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Synthesis of lactones using substituted benzoic anhydride as a coupling reagent

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Abstract

This protocol describes a procedure for the synthesis of a 29-membered macrolactone. The facile mixed-anhydride method is very effective for the preparation of carboxylic esters and lactones using substituted benzoic anhydrides by the promotion of Lewis acid or basic catalysts under mild reaction conditions. Owing to the reaction rapidly proceeding to produce the monomeric compounds with high chemoselectivity, the protocol is quite powerful for the synthesis of not only the giant-sized lactones but also the highly strained cyclic compounds such as medium-sized lactones. The remarkable efficiency of the lactonizations promoted by the substituted benzoic anhydrides has been already shown in the synthesis of many natural complex molecules. It takes approximately 19 h to complete the protocol: 0.5 h to set up the reaction, 13.5 h for the reaction and 5 h for isolation and purification.

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Change history

  • 11 October 2007

    In the version of this article initially published online, on p. 2312, right-hand column, the sentence that began with “This reaction could be promoted by an acidic or basic activator, such as Lewis acids, 4-dimethylaminopyridine N-oxide (DMAP or DMAPO)” should have read “This reaction could be promoted by an acidic or basic activator, such as Lewis acids, DMAP or 4-dimethylaminopyridine N-oxide (DMAPO)”. This error has been corrected in all versions of the article.

References

  1. Lukacs, G. & Ohno, M. Recent Progress in the Chemical Synthesis of Antibiotics (Springer-Verlag, Berlin, 1990).

    Book  Google Scholar 

  2. Omura, S. Macrolide Antibiotics, 2nd edn. (Academic Press, San Diego, CA, 2002).

    Google Scholar 

  3. Nicolaou, K.C. Synthesis of macrolides. Tetrahedron 33, 683–710 (1977).

    Article  CAS  Google Scholar 

  4. Masamune, S., Bates, G.S. & Corcoran, J.W. Macrolides recent progress in chemistry and biochemistry. Angew. Chem. Int. Ed. Engl. 16, 585–607 (1977).

    Article  CAS  Google Scholar 

  5. Paterson, I. & Mansuri, M.M. Recent developments in the total synthesis of macrolide antibiotics. Tetrahedron 41, 3569–3624 (1985).

    Article  CAS  Google Scholar 

  6. Mulzer, J. Synthesis of esters, activated esters and lactones. in Comprehensive Organic Synthesis Vol. 6 (eds. Trost, B.M. & Fleming, I.) 323–380 (Pergamon Press, Oxford, 1991).

    Chapter  Google Scholar 

  7. Rousseau, G. Medium ring lactones. Tetrahedron 51, 2777–2849 (1995).

    Article  CAS  Google Scholar 

  8. Norcross, R.D. & Paterson, I. Total synthesis of bioactive marine macrolides. Chem. Rev. 95, 2041–2114 (1995).

    Article  CAS  Google Scholar 

  9. Nakata, T. Total synthesis of macrolides. in Macrolide Antibiotics 2nd edn. (ed. Omura, S.) 181–284 (Academic Press, San Diego, CA, 2002).

    Google Scholar 

  10. Parenty, A., Moreau, X. & Campagne, J.-M. Macrolactonizations in the total synthesis of natural products. Chem. Rev. 106, 911–939 (2006).

    Article  CAS  Google Scholar 

  11. Corey, E.J. & Nicolaou, K.C. Efficient and mild lactonization method for the synthesis of macrolides. J. Am. Chem. Soc. 96, 5614–5616 (1974).

    Article  CAS  Google Scholar 

  12. Corey, E.J., Brunelle, D.J. & Stork, P.J. Mechanistic studies on the double activation method for the synthesis of macrocyclic lactones. Tetrahedron Lett. 17, 3405–3408 (1976).

    Article  Google Scholar 

  13. Corey, E.J. & Brunelle, D.J. New reagents for the conversion of hydroxy acids to macrolactones by the double activation method. Tetrahedron Lett. 17, 3409–3412 (1976).

