Towards the Rubromycins: An Efficient Synthesis of a Suitable Isocoumarin Precursor, its Lactam Analogue, and Palladium-Catalyzed Couplings

Abstract

6-Iodoisocoumarin 4 and its aza-analogue, 6-iodo-1-oxo-isoquinoline 29, were efficiently prepared from vanillin in seven and six steps, respectively. Key transformations in their syntheses were achieved by directed ortho-lithiation and variations of Horner-Wadsworth-Emmons reactions. Both 6-iodoisocoumarin 4 and its aza-analogue were designed for insertion into syntheses of rubromycin type target structures via palladium-catalyzed coupling reactions. For the isocoumarin subunit, this plan could be confirmed through Heck, Sonogashira, and Suzuki reactions of our building block with various substrates.

Key words

isocoumarins - rubromycins - ortho-lithiation - Horner-Wadsworth-Emmons reaction - palladium catalysis

References

• 1 Barry RD. Chem. Rev.  1964,  64:  239 
• Selected examples:
• 2a Sturtz G. Meepagala K. Wedge D. J. Agric. Food Chem.  2002,  50:  6989 
• 2b Krupke OA. Castle AJ. Rinker DL. Mycol. Res.  2003,  107:  1467 
• Selected examples:
• 3a Whyte AC. Gloer JB. Scott JA. Malloch D. J. Nat. Prod.  1996,  59:  765 
• 3b Cai Y. Kleiner H. Johnston D. Dubowski A. Botic S. Ivie W. Di Giovanni J. Carcinogenesis  1997,  18:  1521 
• 3c Devienne KF. Raddi MSG. Varanda EA. Vilegas W. Z. Naturforsch., C: J. Biosci.  2002,  57:  85 
• 3d Rossi R. Carpita A. Bellina F. Stabile P. Mannina L. Tetrahedron  2003,  59:  2067 
• 3e Lim D.-S. Kwak Y.-S. Kim J.-H. Ko S.-H. Yoon W.-H. Kim C.-H. Chemotherapy  2003,  49:  146 
• 4 Powers JC. Asgian JL. Ekici D. James KE. Chem. Rev.  2002,  102:  4639 ; and references therein
• Isolation and structure elucidation of α-, β-, and γ-rubromycin:
• 5a Brockmann H. Lenk W. Schwantje G. Zeeck A. Tetrahedron Lett.  1966,  3525 
• 5b Brockmann H. Lenk W. Schwantje G. Zeeck A. Chem. Ber.  1969,  102:  126 
• 5c Brockmann H. Zeeck A. Chem. Ber.  1970,  103:  1709 
• 5d Puder C. Loya S. Hizi A. Zeeck A. Eur. J. Org. Chem.  2000,  729 
• Isolation and structure elucidation of purpuromycin:
• 5e Coronelli C. Pagani H. Bardone MR. J. Antibiot.  1973,  27:  161 
• 5f Bardone MR. Martinelli E. Zerilli LF. Coronelli C. Tetrahedron  1974,  30:  2747 
• Isolation and structure elucidation of heliquinomycin:
• 5g Chino M. Nishikawa K. Umekita M. Hayashi C. Yamazaki T. Tsuichida T. Sawa T. Hamada M. Takeuchi T. J. Antibiot.  1996,  49:  752 
• 5h Chino M. Nishikawa K. Tsuchida T. Sawa R. Nakamura H. Nakamura KT. Muraoka Y. Ikeda D. Naganawa H. Sawa T. Takeuchi T. J. Antibiot.  1997,  50:  143 
• 6a α- and β-Rubromycin inhibit human DNA polymerase as well as HIV reverse transcriptase: Mizushina Y. Ueno T. Oda M. Yamaguchi T. Saneyoshi M. Sakaguchi K. Biochim. Biophys. Acta  2000,  1523:  172 
• 6b Purpuromycin and other rubromycins inhibit human telomerase: Ueno T. Takahashi H. Oda M. Mizunuma M. Yokoyama A. Goto Y. Mizushima Y. Sakaguchi K. Hayashi H. Biochemistry  2000,  39:  5995 
• 6c Heliquinomycin is an inhibitor of human DNA helicase: Chino M. Nishikawa K. Yamada A. Ohsono M. Sawa T. Hanaoka F. Ishizuka M. Takeuchi T. J. Antibiot.  1998,  51:  480 
• 7a Capecchi T. de Koning CB. Michael JP. J. Chem. Soc., Perkin Trans. 1  2000,  2681 
• 7b Total synthesis of the heliquinomycin aglycone: Siu T. Qin D. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4713 ; Angew. Chem. 2001, 113, 4849
• 7c Tsang KY. Brimble MA. Bremner JB. Org. Lett.  2003,  5:  4425 
• 8a Trash TP. Welton TD. Behar V. Tetrahedron Lett.  2000,  41:  29 
• 8b Qin D. Ren RX. Siu T. Zheng C. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4709 ; Angew. Chem. 2001, 113, 4845
• 8c Waters SP. Kozlowski MC. Tetrahedron Lett.  2001,  42:  3567 
• 8d Xie X. Kozlowski MC. Org. Lett.  2001,  3:  2661 
• 9 Preliminary communication: Brasholz M. Reissig H.-U. Synlett  2004,  2736 
• 10a Heck RF. Nolley JP. J. Am. Chem. Soc.  1968,  90:  5518 
• 10b Heck RF. Acc. Chem. Res.  1979,  12:  146 
• 10c Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
• 10d Bräse S. de Meijere A. In Metal-Catalyzed Cross-Coupling Reactions   2nd ed.:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
• 11a Azap C. Dissertation   Freie Universität Berlin; Germany: 2004. 
• 11b

  Sörgel, S. unpublished results, Freie Universität Berlin, Germany, 2004.

