Synthesis 2022; 54(07): 1733-1744
DOI: 10.1055/s-0041-1737242
feature

On the Structure of Thailandene A: Synthetic Examination of the Cryptic Natural Product Aided by a Theoretical Approach

Karoline G. Primdahl
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
,
Åsmund Kaupang
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
,
Jong-Duk Park
b   Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
,
Mohammad R. Seyedsayamdost
b   Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
,
Jens M. J. Nolsøe
c   Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, 1432 Ås, Norway
,
Marius Aursnes
a   Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316 Oslo, Norway
› Author Affiliations
M.A. is grateful to the Research Council of Norway (RCN, Norges Forskningsråd) for a grant (FRINATEK, 262901). A research scholarship to J. M. J. N. (FRIPRO, 287416) from the Research Council of Norway (RCN) is gratefully recognized. This work was partly supported by the Research Council of Norway through the Norwegian NMR Package in 1994 and partly supported by the Research Council of Norway through the Norwegian NMR Platform, NNP (226244/F50). Additional support by the Department of Chemistry and the Faculty of Mathematics and Natural Sciences at University of Oslo (Universitet i Oslo) is also appreciated.


Abstract

Phenotype-guided transposon mutagenesis has emerged as a valuable tool to access cryptic metabolites encoded in bacterial genomes. Recently, the method was demonstrated by inducing silent biosynthetic gene clusters in Burkholderia thailandensis. Amongst the isolated metabolic products, thailandene A exhibited promising antibiotic activity. By assignment, the linear polyenic aldehyde contained a labile motif, where an ostensible chiral secondary alcohol was interlaced in an allylic and a homoallylic constellation. Our attention was drawn to the pseudo-symmetric relationship between the heterofunctionalities, indicating the transformation of a dodecapentaenedial scaffold. Centering on an iterative cross-coupling protocol, the assigned all-E-(12R)-hydroxydodecapentaenal moiety was assembled by combining Zincke chemistry with the MIDA-attenuated Suzuki reaction developed in the Burke laboratory. Thus, according to the devised strategy, the mixed 1,2-bisborylated vinyl linchpin was consecutively functionalized with 5-bromodienal derivatives in a doubly orthogonal fashion. However, when the synthetic material was matched against the bacterial isolate, inconsistencies were observed. A re-examination of the cryptic natural product was conducted by juxtaposing analytical data from experiment and density functional theory calculations, in which hydroperoxide was evaluated as a candidate metabolite present in the bacterial isolate.

Supporting Information



Publication History

Received: 10 July 2021

Accepted after revision: 19 November 2021

Publication Date:
17 January 2022 (online)

