title: Total Synthesis and Biological Assessment of Mandelalide A.
abstract: A new convergent total synthesis of the marine macrolide mandelalide A (1) has been developed that is based on macrocyclic ring closure by a Shiina-type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross-coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid-catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α- and β-AD-mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A (1) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK-N-SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 μm).
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
authors.forename: Tobias Michael
authors.initials: TM
authors.lastname: Brütsch
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bucher
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland. karl-heinz.altmann@pharma.ethz.ch.
authors.forename: Karl-Heinz
authors.identifier: http://orcid.org/0000-0002-0747-9734
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001685:Biological Factors; D002384:Catalysis; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D001685:Biological Factors; D018942:Macrolides; C000589407:mandelalide A
keywords: cancer; macrolactonization; mandelalide; marine natural products; total synthesis