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.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
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.
Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996;39:2103–17.
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.
Wolkenberg SE, Boger DL. Mechanisms of in situ activation for DNA-targeting antitumor agents. Chem Rev. 2002;102:2477–596.
Glam U, et al. Antitumor antibiotics: bleomycin, enediynes, and mitomycin. Chem Rev. 2005;105:739–58.
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.
Hirama M. Design and synthesis of neocarzinostatin analogues. J Synth Org Chem Jpn. 1991;49:1032–42.
Nicolaou KC, Dai W-M. Chemistry and biology of the enediyne anticancer antibiotics. Angew Chem Int Ed Engl. 1991;30:1387–416.
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.
Grissom JW, Gunawardena GU, Klingberg D, Huang D. The chemistry of enediynes, enyne allenes and related compounds. Tetrahedron. 1996;52:6453–518.
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.
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.
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.
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.
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.
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.
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.
Hirama M, et al. Direct observation of ESR spectra of bicyclic nine-membered enediynes at ambient temperature. Heterocycles. 2006;69:83–89.
Jean M, Tomas S, van de Weghe P. When the nine-membered enediynes play hide and seek. Org Biomol Chem. 2012;10:7453–6.
Nicolaou KC, Tang Y, Wang J. Total synthesis of sporolide B. Angew Chem Int Ed. 2009;48:3449–553.
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.
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.
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.
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.
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.
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.
Leet JE, et al. Kedarcidin, a new chromoprotein antitumor antibiotic: structure elucidation of kedarcidin chromophore. J Am Chem Soc. 1992;114:7946–8.
Leet JE, et al. Chemistry and structure elucidation of the kedarcidin chromophore. J Am Chem Soc. 1993;115:8432–43.
Constantine KL, et al. Sequential 1H, 13C, and 15N-NMR assignments and solution conformation of apokedarcidin. Biochemistry. 1994;33:11438–52.
Zein N, et al. Selective proteolytic activity of the antitumor agent kedarcidin. Proc Natl Acad Sci USA. 1993;90:8009–12.
Kawata S, Ashizawa S, Hirama M. Synthetic study of kedarcidin chromophore: revised structure. J Am Chem Soc. 1997;119:12012–3.
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.
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.
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.
Das P, Mita T, Lear MJ, Hirama M. Synthesis of 13C-labelled, bicyclic mimetics of natural enediynes. Chem Commun. 2002;2624–5.
Koyama Y, et al. Efficient construction of the kedarcidin chromophore ansamacrolide. Org Lett. 2005;7:267–70.
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.
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.
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.
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.
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.
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.
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.
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.
Carpino LA. 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J Am Chem Soc. 1993;115:4397–8.
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.
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.
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.
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.
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.
Mitsunobu O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis. 1981;1–28.
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.
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.
Jobron L, Hindsgaul O. Novel para-substituted benzyl ethers for hydroxyl group protection. J Am Chem Soc. 1999;121:5835–6.
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.
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.
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.
Myers AG, Harrington PM, Kuo EY. Enantioselective synthesis of the epoxy diyne core of neocarzinostatin chromophore. J Am Chem Soc. 1991;113:694–5.
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.
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.
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.
Komano K, Shimamura S, Inoue M, Hirama M. Total synthesis of the maduropeptin chromophore aglycon. J Am Chem Soc. 2007;129:14184–6.
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.
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.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dedication: Dedicated to Professor Samuel J. Danishefsky for his outstanding contributions to the total synthesis of highly complex and biologically important natural products.
Rights and permissions
About this article
Cite this article
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