Metathesis Step Research Articles

Generation of low-valent tantalum species by reversible C-H activation in a cyclometallated tantalum hydride complex.

The cyclometallated tantalum(v) hydride complex {ArNC(Me)CHC(Me)N[2-(CHMeCH2)-6-(i)Pr-C6H3]}Ta(N(t)Bu)H (2) was prepared from hydrogenolysis of (BDI)TaN(t)BuMe2 (BDI = N,N'-diaryl-β-diketiminate, aryl = 2,6-(i)Pr2-C6H3). Based on mechanistic studies, formation of 2 likely proceeds through a dihydride intermediate generated from successive σ-bond metathesis steps. Compound 2 was found to undergo reductive elimination under certain conditions to form trivalent tantalum species. Coordination of DMAP to 2, followed by gentle heating under H2, gives (MAD)Ta(N(t)Bu)(NAr)(DMAP), which is produced through reductive C-N bond cleavage of the BDI ligand in a Ta(iii) intermediate. Ta(iii) dicarbonyl derivatives have been accessed by either introducing CO atmosphere to the DMAP adduct of 2 at room temperature, or by directly adding CO to 2 at low temperature.

Intramolecular Transannulation of Alkynyl Triazoles via Alkyne–Carbene Metathesis Step: Access to Fused Pyrroles

An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility. A rhodium carbene-alkyne metathesis mechanism is proposed for this transformation.

Theoretical Investigations of Heterogeneous Olefin Metathesis Catalysts

Olefin metathesis catalysed by solid systems has found a number of industrial applications. During the last decade, heterogeneous catalysts for olefin metathesis were comprehensively studied by experimental and theoretical methods. A great progress has been achieved in the field of both conventional and well-defined catalytic systems. The computational approach, taking advantage of growing computer power, enabled for the development of advanced models representing surface species relevant to olefin metathesis. In the case of the conventional ill-defined heterogeneous catalysts, the main achievements concern detailed description of the mechanism of the propagation steps and understanding the role of the support. The initiation stage of the olefin metathesis process was also explored, however, further investigations of the active sites generation, and, especially, catalyst deactivation are still required. Quantum chemistry methods, being complementary to experimental techniques, have become a standard tool for the characterization of the well-defined heterogeneous systems. The propagation and deactivation routes for olefin metathesis catalysed by various silicasupported Re, Mo and W alkylidene complexes were recognized in detail and the structure-activity relationships are now well established. Computational studies of alkane metathesis confirmed that olefin metathesis steps play a key role in the mechanism of this process. Keywords: Alkylidene complexes, Cluster model, DFT, Heterogeneous catalyst, Mechanism, Olefin metathesis, Periodic model.

Enabling Access to Diverse Bioactive Molecules Through Enyne Metathesis Concepts

This paper surveys recent advances in valorization of transition-metal-catalyzed enyne metathesis as key events in the total synthesis of naturally occurring compounds of biological and medicinal importance. Special attention is devoted to methodologies based on dienyne ring-closing metathesis (RCM) applied in tandem and sequential processes, on relay ring-closing metathesis (RRCM), ringrearrangement metathesis (RRM), enyne cross-metathesis (CM) and enyne skeletal bond reorganization, all proceeding under metalcarbenes (Ru or Mo alkylidenes) or metal-salts (Pd or Pt) catalysis. The high potential of these procedures in constructing versatile scaffolds as essential structural cores of a diversity of bioactive natural products is highlighted. Inventive functionalizations by nonmetathesis transformations intervening in the total synthesis of the targeted natural compounds, prior to (Michael addition, Wittig olefination, allylation etc.) or after (Diels-Alder cycloaddion, Heck and Suzuki-Miyaura reactions, Dess-Martin oxidation, dihydroxylation, epoxidation etc.) the pivotal metathesis step have also been included.

Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis

A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.

Catalyst-Dependent Routes to Ring-Opening Metathesis Alternating Copolymers of Substituted Oxanorbornenes and Cyclooctene

The alternating copolymerization of cis-cyclooctene and 1-substituted oxanorbornenes with commercially available ruthenium-based olefin metathesis catalysts was investigated. We determined that RuCl2(CHPh)(PCy3)2 performs a standard alternating copolymerization with these monomers. Unexpectedly, another route to the desired alternating copolymer was revealed. The “sequence editing” route involves the initial polymerization of cis-cyclooctene, followed a ring-opening cross metathesis step that introduces the 1-substituted oxanorbornene monomer in the polycyclooctene chain and largely avoids oxanorborene homopolymerization. Selectivity for alternating diads in the polymer exceeds 90%. Polymer molecular weight can be controlled by linear olefin chain-transfer reagents during sequence editing.

