 
  22. ↑ Wender, Paul A.; Zhang, Lei (2000). "Asymmetric Total Synthesis of (+)-Aphanamol I Based on the Transition Metal Catalyzed [5 + 2] Cycloaddition of Allenes and Vinylcyclopropanes" (in en). Organic Letters 2 (15): 2323–2326. doi:10.1021/ol006085q. ISSN 1523-7060. PMID 10930274. 
  23. ↑ Wender, Paul A.; Bi, F. Christopher; Brodney, Michael A.; Gosselin, Francis (2001). "Asymmetric Synthesis of the Tricyclic Core of NGF-Inducing Cyathane Diterpenes via a Transition-Metal-Catalyzed [5 + 2] Cycloaddition" (in en). Organic Letters 3 (13): 2105–2108. doi:10.1021/ol0160699. ISSN 1523-7060. PMID 11418060. 
  24. ↑ "Total synthesis of (-)-pseudolaric acid B". Journal of the American Chemical Society 129 (47): 14556–7. November 2007. doi:10.1021/ja076165q. PMID 17985906. 
  25. ↑ "Total synthesis of (-)-pseudolaric acid B". Journal of the American Chemical Society 130 (48): 16424–34. December 2008. doi:10.1021/ja806724x. PMID 18998641. 
  26. ↑ "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. doi:10.1021/ja073272b. PMID 17760442. 



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