User:Jamesmkidd/Sandbox

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The enediyne functional group is a versatile structure that can undergo electrocyclic relactions to generate benzyne diradicals. The ability of the diradical to cleave DNA explains the presence of the group in bacterial fermentation products and makes it a potent anti-cancer agent. Enediynes are also used to provide an alternative route to the synthesis of aromatic hydrocarbons when the typical Diels-Alder protocols are inappropriate.

Enediyne functional group[edit]

Structure[edit]

The enediyne moiety consists of two carbon-carbon triple bonds separated by a carbon-carbon double bond. Three configurations are possible: conjugated E- and Z-enediynes and cross-conjugated geminal enediynes.

Reactivity[edit]

Bergman cyclization[edit]

Bergman (C1-C6) cyclization (above) compared with C1-C5 cyclization

Enediynes may undergo endothermic Bergman cyclization to form a 1,4-dehydrobenzene diradical from C1-C6 electrocyclic closure. The diradical will abstract hydrogen atoms from any appropriate donor, such a 1,4-cyclohexadiene or DNA, with the rate of abstraction dependent only on the donor concentration[1]. Thermal and, for cyclic enediynes, photoinduced[2] pathways are possible. Unlike the categorically similar Cope rearrangement, which is thought to proceed through a concerted mechanism, the Bergman cyclization proceeds through a diradical intermediate, which is stabilized by aromatic resonance[3].

File:Bergman vs cope cyclizations by schreiner et al.png
Reaction coordinates for the Cope rearrangement (above) and the Bergman cyclization (below). [4]

The activation energy of the Bergman cyclization depends on several factors: the C1-C6 distance[5], acetylenic substituents, and, for cyclic enediynes, ring strain[6]. Natural bond orbital analysis of factors intrinsic to the enediyne moiety shows that most ground state destabilization of the reactant comes from electronic repulsion of filled, in-plane acetylenic π-orbitals. As the C1-C6 distance decreases, the magnitude of the destabilizing π-π interaction increases, while the magnitude of forming bond π-π* interaction remains constant. This early stage of bond formation resembles the antiaromatic, thermally forbidden [2s+2s] ethene cycloaddition. Only when the C1-C6 distance goes below 3Å does the magnitude of the π-π* interaction increase, allowing the nascent σ-bond to form[7]

Substituent effects can also affect the facility of Bergman cyclization. A linear free energy relationship was found between enediynes with an ene-containing aromatic backbone and the Hammett σ-meta parameter, indicating a small acceleration for electron-withdrawing groups at the meta position. This substitution reduces the effective charge at the terminal acetylene carbons, which reduces repulsion by in-plane π-orbitals and thus activation energy[8].

Ortho-substitution of ene-containing aromatic backbones is more complex. Steric effects from ortho substituents can destabilize the ground state (and decrease activation energy) by decreasing the C1-C6 distance due to the proximity of the ortho position to the alkyne moiety. In contrast, electronegative hydrogen bond donors can stabilize the ground state (and increase activation energy) by hydrogen bonding with the in-plane alkyne π-orbitals. However, in acidic environments (like cancerous cells), positively charged hydrogen bond donors like R-NH3+ can decrease activation energy by stabilizing the transition state[9]

C1-C5 cyclization[edit]

Less commonly studied is the thermal C1-C5 cyclization, which can become thermodynamically competitive for diaryl-substituted benzannulated enediynes. The effect is twofold: the Bergman transition state is destabilized due to steric effects from bring the two aryl groups together, and the vinyl radical in the C1-C5 transition state is stabilized by the adjacent aryl substituent, which is not possible in the Bergman transition state[10]. The C1-C5 cyclization may also proceed through a radical cation intermediate upon oxidation of the enediyne[11], or by reaction with electrophiles[12].

