α-Amino Acids and Peptides as Bifunctional Reagents: Carbocarboxylation of Activated Alkenes via Recycling CO₂

Abstract

Carboxylic acids, including amino acids (AAs), have been widely used as reagents for decarboxylative couplings. In contrast to previous decarboxylative couplings that release CO 2 as a waste byproduct, herein we report a novel strategy with simultaneous utilization of both the alkyl and carboxyl components from carboxylic acids. Under this unique strategy, carboxylic acids act as bifunctional reagents in the redox-neutral carbocarboxylation of alkenes. Diverse, inexpensive, and readily available α-AAs take part in such difunctionalizations of activated alkenes via visiblelight photoredox catalysis, affording a variety of valuable but otherwise difficult to access γ-aminobutyric acid derivatives (GABAs). Additionally, a series of dipeptides and tripeptides also participate in this photocatalytic carbocarboxylation. Although several challenges exist in this system due to the low concentration and quantitative amount of CO 2 , as well as unproductive side reactions such as hydrodecarboxylation of the carboxylic acids and hydroalkylation of the alkenes, excellent regioselectivity and moderate to high chemoselectivity are achieved. This process features low catalyst loading, mild reaction conditions, high step and atom economy, and good functional group tolerance, and it is readily scalable. The resulting products are subject to efficient derivations, and the overall process is amenable to applications in the latestage modification of complex compounds. Mechanistic studies indicate that a carbanion is generated catalytically and it acts as the key intermediate to react with CO 2 , which is also generated catalytically in situ and thus remains in low concentration. The overall transformation represents an efficient and sustainable system for organic synthesis, pharmaceutics, and biochemistry.

Photo-induced trifunctionalization of bromostyrenes via remote radical migration reactions of tetracoordinate boron species

“…Of note, in the above examples, the in situ formed benzylic radicals should be reduced to carbanions in the last step, which therefore further trapped protons to render the final products. Instead of proton, the benzylic carbanion could serve as nucleophiles to react with various electrophiles to lead to difunctionalization of the olefin moiety 45 , which also highlights the potential for the synthesis of more diversified and complex products. A plethora of electrophiles, such as benzyl bromide ( 7a ), para- fluorine and para- methyl substituted benzyl bromide ( 7b , 7c ), meta- bromine substituted benzyl bromide ( 7d ) as well as meta- methoxy substituted benzyl bromide ( 7e ) were all tolerated well to give the corresponding products in moderate to good yields ( 8a – 8e ).…”

Tandem Functionalization‐Carboxylation Reactions of π‐Systems with CO2

“…Continuing their interest for light‐driven functionalization‐ carboxylation reactions, in 2021, Yu and co‐workers developed a carbo‐carboxylation of alkenes 15 employing α‐amino acids 16 as bifunctional reagents. [ 11 ] Thus, γ‐aminobutyric acids 17 were synthesized through a light‐promoted process (cat. B ), where α‐amino acids 16 are first decarboxylated, generating an alkyl radical that is added onto the double bond of 15 (carbofunctionalization).…”

Direct decarboxylative Giese reactions

“…It is worth noting that the Giese reaction can be interrupted, whereby radical II has been exploited to participate in other pathways allowing the final HAT process to be bypassed. 8 These examples will not be discussed as they are beyond the scope of this review.…”