A convergent total synthesis of the kedarcidin chromophore: 20-years in the making

Abstract

The kedarcidin chromophore is a formidible target for total synthesis. Herein, we describe a viable synthesis of this highly unstable natural product. This entailed the early introduction and gram-scale synthesis of 2-deoxysugar conjugates of both l-mycarose and l-kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an epoxyalkyne; (2) α-selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis-configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine-membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive olefination and global HF-deprotection end-game. The longest linear sequence from gram-scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained for the first time.

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References

  1. 1.

    Danishefsky SJ, Shair MD. Observations in the chemistry and biology of cyclic enediyne antibiotics: total syntheses of calicheamicin γ1I and dynemicin A. J Org Chem. 1996;61:16–44.

    CAS  Article  Google Scholar 

  2. 2.

    Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996;39:2103–17.

    CAS  Article  Google Scholar 

  3. 3.

    Xi Z, Goldberg IH. DNA damaging enediyne compounds. In Barton DHR, Nakanishi K, editors. Comprehensive natural product chemistry. Vol. 7 Oxford: Pergamon; 1999. p. 553.

    Google Scholar 

  4. 4.

    Wolkenberg SE, Boger DL. Mechanisms of in situ activation for DNA-targeting antitumor agents. Chem Rev. 2002;102:2477–596.

    CAS  Article  Google Scholar 

  5. 5.

    Glam U, et al. Antitumor antibiotics: bleomycin, enediynes, and mitomycin. Chem Rev. 2005;105:739–58.

    Article  Google Scholar 

  6. 6.

    Hamann PR, Upeslacis J, Borders DB. Enediynes. In Cragg GM, Kingston GGI, Newman DJ, editors. Anticancers agents from natural products. 2nd ed. Boca Raton: CRC Press; 2011. p. 575–621.

    Google Scholar 

  7. 7.

    Hirama M. Design and synthesis of neocarzinostatin analogues. J Synth Org Chem Jpn. 1991;49:1032–42.

    CAS  Article  Google Scholar 

  8. 8.

    Nicolaou KC, Dai W-M. Chemistry and biology of the enediyne anticancer antibiotics. Angew Chem Int Ed Engl. 1991;30:1387–416.

    Article  Google Scholar 

  9. 9.

    Lhermitte H, Grierson DS. The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2. Contemp Org Synth. 1996;3:93–124.

    CAS  Article  Google Scholar 

  10. 10.

    Grissom JW, Gunawardena GU, Klingberg D, Huang D. The chemistry of enediynes, enyne allenes and related compounds. Tetrahedron. 1996;52:6453–518.

    CAS  Article  Google Scholar 

  11. 11.

    Brückner R, Suffert J. The bis (enol triflate) route to dienediyne models of the biradical forming and DNA-cleaving natural product neocarzinostatin chromophore. Synlett. 1999;657–79.

  12. 12.

    Sato I, Hirama M. Recent advances in the synthetic studies of nine-membered enediyne antitumor antibiotics. J Synth Org Chem Jpn. 2010;68:1123–31.

    CAS  Article  Google Scholar 

  13. 13.

    Kobayashi S, et al. The first total synthesis of N1999-A2: absolute stereochemistry and stereochemical implications into DNA cleavage. J Am Chem Soc. 2001;123:11294–5.

    CAS  Article  Google Scholar 

  14. 14.

    Iida K, Hirama M. Synthesis and characterization of nine-membered cyclic enediynes, models of the C-1027 and kedarcidin chromophores: Equilibration with a p-benzyne biradical and kinetic stabilization. J Am Chem Soc. 1995;117:8875–6.

    CAS  Article  Google Scholar 

  15. 15.

    Hirama M. Synthesis and chemistry of chromoprotein antitumor antibiotics: nine-membered enediynes are equilibrated with p-benzyne type biradicals. Pure Appl Chem. 1997;69:525–30.

    CAS  Article  Google Scholar 

  16. 16.

    Myers AG, Hurd AR, Hogan PC. Evidence for facile atropisomerism and simple (non-nucleophilic) biradical-forming cycloaromatization within kedarcidin chromophore aglycon. J Am Chem Soc. 2002;124:4583–5.

    CAS  Article  Google Scholar 

  17. 17.

