Olefin Cross-metathesis Reaction Research Articles

The Synthesis and Ring‐closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side‐chains at C2.

Two epimeric pairs of N‐Ts‐protected cyclohexylamines that incorporate an unsaturated side‐chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically‐induced intramolecular hydroamination reactions to give the corresponding perhydro‐indole or ‐quinolines. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so‐formed engaged in base‐promoted and completely diastereoselective, intramolecular aza‐Michael addition (cyclisation) reactions to give the isomeric and C2‐substituted perhydro‐indoles or ‐quinolines with the structures of these being confirmed by single‐crystal X‐ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n‐propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C.

Recent Synthesis of Nucleoside Phosphonate Analogs Using Olefin Cross-metathesis.

Nucleotide analogs known as acyclic and cyclic nucleoside phosphonates (ANPs and CNPs, respectively) have a variety of biological properties, including antibacterial, antiviral, antiparasitic, antineoplastic, and immunomodulatory. A strong reaction that has emerged in the last several decades has fundamentally changed our knowledge of the chemistry of nucleoside phosphonates. In particular, Olefin cross-metathesis (CM) has been a potent and practical synthesis route to produce functionalized olefins from essential alkene precursors. This review describes recent synthesis examples of ANPs and CNPs analogs using the Ru-catalyzed olefin cross-metathesis reactions. Olefin cross-metathesis reactions are performed in the olefinic parts of nucleoside and phosphonate produced by Grubbs, Hoveyda-Grubbs, and Nolan. This review presents a synthetic overview of a few chosen nucleosides with biological significance. Their biological activity results are briefly discussed.

(NHC)Ni(II)-Directed Insertions and Higher Substituted Olefin Synthesis from Simple Olefins

ConspectusWell-controlled olefin insertion is critical for achieving catalytic and productive bulk and fine-chemical synthesis. Developing efficient and selective methods for meeting diverse insertion demands is extremely noteworthy, as it supports numerous transformations. The challenges are related to improving catalyst performance and selectivity control and uniting previously unreactive substrate pairs to achieve higher molecular structural complexity and utility. Nickel catalysts have received persistent attention in higher substituted olefin synthesis and polymerization, and numerous new strategies have been established to fulfill the ever-changing demands. This Account focuses on the recent progress based on N-heterocyclic carbene (NHC) ligands and nickel catalysts in our laboratory in using simple terminal olefins as olefin donors or acceptors.It begins with a brief history of olefin codimerization and the major advances in hydrovinylation achieved by other research groups using ethylene as an olefin donor. It then describes problems related to the reductive elimination that can occur when both the hydrometalated alkene and NHC are on the catalyst. It emphasizes the impact of NHC catalyst generation methods on the competing reactivity. Next, it explains the principal challenges and great opportunities in using our method (with α-olefins as olefin donors and alkenyl sources) to replace intermolecular reductive hydroalkenylation reactions (which require rare and more expensive alkenyl halides and boronic acids as reactants, alongside a stoichiometric amount of metallic reagents). The Account then illustrates the potential uses of our method for solving challenging organic synthesis problems using tailor-made (NHC)Ni(II) catalysts to allow redox-neutral catalytic cycles based on high chemo- and regioselective cross-insertion controls. It shows that upon optimal steric and electronic cooperation between the NHC, olefin donor, and olefin acceptor, regiodivergent insertion and convergent synthesis can be achieved easily.In the course of our work, we uncovered several unique insights into regulating (anti-)Markovnikov hydronickelation, carbonickelation, hydrocarbonation, ring closure, 1,3-allyl shift, isomerization, and catalyst regeneration under green, neutral, and mild-temperature conditions. These insights are also outlined here, along with theoretical calculations that offer additional understandings of the insertion reactivity and selectivity differences observed between the NHC and the highly related phosphorus-based Ni(II) hydride-catalyzed cross-hydroalkenylation and cycloisomerization systems.Compared to traditional olefin and cyclic structure synthesis technology, such as olefin cross-metathesis, enyne cyclization, and cross-coupling reactions, the new catalyst systems often offer previously inaccessible product structural characteristics, substrate scope, and outcomes. In particular, the method is effective for the catalytic synthesis of unsymmetrical and functionalized 1,1-disubstituted olefins (a.k.a. gem-olefins), 1,4-dienes (a.k.a. skipped dienes), conjugated dienes, endo- and exocyclic olefins, fused and spiro rings, and aromatic products. These syntheses are variously achieved by cross-hydroalkenylation, insertion-induced rearrangement, cycloadditions, and other approaches inspired by our investigations and detailed in this Account. Cross-hydroalkenylation can be achieved with high enantioselectivity by application of carefully designed and structurally flexible C1 and C2 chiral NHC ligands, yielding a pool of chiral branched alkenes and 1,4-dienes directly from simple chemical feedstocks used in industry. This Account will draw further attention to green alkenylation and the related development of redox-neutral catalytic cycles.