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References

  • 1 Madden KS, Mosa FA, Whiting A. Org. Biomol. Chem. 2014; 12: 7877
    • 2a Kotler-Brajtburg J, Medoff G, Kobayashi GS, Boggs S, Schlessinger D, Pandey RC, Rinehart KL. Antimicrob. Agents Chemother. 1979; 15: 716
    • 2b Stubbendieck RM, Brock DJ, Pellois J.-P, Gill JJ, Straight PD. J. Antibiot. 2018; 71: 372
  • 3 Stubbendieck RM, Straight PD. J. Bacteriol. 2016; 198: 2145
  • 4 Thirsk C, Whiting A. J. Chem. Soc., Perkin Trans. 1 2002; 999
  • 5 Park J.-D, Moon K, Miller C, Rose J, Xu F, Ebmeier CC, Jacobsen JR, Mao D, Old WM, DeShazer D, Seyedsayamdost MR. ACS Chem. Biol. 2020; 15: 1195
  • 6 Feddersen CR, Wadsworth LS, Zhu EY, Vaughn HR, Voigt AP. BMC Genomics 2019; 20: 497
  • 7 Nolsøe JM. J, Aursnes M, Tungen JE, Hansen TV. J. Org. Chem. 2015; 80: 5377
    • 8a Aursnes M, Tungen JE, Vik A, Dalli J, Hansen TV. Org. Biomol. Chem. 2014; 12: 432
    • 8b Aursnes M, Tungen JE, Vik A, Colas R, Cheng C.-YC, Dalli J, Serhan CN, Hansen TV. J. Nat. Prod. 2014; 77: 910
    • 8c Tungen JE, Aursnes M, Vik A, Ramon S, Colas RA, Dalli J, Serhan CN, Hansen TV. J. Nat. Prod. 2014; 77: 2241
    • 8d Primdahl KG, Tungen JE, Aursnes M, Hansen TV, Vik A. Org. Biomol. Chem. 2015; 13: 5412
    • 8e Primdahl KG, Aursnes M, Walker ME, Colas RA, Serhan CN, Dalli J, Hansen TV, Vik A. J. Nat. Prod. 2016; 79: 2693
    • 8f Tungen JE, Aursnes M, Vik A. Synlett 2016; 27: 2497
    • 8g Primdahl KG, Nolsøe JM. J, Aursnes M. Org. Biomol. Chem. 2020; 18: 9050
    • 8h Reinertsen AF, Primdahl KG, Shay AE, Serhan CN, Hansen TV, Aursnes M. J. Org. Chem. 2021; 86: 3535
    • 9a Zincke T, Heuser G, Moller W. Justus Liebigs Ann. Chem. 1904; 333: 296
    • 9b Zincke T, Heuser G, Moller W. Justus Liebigs Ann. Chem. 1904; 330: 361
    • 9c Zincke T, Weisspfenning G. Justus Liebigs Ann. Chem. 1913; 396: 103
    • 10a Baumgarten P. Ber. Dtsch. Chem. Ges. 1924; 57: 1622
    • 10b Baumgarten P. Ber. Dtsch. Chem. Ges. 1925; 58: 2018
    • 10c Baumgarten P. Ber. Dtsch. Chem. Ges. 1926; 59: 1166
    • 10d Becher J. Synthesis 1980; 589
    • 10e Becher J, Finsen L, Winckelmann I. Tetrahedron 1981; 37: 2375
    • 10f Kiselev AS, Gakh AA, Samet AV, Semenov VV. Mendeleev Commun. 1992; 2: 25
    • 10g Bull JA, Mousseau JJ, Pelletier G, Charette AB. Chem. Rev. 2012; 112: 2642
    • 11a Steinhardt SE, Silverston JS, Vanderwal CD. J. Am. Chem. Soc. 2008; 130: 7560
    • 11b Martin DB. C, Vanderwal CD. J. Am. Chem. Soc. 2009; 131: 3472
    • 11c Steinhardt SE, Vanderwal CD. J. Am. Chem. Soc. 2009; 131: 7546
    • 11d Michels TD, Kier MJ, Kearney AM, Vanderwal CD. Org. Lett. 2010; 12: 3093
    • 11e Paton RS, Steinhardt SE, Vanderwal CD, Houk KN. J. Am. Chem. Soc. 2011; 133: 3895
    • 11f Vanderwal CD. J. Org. Chem. 2011; 76: 9555
    • 11g Martin DB. C, Vanderwal CD. Chem. Sci. 2011; 2: 649
    • 11h Martin DB. C, Nguyen LQ, Vanderwal CD. J. Org. Chem. 2012; 77: 17
