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Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

A transformative advance in chemistry has been the development of catalyst-controlled stereoselective olefin metathesis reactions; the original discovery, disclosed in 2009, and many of the subsequent related breakthroughs have been the result of research carried out in the laboratories of Professor Amir Hoveyda. During the past eight years the BC team has shown that incorporation of appropriate ligands within molybdenum-, tungsten (in collaboration with Professor Richard Schrock and co-workers at MIT) as well as ruthenium-based complexes has made formerly inaccessible reactivity and selectivity levels feasible. Now, graduate students Ming Joo Koh and Thach Nguyen and senior research fellow, Dr. Sebastian Torker, from the Hoveyda group together with postdoctoral fellows Dr. Jonathan Lam and Dr. Jakob Hyvl of the Schrock laboratories report in a Letter published in Nature (doi:10.1038/nature21043). that molybdenum monoaryloxide chloride (MAC) complexes furnish higher energy Z isomers of trifluoromethyl-substituted alkenes through cross-metathesis with commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. The latter reagent is an inexpensive, non-flammable widely used commercially as foam blowing agent and; additionally, it has zero ozone depleting potential and minimal global warming potential. Otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloro- and 1,2- dibromoethene can also be effected with substantially improved efficiency and Z selectivity. The importance of the new advance is highlighted through synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. With the aid of DFT calculations, a logical basis for the origins of activity and selectivity levels, which contradict the previously proposed principles, has been provided.

See the recent publication by Richard Schrock and Amir Hoveyda:
Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

(Ming Joo Koh, Thach T. Nguyen, Jonathan K. Lam, Sebastian Torker, Jakub Hyvl, Richard R. Schrock & Amir H. Hoveyda, Nature, doi:10.1038/nature21043) 

Read a review of this publication in Chemistry World Magazine:
Unusual metathesis catalyst holds stereoselectivity promise

23 January 2017

 

Kinetically E-selective macrocyclic ring-closing metathesis

Macrocyclic organic molecules are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor. Ring-closing metathesis (RCM) is a widely used catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms). The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation). Professor Amir Hoveyda and his research group reported in a paper in Nature in 2011 the discovery of kinetically controlled Z-selective RCM. However, a generally applicable kinetically E-selective strategy has remained elusive until now. In a new paper just published by the journal Nature (doi:10.1038/nature 20800), the same research group at Boston College chemistry department show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. The team, which includes postdoctoral fellows Dr. Xiao Shen (soon to join the faculty at Wuhan University in China) and Dr. Alex Speed (now a faculty member at Dalhousie University in Canada), graduate students Thach Nguyen and Ming-Joo Koh and undergraduate scholar Dongmin Xu, finds that reactions can be promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib the Z isomer of which has lower potency than the E. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed. This study is part of a 20-year old collaboration between the Hoveyda group and the research team of Professor Richard Schrock at MIT.

See the recent publication by Richard Schrock and Amir Hoveyda:
Kinetically E-selective macrocyclic ring-closing metathesis

(Xiao Shen, Thach T. Nguyen, Ming Joo Koh, Dongmin Xu, Alexander W. H. Speed, Richard R. Schrock & Amir H. Hoveyda, Nature, doi:10.1038/nature 20800)

09 January 2017

 

From Box to Bench: Air-Stable Molybdenum Catalyst Tablets for Everyday Use in Olefin Metathesis

(Ondi L, Nagy GM, Czirok JB, Bucsai A, Frater GE. From Box to Bench: Air-Stable Molybdenum Catalyst Tablets for Everyday Use in Olefin Metathesis. Org. Process Res. Dev., Article ASAP, 2016 Oct 11.)

