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Nickel Catalysis: Synergy between Method Development and Total Synthesis.
Acc Chem Res 2015; 48(5):1503-14AC

Abstract

Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (-)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne-aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne-aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (-)-terpestacin, amphidinolides T1 and T4, (-)-gloeosporone, and pumiliotoxins 209F and 251D. We subsequently determined that alkenes could be used in place of alkynes in several nickel-catalyzed reactions when a silyl triflate activating agent was added. We reason that such an additive functions largely to enhance the electrophilicity of the metal center by coordination to the electrophilic π component, such that less nucleophilic alkene π donors can undergo productive combination with nickel complexes. This activation manifold was further demonstrated to be effective for alkene-aldehyde couplings. In a related manner, electrophilic promoters were also successfully employed for allylic substitution reactions of allylic carbonates with simple alkenes and in the Mizoroki-Heck reaction of both benzyl and aryl electrophiles. In these instances, it is proposed that counterion exchange from a more strongly coordinating anion to the weakly or noncoordinating triflate counterion enables reaction at an electrophilic Ni(II) center rather than by coordination to one of the coupling components. Mechanistic insights also played an important role in the development of mixed N-heterocyclic carbene/phosphite ligand systems to overcome challenges in regioselective alkene-aldehyde coupling reactions. We hope that, taken together, the body of work summarized in this Account demonstrates the constructive interplay among total synthesis, methodological development, and mechanistic investigation that has driven our research program.

Authors+Show Affiliations

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25905431

Citation

Standley, Eric A., et al. "Nickel Catalysis: Synergy Between Method Development and Total Synthesis." Accounts of Chemical Research, vol. 48, no. 5, 2015, pp. 1503-14.
Standley EA, Tasker SZ, Jensen KL, et al. Nickel Catalysis: Synergy between Method Development and Total Synthesis. Acc Chem Res. 2015;48(5):1503-14.
Standley, E. A., Tasker, S. Z., Jensen, K. L., & Jamison, T. F. (2015). Nickel Catalysis: Synergy between Method Development and Total Synthesis. Accounts of Chemical Research, 48(5), pp. 1503-14. doi:10.1021/acs.accounts.5b00064.
Standley EA, et al. Nickel Catalysis: Synergy Between Method Development and Total Synthesis. Acc Chem Res. 2015 May 19;48(5):1503-14. PubMed PMID: 25905431.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nickel Catalysis: Synergy between Method Development and Total Synthesis. AU - Standley,Eric A, AU - Tasker,Sarah Z, AU - Jensen,Kim L, AU - Jamison,Timothy F, Y1 - 2015/04/23/ PY - 2015/4/24/entrez PY - 2015/4/24/pubmed PY - 2016/3/29/medline SP - 1503 EP - 14 JF - Accounts of chemical research JO - Acc. Chem. Res. VL - 48 IS - 5 N2 - Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (-)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne-aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne-aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (-)-terpestacin, amphidinolides T1 and T4, (-)-gloeosporone, and pumiliotoxins 209F and 251D. We subsequently determined that alkenes could be used in place of alkynes in several nickel-catalyzed reactions when a silyl triflate activating agent was added. We reason that such an additive functions largely to enhance the electrophilicity of the metal center by coordination to the electrophilic π component, such that less nucleophilic alkene π donors can undergo productive combination with nickel complexes. This activation manifold was further demonstrated to be effective for alkene-aldehyde couplings. In a related manner, electrophilic promoters were also successfully employed for allylic substitution reactions of allylic carbonates with simple alkenes and in the Mizoroki-Heck reaction of both benzyl and aryl electrophiles. In these instances, it is proposed that counterion exchange from a more strongly coordinating anion to the weakly or noncoordinating triflate counterion enables reaction at an electrophilic Ni(II) center rather than by coordination to one of the coupling components. Mechanistic insights also played an important role in the development of mixed N-heterocyclic carbene/phosphite ligand systems to overcome challenges in regioselective alkene-aldehyde coupling reactions. We hope that, taken together, the body of work summarized in this Account demonstrates the constructive interplay among total synthesis, methodological development, and mechanistic investigation that has driven our research program. SN - 1520-4898 UR - https://www.unboundmedicine.com/medline/citation/25905431/Nickel_Catalysis:_Synergy_between_Method_Development_and_Total_Synthesis_ L2 - https://dx.doi.org/10.1021/acs.accounts.5b00064 DB - PRIME DP - Unbound Medicine ER -