Always Be Coupling

Citations: Ramakrishna, G.V.; Latif, Z.; Romiti, F. Enantioselective Total Syntheses of Vallesamidine and Schizozygane Alkaloids. J. Am. Che. Soc. 2025 , ASAP. https://pubs.acs.org/doi/full/10.1021/jacs.4c16900# Summary Figures: Background: There is a philosophical debate to be had about the merits of total synthesis and whether having graduate students spend half a decade making an obscure molecule found in a sea sponge or cactus is worth it. One thing total synthesis is good for is showing trends in reaction development- when a class of reactions starts showing up in total syntheses, it means they're getting common enough to be worth trying, and robust enough to work on materials that have >1 functional group.  Here's a cross-coupling reaction that was used in a recent total synthesis: How it works: Here is a nickel-catalyzed enantioselective cross-coupling of a vinyl zirconium reagent and an alkyl chloride. The original reaction was developed by the Fu group in 2021, but ...

Citation: Pierson, C.N.; Hartwig, J.F. Mapping the mechanisms of oxidative addition in cross-coupling reactions catalysed by phosphine-ligated Ni(0). Nat. Chem. 2024 , 16 , 930-937.  https://www.nature.com/articles/s41557-024-01451-x Old paper today as I go through papers I missed from 2024. This one is too good not to do! Summary Figure: Background: Oxidative addition of low-valent nickel species into aryl halides works. We know it works, because there are tens of thousands of papers that rely on this elementary step as the backbone of their catalytic cycles. However, just because we know that it works, doesn't mean that exactly how it works is known. The difficult question to answer is: how do the electrons move? There are four reasonable pathways for oxidative addition: In order: (Top left) Nickel can attack the π* orbital of the aromatic system in an addition-elimination sequence common in SnAr reactions.  (Top right) Nickel can conduct halogen atom abstraction, attacking ...

Citation:  Wang, Z.; Gao, L.; Liu, S.; Wang, P.; Shi, S. Facile Access to Quaternary Carbon Centers via Ni-Catalyzed Arylation of Alkenes with Organoborons. J. Am. Chem. Soc. ASAP.  https://pubs.acs.org/doi/10.1021/jacs.4c17313 Summary Figure: Background: The Shi lab has done a number of reactions that can loosely be considered cross-coupling, usually with nickel or palladium, and takes advantage of different ligand systems than the extremely common phosphine, pyridine, or bisoxazoline manifolds.  Hydroarylation is the process of adding a hydrogen and an aryl group across a pi bond, and can be fairly challenging. For one, there often are selectivity issues- which way do the functional groups go? Sometimes you can rely on selectivity in the substrate (Markovnikov vs anti-Markovnikov), while many other reactions just get a mix. Second, you need two different coupling partners because the hydrogen and the aryl group need to come from different places. That makes this reactio...

Citation: Simek, M.; Mahato, S.; Dehnert, B.W.; Kwon, O. Deacylative Homolysis of Ketone C(sp3)-C(sp2) Bonds: Streamlining Natural Product Transformations. J. Am. Chem. Soc. ASAP.  https://pubs.acs.org/doi/10.1021/jacs.4c15045 Summary Figure: Background: For the most part, cross-coupling chemistry is about finding new ways of making C-C bonds. Some researchers care more about finding ways to break C-C bonds. This is not an easy task, not because the C-C bond is particularly strong (~80 kCal/mol, weaker than a C-H bond at ~95 kCal/mol), but because organic molecules have an unsurprisingly high number of different C-C bonds and distinguishing between them is difficult. Additionally, the same strategies for well-established C-H activation reactions are not as effective with C-C activation. Recently, the Kwon lab at UCLA reported a wild de-alkenylation reaction, where they cleave a vinyl group using ozonolysis. It is important to note that this is not your grandparent's alkene cleavage...

Citation: Sun, J.; Wang, S.; Harper, K.C.; Kawamata, Y.; Baran, P.S. Stereoselective amino alcohol synthesis via chemoselective electrocatalytic radical cross-couplings. Nat. Chem. 2025 , 17 , 44-53.  Summary Figure: Background: Over the past several years, the Baran lab has been developing electrochemical nickel-catalyzed cross-electrophile coupling reactions. These reactions work by using a nickel catalyst to take two different electrophiles and stitch them together, forming a carbon-carbon bond. The overall transformation is reductive, so it requires an electron source. In some reactions, this is an organic reductant (amines, alkenes), while in many others it is a metallic reductant (zinc, manganese, or magnesium powder). Electrochemistry can be used to control the rate of consumption of these reductants- instead of throwing metal powders into the flask, you hook up a bar of metal to an electrochemical circuit, and the electrons are  released through the circuit at the othe...

Kim, S.F.; Liles, J.P.; Lux, M.C.; Park, H.; Jurczyk, J.; Soda, Y.; Yeung, C.S.; Sigman, M.S.; Sarpong, R. Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles. J. Am. Chem. Soc. ASAP.  https://pubs.acs.org/doi/10.1021/jacs.4c13999 Summary Figure: Background: The Sarpong lab (in collaboration with Merck) had previously identified an interesting ring contraction with piperidines. This sort of "skeletal editing" is popular right now, because changing the internal structure of drug candidates makes medicinal chemistry screening more effective. This one is particularly great because it's a saturated system, and pharma companies are trying to include a higher fraction of sp3 centers in their targets, because it's correlated with better clinical outcomes. Weirdly, the enantioselectivity of the reaction varied depending on substrate (anywhere between 0-99%). This is where the Sigman lab appears to have come in to collaborate. T...