Alkene Metathesis in total synthesis Valienamine, Agelastatin and

Alkene Metathesis in Total Synthesis Valienamine, Agelastatin and Tonantzitlolone 

Applications to natural product synthesis probe the limits of any synthetic method, as situations arise that would never have been considered in the course of first developing the method- Recent syntheses of valienamine 6, agelastatin 9 and tonantzitlolone 15 pressed the limits of ring-closing metathesis. 

Although the tetracycline antibiotics have been mainstays of antibacterial chemotherapy for decades, they had eluded efficient total synthesis. In a landmark accomplishment, Andrew G. Myers of Harvard University recently reported Science 2005, 308, 395 J. Am. Chem. Soc. 2005, 127, 8292) the first such syntheses. 

The alcohol 5 was the common intermediate for both syntheses. For the deoxy series, 5 was carried on to the enone 6. Conjugate addition of the anion 7 proceeded with remarkable diastereoselectivity, to give, after intramolecular acylation and deprotection, doxycycline 9. 

The JACS paper describes the total synthesis of the more highly oxygenated (-)-tetracycline Ifi, To this end, the alcohol 5 was carried on to the enone TO. Opening of the cyclobutanc 11 to the o-quinone methide followed by Diels-Alder cycloaddition to 10 delivered the endo adduct 12. 

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Alkene Metathesis in Total Synthesis Valienamine, Agelastatin and Tonantzitlolone October 31, 2005... 

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