Nickel Catalysis: Synergy between Method Development and Total Synthesis

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.

Figure 1

Natural product inspirations for nickel-catalyzed methodology.

FIGURE 2

Applications of nickel-catalyzed methods to natural product synthesis.

SCHEME 1

Intermolecular a) alkylative and b) reductive alkyne–aldehyde coupling reactions.

SCHEME 2

Mechanism of reductive and alkylative alkyne–aldehyde coupling.

SCHEME 3

Enantioselective alkyne–aldehyde reductive coupling.

SCHEME 4

Alkene directing effects in alkyne–aldehyde reductive coupling reactions for a) 1,3-enynes and b) tethered enynes.

SCHEME 5

Mechanistic rationale of tethered alkene reductive coupling regioselectivity.

SCHEME 6

Selected examples of reductive coupling of alkynes and imines using a) borane and b) boronic acid alkylating agents. c) Enantioselective reductive coupling of imines.

SCHEME 7

a) Inter- and b) intramolecular reductive couplings of alkynes and epoxides.

SCHEME 8

Mechanism of the reductive coupling reaction of alkynes and epoxides.

SCHEME 9

Total synthesis of (−)-terpestacin and 11-epi-terpestacin using an enantioselective alkyne–aldehyde reductive coupling reaction to couple key fragments.

SCHEME 10

Total synthesis of amphidinolide T1 leveraging both alkyne–epoxide and alkyne–aldehyde reductive couplings.

SCHEME 11

a) Highly selective coupling of allenes, aldehydes, and silanes. b) Proposed mechanism.

SCHEME 12

a) Highly regioselective cross–coupling of N-tosyl aziridines and alkylzinc reagents. b) Proposed mechanism for azanickelacyclobutane formation.

SCHEME 13

The nickel-catalyzed carbonyl–ene reaction.

SCHEME 14

Nickel-catalyzed conjugate addition of alkenes to enals and enones.

SCHEME 15

Allylic substitution reactions of a) ethylene and b) terminal aliphatic alkenes.

SCHEME 16

Mizoroki–Heck benzylation of a) ethylene and b) terminal alkenes and c) the development of an air-stable Ni(II) precatalyst.

SCHEME 17

Branch-selective Mizoroki–Heck arylation of terminal aliphatic alkenes.