    Usuki T, et al. Spin trapping of 13C-labeled p-benzynes generated by Masamune–Bergman cyclization of bicyclic nine-membered enediynes. Angew Chem Int Ed. 2004;43:5249–53.

    CAS  Article  Google Scholar 

  18. 18.

    Hirama M, et al. Direct observation of ESR spectra of bicyclic nine-membered enediynes at ambient temperature. Heterocycles. 2006;69:83–89.

    CAS  Article  Google Scholar 

  19. 19.

    Jean M, Tomas S, van de Weghe P. When the nine-membered enediynes play hide and seek. Org Biomol Chem. 2012;10:7453–6.

    CAS  Article  Google Scholar 

  20. 20.

    Nicolaou KC, Tang Y, Wang J. Total synthesis of sporolide B. Angew Chem Int Ed. 2009;48:3449–553.

    CAS  Article  Google Scholar 

  21. 21.

    Nam S-J, et al. Fijiolides A and B, inhibitors of TNF-α-induced NFκB activation, from a marine-derived sediment bacterium of the genus Nocardiopsis. J Nat Prod. 2010;73:1080–6.

    CAS  Article  Google Scholar 

  22. 22.

    Oh D-C, Williams PG, Kauffman CA, Jensen PR, Fenical W. Cyanosporasides A and B, chloro- and cyano-cyclopenta[a]indene glycosides from the marine actinomycete “Salinispora pacifica”. Org Lett. 2006;8:1021–4.

    CAS  Article  Google Scholar 

  23. 23.

    Yamada K, et al. Biomimetic total synthesis of cyanosporaside aglycons from a single enediyne precursor through site-selective p-benzyne hydrochlorination. Angew Chem Int Ed. 2014;53:13902–6.

    CAS  Article  Google Scholar 

  24. 24.

    Lam S, et al. Kedarcidin, a new chromoprotein antitumor antibiotic. I. Taxonomy of producing organism, fermentation and biological activity. J Antibiot. 1991;44:472–8.

    CAS  Article  Google Scholar 

  25. 25.

    Hofstend SJ, Matson JA, Malacko AR, Marquardt H. Kedarcidin, a new chromoprotein antitumor antibiotic II. Isolation, purification and physico-chemical properties. J Antibiot. 1992;45:1250–4.

    Article  Google Scholar 

  26. 26.

    Lohman JR, et al. Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics. Mol BioSyst. 2013;9:478–91.

    CAS  Article  Google Scholar 

  27. 27.

    Leet JE, et al. Kedarcidin, a new chromoprotein antitumor antibiotic: structure elucidation of kedarcidin chromophore. J Am Chem Soc. 1992;114:7946–8.

    CAS  Article  Google Scholar 

  28. 28.

    Leet JE, et al. Chemistry and structure elucidation of the kedarcidin chromophore. J Am Chem Soc. 1993;115:8432–43.

    CAS  Article  Google Scholar 

  29. 29.

    Constantine KL, et al. Sequential 1H, 13C, and 15N-NMR assignments and solution conformation of apokedarcidin. Biochemistry. 1994;33:11438–52.

    CAS  Article  Google Scholar 

  30. 30.

    Zein N, et al. Selective proteolytic activity of the antitumor agent kedarcidin. Proc Natl Acad Sci USA. 1993;90:8009–12.

    CAS  Article  Google Scholar 

  31. 31.

    Kawata S, Ashizawa S, Hirama M. Synthetic study of kedarcidin chromophore: revised structure. J Am Chem Soc. 1997;119:12012–3.

    CAS  Article  Google Scholar 

  32. 32.

    Huanga S-X, Lohmana JR, Huanga T, Shen B. A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway. Proc Nat Acad Sci. 2013;110:8069–74.

    Article  Google Scholar 

  33. 33.

    Ren F, Hogan PC, Anderson AJ, Myers AG. Kedarcidin chromophore: synthesis of its proposed structure and evidence for a stereochemical revision. J Am Chem Soc. 2007;129:5381–3.

    CAS  Article  Google Scholar 

  34. 34.

    Ogawa K, Koyama Y, Ohashi I, Sato I, Hirama M. Total synthesis of a protected aglycon of the kedarcidin chromophore. Angew Chem Int Ed. 2009;48:1110–3.

