Synlett 2015; 26(04): 501-507
DOI: 10.1055/s-0034-1379893
© Georg Thieme Verlag Stuttgart · New York

Thermal and Photochemical Mechanisms for Cyclobutane Formation in Bielschowskysin Biosynthesis

Bencan Tanga, b, Robert Simiona, c, Robert S. Paton*a, c
  • aChemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
  • bDepartment of Chemical and Environment Engineering, The University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, P. R. of China
  • cPhysical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK   Email:
Further Information

Publication History

Received: 04 November 2014

Accepted: 14 January 2015

Publication Date:
09 February 2015 (eFirst)


The unique structure of furanocembranoid natural product bielschowskysin has provoked a number of biosynthetic hypotheses: quantum chemical calculations provide a means to assess the feasibility of postulated mechanisms in the construction of this unusual carbon skeleton. Calculations reveal that thermal closure is possible in water via an unusual concerted cyclobutane-forming transition state without the intervention of an enzyme. Photocycloaddition is computed to be extremely efficient, provided enol ether triplet sensitization can be achieved by an appropriate light source. The possible existence of a stable dicarbonyl intermediate presents a challenge for the thermal route, implicating a photochemical pathway in bielschowskysin biosynthesis.

Supporting Information

  • References and Notes

  • 1 Marrero J, Rodríguez AD, Baran P, Raptis RG, Sánchez JA, Ortega-Barria E, Capson TL. Org. Lett. 2004; 6: 1661
  • 2 Doroh B, Sulikowski GA. Org. Lett. 2006; 8: 903
  • 3 Miao R, Gramani SG, Lear MJ. Tetrahedron Lett. 2009; 50: 1731
  • 4 Nicolaou KC, Adsool VA, Hale CR. H. Angew. Chem. Int. Ed. 2011; 50: 5149
  • 5 Jana A, Mondal S, Hossain MF, Ghosh S. Tetrahedron Lett. 2012; 53: 6830
  • 6 Himmelbauer M, Farcet J.-B, Gagnepain J, Mulzer J. Org. Lett. 2013; 15: 3098
  • 7 Roethle PA, Trauner D. Nat. Prod. Rep. 2008; 25: 298
  • 8 Bach T, Hehn JP. Angew. Chem. Int. Ed. 2011; 50: 1000
  • 9 Hong YJ, Tantillo DJ. Chem. Soc. Rev. 2014; 43: 5042
  • 10 Saitman A, Sullivan SD. E, Theodorakis EA. Tetrahedron Lett. 2013; 54: 1612
    • 11a Hong YJ, Tantillo DJ. Nat. Chem. 2009; 1: 384
    • 11b Hong YJ, Tantillo DJ. Nat. Chem. 2014; 6: 104
    • 11c Hornsby CE, Paton RS. Nat. Chem. 2014; 6: 88
  • 12 Roethle PA, Hernandez PT, Trauner D. Org. Lett. 2006; 8: 5901
  • 13 Tang B, Bray CD, Pattenden G. Tetrahedron Lett. 2006; 47: 6401
  • 14 Wang SC, Tantillo DJ. J. Org. Chem. 2008; 73: 1516
  • 15 Li Y, Pattenden G. Nat. Prod. Rep. 2011; 28: 1269
    • 16a Palframan MJ, Pattenden G. Synlett 2013; 24: 2720
    • 16b Li Y, Palframan MJ, Pattenden G, Winne JM. Tetrahedron 2014; 70: 7229
  • 17 Lygo B, Palframan MJ, Pattenden G. Org. Biomol. Chem. 2014; 12: 7270
  • 18 All calculations were performed with Gaussian 09, rev. D.01. Structures were optimized using the range-separated hybrid ωB97XD density functional, which incorporates an atom-pairwise, density-independent (D2)-correction for the effects of London dispersion, in conjunction with the 6-31G (d) basis set for all atoms. Solvation effects were including during optimizations with an implicit conductor-like polariazble continuum model (CPCM) of water, ρ = 78.4. Stationary points were classified as either minima or transition structures following analysis of the harmonic vibrations, possessing zero and exactly one imaginary frequency, respectively. Transition structures were connected to corresponding minima by computation of the Intrinsic Reaction Coordinate (IRC). Free energies include unscaled vibrational zero-point energies and were evaluated at a temperature of 298 K and solution-phase concentration of 1 mol/l. Single point energetics were evaluated for all optimized structures with a larger triple-ζ valence basis set, at the CPCM-ωB97XD/def2-TZVPP level of theory. Molecular graphics were produced with PyMol, CYLview and MATLAB. A full list of computational references is provided in the Supporting Information with absolute energies and Cartesian coordinates.
  • 19 We used a CPCM description of water to assess the uncatalyzed biosynthesis. Geometry optimizations were performed in solution due to the sizable change in dipole moment occurring in the thermal reaction. Calculations designed to mimic the apolar interior of an enzyme employed a CPCM description of diethyl ether, ρ = 4.2.
    • 20a von Ragué Schleyer P, Maerker C, Dransfeld A, Jiao H, van Eikema Hommes NJ. R. J. Am. Chem. Soc. 1996; 118: 6317

