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Total Synthesis of (−)-Lasonolide A

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Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
Cite this: J. Am. Chem. Soc. 2016, 138, 36, 11690–11701
Publication Date (Web):August 22, 2016
https://doi.org/10.1021/jacs.6b05127
Copyright © 2016 American Chemical Society

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    Abstract

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    The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene–alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b05127. Data for the compounds reported in the preliminary communication appear in the Supporting Information of the communication. (7a)

    • Experimental procedures, analytical data (1H NMR, 13C NMR, MS, IR, and [α]D) for all new compounds, additional reaction optimization tables (PDF)

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