Hetero-dehydrocoupling of silanes and amines by heavier alkaline earth catalysis

The homoleptic alkaline earth hexamethyldisilazides, [M{N(SiMe3)2}2]2 (1: M = Mg; 2: M = Ca; 3: M = Sr), have been demonstrated as active pre-catalysts for the cross-dehydrocoupling of Si–H and N–H bonds under mild (25–60 °C) conditions. The reactions are applicable to the coupling of a wide variety of amine and silane substrates and are proposed to occur via a sequence of discrete Si–H/M–N and N–H/M–H metathesis steps. Whereas reactions of dialkyl group 2 species with 2,6-di-iso-propylaniline and phenylsilane delivered a series of well-defined compounds consistent with this rationale, kinetic analysis of the cross-coupling of diethylamine with diphenylsilane provided evidence for a more complex and subtly variable mechanistic landscape. Although reactions performed with all three pre-catalysts presented a number of common features, in every case the calcium species, 2, was found to provide notably superior catalytic activity, an order of magnitude higher than both 1 and 3 and in excess of many previously described benchmark transition metal- or f-element-mediated processes. Variations in overall reaction order, mode of pre-catalyst activation and the nature of the rate determining process are postulated to arise as a consequence of the marked change in M2+ radius and resultant charge density as group 2 is descended.

P–N/P–P Bond Metathesis for the Synthesis of Complex Polyphosphanes

A unique hexaphosphane featuring a 2,2'-bi(1,2,3-triphosphacyclopentane) moiety (19) and an ethylene-bridged bis-isotetraphosphane (27(c,m)) were both selectively prepared in efficient one-pot syntheses from easily accessible tris(3,5-dimethyl-1-pyrazolyl)phosphane (14) and 1,2-bis(phenylphosphanyl)ethane (18(c,m)). The formation of 27(c,m) is an example of a highly efficient P-P bond formation via protolysis. In contrast, the formation of 19 comprises P-N/P-P bond metathesis steps. This constitutes a novel synthetic approach toward the preparation of complex polyphosphanes. Detailed spectroscopic investigations form the basis for a mechanistic understanding of this unprecedented methodology. Furthermore, the preparation of a unique dinuclear iron-carbonyl complex which features hexaphosphane 19 as a bridging ligand illustrates the potential use of complex polyphosphanes such as 19 as ligands in transition metal chemistry.

Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies

Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was 29 (BRD-6851), with an IC50 of 0.4 μM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch–/–) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.

Application of the intramolecular PIFA-mediated amidation of alkynes to the synthesis of substituted indolizidinones

The construction of the title compounds has been achieved from properly substituted linear alkynylamides through the suitable combination of two key cyclization steps. First, an intramolecular PIFA-mediated alkyne amidation protocol leads to the creation of the pyrrolidinone nucleus, which under proper manipulation of the generated keto–carbonyl group permits the assembling of the indolizidinone skeleton by the introduction of a subsequent ring closing olefin metathesis step. Finally, its transformation into a series of substituted mono- and trihydroxylated indolizidinone derivatives is achieved by manipulation of the remaining unsaturated fragment under hydrogenation and dihydroxylation conditions.

Alkene Metathesis Approach to β-Unsubstituted Anti-Allylic Alcohols and Their Use in Ene–Yne Metathesis

The synthesis of β-unsubstituted, anti-allylic alcohols using a catalytic Evans aldol reaction conjoined with a relay-type ring-closing alkene metathesis is reported. The metathesis step serves to remove a β-alkenyl group, which facilitated the aldol step. The β-substituted enals serve as acrolein surrogates. The products were employed in ene-yne cross metathesis.

Magnesium-Catalyzed Hydroboration of Pyridines

Reaction of catalytic quantities of a β-diketiminato n-butylmagnesium complex with pinacol–borane in the presence of pyridine derivatives provides facile access to borylated dihydropyridines. The reaction is applicable to a wide range of monocyclic and fused-ring pyridine derivatives and catalytic turnover is proposed to occur through a well-defined sequence of Mg–H/pyridine dearomatization and Mg–N/B–H sigma bond metathesis steps.

Expedient Route to the Functionalized Calyciphylline A-Type Skeleton via a Michael Addition–RCM Strategy

An efficient, robust, and scalable strategy to access the functionalized core of calyciphylline A-type alkaloids has been developed starting from commercially available 3-methylanisole. Key features of this approach are an intramolecular Michael addition/allylation sequence and a ring-closing metathesis step.

Metathesis access to monocyclic iminocyclitol-based therapeutic agents.