    Article  Google Scholar 

  14. Gerlach, H. & Thalmann, A. Bildung von estern und lactonen durch silberionen-katalyse. Helv. Chim. Acta 57, 2661–2663 (1974).

    Article  CAS  Google Scholar 

  15. Gerlach, H., Oertle, K. & Thalmann, A. Neue ambra-riechstoffe durch photochemische reaktionen von 15, 16-dinorlabd-8(20)-en-13-on. photochemische reaktionen. 84. Mitteilung. Helv. Chim. Acta 59, 75–81 (1976).

    Article  Google Scholar 

  16. Endo, T., Ikenaga, S. & Mukaiyama, T. Preparation of thiolesters. Bull. Chem. Soc. Jpn. 43, 2632–2633 (1970).

    Article  CAS  Google Scholar 

  17. Mukaiyama, T., Araki, M. & Takei, H. Reaction of S-(2-pyridyl) thioates with grignard reagents. Convenient method for the preparation of ketones. J. Am. Chem. Soc. 95, 4763–4765 (1973).

    Article  CAS  Google Scholar 

  18. Mukaiyama, T. Oxidation–reduction condensation. Angew. Chem. Int. Ed. Engl. 15, 94–103 (1976).

    Article  Google Scholar 

  19. Corey, E.J., Ulrich, P. & Fitzpatrick, J.M. A stereoselective synthesis of (±)-11-hydroxy-trans-8-dodecenoic acid lactone, a naturally occurring macrolide from Cephalosporium recifei. J. Am. Chem. Soc. 98, 222–224 (1976).

    Article  CAS  Google Scholar 

  20. Masamune, S., Hirama, M., Mori, S., Ali, S.A. & Garvey, D.S. Total synthesis of 6-deoxyerythronolide B. J. Am. Chem. Soc. 103, 1568–1571 (1981).

    Article  CAS  Google Scholar 

  21. Masamune, S. et al. Syntheses of macrolide antibiotics. I. Methymycin. J. Am. Chem. Soc. 97, 3512–3513 (1975).

    Article  CAS  Google Scholar 

  22. Masamune, S., Yamamoto, H., Kamata, S. & Fukuzawa, A. Syntheses of macrolide antibiotics. II. Methymycin. J. Am. Chem. Soc. 97, 3513–3515 (1975).

    Article  CAS  Google Scholar 

  23. Masamune, S., Kamata, S. & Schilling, W. Syntheses of macrolide antibiotics. III. Direct ester and lactone synthesis from S-tert-butyl thioate (thiol ester). J. Am. Chem. Soc. 97, 3515–3516 (1975).

    Article  CAS  Google Scholar 

  24. Masamune, S., Hayase, Y., Schilling, W., Chan, W.K. & Bates, G.S. Activation of thiol esters. Partial synthesis of cytochalasins A and B. J. Am. Chem. Soc. 99, 6756–6758 (1977).

    Article  CAS  Google Scholar 

  25. Mukaiyama, T., Usui, M., Shimada, E. & Saigo, K. Convenient method for the synthesis of carboxylic esters. Chem. Lett. 1045–1048 (1975).

  26. Mukaiyama, T., Usui, M. & Saigo, K. The facile synthesis of lactones. Chem. Lett. 49–50 (1976).

  27. Saigo, K., Usui, M., Kikuchi, K., Shimada, E. & Mukaiyama, T. New method for the preparation of carboxylic esters. Bull. Chem. Soc. Jpn. 50, 1863–1866 (1977).

    Article  CAS  Google Scholar 

  28. Mukaiyama, T. New synthetic reactions based on the onium salts of aza-arenes. Angew. Chem. Int. Ed. Engl. 18, 707–721 (1979).

