| Autor: |
Alexander BW; Department of Chemistry, Yale University, New Haven, CT 06511, USA., Bartfield NM; Department of Chemistry, Yale University, New Haven, CT 06511, USA., Gupta V; Department of Chemistry, Yale University, New Haven, CT 06511, USA., Mercado BQ; Department of Chemistry, Yale University, New Haven, CT 06511, USA.; Chemical and Biological Instrumentation Center, Yale University, New Haven, CT 06511, USA., Del Campo M; Rigaku Americas Corporation, The Woodlands, TX 77381, USA., Herzon SB; Department of Chemistry, Yale University, New Haven, CT 06511, USA.; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA. |
| Abstrakt: |
Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines. |
