Brief Communication | Published:

Computational study on formation of 15-membered azalactone by double reductive amination using molecular mechanics and density functional theory calculations

The Journal of Antibioticsvolume 71pages549556 (2018) | Download Citation

Abstract

Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 Å, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W. What can a chemist learn from nature’s macrocycles? – A brief, conceptual view. Mol Divers. 2005;9:171–86.

  2. 2.

    Toya T. Method of manufacturing for biphenyl derivative. JP2001-131114A2 (Nippon Kayaku, 2001).

  3. 3.

    Mukai C, Ueda M, Takahashi Y, Inagaki F. Concise construction of bicycle[6.4.0] and –[7.4.0] frameworks by [4+2] cycloaddition of 3,4-dimethylene-2,5-bis(phenylsulfonyl)cycloalk-1-enes. Eur J Org Chem. 2015;2015:4412–22.

  4. 4.

    Kubota D, Ishikawa M, Ishikawa M, Yahata N, Murakami S, Fujishima K, Kitakaze M, Ajito K. Tricyclic pharmacophore-based molecules as novel integrin αVβ3 antagonists. Part IV: preliminary control of αVβ3 selectivity by meta-oriented substitution. Bioorg Med Chem. 2006;14:4158–81.

  5. 5.

    Tatsuta K, Amemiya Y, Maniwa S, Kinoshita M. Total synthesis of carbomycin B and josamycin (leucomycin A3). Tetrahedron Lett. 1980;21:2837–40.

  6. 6.

    Woodward RB, Logusch E, Nambiar KP, Sakan K, Ward DE, Au-Yeung B-W. et al. Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system. J Am Chem Soc. 1981;103:3213–15.

  7. 7.

    Hikota M, Sakurai Y, Hirota K, Yonemitsu O. Synthesis of erythronolide A via a very efficient macrolactonization under usual acylation conditions with the Yamaguchi reagent. Tetrahedron Lett. 1990;31:6367–70.

  8. 8.

    Hikota M, Tone H, Horita K, Yonemitsu O. Stereoselective synthesis of erythronolide A via an extremely efficient macrolactonization by the modified Yamaguchi method. J Org Chem. 1990;55:7–9.

  9. 9.

    Matsushima T, Nakajima N, Zheng B-Z, Yonemitsu O. Synthetic studies of an 18-membered antitumor macrolide, tedanolide. 6. Synthesis of a key intermediate via a highly efficient macrolactonization of computer-aid designed seco-acid. Chem Pharm Bull. 2000;48(6):855–60.

  10. 10.

    Tatsuta K, Ishiyama T, Tajima S, Koguchi Y, Gunji H. The total synthesis of oleandomycin. Tetrahedron Lett. 1990;31:709–12.

  11. 11.

    Nakajima N, Uoto K, Yonemitsu O, Hata T. Facile total synthesis of carbonolides by Wittig-Horner macro-cyclization and stereoselective epoxidation. Chem Pharm Bull. 1991;39(1):64–74.

  12. 12.

    Nicolaou KC, Chakraborty TK, Piscopio AD, Minowa N, Bertinato P. Total synthesis of rapamycin. J Am Chem Soc. 1993;115:4419–20.

  13. 13.

    Yang Z, He Y, Vourloumis D, Vallberg H, Nicolaou KC. Total synthesis of epothilone A: The olefin metathesis approach. Angew Chem Int Ed Engl. 1997;36:166–68.

  14. 14.

    Yu X, Sun D. Macrocyclic drugs and synthetic methodologies toward macrocycles. Molecules. 2013;18:6230–68.

  15. 15.

    Shen L, Sun D. Total synthesis and structural revision of engelhardione. Tetrahedron Lett. 2011;52:4570–74.

  16. 16.

    Butora G, Gobel SD, Moyer CR, Pasternak A, Yang L & Zhou C. Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity. WO 2004 094371 A2 (Merck Sharp & Dohme Ltd, 2004).

  17. 17.

    Xu X, Lu J, Li R, Ge Z, Dong Y, Hu Y. Diastereopure preparation of α-benzotriazolyl 1-azacycloalka[2,1-b][1,3]oxazines and their application as versatile chiral precursors. Synlett. 2004;2004:122–24.