Molybdenum- and tungsten-based olefin metathesis catalysts have demonstrated excellent results in the control of cis (Z-) selectivity as well as enantioselectivity (Yu et al. Nature 2011, 479, 88). However, their air and moisture sensitivity, which requires the use of a glovebox, has prevented their widespread use by organic chemists. Now we report preweighed Mo catalysts formulated in paraffin tablets. Paraffin wax is particularly attractive as a protective matrix or carrier for reagents since it releases the active ingredients upon melting and/or adding appropriate solvents. Our procedure, in which the metathetically active Mo-complexes are perfectly dissolved or dispersed in melted macrocrystalline paraffin before formulation leads to homogeneous, preweighed paraffin droplets, containing predetermined, constant amount of active ingredient.

Two different Mo-based complexes were packed into tablets: XiMoPac-Mo001 (1) and XiMoPac-Mo003 (2).

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For the evaluation of the wax-protected catalysts commonly used, highly reproducible robust model reactions were chosen, e.g. homo cross-metathesis of 9-decenoic acid methyl ester (3).

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Up to now, this transformation was carried out in a N2-filled glovebox. In this study homocoupling of 3 was performed out of a glovebox, in a regular fume hood with 1.0 mol% of XiMoPac-Mo001. The yields and conversions were comparable with those that can be achieved in a glovebox with nonformulated catalysts.

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(Table 2, in part)
*isolated yield: 69%
**addition of triethylaluminum (TEAL) efficiently reduced the amount of polar impurities that are poisonous to the catalyst, thus, enabled the catalyst loading to be reduced. Formulation of neat TEAL into macrocrystalline paraffin was also successfully accomplished and applied (see Table 4).
Further examples, including ring closing metathesis were also examined, the yields and conversions were comparable high with those that can be achieved in a glovebox using nonformulated catalysts (see Scheme 3,4 and Table 4,5).

Exposure to air did not cause any significant reduction in conversion while the product selectivity remained high. In contrast, exposure to air caused a measurable drop in the conversion with the nonprotected catalyst. Furthermore, the formulated catalysts remained unaffected even after 4 h of exposure to air.

Our preweighed homogeneous tablets have the following advantages: (a) their uniformity and homogeneity assures a robustness and resistance to any mechanical impacts; (b) their homogeneity and accurate active ingredient content allows the user to cut them into smaller pieces, thus adjusting the loading according to their needs; (c) the automatized mass-production guarantees high reproducibility for weight and loading accuracy.

In conclusion, these commercially available air-stable Mo-catalyst tablets allow the reactions to be accomplished using ordinary Schlenk techniques, and hence simplify catalyst handling in pilot laboratories and plants.

Learn more about our CatPac catalysts by clicking here.

 

Kinetically Controlled E-Selective Catalytic Olefin Metathesis

A significant shortcoming in olefin metathesis, a chemical process that is central to research in several branches of chemistry, is the complete lack of efficient methods that kinetically favor E-isomers in the product distribution. Now a team of chemists report in a recent issue of the journal Science (2016, 352, 569–575) that kinetically E-selective cross-metathesis reactions may be designed to generate thermodynamically disfavored alkenyl chlorides and fluorides in high yield and with exceptional stereoselectivity. The researchers demonstrate that with 1.0–5.0 mol % of a molybdenum-based catalyst, which may be delivered in the form of air- and moisture-stable paraffin pills soon to be commercially available by Aspira, Inc., reactions typically proceed to completion within four hours at ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic cross-coupling transformations and found in biologically active entities, thus become easily and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler compounds or more complex molecules.

See the recent publication by Richard Schrock and Amir Hoveyda:
Kinetically Controlled E-Selective Catalytic Olefin Metathesis
(Thach T. Nguyen, Ming Joo Koh, Xiao Shen, Filippo Romiti, Richard R. Schrock, Amir H. Hoveyda, Science, 2016, 352, 569–575)

29 April 2016

 

Direct Synthesis of Z-Alkenyl Halides through Catalytic Cross-Metathesis

Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-Alkenyl halides.

