Total Synthesis of Bis-anthraquinone Antibiotic BE-43472B

Abstract

This is a full account of our synthetic endeavor on the total synthesis of bis-anthraquinone antibiotic BE-43472B, an unusual octacyclic aromatic polyketide with a bis-anthraquinone scaffold. Three key steps enabled a facile access to the anthraquinone unit corresponding to the ABCF rings; (1) cyclo-condensation or -addition of benzonitrile oxides with cyclic enone derivatives, (2) benzoin cyclization for the stereoselective ring fusion with an angular hydroxy group, and (3) pinacol rearrangement for stereoselective installation of the angular aryl group. Other keys for the success include, (4) diastereoselective methylation of a lactol derivative, and (5) late-stage installation of the C3 hydroxy group through stereoselective oxirane ring formation via halohydrin derivatives. Whereas oxidation of the double bond in the enone with an adjacent 1,3-diketone moiety failed, the projected oxidation was achieved with the alkene keeping the isoxazole moiety intact as a 1,3-diketone equivalent. In the racemic total synthesis, X-ray crystal structure analysis of the target was achieved, proving the three-dimensional architecture for the first time. The asymmetric total synthesis was also achieved by exploiting a cycloadduct of the nitrile oxide and the enantiomerically pure cyclohexenone, which was convertible to the common intermediate via dehydrogenation followed by alkoxycarbonylation.

Key words

antibiotics - bis-anthraquinone - isoxazole - natural products - total synthesis

• References

• 1 Current address: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan).
• 2 Kushida H. Nakajima S. Koyama T. Suzuki H. Ojiri K. Suda H. JP 08143569, 1996
• 3a Socha AM. Garcia D. Sheffer R. Rowley DC. J. Nat. Prod. 2006; 69: 1070
• 3b Socha AM. LaPlante KL. Rowley DC. Bioorg. Med. Chem. 2006; 14: 8446
• 4a Thomas R. ChemBioChem 2001; 2: 612
• 4b Hertweck C. Luzhetskyy A. Rebets Y. Bechthold A. Nat. Prod. Rep. 2007; 24: 162
• 4c Staunton J. Weissman KJ. Nat. Prod. Rep. 2001; 18: 380
• 4d Rawlings BJ. Nat. Prod. Rep. 1999; 16: 425
• 4e Zhou H. Li Y. Tang Y. Nat. Prod. Rep. 2010; 27: 839
• 5 Thomson RH. Naturally Occurring Quinones:Recent Advances . Blackie; London: 1997. 4th ed.