• 13 Chatterjea JN. Banerjee BK. Jha HC. Chem. Ber.  1965,  98:  3279 ; see also refs. 8a,8b
• 14 Oberhauser T. J. Org. Chem.  1997,  62:  4504 
• 15 The crude 8-demethylated product was obtained in 96% yield and not purified further: Luan X. Master Thesis   Freie Universität Berlin; Germany: 2002. mp 189-192 °C (Lit. 195 °C)
• 16a Horner L. Hoffmann H. Wippel HG. Klahre G. Chem. Ber.  1959,  92:  2499 
• 16b Wadsworth WS. Emmons WO. J. Am. Chem. Soc.  1961,  83:  1733 
• 16c Boutagy J. Thomas R. Chem. Rev.  1974,  74:  87 
• 16d Maryanoff BE. Reitz AB. Chem. Rev.  1989,  89:  863 
• 17a Hu Y.-Z. Clive DLJ. J. Chem. Soc., Perkin Trans. 1  1997,  1421 
• 17b Hill RA. Kirby GW. O’Loughlin GJ. Robins DJ. J. Chem. Soc., Perkin Trans. 1  1993,  1967 
• Selected examples involving aromatic acetals:
• 18a Plaumann HP. Keay BA. Rodrigo R. Tetrahedron Lett.  1979,  4921 
• 18b Winkle MR. Ronald RC. J. Org. Chem.  1982,  47:  2101 
• 18c Napolitano E. Giannone E. Fiaschi R. Marsili A. J. Org. Chem.  1983,  48:  3653 
• 18d Li C. Lobkovsky E. Porco JA. J. Am. Chem. Soc.  2000,  122:  10484 
• 18e Review: Snieckus V. Chem. Rev.  1990,  90:  879 
• 19 Hajipour AR. Arbabian M. Ruoho AE. J. Org. Chem.  2002,  67:  8622 
• 20a α-Bromination of methyl methoxyacetate: Gagliardi S. Nadler G. Consolandi E. Parini C. Morvan M. Legave M.-N. Belfiore P. Zocchetti A. Clarke GD. James I. Nambi P. Gowen M. Farina C. J. Med. Chem.  1998,  41:  1568 
• 20b Arbuzov reaction to 15: Guay V. Brassard P. Synthesis  1987,  294 
• 21 This diastereomeric ratio is in agreement with previously reported observations: Seneci P. Leger I. Souchet M. Nadler G. Tetrahedron  1997,  53:  17097 
• 22a Horne D. Gaudino J. Thompson WJ. Tetrahedron Lett.  1984,  25:  3529 
• 22b Itoh H. Kaneko T. Tanami K. Yoda K. Bull. Chem. Soc. Jpn.  1988,  61:  3356 
• 23a Regitz M. Anschütz W. Liedhegener A. Chem. Ber.  1968,  101:  3734 
• 23b Maas G. Regitz M. Chem. Ber.  1976,  109:  2039 
• 24 Nakamura Y. Ukita T. Org. Lett.  2002,  4:  2317 
• 25a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 
• 25b Sonogashira K. J. Organomet. Chem.  2002,  653:  46 
• 25c Marsden JA. Haley MM. In Metal-Catalyzed Cross-Coupling Reactions   2nd ed.:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
• 26a Jeffery T. J. Chem. Soc., Chem. Commun.  1984,  1287 
• 26b Jeffery T. Tetrahedron Lett.  1985,  26:  2667 
• 27a Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
• 27b Miyaura N. In Metal-Catalyzed Cross-Coupling Reactions   2nd ed.:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
• 28 Wright SW. Hageman DL. McClure LD. J. Org. Chem.  1994,  59:  6095 
• 29 Beletskaya IP. Ganina OG. Tsvetkov AV. Fedorov AY. Finet J.-P. Synlett  2004,  2797 
• 30 Hiebl J. Kollmann H. Levinson SH. Offen P. Shetzline SB. Badlani R. Tetrahedron Lett.  1999,  40:  7935 
• 31 Ferris L. Haigh D. Moody CJ. J. Chem. Soc., Perkin Trans. 1  1996,  2885 
• 32 Cardona L. Fernandez I. Garcia B. Pedro JR. Tetrahedron  1986,  42:  2725 
• 33 Gopinath R. Haque SJ. Patel BK. J. Org. Chem.  2002,  67:  5842 

12

Opianic acid (5) was prepared according to ref. 18c.