Ring‐Closing Olefin Metathesis on Ruthenium Carbene Complexes: Model DFT Study of Stereochemistry

Abstract

Ring-closing metathesis (RCM) is the key step in a recently reported synthesis of salicylihalamide and related model compounds. Experimentally, the stereochemistry of the resulting cycloolefin (cis/trans) depends strongly on the substituents that are present in the diene substrate. To gain insight into the factors that govern the observed stereochemistry, density functional theory (DFT) calculations have been carried out for a simplified dichloro(2-propylidene)(imidazole-2-ylidene)ruthenium catalyst I, as well as for the real catalyst II with two mesityl substituents on the imidazole ring. Four model substrates are considered, which are closely related to the systems studied experimentally, and in each case, two pathways A and B are possible since the RCM reaction can be initiated by coordination of either of the two diene double bonds to the metal center. The first metathesis yields a carbene intermediate, which can then undergo a second metathesis by ring closure, metallacycle formation, and metallacycle cleavage to give the final cycloolefin complex. According to the DFT calculations, the stereochemistry is always determined in the second metathesis reaction, but the rate-determining step may be different for different catalysts, substrates, and pathways. The ancillary N-heterocyclic carbene ligand lies in the Ru-Cl-Cl plane in the simplified catalyst I, but is perpendicular to it in the real catalyst II, and this affects the relative energies of the relevant intermediates and transition states. Likewise, the introduction of methyl substituents in the diene substrates influences these relative energies appreciably. Good agreement with the experimentally observed stereochemistry is only found when using the real catalyst II and the largest model substrates in the DFT calculations.

A Formal Total Synthesis of Eleutherobin Using the Ring‐Closing Metathesis (RCM) Reaction of a Densely Functionalized Diene as the Key Step: Investigation of the Unusual Kinetically Controlled RCM Stereochemistry

“…[38] Calculations performed on olefins lacking substitution at the allylic position (i.e., different from our case) suggest that with N-heterocyclic carbene (NHC)-based catalysts (e.g., the secondgeneration Grubbs catalyst), the rate-determining step is the cleavage of the ruthenacyclobutane intermediate. [36][37][38] This implies that the less stable cis-ruthenacyclobutane intermediates (from Tables 2 and 3) would face a smaller cleavage barrier compared to the more stable trans-ruthenacycloScheme 5. Working hypothesis for the RCM reaction under kinetic control, leading to the thermodynamically less stable E stereoisomer 14.…”

“…www.chemeurj.org butanes, thus determining the preferential formation of the (Z)-cycloolefin, which is not observed experimentally. However, DFT calculations for more hindered diene substrates (either methyl-disubstituted olefins [38] or cyclic with allylic substitution as in the case of norbornene [37] ) have shown that the relative importance of the ruthenacycle formation and cleavage steps is inverted and the formation of the ruthenacyclobutane is the rate-determining step in those cases. The increased ruthenacycle formation barrier and decreased cleavage barrier are mainly due to the generation/release of repulsive nonbonded interactions during the formation/ cleavage of the ruthenacyclobutane.…”

“…[36,37] Recently, DFT calculations have been carried out to gain insight into the factors that govern the stereochemistry of the cycloolefin formed by a RCM reaction. [38] These studies have identified either the formation or the cleavage of the ruthenacyclobutane intermediate as the rate-determining step, which ultimately determines the stereochemical (Z/E) outcome of the cycloolefin under kinetic control, depending on the types of catalysts used, olefins, and reaction pathway. [38] Calculations performed on olefins lacking substitution at the allylic position (i.e., different from our case) suggest that with N-heterocyclic carbene (NHC)-based catalysts (e.g., the secondgeneration Grubbs catalyst), the rate-determining step is the cleavage of the ruthenacyclobutane intermediate.…”

“…[38] These studies have identified either the formation or the cleavage of the ruthenacyclobutane intermediate as the rate-determining step, which ultimately determines the stereochemical (Z/E) outcome of the cycloolefin under kinetic control, depending on the types of catalysts used, olefins, and reaction pathway. [38] Calculations performed on olefins lacking substitution at the allylic position (i.e., different from our case) suggest that with N-heterocyclic carbene (NHC)-based catalysts (e.g., the secondgeneration Grubbs catalyst), the rate-determining step is the cleavage of the ruthenacyclobutane intermediate. [36][37][38] This implies that the less stable cis-ruthenacyclobutane intermediates (from Tables 2 and 3) would face a smaller cleavage barrier compared to the more stable trans-ruthenacycloScheme 5.…”

Kinetically Controlled Ring‐Closing Metathesis: Synthesis of a Potential Scaffold for 12‐Membered Salicylic Macrolides

“…[11][12][13][14][15] In particular, DFT-calculation studies have suggested the energy levels of intermediates in olefin-metathesis catalytic cycles, including those with firstand second-generation ruthenium complexes. [16] To explain our experimental results, we would like to set forth a hypothesis that the energy level of the intermediate ruthenacyclobutane is higher than that of olefin-ruthenium p complex in the case of bisphosphane-type catalysts, but lower in the case of NHC-containing catalysts. [17] This idea is consistent with the fact that NHCs, being stronger two-electron s donors, can better stabilize the Ru 4 + center of the metallacyclobutane than a phosphine group.…”