See the recent publication by Richard Schrock and Amir Hoveyda:
Direct Synthesis of Z-Alkenyl Halides through Catalytic Cross-Metathesis
(M. J. Koh, T. T. Nguyen, H. Zhang, R. R. Schrock, A. H. Hoveyda, Nature 2016, 531, 459.)

23 March 2016

 

Efficient Synthesis of Metathesis Catalysts

Despite the lack of literature precedents, Mo and W based metathesis catalysts excel in extreme low catalyst loadings. Feedstock quality granted loadings of 6 – 50 ppm (by mole) are common.

Read the entire summary:
High activity, stabilized formulations, efficient synthesis and industrial use of Mo- and W-based metathesis catalysts
(Levente Ondi a, Henrik Gulyas a, Csaba Hegedus a, Georg Frater a,b, a XiMo Hungary, b XiMo Ag)

11 March 2015

 

Ring-Opening Metathesis Polymerization

It has been shown that Z-selective reactions in ROMP have some generality and that syndiotacticity (for cis polymers) is predictable as a consequence of the mechanism through which MAP catalysts operate, i.e., inversion of configuration at the metal center with each forward metathesis step (stereogenic metal control).

Read the entire summary of this article:
Z-Selective and Syndioselective Ring-Opening Metathesis Polymerization (ROMP) Initiated by Monoaryloxidepyrrolide (MAP) Catalysts
(Richard R. Schrock et al. Macromolecules, 2010, 43, 7515–7522)

19 May 2014

 

Activation of Oxo Tungsten Complexes

The coordination of B(C6F5)3 to an oxo ligand in tungsten oxo alkylidene bis(aryloxide) complexes, where the aryloxide is O-2,6-(mesityl)2C6H3 (HMTO) or 2,6-diadamantyl-4-methylphenoxide (dAdPO), accelerates the formation of metallacyclobutane complexes from alkylidenes as well as the rearrangement of metallacyclobutane complexes.

Read the entire summary of this article:
B(C6F5)3 Activation of Oxo Tungsten Complexes That Are Relevant to Olefin Metathesis
(Dmitry V. Peryshkov, and Richard R. Schrock et al, Organometallics 2013, 32, 5256−5259)

15 May 2014

 

Ring-Opening Cross-Metathesis

Ring-opening cross-metathesis (ROCM, particularly ethenolysis) of norbornenes/norbornadienes are important processes, however, using standard metathesis catalysts ring-opening metathesis polymerization (ROMP) is the predominant process.

Read the entire summary of this article:
Synthesis of Methylidene Complexes that Contain a 2,6-Dimesitylphenylimido Ligand and Ethenolysis of 2,3-Dicarbomethoxynorbornadiene
(Laura C. H. Gerber and Richard R. Schrock, Organometallics 2013, 32, 5573−5580)

13 May 2014

 

Stereogenic Olefin Metathesis

Description of recent advances in olefin metathesis by molybdenum, tungsten, and ruthenium alkylidene complexes that have focused on initiators in which the metal is a stereogenic center.

Read the entire summary of this article:
Syntheses of Variations of Stereogenic-at-Metal Imido Alkylidene Complexes of Molybdenum
(Marinescu, et al. Organometallics 2012, 31, 6336-6343)

17 June 2013

 

Ring-Opening Metathesis

The development of alkylidene complexes of Mo and W with known structures and modes of reaction have allowed an increasing number of Ring-Opening Metathesis polymers to be prepared that have a single microstructure. A polymer that has a single microstructure often is more desirable since its properties are more sharply defined relative to those of a polymer with a random structure.

Read the entire summary of this article:
Synthesis of cis,syndiotactic ROMP Polymers Containing Alternating Enantiomers
(Flook, et al. J. Am. Chem. Soc. 2011, 133, 1784–1786)

17 June 2013

 

Macrocyclic Ring-Closing Metathesis

Macrocyclic ring-closing metathesis (RCM) has had an enormous impact on organic chemistry in spite of the absence of reliable stereoselective catalyst-controlled protocols.