    Article  Google Scholar 

  29. Bartlett, P.A. & Green, F.R. III. Total synthesis of brefeldin A. J. Am. Chem. Soc. 100, 4858–4865 (1978).

    Article  CAS  Google Scholar 

  30. Danishefsky, S.J., Armistead, D.M., Wincott, F.E., Selnick, H.G. & Hungate, R. The total synthesis of avermectin A1a . J. Am. Chem. Soc. 111, 2967–2980 (1989).

    Article  CAS  Google Scholar 

  31. Ley, S.V. et al. Total synthesis of the anthelmintic macrolide avermectin B1a . J. Chem. Soc. [Perkin Trans. I] 667–692 (1991).

  32. White, J.D. et al. Total synthesis of the antiparasitic agent avermectin B1a . J. Am. Chem. Soc. 117, 1908–1939 (1995).

    Article  CAS  Google Scholar 

  33. Inanaga, J., Hirata, K., Saeki, H., Katsuki, T. & Yamaguchi, M. A rapid esterification by mixed anhydride and its application to large-ring lactonization. Bull. Chem. Soc. Jpn. 52, 1989–1993 (1979).

    Article  CAS  Google Scholar 

  34. Hikota, M., Sakurai, Y., Horita, K. & Yonemitsu, O. Synthesis of erythronolide A via a very efficient macrolactonization under usual acylation conditions with the Yamaguchi reagent. Tetrahedron Lett. 31, 6367–6370 (1990).

    Article  CAS  Google Scholar 

  35. Hikota, M., Tone, H., Horita, K. & Yonemitsu, O. Chiral synthesis of polyketide-derived natural products. 27. Stereoselective synthesis of erythronolide A via an extremely efficient macrolactonization by the modified Yamaguchi method. J. Org. Chem. 55, 7–9 (1990).

    Article  CAS  Google Scholar 

  36. Hikota, M., Tone, H., Horita, K. & Yonemitsu, O. Stereoselective synthesis of erythronolide a by extremely efficient lactonization based on conformational adjustment and high activation of seco-acid. Tetrahedron 46, 4613–4628 (1990).

    Article  CAS  Google Scholar 

  37. Inanaga, J. et al. Total synthesis of methynolide. Chem. Lett. 1021–1024 (1979).

  38. Boden, E.P. & Keck, G.E. Proton-transfer steps in Steglich esterification: a very practical new method for macrolactonization. J. Org. Chem. 50, 2394–2395 (1985).

    Article  CAS  Google Scholar 

  39. Neises, B. & Steglich, W. Simple method for the esterification of carboxylic acids. Angew. Chem. Int. Ed. Engl. 17, 522–524 (1978).

    Article  Google Scholar 

  40. Höfle, G., Steglich, W. & Vorbrüggen, H. 4-Dialkylaminopyridines as highly active acylation catalysts. Angew. Chem. Int. Ed. Engl. 17, 569–583 (1978).

    Article  Google Scholar 

  41. Keck, G.E., Boden, E.P. & Wiley, M.R. Total synthesis of (+)-colletodiol: new methodology for the synthesis of macrolactones. J. Org. Chem. 54, 896–906 (1989).

    Article  CAS  Google Scholar 

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

  43. Kurihara, T., Nakajima, Y. & Mitsunobu, O. Synthesis of lactones and cycloalkanes. Cyclization of ω-hydroxy acids and α-ethyl-cyano-ω-hydroxycarboxylates. Tetrahedron Lett. 17, 2455–2458 (1976).

    Article  Google Scholar 

  44. Tsutsui, H. & Mitsunobu, O. Total synthesis of colletodiol. Tetrahedron Lett. 25, 2163–2166 (1984).

    Article  CAS  Google Scholar 

  45. Dvorak, C.A. et al. The synthesis of streptogramin antibiotics: (−)-griseoviridin and its C-8 epimer. Angew. Chem. Int. Ed. Engl. 39, 1664–1666 (2000).

    Article  CAS  Google Scholar 

  46. Shiina, I. Total synthesis of natural 8- and 9-membered lactones: recent advancements in medium-sized ring formation. Chem. Rev. 107, 239–273 (2007).