Synthesis of Enediynes[edit]

Coupling methods[edit]

File:Sonogashira coupling in the synthesis of dynemicin a.svg
The Sonogashira reaction used in the synthesis of dynemicin-A[13]
File:Negishi coupling in synthesis mcmahon and bowling 2005.svg
Negishi coupling utilized in the synthesis of an enediyne isomer of tetraethynylethene[14]

One strategy to synthesize the delicate enediyne moiety is to begin with the alkene unit and attach alkyne groups under palladium catalysis. The versatile Sonogashira reaction allows the coupling of aryl and vinyl halides with terminal alkynes in a configuration-retaining, stereospecific manner[15]. Negishi coupling is another palladium catalyzed coupling method in which aryl or vinyl halides are coupled to ethynyl metal halides, such as readily available Grignard reagents. Unlike Sonogashira coupling, Negishi coupling can be used to access enediynes with terminal acetylenes[16].

Olefination methods[edit]

File:Ramberg backlund elimination to synthesize enediynes nicolaou 1988.svg
Synthesis of cyclic enediyne via Ramberg-Backlund reaction[17]

Conversely, one may begin with with a dialkyne and generate the alkene. The Ramberg-Backlund elimination[18] and Corey-Winter olefination[19] can both be used to generate E- and Z-enediynes. Additionally, condensation of trialkylsilyl allenyl boranes with acetylenic aldehydes provides a diastereoselective route to Z- and E-enediynes:[20]

File:Enediyne synthesis by condensation of aldehyde with trialkylallenylboranes Wang 1993.png

Use of Enediynes in Synthesis[edit]

Tetrahydronaphthalenes[edit]

Enediynes can be used to efficiently create stereoselective tetrahydronaphthalene derivatives such as the antitumor agent etoposide[21].

File:Tetrahydronaphthalene synthesis with ireland claisen bergman cyclization of enediynes.png

Acenes[edit]

An iterative Bergman cyclization of enediynes provides a novel route to acenes, which have potential applications in organic transistors. The iterative nature of this technique lends it to assembly of larger acene structures[22].

File:Acenes iterative scheme bowles anthony 2000.png


Fulvenes[edit]

Electrophilic C1-C5 cyclization can be used to produce twisted polyaromatic hydrocarbons[23].

Enediyne antitumor antibiotics[edit]

Enediyne functional groups appear in bacterial fermentation products, particularly those of micromonospora echinospora ssp. calichensis, micromonospora chersina, and actinomadura verrucosospora, from which calicheamicin, esperamicin, and dynemicin, respectively, are derived[24]. These natural products are able to intercalate with the minor groove of DNA, where the enediyne "warhead" undergoes Bergman cyclization. The resulting diradical abstracts hydrogen atoms from DNA, creating a DNA diradical, which reacts with O2 causing double strand cleavage. All known enediyne natural products contain the moiety in 9- or 10-membered ring, reducing the C1-C6 distance which results in a lower activation energy for Bergman cyclization, making it possible at biological temperature. Because of the temperature and light lability of the ring-strained enediyne, it must be protected until activation in vivo by nucleophilic attack.[25]

The use of visible light as a photochromic molecular switch is a novel strategy to activate the diradical warhead that has not yet been utilized therapeutically. Upon irradiation with UV light, enediynes with dithienylethene backbones undergo hexatriene cycliation, rearranging the pi system and rendering the molecule inert to Bergman cyclization at physiological temperatures. Irradiation with visible light opens the ring, activating the molecule by regenerating the enediyne pi system. [26]

Three classes of enediyne antitumor antibiotics exist:

File:Calicheamicin activation and bergman cyclization nicolaou 1991.png
The activation of calicheamicin-γ11. After nucleophilic attack, the C1-C6 distance is reduced from 3.35Å to 3.16Å[27]
  1. Calicheamicins/esperamicins, two very similar classes of natural products with identical DNA cleavage mechanisms[28]. Each contain an allylic trisulfide moiety that functions as the trigger. Calicheamicins have specificity for TCCT sites within the DNA[29], with cleavage ability related to binding ability rather than cyclization kinetics[30]
  2. Dynemicins are less efficient at DNA cleavage than calicheamicins and esperamicins, but show the greatest cleavage activity at bases adjacent to the 3' side of guanine, the base that is most resistant to cleavage by other enediynes. Dynemicins contain an anthraquinone core that facilitates minor groove binding. Activation is complex and may occur through nucleophilic attack, causing a reduction of the quinone, followed by epoxide opening and Bergman cyclization[31]; or by visible light [32]
  3. Chromoproteins, such as neocarzinostatin and C-1027, have an enediyne chromophore and an apoprotein carrier. Like other enediynes, neocarzinostatin intercalates into the minor groove of DNA via its naphthoate group. It is activated by nucleophilic attack and forms a diradical via a cumulene intermediate[33]. C-1027 readily cyclizes at room temperature without activation due to its highly strained 9-membered ring enediyne, and thus the molecule degrades over time.
File:Ncs myers saito cyclization myers 1987.png
Following activation by nucleophilic thiol attack, neocarzinostatin forms an enyne-allene that undergoes C2-C7 Myers-Saito cyclization[34].

References[edit]