  18. 18.

    Bonnet V, Duval R, Tran V, Rabiller C. Mono-N-glycosidation of β-cyclodextrin–Synthesis of (6-β-cyclodextrinylamino)-6-deoxy-D-galactosides and of N-(6-deoxy-β-cyclodextrinyl)galacto-azepine. Eur J Org Chem. 2003;2003:4810–18.

  19. 19.

    Painter GF, Eldridge PJ, Falshaw A. Syntheses of tetrahydroxyazepanes from chiro-inositols and their evaluation as glycosidase inhibitors. Bioorg Med Chem. 2004;12:225–32.

  20. 20.

    Ajito K, Miura T, Furuuchi T, Tamura A. Sixteen-membered macrolides: chemical modifications and future applications. Heterocycles. 2014;89:281–52.

  21. 21.

    Miura T, Kanemoto K, Ajito K. Chemical transformation of lactone starting from 16-membered macrolides, leucomycins, and generation of novel azalides. J Synth Org Chem Jpn. 2011;69:1339–51.

  22. 22.

    Bright GM, Nagel AA, Bordner J, Desai KA, Dibrino JN, Nowakowska J, Vincent L, Watrous RM, Sciavolino FC, English AR, Retsema JA, Anderson MR, Brennan LA, Borovoy RJ, Cimochowski CR, Faiella JA, Girard AE, Girard D, Herbert C, Manousos M, Mason R. Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-aza-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides. J Antibiot. 1988;41:1029–47.

  23. 23.

    Vriesema BK, Buter J, Kellogg M. Synthesis of aza macrocycles by nucleophilic ring closure with cesium tosylamides. J Org Chem. 1984;49:110–13.

  24. 24.

    Miura T, Natsume S, Kanemoto K, Atsumi K, Fushimi H, Sasai H, Arai T, Yoshida T, Ajito K. Novel azalides derived from sixteen-membered macrolides I. Isolation of the mobile dialdehyde and its one-pot macrocyclization with an amine. J Antibiot. 2007;60:407–35.

  25. 25.

    Tatsuta K, Tanaka A, Fujimoto K, Kinoshita M, Umezawa S. Synthesis of carbomycin B. Introduction of the amino disaccharide onto the 16-membered-ring aglycone. J Am Chem Soc. 1977;99:5826–27.

  26. 26.

    Tatsuta K, Kobayashi T, Gunji H, Masuda H. Synthesis of oleandomycin through the intact aglycone, oleandolide. Tetrahedron Lett. 1988;29:3975–78.

  27. 27.

    Illuminati G, Mandolini L. Ring closure reactions of bifunctional chain molecules. Acc Chem Res. 1981;14:95–102.

  28. 28.

    Eliel EL, Wilen SH & Mander LN. Configuration and Conformation of Cyclic Molecules, Stereochemistry of Organic Compounds Chapter 11, 677 (John Wiley & Sons, Inc., New York, NY, 1994).

  29. 29.

    Waddell ST & Blizzard TA. 8a-Aza and 9a-aza macrolide antibiotics, and a process for producing same and methods of use. WO 94/15617, 21 July (Merck & Co. Inc., 1994).

  30. 30.

    Jones AB. New macrolide antibiotics: Synthesis of a 14-membered azalide. J Org Chem. 1992;57:4361–67.

  31. 31.

    Shankaran K & Wilkening RR. Methods of making 4” derivatives of 9-deoxo-8a-aza-8a-alkyl-8a-homoerythromycin A. EP 0549040 A1, 30 June (Merck & Co. Inc., 1993).

  32. 32.

    Lazarevski G, Kobrehel G & Kelneric Z. 15-Membered lactams ketolides with antibacterial activity. WO 99/51616, 14 October (Pliva, 1999).

  33. 33.

    Waddell ST, Blizzard TA. Chimeric azalides with simplified western portions. Tetrahedron Lett. 1993;34:5385–88.

  34. 34.

    N. Lopotar, N & Djokić, S, Tylosin derivatives. EP0410433, A2, 30 January (Pliva, 1991).

  35. 35.