    • For recent discussions on NICSZZ, see:
    • 20b Gilmore K, Manoharan M, Wu JI.-C, von Ragué Schleyer P, Alabugin IV. J. Am. Chem. Soc. 2012; 134: 10584
    • 20c Knipe PC, Gredičak M, Cernijenko A, Paton RS, Smith MD. Chem. Eur. J. 2014; 11: 3005
    • 21a Woodward RB, Hoffmann R. Angew. Chem., Int. Ed. Engl. 1969; 8: 781
    • 21b Hoffmann R, Woodward RB. J. Am. Chem. Soc. 1965; 87: 2046
  • 22 Painter PP, Pemberton RP, Wong BM, Ho KC, Tantillo DJ. J. Org. Chem. 2014; 79: 432
  • 23 Natural Population Analysis (NPA) was performed using the ωB97XD/6-31G (d) ‘wavefunction’ with the NBO 6.0 package.
    • 24a Tantillo DJ, Chen J, Houk KN. Curr. Opin. Chem. Biol. 1998; 2: 743
    • 24b Tantillo DJ, Houk KN In Stimulating Concepts in Chemistry . Vögtle F, Stoddart JF, Shibasaki M. Wiley-VCH; Weinheim; 2005

    • Application to biosynthesis, see:
    • 24c Hotta K, Chen X, Paton RS, Minami A, Li H, Swaminathan KT, Mathews II, Watanabe K, Oikawa H, Houk KN, Kim CY. Nature (London, UK) 2012; 483: 355
  • 25 Krenske EH, Patel A, Houk KN. J. Am. Chem. Soc. 2013; 135: 17638
    • 26a Xie X, Meehan MJ, Xu W, Dorrestein PC, Tang Y. J. Am. Chem. Soc. 2009; 131: 8388
    • 26b Chooi Y.-H, Wang P, Fang J, Li Y, Wu K, Wang P, Tang Y. J. Am. Chem. Soc. 2012; 134: 9428
  • 27 TD-ωB97XD/def2-TZVPP vertical excitation energies were obtained for excited singlet and triplet states with nonequilibrium CPCM water solvation. The triplet potential energy surface was computed at spin-unrestricted CPCM-ωB97XD/6-31G(d) level of theory.
  • 28 Cucarull-González JR, Hernando J, Alibés R, Figueredo M, Font J, Rodríguez-Santiago L, Sodupe M. J. Org. Chem. 2010; 75: 4392
  • 29 Li Y, Pattenden G. Tetrahedron Lett. 2011; 52: 3315
  • 30 Schuster DI, Lem G, Kaprinidis NA. Chem. Rev. 1993; 93: 3
  • 31 Andrew D, Hastings DJ, Weedon AC. J. Am. Chem. Soc. 1994; 116: 10870
  • 32 Matute RA, Houk KN. Angew. Chem. Int. Ed. 2012; 51: 13097
  • 33 Jiménez-Osés G, Liu P, Matute RA, Houk KN. Angew. Chem. Int. Ed. 2014; 53: 8664
  • 34 Li Y, Palframan MJ, Pattenden G, Winne JM. Tetrahedron 2014; 70: 7229
  • 35 The photochemical formation of intracarene has now been shown from a diene dione intermediate: Stichnoth D, Kölle P, Kimbrough TJ, Riedle E, de Vivie-Riedle R, Trauner D. Nat. Commun. 2014; 6: 5597