An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids

Author:

Alexander Brandon W.1ORCID,Bartfield Noah M.1ORCID,Gupta Vaani1ORCID,Mercado Brandon Q.12ORCID,Del Campo Mark3ORCID,Herzon Seth B.145ORCID

Affiliation:

1. Department of Chemistry, Yale University, New Haven, CT 06511, USA.

2. Chemical and Biological Instrumentation Center, Yale University, New Haven, CT 06511, USA.

3. Rigaku Americas Corporation, The Woodlands, TX 77381, USA.

4. Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.

5. Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Molecular structure and selective theophylline complexation by conformational change of diethyl N,N′-(1,3-phenylene)dicarbamate;Acta Crystallographica Section C Structural Chemistry;2024-05-07

2. Applying 3D ED/MicroED workflows toward the next frontiers;Acta Crystallographica Section C Structural Chemistry;2024-05-07

3. Total Synthesis of Securamine D;Synfacts;2024-04-15

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