Enrico

We present a novel convergent strategy that integrates Pd/Ag-promoted Suzuki–Miyaura coupling with Ir-catalyzed radical-relay cyclization, enabling the first total synthesis of 16β-hydroxylpseudobufarenogin. This approach is broadly applicable to the total synthesis of various oxygenated bufadienolides by simply modifying the fragment structures.

ABSTRACT

16β-Hydroxylpseudobufarenogin (1), isolated from the venom of Bufo bufo gargarizans, has potent anticancer activity. The U-shaped steroidal structure of 1 possesses a cis-fused AB-ring system, a densely oxidized cis-fused CD-ring system, and a β-oriented 2-pyrone at C17. Herein, we present a new convergent strategy for assembling this complex steroidal architecture, culminating in the first total synthesis of 1 in 28 steps from (+)-Wieland–Miescher ketone. The AB- and D-ring fragments were coupled by Pd/Ag-promoted Suzuki–Miyaura coupling. Following the Co-catalyzed hydration of the D-ring, the C-ring was stereoselectively constructed by Ir-catalyzed radical-relay cyclization. Subsequent C-ring hydroxylation and installation of the β-oriented 2-pyrone through Pd/Cu-promoted Stille coupling and stereospecific epoxide rearrangement delivered 1. Because of its high chemo- and stereoselectivity, the present methodology would be applicable to the total synthesis of diverse oxygenated bufadienolides by simply altering the fragment structures.

Silver-catalyzed [3 + 2] cycloaddition of aryldiazonium salts and (diazomethyl)dimethylphosphine oxide is developed as an approach to 2,5-disubstituted tetrazoles bearing a P(O)(Alkyl)₂ group. The method has wide scope and low susceptibility toward electronic and steric effects in the diazonium salt component.

A convenient approach to 2,5-disubstituted tetrazoles bearing a dialkylphosphine oxide substituent at the C-5 position is developed. The method involves silver-catalyzed [3 + 2] cycloaddition of (diazomethyl)dialkylphosphine oxide and aryl diazonium salts. The proposed reaction is compatible with various substituents at the aryl ring and has low susceptibility to their electronic and steric effects. Several heterocyclic diazonium salts were also involved into the transformation successfully. The proposed reaction pathway may include synchronous [3 + 2] cycloaddition or two-step formation of the tetrazole ring starting with electrophilic attack of aryl diazonium salt at the diazoalkane carbon atom.

Electrochemical dehydration of carboxamides to nitriles is achieved using thiocyanate-mediated activation, avoiding stoichiometric reagents. In an undivided cell at ambient conditions, 18 aromatic and aliphatic substrates give good-to-excellent yields (up to 84%) with functional-group tolerance. Cyclic voltammetry supports an EC-type-mediated oxidation. The method is scalable with minimal loss in efficiency, offering a mild and sustainable route to nitriles.

An efficient electrochemical strategy for the dehydration of carboxamides to their corresponding nitriles is reported. This method replaces conventional dehydrating reagents with a thiocyanate-mediated electrochemical activation, providing a safer, milder, and more sustainable alternative. Under optimized conditions in an undivided cell, 18 examples of aromatic and aliphatic carboxamides were smoothly converted to the corresponding nitriles at ambient temperature in good-to-excellent yields (up to 84%). Hexafluoroisopropanol proved to be essential for reaction efficiency, while tetrabutylammonium thiocyanate acted as a redox mediator, as confirmed by cyclic voltammetry studies, which revealed an EC-type-mediated oxidation process. The method demonstrates broad functional-group tolerance, including halogenated, methoxylated, and sterically hindered substrates, as well as complex molecules derived from pharmaceuticals and natural products. Importantly, the protocol was successfully scaled up eightfold with minimal loss in yield, illustrating its robustness and practical applicability. Mechanistically, anodic oxidation of thiocyanate generates highly reactive species that activate the amide functionality, leading to nitrile formation via an oxidative dehydration pathway, while hydrogen evolution occurs at the cathode. This work expands the synthetic utility of electrochemical dehydration reactions and offers a valuable, environmentally responsible route to nitrile-containing compounds of broad relevance for pharmaceuticals, agrochemicals, and materials science.