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1. alpha- and beta-Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- and Enantioselectivity in Hydroacylation of 1,3-Dienes

   https://doi.org/10.1021/jacs.1c06245  

   Parsutkar, M. M.; RajanBabu, T. V. (July 2021, Journal of the American Chemical Society)

   Carreira, E. M.; Schoenebeck, F. (Ed.)

   Ketones are among the most widely used intermediates in organic synthesis and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstitued 1,3-dienes undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes isoprene ($1.4 /kg) and myrcene ($129/kg) and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds. 

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2. Enantioselective Hydroalkoxylation of 1,3-Dienes via Ni-Catalysis

   https://doi.org/10.1021/jacs.2c12779  

   Li, Qi; Wang, Zhen; Dong, Vy M.; Yang, Xiao-Hui (February 2023, Journal of the American Chemical Society)
3. Stereoconvergent Synthesis of Z ‐1,3‐Disubstituted‐1,3‐Dienes by Uphill Photocatalysis

   https://doi.org/10.1002/chem.202202635  

   Diver, Steven_T; Glickert, Elise; Rohde, Jr., Laurence_N; Wild, Thérèse (November 2022, Chemistry – A European Journal)

   Abstract A variety of 1‐aryl‐1,3‐dienes were isomerized fromEtoZisomers by photocatalysis using Ru(bpy)₃[PF₆]₂and blue LED light. Enrichment of theZ‐isomer is thought to occur by selective triplet energy transfer from the photocatalyst to the stereoisomeric mixture. The 1,3‐diene starting materials are easily made by catalytic ene‐yne metathesis (EYM). To access 1,3‐dieneZ‐stereoisomers directly, a one pot procedure was developed. Additional 1,3‐dienes were investigated for both isomerization andZ‐enrichment. The combination of cross EYM with photocatalysis allows for the stereoconvergent synthesis ofZ‐1,3‐dienes. 

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4. Iron-Catalyzed Site- and Regioselective 1,2-Azidoamidations of 1,3-Dienes

   https://doi.org/10.1021/acs.orglett.3c03947  

   Dai, Zhen-Yao; Guzei, Ilia A.; Schomaker, Jennifer M. (January 2024, Organic Letters)
5. Ligand control of regioselectivity in palladium-catalyzed heteroannulation reactions of 1,3-Dienes

   https://doi.org/10.1038/s41467-024-49803-y  

   Rodina, Dasha; Vaith, Jakub; Paradine, Shauna_M (June 2024, Nature Communications)

   Abstract Olefin carbofunctionalization reactions are indispensable tools for constructing diverse, functionalized scaffolds from simple starting materials. However, achieving precise control over regioselectivity in intermolecular reactions remains a formidable challenge. Here, we demonstrate that using PAd₂ⁿBu as a ligand enables regioselective heteroannulation ofo-bromoanilines with branched 1,3-dienes through ligand control. This approach provides regiodivergent access to 3-substituted indolines, showcasing excellent regioselectivity and reactivity across a range of functionalized substrates. To gain further insights into the origin of selectivity control, we employ a data-driven strategy, developing a linear regression model using calculated parameters for phosphorus ligands. This model identifies four key parameters governing regioselectivity in this transformation, paving the way for future methodology development. Additionally, density functional theory calculations elucidate key selectivity-determining transition structures along the reaction pathway, corroborating our experimental observations and establishing a solid foundation for future advancements in regioselective olefin difunctionalization reactions. 

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