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- Title
Total Synthesis and Biological Assessment of Mandelalide A.
- Authors
Brütsch, Tobias Michael; Bucher, Pascal; Altmann, Karl‐Heinz
- 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 μ m).
- Subjects
BIOSYNTHESIS; ACETYLENE crystals; CROTONIC acid; CROTONALDEHYDE; ACETYLENE; LUNG cancer; ORGANOIODINE compounds
- Publication
Chemistry - A European Journal, 2016, Vol 22, Issue 4, p1292
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201504230