Fluorescently Labeled Ceramides and 1-Deoxyceramides: Synthesis, Characterization, and Cellular Distribution Studies.

Ceramides (Cer) are bioactive sphingolipids that have been proposed as potential disease biomarkers since they are involved in several cellular stress responses, including apoptosis and senescence. 1-Deoxyceramides (1-deoxyCer), a particular subtype of noncanonical sphingolipids, have been linked to the pathogenesis of type II diabetes. To investigate the metabolism of these bioactive lipids, as well as to have a better understanding of the signaling processes where they participate, it is essential to expand the toolbox of fluorescent sphingolipid probes exhibiting complementary subcellular localization. Herein, we describe a series of new sphingolipid probes tagged with two different organic fluorophores, a far-red/NIR-emitting coumarin derivative (COUPY) and a green-emitting BODIPY. The assembly of the probes involved a combination of olefin cross metathesis and click chemistry reactions as key steps, and these fluorescent ceramide analogues exhibited excellent emission quantum yields, being the Stokes' shifts of the COUPY derivatives much higher than those of the BODIPY counterparts. Confocal microscopy studies in HeLa cells confirmed an excellent cellular permeability for these sphingolipid probes and revealed that most of the vesicles stained by COUPY probes were either lysosomes or endosomes, whereas BODIPY probes accumulated either in Golgi apparatus or in nonlysosomal intracellular vesicles. The fact that the two sets of fluorescent Cer probes have such different staining patterns indicates that their subcellular distribution is not entirely defined by the sphingolipid moiety but rather influenced by the fluorophore.

Revisiting the surface olefin cross-metathesis of nitrile butadiene rubber on palygorskite nanorods: Product controlling for specific applications

Clays have been widely used for various fields after surface modification. In our previous work, nitrile butadiene rubber (NBR) had been successfully grafted onto palygorskite nanorods (Pal NRs) via the surface olefin cross-metathesis (OCM) reaction and their potential applications were preliminarily explored as nano-reinforcing agent, self-separable adsorbent, or Pickering surfactant. Aimed on a precise manipulation of the products for better performance in such specific applications, the modification of Pal NRs with NBR via OCM was optimized, including different vinyl groups modified on Pal NRs, feeding ratios, solid contents, solvents and reaction times. The reaction time was found as a critical factor for the manufacturing of nitrile butadiene rubber modified palygorskite nanorods (NBR-Pal NRs) as potential nano-reinforcing agent and Pickering surfactant. Overreaction with prolonged reaction time would produce the crosslinked nitrile butadiene rubber-palygorskite nanorods microgels (NBR-Pal MGs) as self-separable adsorbent. Furthermore, the better dispersibility of the Pal NRs and the better dissolubility of NBR could be achieved with the polar solvent, favoring the OCM reaction between the V-Pal NRs and accelerating the formation of the NBR-Pal MGs.

Enantiospecific Total Synthesis and Absolute Configuration Assignment of Chabrolobenzoquinone H.

Chabrolobenzoquinone H (1), a meroditerpene metabolite with cytotoxic activity, is synthesized via a stereoselective Julia-Kocienski olefination between a chiral pool derived aliphatic PT-sulfone and a benzoquinone aldehyde partner. The latter was obtained via consecutive chain extension steps involving a Stille coupling and a stereospecific olefin cross-metathesis reaction followed by malonic ester synthesis and a Krapcho decarboxylation. Furthermore, this total synthesis securely determined the absolute configuration of the targeted natural product.

Synthesis and in vitro antiproliferative profile of novel isomeric aza-analogues of natural jaspine B

A successful strategy for the construction of novel isomeric aza-analogues 13. HCl and 14. HCl of natural jaspine B was developed by constructing a vicinal diamino motif via a sequential Overman rearrangement, followed by a pyrrolidine core formation through SN2 type cyclisation. The olefin cross metathesis reaction was selected to incorporate the alkyl side chain unit. Based on an antiproliferative/cytotoxic evaluation study, it was observed that the final products display significant potency on Jurkat and HeLa cell lines, with IC50 values in the low micromolar range.

Enantioselective Total Syntheses of the Proposed and Revised Structures of Methoxystemofoline: A Stereochemical Revision.

This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.