By focusing on recent developments on natural and non-natural azasugars (iminocyclitols), this review bolsters the case for the role of olefin metathesis reactions (RCM, CM) as key transformations in the multistep syntheses of pyrrolidine-, piperidine- and azepane-based iminocyclitols, as important therapeutic agents against a range of common diseases and as tools for studying metabolic disorders. Considerable improvements brought about by introduction of one or more metathesis steps are outlined, with emphasis on the exquisite steric control and atom-economical outcome of the overall process. The comparative performance of several established metathesis catalysts is also highlighted.

Alkane Metathesis by Tantalum Metal Hydride on Ferrierite: A Computational Study

The full catalytic cycle for the self-metathesis of ethane was studied by density functional theory (DFT). The active site was a Ta-dihydride grafted on a Brønsted acid site [(≡AlO)2Ta(H2)] of the internal pore surface of the FER zeolite. The transition state geometries and activation energies were determined through the nudged elastic band (NEB) method for each elementary step, and the complete cycle was found to be thermodynamically consistent. Investigated elementary steps include ethane C–H σ-bond activation, ethylene desorption through α and β hydrogen elimination mechanisms, Ta-ethylcarbene formation, olefin metathesis, and hydrogenation of olefin metathesis products. For the activation of ethane, as compared to catalytic systems involving zeolite-supported Ga and Zn, a low barrier (∼64 kJ mol–1) was observed. In the olefin metathesis step, where Ta-ethylcarbene reacts with ethylene, it was found that the Ta-metallacyclobutane has a relatively high stability (∼143 kJ mol–1) as compared to similar metallacyclobutane species and that the forward decomposition of the Ta-metallacyclobutane is the most energetically demanding step.

Studies towards the Synthesis of Pentalenene: Mechanistic Insights into the Isomerization Phenomenon During RCM of Medium‐Sized Rings

AbstractIsomerization issues have been encountered during the ring‐closing metathesis (RCM) step of a new approach towards pentalenene. This paper describes the mechanistic insights gained during the study of this side reaction from a substrate perspective. Isomerization issues have been encountered during the RCM step of a new approach towards pentalenene.

Synthesis of cis,syndiotactic ROMP Polymers Containing Alternating Enantiomers

Ring-opening metathesis polymerization (ROMP) of rac-endo,exo-5,6-dicarbomethoxynorbornene (inter alia) yields a cis,syndio,alt-polymer, one in which the sequential units in the cis,syndiotactic polymer consist of alternating enantiomers. Cis selectivity arises through addition of the monomer to produce an all-cis-metallacyclobutane intermediate, while syndioselectivity and alternating enantiomer structures arise as a consequence of inversion of configuration at the metal center with each metathesis step.

The bigger, the better: Ring-size effects of macrocyclic oligomeric Co(iii)-salen catalysts

Macrocyclic oligomeric Co(III)-salen complexes derived from cyclooctene salen monomers are among the most active catalysts for asymmetric epoxide ring-opening reactions. Due to the uncontrollable feature of the ring-expanding olefin metathesis step during catalyst synthesis, the macrocyclic oligomeric Co(III)-salen complexes are produced as mixtures of oligomers with different ring sizes. We rationalize that the ring size of the Co(III)-salen oligomers might have a significant effect on the catalytic efficiency and selectivity and report here a purification protocol to isolate macrocyclic dimers, trimers, tetramers and oligomeric mixtures with larger size rings. Hydrolytic kinetic resolution (HKR) tests using allyl glycidyl ether as substrate show that the dimer is inactive at a catalyst loading of 0.01 mol%. Increasing ring size shows a remarkable effect on reaction rates with the largest ring-size species exhibiting superior selectivities and activities. NMR studies reveal that the dimeric catalyst is strained which is not observed for the larger ring-size catalysts. Computational modeling studies indicate that the dimer is lacking the flexibility to allow adjacent Co(III)-salen groups to form a bimetallic complex. Further catalytic tests of larger ring-size Co(III)-salen complexes (tetramer to hexamer mixture) by investigating the HKR of various racemic terminal epoxides and the asymmetric epoxide ring-opening with different nucleophiles demonstrate the superior catalytic activity of large ring-size macrocyclic catalysts. Furthermore, this study demonstrates again the structural (or configurational) sensitivity of Co(III)-salen catalyst towards the selectivity and efficiency of cooperative bimetallic reactions.

Concerning the Structures of Alkali-Metal-MediatedorthoZincation of Benzamides and PhenylO-Carbamate

As a further contribution to alkali-metal-mediated metalation, a method for converting C−H bonds directly to C−Zn bonds without the need for an additional salt metathesis step, reactions of the sod...

Synthesis of the Ecklonialactones

The ecklonialactones are a family of C18 oxylipins isolated from various brown algae. This first synthesis is protecting-group-free and features two ring-closing metathesis steps. This route was also used to access ecklonialactone A (which is saturated between C6 and C7) from common intermediate I.