Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors

Ruthenium-Olefin Complexes: Effect of Ligand Variation upon Geometry

The development of a model system to study ruthenium-olefin complexes relevant to the mechanism of olefin metathesis has been reported recently. Upon addition of the ligand precursor 1,2-divinylbenzene to [RuCl2(Py)2(H2IMes)(CHPh)] (H2IMes=1,3-dimesityl-4,5-dihydroimidazol-2-ylidene), two ruthenium-olefin adducts are formed. Based on 1H NMR spectroscopy experiments and X-ray crystallographic analysis, these complexes are assigned as side-bound isomers in which the olefin and H2IMes ligands are coordinated cis to each other. Herein is reported an investigation of the generality of these observations through variation of the N-heterocyclic carbene ligand and the ligand precursor

Conformations of N-Heterocyclic Carbene Ligands in Ruthenium Complexes Relevant to Olefin Metathesis

The structure of ruthenium-based olefin metathesis catalyst 3 and model π-complex 5 in solution and in the solid state are reported. The N-tolyl ligands, due to their lower symmetry than the traditional N-mesityl substituents, complicate this analysis, but ultimately provide explanation for the enhanced reactivity of 3 relative to standard catalyst 2. The tilt of the N-tolyl ring provides additional space near the ruthenium center, which is consistent with the enhanced reactivity of 3 toward sterically demanding substrates. Due to this tilt, the more sterically accessible face bears the two methyl substituents of the N-aryl rings. These experimental studies are supported by computational studies of these complexes by DFT. The experimental data provides a means to validate the accuracy of the B3LYP and M06 functionals. B3LYP provides geometries that match X-ray crystal structural data more closely, though it leads to slightly less (0.5 kcal mol^(−1)) accuracy than M06 most likely because it underestimates attractive noncovalent interactions

Synthesis and reactivity of olefin metathesis catalysts bearing cyclic (alkyl) (amino) carbenes

All it's CAACed up to be! Cyclic (alkyl)(amino)carbenes (CAACs) can be used as ligands for olefin metathesis catalysis. A dramatic steric effect of the N-aryl group of the CAAC on catalyst activity was observed and utilized to develop a new catalyst with activity comparable to standard commercially available catalysts

Carboxylate-Assisted C(sp^3)–H Activation in Olefin Metathesis-Relevant Ruthenium Complexes

The mechanism of C–H activation at metathesis-relevant ruthenium(II) benzylidene complexes was studied both experimentally and computationally. Synthesis of a ruthenium dicarboxylate at a low temperature allowed for direct observation of the C–H activation step, independent of the initial anionic ligand-exchange reactions. A first-order reaction supports an intramolecular concerted metalation–deprotonation mechanism with ΔG^(‡)_(298K) = 22.2 ± 0.1 kcal·mol^(–1) for the parent N-adamantyl-N′-mesityl complex. An experimentally determined ΔS^(‡) = −5.2 ± 2.6 eu supports a highly ordered transition state for carboxylate-assisted C(sp^3)–H activation. Experimental results, including measurement of a large primary kinetic isotope effect (k_(H)/k_(D) = 8.1 ± 1.7), agree closely with a computed six-membered carboxylate-assisted C–H activation mechanism where the deprotonating carboxylate adopts a pseudo-apical geometry, displacing the aryl ether chelate. The rate of cyclometalation was found to be influenced by both the electronics of the assisting carboxylate and the ruthenium ligand environment

Facile and E-Selective Intramolecular Ring-Closing Metathesis Reactions in 3_(10)-Helical Peptides: A 3D Structural Study

The ring-closing metathesis reaction can be used to cross-link allylated serine residues situated at the i and i + 3 positions in 3_(10)-helical peptides containing the helicogenic amino acid, α-aminoisobutyric acid (Aib). An octapeptide with the sequence Boc-Aib-Aib-Aib-Ser(Al)-Aib-Aib-Ser(Al)-Aib-OMe was found to undergo a facile and >20:1 E-selective ring-closing metathesis (RCM) reaction catalyzed by the Grubbs second-generation catalyst to yield an 18-membered macrocycle. The formation of this cross-link does not significantly disturb the peptide's native 3_(10)-helicity, as judged by an X-ray diffraction study of the acyclic diene, the E-olefin RCM product, and its hydrogenated derivative. A heptapeptide system with the sequence Boc-Val-Ser(Al)-Leu-Aib-Ser(Al)-Val-Leu-OMe also underwent an efficient RCM reaction, albeit with diminished E-selectivity. It is apparent from these studies that a minimal, RCM-derived, macrocyclic constraint can be readily incorporated into 3_(10)-helical peptides

New Approaches to Olefin Cross-Metathesis

New methodology for the selective cross-metathesis (CM) of terminal olefins employing ruthenium benzylidene 1 is described.1 CM with symmetric internal olefins was found to provide a useful means for homologating terminal olefins to protected allylic alcohols, amines, and esters. Due to the limited commercial availability of symmetric internal olefins, a two-step CM procedure was developed in which terminal olefins were first homodimerized prior to the CM reaction. Terminal olefins with allylic methyl substituents were observed to provide CM products in diminished yield albeit with markedly improved trans-selectivity. Reaction rates were measured for CM reactions utilizing butenediol and allyl alcohol derivatives, and the results demonstrated distinct advantages in reaction rate and stereoselectivity for reactions employing the disubstituted olefins. In the course of studies of substrates with allylic oxygen substituents, a new CM application was discovered involving the metathesis of acrolein acetal derivatives with terminal olefins. Acrolein acetals, including asymmetric variants derived from tartaric acid, proved to be exceptionally robust and trans-selective CM substrates. In related work, a pinacol-derived vinyl boronate was also found to be a reactive CM partner, providing a novel means for converting terminal olefins into precursors for the Suzuki coupling reaction