    • 11i Lam JK, Joseph SB, Vanderwal CD. Tetrahedron Lett. 2015; 56: 3165
  • 12 Michels T, Rhee JU, Vanderwal CD. Org. Lett. 2008; 10: 4787
  • 13 Miyaura N, Yamada K, Suzuki A. Tetrahedron Lett. 1979; 20: 3437
  • 14 Gillis EP, Burke MD. J. Am. Chem. Soc. 2007; 129: 6716
    • 15a Fujii S, Chang SY, Burke MD. Angew. Chem. Int. Ed. 2011; 50: 7862
    • 15b Woerly EM, Roy J, Burke MD. Nat. Chem. 2014; 6: 484
    • 16a Nagao Y, Yamada S, Kumagai T, Ochiai M, Fujita E. J. Chem. Soc., Chem. Commun. 1985; 1418
    • 16b Nagao Y, Hagiwara Y, Kumagai T, Ochiai M, Inoue T, Hashimoto K, Fujita E. J. Org. Chem. 1986; 51: 2391
  • 17 Wittig G, Schöllkopf U. Chem. Ber. 1954; 87: 1318
  • 18 Primdahl KG, Nolsøe JM. J, Aursnes M. Org. Biomol. Chem. 2020; 18: 9050
  • 19 Becher J. Org. Synth. 1979; 59: 79
  • 20 Appel R. Angew. Chem., Int. Ed. Engl. 1975; 14: 801
    • 21a Soullez D, Plé G, Duhamel L, Duhamel P. J. Chem. Soc., Chem. Commun. 1995; 563
    • 21b Vicart N, Castet-Caillabet D, Ramondenc Y, Plé G, Duhamel L. Synlett 1998; 411
  • 22 Cornil J, Echeverria P.-G, Phansavath P, Ratovelomanana-Vidal V, Gueŕinot A, Cossy J. Org. Lett. 2015; 17: 948
  • 23 Wang G, Mohan S, Negishi E. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 11344
  • 24 Pettei MJ, Yudd AP, Nakanishi K, Henselman R, Stoeckenius W. Biochemistry 1977; 16: 1955
    • 25a Bruno NC, Tudge MT, Buchwald SL. Chem. Sci. 2013; 4: 916
    • 25b Bruneau A, Roche M, Alami M, Messaoudi S. ACS Catal. 2015; 5: 1386
  • 26 Reinertsen AF, Primdahl KG, Shay AE, Serhan CN, Hansen TV, Aursnes M. J. Org. Chem. 2021; 86: 3535
    • 27a Mari SH, Varras PC, tia-tul-Wahab Choudhary IM, Siskos MG, Gerothanassis IP. Molecules 2019; 24: 2290
    • 27b Jednačak T, Majerić Elenkov M, Hrenar T, Sović K, Parlov Vuković J, Novak P. New J. Chem. 2020; 44: 6456
  • 28 Epp N, Fürstenberger G, Müller K, de Juanes S, Leitges M, Hausser I, Thieme F, Liebisch G, Schmitz G, Krieg P. J. Cell Biol. 2007; 177: 174
  • 29 Gaschler MM, Stockwell BR. Biochem. Biophys. Res. Commun. 2017; 482: 419
  • 30 Pierens GK. J. Comput. Chem. 2014; 35: 1388
    • 31a Carless HA. J, Batten RJ. J. Chem. Soc., Perkin Trans. 1 1987; 1999
    • 31b Nagata R, Kawakami M, Matsuura T, Saito I. Tetrahedron Lett. 1989; 30: 2817
    • 31c Onyango AN, Nitoda T, Kaneko T, Matsuo M, Nakajima S, Baba N. J. Chem. Soc., Perkin Trans. 1 2002; 1941
  • 32 Møller KH, Tram CM, Kjaergaard HG. J. Phys. Chem. A 2017; 121: 2951
    • 33a Guo F, Xiang S, Li L, Wang B, Rajasärkkä J, Gröndahl-Yli-Hannuksela K, Ai G, Metsä-Ketelä M, Yang K. Metab. Eng. 2015; 28: 134
    • 33b Yoshimura A, Covington BC, Gallant E, Zhang C, Li A, Seyedsayamdost MR. ACS Chem. Biol. 2020; 15: 2766
    • 33c Mao D, Yoshimura A, Wang R, Seyedsayamdost MR. ChemBioChem 2020; 21: 1826
    • 34a Mohamed YM. A, Hansen TV. Tetrahedron 2013; 69: 3872
    • 34b Gudmundsson HG, Kuper CJ, Cornut D, Urbitsch F, Elbert BL, Anderson EA. J. Org. Chem. 2019; 84: 14868