For the studies of unusual bisanthraquinone natural products with a cage-like structure, see:
• 6a Takeda N. Seo S. Ogihara Y. Sankawa U. Iitaka I. Kitagawa I. Shibata S. Tetrahedron 1973; 29: 3703
• 6b Ogihara Y. Kobayashi N. Shibata S. Tetrahedron Lett. 1968; 9: 1881
• 6c Seo S. Sankawa U. Shibata S. Tetrahedron Lett. 1972; 13: 731
• 6d Shibata S. Pure Appl. Chem. 1973; 33: 109
• 6e Seo S. Sankawa U. Ogihara Y. Iitaka Y. Shibata S. Tetrahedron 1973; 29: 3721
• 6f Yang D.-M. Sankawa U. Ebizuka Y. Shibata S. Tetrahedron 1976; 32: 333
• 6g Nicolaou KC. Papageorgiou CD. Piper JL. Chadha RK. Angew. Chem. Int. Ed. 2005; 44: 5846
• 6h Nicolaou KC. Lim YH. Papageorgiou CD. Piper JL. Angew. Chem. Int. Ed. 2005; 44: 7917
• 6i Nicolaou KC. Lim YH. Piper JL. Papageorgiou CD. J. Am. Chem. Soc. 2007; 129: 4001
• 7a Nicolaou KC. Lim YH. Becker J. Angew. Chem. Int. Ed. 2009; 48: 3444
• 7b Nicolaou KC. Becker J. Lim YH. Lemire A. Neubauer T. Montero A. J. Am. Chem. Soc. 2009; 131: 14812
• 7c Hayden AE. Paton RS. Becker J. Lim YH. Nicolaou KC. Houk KN. J. Org. Chem. 2010; 75: 922
• 7d Highlight: Rowley DC. Nat. Chem. 2009; 1: 110
• 8 Yamashita Y. Hirano Y. Takada A. Takikawa H. Suzuki K. Angew. Chem. Int. Ed. 2013; 52: 6658
• 9a Bode JW. Hachisu Y. Matuura T. Suzuki K. Tetrahedron Lett. 2003; 44: 3555
• 9b Bode JW. Hachisu Y. Matsuura T. Suzuki K. Org. Lett. 2003; 5: 391
• 9c Matsuura T. Bode JW. Hachisu Y. Suzuki K. Synlett 2003; 1746
• 9d Takikawa H. Hikita K. Suzuki K. Synlett 2007; 2252
• 10a Hashimoto Y. Takikawa H. Takada A. Suzuki K. Org. Biomol. Chem. 2012; 10: 6003
• 10b Takikawa H. Hashimoto Y. Suzuki K. Chem. Lett. 2014; 43: 1607
• 11a Hachisu Y. Bode JW. Suzuki K. J. Am. Chem. Soc. 2003; 125: 8432
• 11b Hachisu Y. Bode JW. Suzuki K. Adv. Synth. Catal. 2004; 346: 1097
• 11c Takikawa H. Hachisu Y. Bode JW. Suzuki K. Angew. Chem. Int. Ed. 2006; 45: 3492
• 11d Takikawa H. Suzuki K. Org. Lett. 2007; 9: 2713
• 12a Koyama Y. Yamaguchi R. Suzuki K. Angew. Chem. Int. Ed. 2008; 47: 1084
• 12b Takada A. Hashimoto Y. Takikawa H. Hikita K. Suzuki K. Angew. Chem. Int. Ed. 2011; 50: 2297
• 12c Takikawa H. Ishikawa Y. Yoshinaga Y. Hashimoto Y. Kusumi T. Suzuki K. Bull. Chem. Soc. Jpn. 2016; 89: 941
• 12d Sato S. Sakata K. Hashimoto Y. Takikawa H. Suzuki K. Angew. Chem. Int. Ed. 2017; 56: 12608
• 13 Suzuki K. Takikawa H. Hachisu Y. Bode JW. Angew. Chem. Int. Ed. 2007; 46: 3252
• 14a Stork G. Danishefsky S. Ohashi M. J. Am. Chem. Soc. 1967; 89: 5459
• 14b Stagno D’Alcontres G. Gazz. Chim. Ital. 1950; 80: 441
• 14c Kashima C. Heterocycles 1979; 12: 1343
• 14d Baraldi PG. Barco A. Benetti S. Pollini GP. Simoni D. Synthesis 1987; 857
• 14e Kotyatkina AI. Zhabinsky VN. Khripach VA. Russ. Chem. Rev. 2001; 70: 641
• 15 Takikawa H. Hikita K. Suzuki K. Angew. Chem. Int. Ed. 2008; 47: 9887
• 16a Smith MB. March J. In March’s Advanced Organic Chemistry . Wiley; New York: 2001. 5th ed. 435
• 16b Isaacs N. Physical Organic Chemistry . Longman Scientific Technical; Harlow, Essex: 1995. 2nd ed. 454
• 17a Miyashita M. Suzuki T. Yoshikoshi A. Tetrahedron Lett. 1987; 28: 4293
• 17b Miyashita M. Suzuki T. Hoshino M. Yoshikoshi A. Tetrahedron 1997; 53: 12469
• 18 Savard J. Brassard P. Tetrahedron 1984; 40: 3455
• 19a Payack JF. Hughes DL. Cai D. Cottrell IF. Verhoeven TR. Org. Synth. 2002; 79: 19
• 19b Petasis NA. Bzowej EI. J. Am. Chem. Soc. 1990; 112: 6392
• 20 Edafiogho IO. Hinko CN. Chang H. Moore JA. Mulzac D. Nicholson JM. Scott KR. J. Med. Chem. 1992; 35: 2798
• 21 Stetter H. Angew. Chem. Int. Ed. 1976; 15: 639
• 22 Dudding T. Houk KN. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 5770
• 23a Tietze LF. Singidi RR. Gericke KM. Chem.–Eur. J. 2007; 13: 9939
• 23b Tietze LF. Gericke KM. Schuberth I. Eur. J. Org. Chem. 2007; 4563
• 24a Fujisaki S. Eguchi H. Omura A. Akamoto A. Nishida A. Bull. Chem. Soc. Jpn. 1993; 66: 1576
• 24b Uno H. Sakamoto K. Honda E. Fukuhara K. Ono N. Tanaka J. Sakanaka M. J. Chem. Soc. Perkin Trans. 1 2001; 229
• 25 The relative stereochemistry of enaminone 32 was determined by the NOE correlations (Figure 5).
• 26 Mukaiyama T. Matsuo J. Kitagawa H. Chem. Lett. 2000; 29: 1250
• 27a Ohmori K. Tamiya M. Kitamura M. Kato H. Oorui M. Suzuki K. Angew. Chem. Int. Ed. 2005; 44: 3871
• 27b Tamiya M. Ohmori K. Kitamura M. Kato H. Arai T. Oorui M. Suzuki K. Chem.–Eur. J. 2007; 13: 9791
• 28 Olah GA. Olah JA. J. Org. Chem. 1965; 30: 2386
• 29a Murray RW. Jeyaraman R. J. Org. Chem. 1985; 50: 2847
• 29b Murray RW. Chem. Rev. 1989; 89: 1187
• 29c Adam W. Bialas J. Hadjiarapoglou L. Chem. Ber. 1991; 124: 2377
• 29d Murray RW. Singh M. Org. Synth. 1997; 74: 91
• 30a Nunno LD. Scilimati A. Vitale P. Tetrahedron 2005; 61: 11270
• 30b Rajanarendar E. Mohan G. Ramesh P. Karunakar D. Tetrahedron Lett. 2006; 47: 4957
• 30c Adamo MF. A. Nagabelli M. Tetrahedron Lett. 2007; 48: 4703
• 31 Tomooka K. Matsuzawa K. Suzuki K. Tsuchihashi G. Tetrahedron Lett. 1987; 28: 6339
• 32 CCDC 1538315 (β-38), 923754 (42), and 925606 (rac-2) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.au.uk/data_request/cif.
• 33 Miyashita M. Hoshino M. Yoshikoshi A. J. Org. Chem. 1991; 56: 6483