    Article  CAS  Google Scholar 

  47. Shiina, I. An effective method for the synthesis of carboxylic esters and lactones using substituted benzoic anhydrides with Lewis acid catalysts. Tetrahedron 60, 1587–1599 (2004).

    Article  CAS  Google Scholar 

  48. Shiina, I. & Mukaiyama, T. A novel method for the preparation of macrolides from ω-hydroxycarboxylic acids. Chem. Lett. 677–680 (1994).

  49. Shiina, I., Miyoshi, S., Miyashita, M. & Mukaiyama, T. A useful method for the preparation of carboxylic esters from free carboxylic acids and alcohols. Chem. Lett. 515–518 (1994).

  50. Mukaiyama, T., Shiina, I. & Miyashita, M. An efficient method for the preparation of carboxylic esters via mixed anhydrides by the promotion of a catalytic amount of Lewis acid. Chem. Lett. 625–628 (1992).

  51. Mukaiyama, T., Miyashita, M. & Shiina, I. A new and efficient method for the preparation of S-phenyl carbothioates via mixed anhydrides using active titanium(IV) salts. Chem. Lett. 1747–1750 (1992).

  52. Mukaiyama, T., Izumi, J., Miyashita, M. & Shiina, I. Facile synthesis of lactones from silyl ω-siloxycarboxylates using p-trifluoromethylbenzoic anhydride and a catalytic amount of active Lewis acid. Chem. Lett. 907–910 (1993).

  53. Miyashita, M., Shiina, I. & Mukaiyama, T. A convenient synthesis of carboxanilides from silyl carboxylates and weakly nucleophilic anilines using p-trifluoromethylbenzoic anhydride and a catalytic amount of active titanium(IV) salt. Chem. Lett. 1053–1054 (1993).

  54. Miyashita, M., Shiina, I., Miyoshi, S. & Mukaiyama, T. A new and efficient esterification reaction via mixed anhydrides by the promotion of a catalytic amount of Lewis acid. Bull. Chem. Soc. Jpn. 66, 1516–1527 (1993).

    Article  CAS  Google Scholar 

  55. Miyashita, M., Shiina, I. & Mukaiyama, T. An effective method for acylation of weakly nucleophilic anilines with silyl carboxylates via mixed anhydrides. Bull. Chem. Soc. Jpn. 67, 210–215 (1994).

    Article  CAS  Google Scholar 

  56. Shiina, I., Miyashita, M., Nagai, M. & Mukaiyama, T. An effective method for formylation of weakly nucleophilic anilines and indole. Heterocycles 40, 141–148 (1995).

    Article  CAS  Google Scholar 

  57. 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. 69, 1822–1830 (2004).

    Article  CAS  Google Scholar 

  58. Shiina, I., Kubota, M. & Ibuka, R. A novel and efficient macrolactonization of ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride (MNBA). Tetrahedron Lett. 43, 7535–7539 (2002).

    Article  CAS  Google Scholar 

  59. Shiina, I., Ibuka, R. & Kubota, M. An efficient method for the preparation of carboxylic esters from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine in the presence of a catalytic amount of 4-(dimethylamino)pyridine. Chem. Lett. 286–287 (2002).

  60. Shiina, I. An effective use of benzoic anhydride and its derivatives for the synthesis of carboxylic esters and lactones—powerful and convenient mixed anhydride methods promoted by Lewis acids or basic catalysts. J. Synth. Org. Chem. Jpn. 63, 2–17 (2005).

    Article  CAS  Google Scholar 

  61. Shiina, I. & Kawakita, Y. The effective use of substituted benzoic anhydrides for the synthesis of carboxamides. Tetrahedron 60, 4729–4773 (2004).

    Article  CAS  Google Scholar 

  62. Shiina, I., Fukuda, Y., Ishii, T., Fujisawa, H. & Mukaiyama, T. Determination of relative and absolute stereochemistry of cephalosporolide D and its enantioselective total synthesis. Chem. Lett. 831–832 (1998).

