Design and synthesis of some biologically interesting natural and unnatural products based on organosulfur and selenium chemistry

Abstract

Organosulfur and selenium chemistry has provided fertile ground for the discovery of novel synthetic methodology and for the design of bioactive molecules with potential therapeutic applications. Thus, acetylenic sulfones have been employed in novel strategies for the synthesis of nitrogen heterocycles, including several biologically active alkaloids. The conjugate addition of nitrogen nucleophiles containing ester or chloroalkyl substituents to acetylenic sulfones was followed by base-mediated intramolecular alkylation or acylation to afford variously substituted piperidines, pyrrolizidines, indolizidines, quinolizidines, decahydroquinolines, and 4-quinolones. The products include the dendrobatid alkaloids (–)-pumiliotoxin C, indolizidines (–)-167B, 207A, 209B, and 209D, as well as (–)-(ent)-julifloridine, (–)-lasubine II, myrtine, and two recently discovered alkaloids from the medicinal plant Ruta chalepensis , which had not been previously synthesized. Acetylenic sulfones were also incorporated on solid supports and employed in the types of cyclizations mentioned above, as well as for Diels–Alder reactions and a large variety of 1,3-dipolar cycloadditions. Conjugate additions of tertiary cyclic α-vinyl amines to acetylenic sulfones generated zwitterions that underwent exceptionally facile formal aza-Cope rearrangements to afford ring-expanded macrocyclic amines. An iterative version was developed and used in the synthesis of motuporamine A and B. With respect to organoselenium chemistry, two classes of compounds are described that function as novel mimetics of the selenoenzyme glutathione peroxidase (GPx), which protects cells from oxidative stress caused by the formation of peroxides during aerobic metabolism. They include cyclic seleninates and spirodioxyselenuranes, both of which efficiently catalyze the reduction of peroxides with thiols and are of potential value in the mitigation of oxidative stress. Their aromatic derivatives are generally less effective catalysts, but substituent effects can be used to modulate their activities. The mechanism of their catalytic cycles has been elucidated and Hammett plots indicate that the oxidation of Se(II) to Se(IV) is the rate-determining step for both classes. A methoxy-substituted aromatic spirodioxyselenurane provided the fastest rate for a small-molecule selenium compound that we have observed to date for the reduction of hydrogen peroxide with benzyl thiol.