For lithiation of isoxazole derivatives, see:
• 34a Gainer J. Howarth GA. Hoyle W. Roberts SM. Suschitzky H. J. Chem. Soc., Perkin Trans. 1 1976; 994
• 34b Natale NR. Quincy DA. Synth. Commun. 1983; 13: 817
• 35a Reich HJ. Reich IL. Renga JM. J. Am. Chem. Soc. 1973; 95: 5813
• 35b Sharpless KB. Lauer RF. Teranishi AY. J. Am. Chem. Soc. 1973; 95: 6137
• 36 Liotta D. Saindane M. Barnum C. Zima G. Tetrahedron 1985; 41: 4881
• 37 Ali MH. Niedbalski M. Bohnert G. Bryant D. Synth. Commun. 2006; 36: 1751
• 38a Procopiou PA. Baugh SP. D. Flack SS. Inglis GG. A. J. Org. Chem. 1998; 63: 2342
• 38b Procopiou PA. Baugh SP. D. Flack SS. Inglis GG. A. Chem. Commun. 1996; 2625
• 39 Urankar D. Rutar I. Modec B. Dolenc D. Eur. J. Org. Chem. 2005; 2349
• 40a Konradsson P. Mootoo DR. McDevitt RE. Fraser-Reid B. J. Chem. Soc., Chem. Commun. 1990; 270
• 40b Lambert FL. Ellis WD. Parry RJ. J. Org. Chem. 1965; 30: 304
• 40c Olah GA. Wang Q. Sandford G. Prakash GK. S. J. Org. Chem. 1993; 58: 3194
• 41 Epoxide formation from bromo-acetates 51 and 52 was unsuccessful (Scheme 20): Upon treatment of bromo-acetate 51 with K₂CO₃ in MeOH, epoxide 56 was obtained in only 16% yield along with many byproducts. Worse still, the reaction of regioisomeric bromo-acetate 52 under the same conditions did not afford epoxide 56, giving only a complex mixture. These results could be ascribed to the slow solvolysis of acetates, especially for sterically congested acetate 52.
• 42 For isoxazole → benzisoxazole rearrangement reported by our group, see: Bode JW. Uekusa H. Suzuki K. Org. Lett. 2003; 5: 395
• 43a Bauman JG. Hawley RC. Rapoport H. J. Org. Chem. 1985; 50: 1569
• 43b Tsuchiya T. Ohmuro S. Tetrahedron Lett. 2002; 43: 611
• 43c Adachi S. Watanabe K. Iwata Y. Kameda S. Miyaoka Y. Onozuka M. Mitsui R. Saikawa Y. Nakata M. Angew. Chem. Int. Ed. 2013; 52: 2087
• 44 Nitta M. Kobayashi T. J. Chem. Soc., Perkin Trans. 1 1985; 1401
• 45a Mutti S. Daubié C. Decalogne F. Fournier R. Rossi P. Tetra­hedron Lett. 1996; 37: 3125
• 45b Miyashita M. Sasaki M. Hattori I. Sakai M. Tanino K. Science (Washington, D. C.) 2004; 305: 495
• 46 In the isolation paper (ref. 3a), it was mentioned that ‘Attempts to prepare crystals suitable for X-ray analysis were unsuccessful’.
• 47a Wallach O. Justus Liebigs Ann. Chem. 1895; 286: 90
• 47b Brock CP. Schweizer WB. Dunitz JD. J. Am. Chem. Soc. 1991; 113: 9811