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doi:10.1016/j.bmc.2008.02.064 
Copyright © 2008 Elsevier Ltd All rights reserved.
Design and synthesis of novel leucomycin analogues modified at the C-3 position. Part II: 3-O-(3-Aryl-2-propenyl)leucomycin analogues
Takeshi Furuuchi
, a, 
, Tomoaki Miura, a, , Ken-ichi Kuriharaa, Takuji Yoshidaa, Takashi Watanabea and Keiichi Ajitoa
Received 15 January 2008;
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Abstract
The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leucomycin A7 analogues (9a–9m). These leucomycin A7 derivatives showed improved in vitro antibacterial activities against clinically important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at the C-3 and C-3″ positions suggested that single modification at C-3 or C-3″ was effective for in vitro antibacterial activity.
Graphical abstract
The design and synthesis of 16-membered macrolides modified at the C-3 position are described. 3-O-(3-Aryl-2-propenyl)leucomycin A7 analogues showed improved in vitro antibacterial activities against clinically important pathogens.
Keywords: Macrolide antibiotics; 16-Membered macrolides; 3-O-(3-Aryl-2-propenyl)leucomycin A7 analogues; MLS resistant; Heck reaction; Antibacterial activity
Article Outline
- 1. Introduction
- 2. Results and discussion
- 2.1. Synthesis and evaluation of 3-O-[3-(3-quinolyl)-2-propenyl]rokitamycin
- 2.2. Synthesis and evaluation of 3-O-(3-aryl-2-propenyl)leucomycin A7 analogues
- 2.3. Synthesis and biological evaluation of 3″-O-(3-phenylpropionyl)leucomycin A7
- 3. Conclusion
- 4. Experimental
- 4.1. General methods
- 4.2. Antibacterial activity in vitro
- 4.2.1. 2′-O-Acetyl-3-O-allyl-9-O-(tert-butyldimethylsilyl)rokitamycin 18-dimethylacetal (2)
- 4.2.2. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(3-quinolyl)-2-propenyl]rokitamycin 18-dimethylacetal (3)
- 4.2.3. 3-O-[3-(3-Quinolyl)-2-propenyl]rokitamycin (4)
- 4.2.4. 2′-O-Acetyl-3-O-allyl-9-O-(tert-butyldimethylsilyl)leucomycin A7 18-dimethylacetal (6)
- 4.2.5. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(3-quinolyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7a)
- 4.2.6. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-isoquinolyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7b)
- 4.2.7. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-(3-phenyl-2-propenyl)leucomycin A7 18-dimethylacetal (7c)
- 4.2.8. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(3-pyridyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7d)
- 4.2.9. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(5-pyrimidinyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7e)
- 4.2.10. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(1-naphthyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7f)
- 4.2.11. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(2-naphthyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7g)
- 4.2.12. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-nitrophenyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7h)
- 4.2.13. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-methoxyphenyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7i)
- 4.2.14. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-fluorophenyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7j)
- 4.2.15. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-trifluoromethylphenyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7k)
- 4.2.16. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-(4-biphenylyl)-2-propenyl]leucomycin A7 18-dimethylacetal (7l)
- 4.2.17. 2′-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-{3-[4-(1-imidazolyl)phenyl]-2-propenyl}leucomycin A7 18-dimethylacetal (7m)
- 4.2.18. 3-O-[3-(3-Quinolyl)-2-propenyl]leucomycin A7 (9a)
- 4.2.19. 3-O-[3-(4-Isoquinolyl)-2-propenyl]leucomycin A7 (9b)
- 4.2.20. 3-O-(3-Phenyl-2-propenyl)leucomycin A7 (9c)
- 4.2.21. 3-O-[3-(3-Pyridyl)-2-propenyl]leucomycin A7 (9d)
- 4.2.22. 3-O-[3-(5-Pyrimidinyl)-2-propenyl]leucomycin A7 (9e)
- 4.2.23. 3-O-[3-(1-Naphthyl)-2-propenyl]leucomycin A7 (9f)
- 4.2.24. 3-O-[3-(2-Naphthyl)-2-propenyl]leucomycin A7 (9g)
- 4.2.25. 3-O-[3-(4-Nitrophenyl)-2-propenyl]leucomycin A7 (9h)
- 4.2.26. 3-O-[3-(4-Methoxyphenyl)-2-propenyl]leucomycin A7 (9i)
- 4.2.27. 3-O-[3-(4-Fluorophenyl)-2-propenyl]leucomycin A7 (9j)
- 4.2.28. 3-O-[3-(4-Trifluoromethylphenyl)-2-propenyl]leucomycin A7 (9k)
- 4.2.29. 3-O-[3-(4-Biphenylyl)-2-propenyl]leucomycin A7 (9l)
- 4.2.30. 3-O-{3-[4-(1-Imidazolyl)phenyl]-2-propenyl}leucomycin A7 (9m)
- 4.2.31. 2′-O-Acetyl-9,18-di-O-(tert-butyldimethylsilyl)-3″-O-(3-phenylpropionyl)leucomycin A7 3,18-acetal (11)
- 4.2.32. 3″-O-(3-Phenylpropionyl)leucomycin A7 (12)
- Acknowledgements
- References
