Total synthesis confirms laetirobin as a formal Diels-Alder adduct.
Laetirobin, isolated from a parasitic fungus host-plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4-dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)-mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure-activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).
Simon
Oliver
O
Department of Chemistry, Faculty of Science and Medicinal Chemistry Program of the Life Sciences Institute, National University of Singapore, Singapore 117543, Singapore.
Reux
Bastien
B
La Clair
James J
JJ
Lear
Martin J
MJ
D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D001572:Benzofurans; C545391:laetirobin