  1. ^ Pickard et al., “Ortho Effect in the Bergman Cyclization:  Electronic and Steric Effects in Hydrogen Abstraction by 1-Substituted Naphthalene 5,8-Diradicals,” J. Phys. Chem. A 110, no. 7 (2006): 2517-2526.
  2. ^ Raymond L. Funk et al., “Photochemical Cycloaromatization Reactions of ortho-Dialkynylarenes:  A New Class of DNA Photocleaving Agents,” J. Am. Chem. Soc. 118, no. 13 (1996): 3291-3292.
  3. ^ Peter R. Schreiner, Armando Navarro-Vázquez, and Matthias Prall, “Computational Studies on the Cyclizations of Enediynes, Enyne-Allenes, and Related Polyunsaturated Systems†,” Acc. Chem. Res. 38, no. 1 (2004): 29-37.
  4. ^ Peter R. Schreiner, Armando Navarro-Vázquez, and Matthias Prall, “Computational Studies on the Cyclizations of Enediynes, Enyne-Allenes, and Related Polyunsaturated Systems†,” Acc. Chem. Res. 38, no. 1 (2004): 29-37.
  5. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  6. ^ James P. Snyder, “Monocyclic enediyne collapse to 1,4-diyl biradicals: a pathway under strain control,” J. Am. Chem. Soc. 112, no. 13 (1990): 5367-5369.
  7. ^ Igor V. Alabugin and Mariappan Manoharan, “Reactant Destabilization in the Bergman Cyclization and Rational Design of Light- and pH-Activated Enediynes†,” J. Phys. Chem. A 107, no. 18 (2002): 3363-3371.
  8. ^ Nakyen Choy et al., “Linear free energy relationships in the Bergman cyclization of 4-substituted-1,2-diethynylbenzenes,” Tetrahedron Letters 41, no. 36 (September 2000): 6955-6958.
  9. ^ Igor V. Alabugin, Mariappan Manoharan, and Serguei V. Kovalenko, “Tuning Rate of the Bergman Cyclization of Benzannelated Enediynes with Ortho Substituents,” Org. Lett. 4, no. 7 (2002): 1119-1122.
  10. ^ Chandrasekhar Vavilala et al., “Thermal C1−C5 Diradical Cyclization of Enediynes,” J. Am. Chem. Soc. 130, no. 41 (2008): 13549-13551.
  11. ^ Dhruva Ramkumar,† Mahadevan Kalpana,† Babu Varghese,‡ and Sethuraman Sankararaman*† J. Org. Chem., 1996, 61 (6), pp 2247–2250 DOI: 10.1021/jo951524y
  12. ^ Peter R Schreiner, Matthias Prall, and Volker Lutz, “Fulvenes from Enediynes: Regioselective Electrophilic Domino and Tandem Cyclizations of Enynes and Oligoynes,” Angewandte Chemie International Edition 42, no. 46 (December 1, 2003): 5757-5760.
  13. ^ K. C. Nicolaou, A. L. Smith, S. V. Wendeborn, C. K. Hwang J. Am. Chem. Soc., 1991, 113 (8), pp 3106–3114 DOI: 10.1021/ja00008a045
  14. ^ Nathan P. Bowling and Robert J. McMahon J. Org. Chem., 2006, 71 (16), pp 5841–5847 DOI: 10.1021/jo052505j
  15. ^ Rafael Chinchilla and Carmen Nájera, “The Sonogashira Reaction:  A Booming Methodology in Synthetic Organic Chemistry†,” Chem. Rev. 107, no. 3 (2007): 874-922.
  16. ^ Ei-ichi Negishi, Martin Kotora, and Caiding Xu, “Direct Synthesis of Terminal Alkynes via Pd-Catalyzed Cross Coupling of Aryl and Alkenyl Halides with Ethynylmetals Containing Zn, Mg, and Sn. Critical Comparison of Countercations,” J. Org. Chem. 62, no. 25 (1997): 8957-8960.
  17. ^ K. C. Nicolaou, Y. Ogawa, G. Zuccarello, E. J. Schweiger, T. Kumazawa J. Am. Chem. Soc., 1988, 110 (14), pp 4866–4868 DOI: 10.1021/ja00222a077
  18. ^ K. C. Nicolaou et al., “Cyclic conjugated enediynes related to calicheamicins and esperamicins: calculations, synthesis, and properties,” J. Am. Chem. Soc. 110, no. 14 (1988): 4866-4868.
  19. ^ M.F. Semmelhack and James Gallagher, “Cyclic conjugated enediynes via elimination of a thionocarbonate in a latent Z-hex-3-ene-1,5-diyne unit,” Tetrahedron Letters 34, no. 26 (June 25, 1993): 4121-4124.
  20. ^ Kung K. Wang, Zhongguo Wang, and Yu Gui Gu, “Stereoselective synthesis of enediynes and enynes by condensation of aldehydes with γ-(trialkylsilyl)allenylboranes,” Tetrahedron Letters 34, no. 52 (1993): 8391-8394.
  21. ^ Plato A. Magriotis, Kee D. Kim J. Am. Chem. Soc., 1993, 115 (7), pp 2972–2973 DOI: 10.1021/ja00060a054
  22. ^ Daniel M. Bowles and John E. Anthony Org. Lett., 2000, 2 (1), pp 85–87DOI: 10.1021/ol991254w
  23. ^ Peter R Schreiner, Matthias Prall, and Volker Lutz, “Fulvenes from Enediynes: Regioselective Electrophilic Domino and Tandem Cyclizations of Enynes and Oligoynes,” Angewandte Chemie International Edition 42, no. 46 (December 1, 2003): 5757-5760.
  24. ^ Anticancer agents from natural products By Gordon M. L. Cragg, David Kingston, David J. Newman
  25. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  26. ^ David Sud, Tony J Wigglesworth, and Neil R Branda, “Creating a Reactive Enediyne by Using Visible Light: Photocontrol of the Bergman Cyclization,” Angewandte Chemie International Edition 46, no. 42 (October 22, 2007): 8017-8019.
  27. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  28. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  29. ^ R C Hawley, L L Kiessling, and S L Schreiber, “Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322,” Proceedings of the National Academy of Sciences 86, no. 4 (February 1, 1989): 1105 -1109.
  30. ^ Hiroko Kishikawa et al., “Coupled kinetic analysis of cleavage of DNA by esperamicin and calicheamicin,” J. Am. Chem. Soc. 113, no. 14 (1991): 5434-5440.
  31. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  32. ^ Yukio Sugiura et al., “Reductive and nucleophilic activation products of dynemicin A with methyl thioglycolate. A rational mechanism for DNA cleavage of the thiol-activated dynemicin A,” Biochemistry 30, no. 12 (1991): 2989-2992.
  33. ^ K. C Nicolaou and W. ‐M Dai, “Chemistry and Biology of the Enediyne Anticancer Antibiotics,” Angewandte Chemie International Edition in English 30, no. 11 (November 1, 1991): 1387-1416.
  34. ^ Myers Andrew G., “Proposed structure of the neocarzinostatin chromophore-methyl thioglycolate adduct; A mechanism for the nucleophilic activation of neocarzinostatin,” Tetrahedron Letters 28, no. 39 (1987): 4493-4496.
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