Amphiphilic polymer-grafted palygorskite nanorods via surface olefin cross-metathesis for versatile applications

As an abundant natural nanomaterial, clay mineral has been intensely investigated for various applications, especially after surface modification with polymer. Here, amphiphilic polymer-grafted palygorskite (P-Pal) nanorods were prepared via surface olefin cross-metathesis reaction between the vinyl modified palygorskite (V-Pal) nanorods and acrylonitrile-butadiene rubber (NBR). After the surface olefin cross-metathesis reaction under the optimized condition, the resultant P-Pal nanorods could be well dispersed into water and toluene respectively, indicating the amphiphilic property with the grafted polymer molecules as the hydrophobic groups and clay nanorods as hydrophilic substance. The P-Pal nanorods showed promising applications as nano-reinforcing agent in polymer-based nanocomposites, self-separable adsorbent for waste water treatment, and hybrid surfactant for Pickering emulsion.

Olefin Cross Metathesis as a Versatile Method for the Facile Functionalization of Porous Polymers.

Olefin cross metathesis has been employed for the first time for the postpolymerization chemical modification of porous polymers. High quality microspheres of poly(divinylbenzene) were synthesized by the precipitation polymerization of divinylbenzene-55 in porogenic solvents, and the olefin cross metathesis reactions of the pendent (polymer-bound) vinyl groups not consumed by polymerization were performed with diverse coupling partners in dichloromethane using the Grubbs 2 catalyst, leading to microspheres decorated with a wide range of functional groups.

Synthesis of a Bolaamphiphilic Alkenyl Phosphonic Acid by Ru-catalyzed Olefin Cross Metathesis Reaction.

We report the synthesis of bolaamphiphilic alkenyl phosphonic acid (BPC12) through the olefin crossmetathesis reaction of vinylphosphonic acid with 1,11-dodecadiene in the presence of a Ru-carbene catalyst. BPC12 possesses two trans-P-C=C moieties and is thus readily soluble in water up to 3.4 g L-1, as confirmed by 1H nuclear magnetic resonance (NMR) measurements. Surface tension measurements revealed that BPC12 reduced the surface tension of water from 72.0 to 47.0 mN m‒1. The occupied area per molecule at the air/water interface (A) of BPC12 (216 Å2) was ten times larger than that of dodecenyl phosphonic acid PC12 (23 Å2). Moreover, dynamic light scattering measurement of an aqueous BPC12 solution (5 mM) revealed the formation of large aggregates with an average diameter of 81.8±27.0 nm.

Facile synthesis of norbornene–ethylene–vinyl acetate/vinyl alcohol multiblock copolymers by the olefin cross-metathesis of polynorbornene with poly(5-acetoxy-1-octenylene)

New norbornene−ethylene–vinyl acetate/vinyl alcohol multiblock copolymers are synthesized via the olefin cross-metathesis reaction of polynorbornene with poly(5-acetoxy-1-octenylene) followed by CC bond hydrogenation and acetoxy group deprotection.

Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

Summary Whereas most organic molecules can be synthesized from progressively simpler substrates, syntheses of complex organic targets often involve counterintuitive sequence of steps that first complexify the structure but, by doing so, open up possibilities for pronounced structural simplification in subsequent, downstream steps. Such complexifying/simplifying reaction sequences, called tactical combinations (TCs), can be quite powerful and elegant but also inherently hard to spot—indeed, only some 500 TCs have so far been cataloged, and even fewer are routinely used in synthetic practice. This paper describes computer-driven discovery of large numbers of viable TCs (over 46,000 combinations of reaction classes and ∼4.85 million combinations of reaction variants), the vast majority of which have no prior literature precedent. Examples—including a concise wet lab synthesis of a small natural product—are provided to illustrate how the use of these newly discovered TCs can streamline the design of syntheses leading to important drugs and/or natural products.

Conjugation of bile esters to cellulose by olefin cross-metathesis: A strategy for accessing complex polysaccharide structures

Bile salts tend to form micelles in aqueous media and can thereby contribute to drug solubilization; they also exhibit crystallization inhibition properties that can stabilize supersaturated drug solutions. Herein, we explore conjugation of bile salts with polysaccharides to create new, amphiphilic polysaccharide derivatives with intriguing properties, portending broad utility in various applications. We introduce efficient conjugation of cholesterol (as a model steroid), lithocholic acid, and deoxycholic acid by mild, modular olefin cross-metathesis reactions. These small molecules were first modified with an acrylate group from the A-ring hydroxyl, then reacted with cellulose derivatives bearing olefin-terminated metathesis “handles”. Successful conjugation of bile acids has demonstrated chemoselective cross-metathesis with complex, polyfunctional structures, and large multi-ring systems. It also enabled an efficient, general pathway for polysaccharide-bile salt conjugates, which promise synergy for applications such as amorphous solid dispersion (ASD).