    CAS  Article  Google Scholar 

  35. 35.

    Das P, Mita T, Lear MJ, Hirama M. Synthesis of 13C-labelled, bicyclic mimetics of natural enediynes. Chem Commun. 2002;2624–5.

  36. 36.

    Koyama Y, et al. Efficient construction of the kedarcidin chromophore ansamacrolide. Org Lett. 2005;7:267–70.

    CAS  Article  Google Scholar 

  37. 37.

    Yoshimura F, Lear MJ, Ohashi I, Koyama Y, Hirama M. Synthesis of the entire carbon framework of the kedarcidin chromophore. Chem Commun. 2007;3057–9.

  38. 38.

    Ogawa K, Koyama Y, Ohashi I, Sato I Hirama M. Secure route to the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore. Chem Commun. 2008;6327–9.

  39. 39.

    Lear MJ, Hirama M. Convenient route to derivatives of the 2-deoxysugar subunits of the kedarcidin chromophore: L-mycarose and L-kedarosamine. Tetrahedron Lett. 1999;40:4897–900.

    CAS  Article  Google Scholar 

  40. 40.

    Lear MJ, Yoshimura F, Hirama M. A direct and efficient α‐selective glycosylation protocol for the kedarcidin sugar, L-mycarose: AgPF6 as a remarkable activator of 2-deoxythioglycosides. Angew Chem Int Ed. 2001;40:946–9.

    CAS  Article  Google Scholar 

  41. 41.

    Ohashi I, Lear MJ, Yoshimura F, Hirama M. Use of polystyrene-supported DBU in the synthesis and α-selective glycosylation study of the unstable schmidt donor of L-kedarosamine. Org Lett. 2004;6:719–22.

    CAS  Article  Google Scholar 

  42. 42.

    Shiina I, Ibuka R, Kubota M. A new condensation reaction for the synthesis of carboxylic esters from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride. Chem Lett. 2002;286.

    Article  Google Scholar 

  43. 43.

    Shiina I, Kubota M, Ibuka R. A novel and efficient macrolactonization of ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride (MNBA). Tetrahedron Lett. 2002;43:7535–9.

    CAS  Article  Google Scholar 

  44. 44.

    Sakaitani M, Ohfune Y. Syntheses and reactions of silyl carbamates. 1. Chemoselective transformation of amino protecting groups via tert-butyldimethylsilyl carbamates. J Org Chem. 1990;55:870–6.

    CAS  Article  Google Scholar 

  45. 45.

    Carpino LA. 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J Am Chem Soc. 1993;115:4397–8.

    CAS  Article  Google Scholar 

  46. 46.

    Chemla F, Bernard N, Ferreira F, Normant JF. Preparation of propargylic carbenoids and reactions with carbonyl compounds—a stereoselective synthesis of propargylic halohydrins and oxiranes. Eur J Org Chem. 2001;3295–300.

    Article  Google Scholar 

  47. 47.

    Baker JR, Thominet O, Britton H, Caddick S. An efficient synthesis of epoxydiynes and a key fragment of neocarzinostatin chromophore. Org Lett. 2007;9:45–8.

    CAS  Article  Google Scholar 

  48. 48.

    Veeneman GH, van Leeuwen SH, van Boom JH. Iodonium ion promoted reactions at the anomeric centre. II. An efficient thioglycoside mediated approach toward the formation of 1,2-trans linked glycosides and glycosidic esters. Tetrahedron Lett. 1990;31:1331–4.

    CAS  Article  Google Scholar 

  49. 49.

    Matsumoto T, Maeta H, Suzuki K, Tsuchihashi G. New glycosidation reaction 1: combinational use of Cp2ZrCl2-AgClO4 for activation of glycosyl fluorides and application to highly β-selective gylcosidation of D-mycinose. Tetrahedron Lett. 1988;29:3567–70.

    CAS  Article  Google Scholar 

  50. 50.

    Suzuki K, Maeta H, Matsumoto T, Tsuchihashi G. New glycosidation reaction 2. Preparation of 1-fluoro-d-desosamine derivative and its efficient glycosidation by the use of Cp2HfCl2-AgClO4 as the activator. Tetrahedron Lett. 1988;29:3571–4.