    Asaka T, Manaka A, Tanikawa T, Sugimoto T, Shimazaki Y & Sato M. 11a-Azalide compounds and process for producing the same. WO2003/014136 A1, 20 February (Taisho Pharmaceutical, 2003).

  36. 36.

    Sugimoto T, Tanikawa T, Suzuki K, Yamasaki Y. Synthesis and structure–activity relationship of a novel class of 15-membered macrolide antibiotics known as ‘11a-azalides’. Bioorg Med Chem. 2012;20:5787–801.

  37. 37.

    Ōmura S, Miyano K, Matsubara H, Nakagawa A. Novel dimeric derivatives of leucomycins and tylosin, sixteen-membered macrolides. J Med Chem. 1982;25:271–75.

  38. 38.

    Gotō H, Ōsawa E. Corner flapping: a simple and fast algorithm for exhaustive generation of ring conformations. J Am Chem Soc. 1989;111:8950–51.

  39. 39.

    Gotō H, Ōsawa E. An effective algorithm for searching low-energy conformers of cyclic and acyclic molecules. J Chem Soc Perkin Trans 2. 1993;2:187–98.

  40. 40.

    Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem. 1996;17:490–519.

  41. 41.

    Halgren TA. Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J Comput Chem. 1996;17:520–52.

  42. 42.

    Halgren TA. Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J Comput Chem. 1996;17:553–86.

  43. 43.

    Halgren TA, Nachbar RB. Merck molecular force field. IV. Conformational energies and geometries for MMFF94. J Comput Chem. 1996;17:587–615.

  44. 44.

    Halgren TA. Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules. J Comput Chem. 1996;17:615–41.

  45. 45.

    Halgren TA, MMFF VI. MMFF94s option for energy minimization studies. J Comput Chem. 1999;20:720–29.

  46. 46.

    Halgren TA. MMFF VII characterization of MMFF94, MMFF94s, and other widely available force fields for conformational energies and for intermolecular-interaction energies and geometries. J Comput Chem. 1999;20:730–48.

  47. 47.

    Scalmani G, Frisch MJ. Continuous surface charge polarizable continuum models of solvation. I. General formalism. J Chem Phys. 2010;132:114110.

  48. 48.

    Buszek KR, Jeong Y, Sato N, Still PC, Muino PL, Ghosh I. Facile synthesis of saturated eight-membered ring lactones. Synth Commun. 2001;31:1781–91.

Download references

Acknowledgements

We thank Mr. H. Yamaguchi, Dr. T. Kikkoji, and Mr. Y. Sasaki for encouragement and valuable supports. We are grateful to Professor D. Uemura, Professor K. Tadano, and Associate Professor Y. Sakamoto for supervision about macrolactonization for a medium to large sized ring system. We also thank Ms. K. Yasufuku and Mr. I. Kobayashi for direction in intellectual properties and IP administration. We sincerely appreciate very kind supports by Dr. K. Ohta and Mrs. M. Kasuya, Conflex Corporation.

Author information

Author notes

    • Tomoaki Miura

    Present address: Department of Intellectual Property, Meiji Seika Pharma Co., Ltd., Yokohama, Japan

    • Kenichi Kanemoto

    Present address: Technical Department Production Division, Meiji Seika Pharma Co., Ltd., Tokyo, Japan

    • Keiichi Ajito

    Present address: Department of Project Planning & Management, Meiji Seika Pharma Co., Ltd., Tokyo, Japan

Affiliations

  1. School of Pharmacy, Showa University, Shinagawa, Tokyo, Japan

    • Hiroaki Gouda
  2. Conflex Corporation, Minato, Tokyo, Japan

    • Naofumi Nakayama
  3. Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan

    • Tomoaki Miura
    • , Kenichi Kanemoto
    •  & Keiichi Ajito

Authors

  1. Search for Hiroaki Gouda in:

  2. Search for Naofumi Nakayama in:

  3. Search for Tomoaki Miura in:

  4. Search for Kenichi Kanemoto in:

  5. Search for Keiichi Ajito in:

Corresponding author

Correspondence to Keiichi Ajito.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41429-018-0030-6