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Total Synthesis of Monensinby the Kishi group in 1979
Zibin Tan
02/25/17
Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259.
Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260.
Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 262.
Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis 2003, chapter 12.1
Introduction
• A member of polyether antibiotics, an ionophore.
• Produced by Streptomyces cinnamonensis.
• Isolated and characterized in 1967 by Agtarp et al.
• Commercialized in 1971.
• First total synthesis: Kishi et al. in 1979.
Agtarp, A.; Chamberlin, J. W.; Pinkerton, M.; Steinrauf, L. J. Am. Chem. Soc. 1967, 89, 5737Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259.Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260.Karanewsky, D. S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 262.
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Structure and Biological Utilities of Monensin
• A cyclic structure maintained by H-bonding.
• Exterior is almost non polar hydrocarbon like, while
• Interior is lined with numerous Lewis-basic Oxygen atoms
• Can form complex with metal cations and transport them across lipid membranes, thus destroying the normal ion and charge distribution across the membranes.
X-ray crystal structure of monensin A sodium salt acetonitrile clathrateHuczynski, A.; Ratajczak-Sitarz, M.; Katrusiak, A.; Brzezinski, B. J. Mol. Struct. 2007, 832, 84.Picture of ouroboros: https://commons.wikimedia.org/w/index.php?curid=1533358
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Challenges in Total Synthesis
• Of 25 carbon atoms constructing the backbone, 17 are chiral.
• 6 chiral carbon atoms are contiguous.
• A spiro bicyclic ketal, 2 substituted tetrahydrofuran ring and a substituted tetrahydropyran ring.
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Retrosynthetic Analysis and Strategy
Red bonds: bonds to be retrosynthetically cleavedBlue groups: Carbons need to be introduced
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Thermodynamics Drove the Stereo Selectivity Here
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Retrosynthetic Analysis of the Left Arm
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Retrosynthetic Analysis of the Right Arm
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Summary of Retrosynthetic Analysis
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Total Synthesis
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Conclusion
• First total synthesis of Monensin
• Longest linear route: 37 steps
• Total steps: 73
• Overall yield: 0.12%
• The combination of
a. Wittig reaction/similar chemistry with
b. 1,3-allylic strain controlled stereospecific hydroboration/epoxidation
provided very powerful strategy for introduction of vicinal stereo centers.
• Recruiting of stereochemical induction/communication provided good control of relative stereochemistry.
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Thank You!
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