Genetic Incorporation of Olefin Cross-Metathesis Reaction Tags for Protein Modification.

Olefin cross-metathesis (CM) is a viable reaction for the modification of alkene-containing proteins. Although allyl sulfide or selenide side-chain motifs in proteins can critically enhance the rate of CM reactions, no efficient method for their site-selective genetic incorporation into proteins has been reported to date. Here, through the systematic evaluation of olefin-bearing unnatural amino acids for their metabolic incorporation, we have discovered S-allylhomocysteine (Ahc) as a genetically encodable Met analogue that is not only processed by translational cellular machinery but also a privileged CM substrate residue in proteins. In this way, Ahc was used for efficient Met codon reassignment in a Met-auxotrophic strain of E. coli (B834 (DE3)) as well as metabolic labeling of protein in human cells and was reactive toward CM in several representative proteins. This expands the use of CM in the toolkit for "tag-and-modify" functionalization of proteins.

Asymmetric Total Synthesis of (-)-(3 R)-Inthomycin C.

A short (10 step) and efficient (15% overall yield) synthesis of the natural product (-)-(3 R)-inthomycin C is reported. The key steps comprise three C-C bond-forming reactions: (i) a vinylogous Mukaiyama aldol, (ii) an olefin cross-metathesis reaction, and (iii) an asymmetric Mukaiyama-Kiyooka aldol. This route is notable for its brevity and has the advantage of lacking stoichiometric tin-promoted cross-coupling reactions present in previous approaches. Initial investigations on the biological activity of (-)-(3 R)-inthomycin C and structural analogues on human cancer cell lines are also described for the first time.

Total synthesis of Carpatamides A–D

A synthetic strategy was developed for the synthesis of the common core structure of Carpatamides A–D. The total synthesis of Carpatamides A and C was completed in 6 steps and of Carpatamides B and D in 7 steps, by employing the Wittig olefination, olefin cross metathesis and acid amine coupling reactions as key steps.

Liquid-Crystalline Tris[60]fullerodendrimers.

Liquid-crystalline tris[60]fullerodendrimers based on first- and second-generation poly(arylester)dendrons carrying cyanobiphenyl mesogens were synthesized for the first time by the olefin cross-metathesis reaction between type I (terminal) and type II (α,β-unsaturated carbonyl) olefinic precursors, using a second-generation Grubbs or Hoveyda-Grubbs catalyst. The modular synthetic approach developed here also allowed the selective preparation of the [60]fullerene-free, mono[60]fullerodendrimer, and bis[60]fullerodendrimer derivatives from the appropriate precursors. As revealed by polarized optical microscopy, differential scanning calorimetry, and small-angle X-ray scattering, all of the materials displayed liquid-crystalline properties. In agreement with the nature of the dendritic building blocks, the emergence of lamellar mesophases (smectic C and/or smectic A phases), with the segregation of the various constitutive parts, was systematically observed. The small variation of the mesomorphic temperature range and of the mesophase stability suggested that the mesomorphism is essentially dominated by the dendrimer itself and is regulated by a subtle adaptive mechanism, in which the proportion of monolayering and bilayering arrangements of the multisegregated lamellar mesophases is modified in order to compensate the space requirements of each of the elementary building blocks, namely, the [60]fullerene units, the cyanobiphenyl mesogens, and the dendritic matrix.

Stereoselective synthesis of (−)-synargentolide B

A convergent, enantioselective total synthesis of (−)-synargentolide-B has been accomplished from readily available l-arabinose and d-ethyl lactate by a 10-step sequence involving Still-Gennari olefination, one-pot acidic deprotection/lactonization and olefin cross-metathesis reaction as the key step.

Design, Synthesis, and Self-Assembly Behavior of Liquid-Crystalline Bis-[60]Fullerodendrimers.

Bis-[60]fullerodendrimers were synthesized by assembling [60]fullerene-containing type I (terminal olefin) and type II (α,β-unsaturated carbonyl olefin) olefins through the olefin cross-metathesis reaction. The synthetic modular approach developed in this study allowed the preparation of mono-[60]fullerodendrimers and their [60]fullerene-free analogues. First- and second-generation poly(aryl ester) dendrons carrying cyanobiphenyl mesogens were used as liquid-crystalline promoters. The liquid-crystalline properties were studied by polarized optical microscopy, differential scanning calorimetry, and small-angle X-ray scattering. In agreement with the nature and structure of the dendrimers, nematic, smectic, and multisegregated lamellar phases were observed. Owing to its versatility and tolerance towards many functional groups, olefin cross-metathesis proved to be a reaction of choice for the elaboration of molecular materials with complex architectures.