  63. Shiina, I., Fujisawa, H., Ishii, T. & Fukuda, Y. Stereoselective total synthesis of cephalosporolide D. Heterocycles 52, 1105–1123 (2000).

    Article  CAS  Google Scholar 

  64. Ishihara, K., Kubota, M., Kurihara, H. & Yamamoto, H. Scandium trifluoromethanesulfonate as an extremely active Lewis acid catalyst in acylation of alcohols with acid anhydrides and mixed anhydrides. J. Org. Chem. 61, 4560–4567 (1996).

    Article  CAS  Google Scholar 

  65. Ishihara, K., Kubota, M., Kurihara, H. & Yamamoto, H. Scandium trifluoromethanesulfonate as an extremely active acylation catalyst. J. Am. Chem. Soc. 117, 4413–4414, 6639 (1995).

    Article  CAS  Google Scholar 

  66. Stritzke, K., Schultz, S. & Boppré, M. Niaviolides, new macrocyclic sesquiterpenes secreted by males of the African butterfly Amauris niavius. Eur. J. Org. Chem. 1337–1342 (2003).

  67. Métay, E., Léonel, E., Sulpice-Gaillet, C. & Nédélec, J.-Y. Synthesis of precursors for medium-ring aromatic lactones. Synthesis 1682–1688 (2005).

  68. Shiina, I. et al. Enantioselective total synthesis of octalactin A using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring. Chem. Eur. J. 11, 6601–6608 (2005).

    Article  CAS  Google Scholar 

  69. Shiina, I., Oshiumi, H., Hashizume, M., Yamai, Y. & Ibuka, R. Asymmetric total synthesis of octalactin B using a new and rapid lactonization. Tetrahedron Lett. 45, 543–547 (2004).

    Article  CAS  Google Scholar 

  70. Shiina, I., Katoh, T. & Hashizume, M. Efficient Construction of Macrocyclic Skeleton Using MNBA Lactonization. Abstracts of papers, 86th National Meeting of the Chemical Society of Japan, Chiba, Vol. 2 4L428 (2006).

    Google Scholar 

  71. Shiina, I. et al. Synthesis of the Natural Lactones by Effective Intramoleculer Condensation. Abstracts of papers, 48th Symposium on the Chemistry of Natural Products, Sendai 34–37 (2006).

    Google Scholar 

  72. Shiina, I. & Hashizume, M. Synthesis of (9E)-isoambrettolide, a macrocyclic musk compound, using the effective lactonization promoted by symmetric benzoic anhydrides with basic catalysts. Tetrahedron 62, 7934–7939 (2006).

    Article  CAS  Google Scholar 

  73. Shiina, I., Kikuchi, T. & Sasaki, A. The first total synthesis of (−) and (+)-2-hydroxy-24-oxooctacosanolide using an effective lactonization. Org. Lett. 8, 4955–4958 (2006).

    Article  CAS  Google Scholar 

  74. Shiina, I. et al. Stereoselective total synthesis of the proposed structure of 2-epibotcinolide. Org. Lett. 8, 5279–5282 (2006).

    Article  CAS  Google Scholar 

  75. Tian, J., Yamagiwa, N., Matsunaga, S. & Shibasaki, M. Efficient two-step conversion of α,β-unsaturated aldehydes to optically active γ-oxy-α,β-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C. Org. Lett. 5, 3021–3024 (2003).

    Article  CAS  Google Scholar 

  76. Inoue, M., Sasaki, T., Hatano, S. & Hirama, M. Synthesis of the C-1027 chromophore framework through atropselective macrolactonization. Angew. Chem. Int. Ed. Engl. 43, 6500–6505 (2004).

    Article  CAS  Google Scholar 

  77. Inoue, M. Exploring the chemistry and biology of antitumor enediyne chromoprotein C-1027. Bull. Chem. Soc. Jpn. 79, 501–510 (2006).

