Natural‐Like Spirocyclic Δα, β‐Butenolides Obtained from Diazo Homophthalimides. Issue 31 (30th April 2021)

• Record Type: Journal Article
• Authors: Dar'in, Dmitry; Kantin, Grigory; Chupakhin, Evgeny; Sharoyko, Vladimir; Krasavin, Mikhail
• Is Part Of: Chemistry. Volume 27:Issue 31(2021)
• Page Start: 8221
• Page End: 8227
• Publication Date: 2021-04-30
• Subjects: 5-endo-dig cyclization -- Michael acceptors -- spirobutenolides -- synthetic methods -- thioredoxin reductase; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202100880
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: α‐Diazo homophotalimides were reacted with various propiolic acids on Rh2 (esp)2 catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Δ α, β ‐spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural‐like Δ α, β ‐spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities. The Δ α, β ‐spirobutenolides thus obtained were shown to inhibit thioredoxin reductase, a selenocysteine enzyme target for cancer. Moreover, for the best compound in the series (TrxR IC50 1.49±0.08 μM), by using MALDI‐TOF mass‐spectrometry it was shown that it selectively binds selenocysteine in the presence of a 10‐fold excess of cysteine. This validates the new compound as a promising lead for anticancer therapy development. Abstract : Natural‐like Δ α, β ‐spirobutenolides were accessed via Rh(II)‐catalyzed O−H insertion into propiolic acids followed by DIPEA‐catalyzed intramolecular 5‐endo‐dig Michael addition. The resulting spirocyclic Michael acceptors were shown to inhibit thioredoxin reductase, a selenoprotein cancer target. Moreover, some of these compounds were shown to selectively bind selenocysteine in the presence of a 10‐fold excess of cysteine.