Natural‐Like Spirocyclic Δ^α,β‐Butenolides Obtained from Diazo Homophthalimides

Abstract

α-Diazo homophotalimides were reacted with various propiolic acids on Rh 2 (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 -spirobute-nolides thus obtained were shown to inhibit thioredoxin reductase, a selenocysteine enzyme target for cancer. Moreover, for the best compound in the series (TrxR IC 50 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.

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

“…As a first step, we turned to studying the possibility of obtaining spirocyclic butenolides from DAS 1 , based on our previously proposed approach using propiolic acids [ 39 ]. The diazo reagent 1a was introduced in the Rh 2 (esp) 2 -catalyzed insertion into the O–H bond of phenylpropropiolic acid ( 9а ) to form the intermediate compound 10a ( Scheme 2 ).…”

Diazo Tetramic Acids Provide Access to Natural-Like Spirocyclic Δα,β-Butenolides through Rh(II)-Catalyzed O–H Insertion/Base-Promoted Cyclization

“…Spirocyclohexane diazo tetramic acid 6a was chosen for this initial investigation. Conditions identified as workable for α-diazohomophthalimides 1 , for which the Rh 2 (esp) 2 -catalyzed O–H insertion was performed at room temperature, could not be directly applied for 6a (as well as other 3-diazotetramic acids 6 , vide infra). Substrate 6a proved to be less reactive compared to 1 ; the reaction temperature at the O–H insertion step had to be raised, and the reaction time increased to 18–30 h (depending on the specific propiolic acid 2 as controlled by TLC).…”

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

“…However, the methods for the preparation of 1,4-DHIQs with convenient and independent variation of the three lactam substituents are absent in the literature. While pondering possible solutions to fill this void, we drew inspiration in our recent success achieving direct Brønsted acid-catalyzed C-arylation of 4-diazoisoquinoline-1,3-diones 7 [9] which are, in turn, obtainable via the Regitz diazo transfer reaction onto readily available homophthalimides 8 [10][11][12]. We reasoned that a similar strategy could be adopted for the preparation of 1,2,4-trisubsti- tuted 1,4-DHIQs 9 if access to their diazo precursors 10 was gained.…”