Total synthesis of (+)-11,11'-dideoxyverticillin A.
The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly 4 decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Justin
J
Kim
James A
JA
Ashenhurst
Mohammad
M
Movassaghi
D000470:Alkaloids / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D015394:Molecular Structure; D010407:Penicillium / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D000470:Alkaloids; D004220:Disulfides; D010879:Piperazines; C540279:11,11'-dideoxyverticillin A