    Article  CAS  Google Scholar 

  78. Sasaki, T., Inoue, M. & Hirama, M. Synthetic studies toward C-1027 chromophore: construction of a highly unsaturated macrocycle. Tetrahedron Lett. 42, 5299–5303 (2001).

    Article  CAS  Google Scholar 

  79. Morita, M., Mase, N., Yoda, H. & Takabe, K. A simplified synthesis of (R)-(−)-muscone using a ring-opening reaction of (R)-(+)-β-methyl-β-propiolactone. Tetrahedron Asymmetry 16, 3176–3182 (2005).

    Article  CAS  Google Scholar 

  80. Dinh, M.-T., BouzBouz, S., Peglion, J.-L. & Cossy, J. A short and efficient stereoselective synthesis of the octalactin lactone using enantioselective crotyltitanations and a cross-metathesis reaction. Synlett 2851–2853 (2005).

  81. Doi, T., Iijima, Y., Shin-ya, K., Ganesan, A. & Takahashi, T. A total synthesis of spiruchostatin A. Tetrahedron Lett. 47, 1177–1180 (2006).

    Article  CAS  Google Scholar 

  82. Hosokawa, S., Seki, M., Fukuda, H. & Tatsuta, K. Total synthesis of an antitubercular lactone antibiotic, (+)-tubelactomicin A. Tetrahedron Lett. 47, 2439–2442 (2006).

    Article  CAS  Google Scholar 

  83. Nicolaou, K.C. & Xu, H. Total synthesis of floresolide B and Δ6,7-Z-floresolide B. Chem. Commun. 600–602 (2006).

  84. Tsuchikawa, H., Matsushita, N., Matsumori, N., Murata, M. & Oishi, T. Synthesis of 28-19F-amphotericin B methyl ester. Tetrahedron Lett. 47, 6187–6191 (2006).

    Article  CAS  Google Scholar 

  85. Wu, Y. & Yang, Y.-Q. An expeditious enantioselective synthesis of antimycin A3b . J. Org. Chem. 71, 4296–4301 (2006).

    Article  CAS  Google Scholar 

  86. Matsuya, Y. et al. Synthesis of macrosphelides with a thiazole side chain: new antitumor candidates having apoptosis-inducing property. Org. Lett. 8, 4609–4612 (2006).

    Article  CAS  Google Scholar 

  87. Trost, B.M., Yang, H., Thiel, O.R., Frontier, A.J. & Brindle, C.S. Synthesis of a ring-expanded bryostatin analogue. J. Am. Chem. Soc. 129, 2206–2207 (2007).

    Article  CAS  Google Scholar 

  88. Ren, F., Hogan, P.C., Anderson, A.J. & Myers, A.G. Kedarcidin chromophore: synthesis of its proposed structure and evidence for a stereochemical revision. J. Am. Chem. Soc. 129, 5381–5383 (2007).

    Article  CAS  Google Scholar 

  89. Falck, J.R., He, A., Fukui, H., Tsutsui, H. & Radha, A. Synthesis and stereochemical assignment of FR252921, a promising immunosuppressant. Angew. Chem. Int. Ed. Engl. 46, 4527–4529 (2007).

    Article  CAS  Google Scholar 

  90. Scheerer, J.R., Lawrence, J.F., Wang, G.C. & Evans, D.A. Asymmetric synthesis of salvinorin A, a potent κ opioid receptor agonist. J. Am. Chem. Soc. 129, 8968–8969 (2007).

    Article  CAS  Google Scholar 

  91. Pettit, G.R. et al. Antineoplastic agents. 561. Total synthesis of respirantin. J. Nat. Prod. 70, 1073–1083 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

This study was partially supported by research grants from Tokyo Ohka Foundation for the Promotion of Science and Technology, the Center for Green Photo-Science and Technology and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

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Shiina, I., Fukui, H. & Sasaki, A. Synthesis of lactones using substituted benzoic anhydride as a coupling reagent. Nat Protoc 2, 2312–2317 (2007). https://doi.org/10.1038/nprot.2007.316

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