    CAS  Article  Google Scholar 

  51. 51.

    Mitsunobu O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis. 1981;1–28.

    Article  Google Scholar 

  52. 52.

    Sugimura T, Hagiya K. Di-2-methoxyethyl azodicarboxylate (DMEAD): an inexpensive and separation-friendly alternative reagent for the Mitsunobu reaction. Chem Lett. 2007;36:566–7.

    CAS  Article  Google Scholar 

  53. 53.

    Kaburagi Y, Osajima H, Shimada K, Tokuyama H, Fukuyama T. 4-(tert-Butyldimethylsilyloxy) benzylidene acetal: a novel benzylidene-type protecting group for 1, 2-diols. Tetrahedron Lett. 2004;19:3817–21.

    Article  Google Scholar 

  54. 54.

    Jobron L, Hindsgaul O. Novel para-substituted benzyl ethers for hydroxyl group protection. J Am Chem Soc. 1999;121:5835–6.

    CAS  Article  Google Scholar 

  55. 55.

    Imamoto T, Kusumoto T, Tawarayama Y, Sugiura Y, Mita T, Hatanaka Y, Yokoyama M. Carbon-carbon bond-forming reactions using cerium metal or organocerium(III) reagents. J Org Chem. 1984;49:3904–12.

    CAS  Article  Google Scholar 

  56. 56.

    Imamoto T, Takiyama N, Nakamura K, Hatajima T, Kamiya Y. Reactions of carbonyl compounds with Grignard reagents in the presence of cerium chloride. J Am Chem Soc. 1989;111:4392–8.

    CAS  Article  Google Scholar 

  57. 57.

    Nishikawa T, Isobe M, Goto T. Synthetic studies on the bicyclo[7.3.1]tridecenediyne system in an antitumor antibiotic, dynemicin A. Synlett. 1991;393–4.

    Article  Google Scholar 

  58. 58.

    Myers AG, Harrington PM, Kuo EY. Enantioselective synthesis of the epoxy diyne core of neocarzinostatin chromophore. J Am Chem Soc. 1991;113:694–5.

    CAS  Article  Google Scholar 

  59. 59.

    Iida K-i, Hirama M. Efficient route to the nine-membered cyclic diyne system: tuning of the extremely facile Cope rearrangment of 1,5-diyne. J Am Chem Soc. 1994;116:10310–1.

    CAS  Article  Google Scholar 

  60. 60.

    Sonogashira K, Tohda Y, Hagihara N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett. 1975;16:4467–70.

    Article  Google Scholar 

  61. 61.

    Shiina I, Kubota M, Oshiumi H, Hashizume M. An effective use of benzoic anhydride and its derivatives for the synthesis of carboxylic esters and lactones: a powerful and convenient mixed anhydride method promoted by basic catalysts. J Org Chem. 2004;69:1822–30.

    CAS  Article  Google Scholar 

  62. 62.

    Komano K, Shimamura S, Inoue M, Hirama M. Total synthesis of the maduropeptin chromophore aglycon. J Am Chem Soc. 2007;129:14184–6.

    CAS  Article  Google Scholar 

  63. 63.

    Inoue M, Ohashi I, Kawaguchi T, Hirama M. Total synthesis of the C-1027 chromophore core: extremely facile enediyne formation through Sml2-mediated 1,2-elimination. Angew Chem Int Ed. 2008;47:1777–9.

    CAS  Article  Google Scholar 

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Acknowledgements

This work represents over 20-years of collective effort (1997–2017) and was latterly supported by a Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), SORST (Japan), as well as the Science and Technology Agency (JST), Japanese Society for the Promotion of Science, Fellowship and Multidimensional Materials Science Leaders Program (to MJL). We are especially grateful to Dr. John E. Leet at Bristol-Myers Squibb for kindly providing original chromoprotein material and the 1H NMR spectra of the natural kedarcidin chromophore.

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Dedication: Dedicated to Professor Samuel J. Danishefsky for his outstanding contributions to the total synthesis of highly complex and biologically important natural products.

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Lear, M.J., Hirai, K., Ogawa, K. et al. A convergent total synthesis of the kedarcidin chromophore: 20-years in the making. J Antibiot 72, 350–363 (2019). https://doi.org/10.1038/s41429-019-0175-y

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