Propargylic substituted products are an important class of compounds in many natural products and biologically active compounds, for the alkyne moieties attached to the propargylic carbon centers are reactive by further metabolism. To obtain such compounds, transition metal-catalyzed enantioselective propargylic substitution reactions have been recently developed by our group and others, although propargylic alkylation with alkyl nucleophiles, not activated by functional groups such as methyl derivatives attached with ketone, aldehyde, or ether groups, have been found to be difficult due to the requirement of harsh conditions. Free alkyl radicals are available as milder alternative alkylating reagents, although their application to enantioselective propargylic substitution reactions has not yet well explored, for appropriate methods to control the generation and reactivity of free radicals including inhibition of direct reactions of radicals with alkyne moieties are required.
Here we present a strategy to control enantioselective propargylic substitution reactions with alkyl radicals under photoredox conditions by applying dual photoredox and diruthenium catalytic system, where the photoredox catalyst generates alkyl radicals from 4-alkyl-1,4-dihydropyridines, and the diruthenium core with a chiral ligand traps propargylic alcohols and alkyl radicals to guide enantioselective alkylation at the propargylic position, leading to high yields of propargylic alkylated products containing a quaternary stereogenic carbon center at the propargylic position with a high enantioselectivity.
Both experimental results and DFT calculations support that a plausible catalytic reaction pathway can be drawn as consisting of two catalytic reaction cycles: the iridium-based photoredox catalytic cycle and the ruthenium catalytic cycle. Here, the iridium catalyst is excited under visible light irradiation, followed by a single-electron transfer between 4-alkyl-1,4-dihydropyridine and the photoexcited iridium species to afford an alkyl radical and an anionic iridium species. Then, the alkyl radical attacks at the γ-position of the ruthenium allenylidene complex, obtained by the coordination and dehydration of the propargylic alcohol upon the ruthenium catalysts, to afford the alkynyl radical complex, which is further reduced by the anionic iridium complex through single-electron transfer to afford the alkynyl complex, where the propargylic alkylated product is liberated by further protonation and ligand exchange with another propargylic alcohol. Here, the diruthenum core of the ruthenium catalyst acts as an electronic pool to stabilize reactive intermediates including radical species, furnishing the propargylic substitution reactions with free alkyl radicals. The result described in this paper provides the successful example of transition metal-catalyzed enantioselective propargylic substitution reactions with free alkyl radicals.
For more detailed information, see our article "Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals" in Nature Communications. The list of pictures of authors (Dr. Yulin Zhang, Dr. Yoshiaki Tanabe, Dr. Shogo Kuriyama, Prof. Dr. Ken Sakata, and Prof. Dr. Yoshiaki Nishibayashi) is as follows. The content of this article constitutes an important part of Dr. Yulin Zhang's doctoral thesis at The University of Tokyo.
 Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals. Y. Zhang, Y. Tanabe, S. Kuriyama, K. Sakata, Y. Nishibayashi Nat. Commun. 14, 859 (2023) doi: 10.1038/s41467-023-36453-9.