Read the entire summary of this article:
Molybdenum-Based Complexes with Two Aryloxides and a Pentafluoroimido Ligand: Catalysts for Efficient Z-Selective Synthesis of a Macrocyclic Trisubstituted Alkene by Ring-Closing Metathesis
(Chenbo Wang et al. Angew. Chem. Int. Ed. 2013, 52, 1939 – 1943)

24 May 2013

 

Catalytic Ring-Closing Metathesis

Catalytic RCM has played a prominent role in connection with the synthesis of macrocyclic alkenes, a structural motif found in an array of biologically active molecules. There is a high demand to develop catalysts that reliably deliver kinetic control of stereoselectivity in the formation of large-ring olefins.

Read the entire summary of this article:
Efficient and Selective Formation of Macrocyclic Disubstituted Z Alkenes by Ring-Closing Metathesis (RCM) Reactions Catalyzed by Mo- or W-Based Monoaryloxide Pyrrolide (MAP) Complexes: Applications to Total Syntheses of Epilachnene, Yuzu Lactone, Ambrettolide, Epothilone C, and Nakadomarin A
(Wang et al. Chem. Eur. J. 2013, 19, 2726 – 2740)

24 May 2013

 

Z-Selective Metathesis

Molybdenum or tungsten monoaryloxide pyrrolide (MAP) complexes that contain OHIPT as the aryloxide (hexaisopropylterphenoxide) are effective catalysts for homocoupling of simple (E)-1,3-dienes to give (E,Z,E)-trienes in high yield and with high Z selectivities.

Read the entire summary of this article:
Z-Selective Metathesis Homocoupling of 1,3-Dienes by Molybdenum and Tungsten Monoaryloxide Pyrrolide (MAP) Complexes
(Townsend et al. J. Am. Chem. Soc. 2012, 134, 11334−11337)

24 May 2013

 

Stereoselective Catalytic Cross-Metathesis

Unsaturated organoboron compounds are important reagents in organic synthesis e.g. (pinacolato)allylboron [allyl-B(pin)] are involved in many stereoselective additions while (pinacolato)vinylboron [alkenyl-B(pin)] reagents are used in various catalytic cross coupling reactions. The stereochemical outcome of the transformations strongly rely on whether a Z- or an E-organoboron is employed, therefore there is much interest in facile and efficient access to stereodefined acyclic allyl-B(pin) and alkenyl-B(pin) compounds. Contrary to the E isomers protocols for selective synthesis of Z-allyl- or Z-alkenylboron species are uncommon, and catalytic transformations are particularly rare.

Read the entire summary of this article:
Synthesis of Z-(Pinacolato)allylboron and Z-(Pinacolato)alkenylboron Compounds through Stereoselective Catalytic Cross-Metathesis
(Kiesewetter et al. J. Am. Chem. Soc. 2013, 135, 6026−6029)

14 May 2013

 

Stereoselective Olefin Metathesis

Alkenes reside in a vast number of biologically active molecules and are employed in a large assortment of transformations in modern organic chemistry. Many biologically active molecules, useful polymeric structures, and fragrances contain linear or cyclic units that contain one or more C–C double bond (also referred to as an alkene or olefin). Various other derivatives are prepared through modification of olefins, which, while stable, provide a sufficient degree of reactivity to render them of significant utility. The stereochemical identity of the alkene or the resulting moieties can be critical to the beneficial properties of such molecules. Olefin metathesis is class of reactions that allows for transformation of easily accessible, inexpensive C–C double bonds to those that are far more difficult to prepare otherwise, and are of exceptionally high value. XiMo offers olefin metathesis catalysts that generate unique levels of reactivity.

Efficiency, however, is one crucial problem in synthesis of olefins, which, linear or cyclic, can exist as E (or trans) or higher energy Z (or cis) isomers. Catalytic procedures for stereoselective formation of alkenes are therefore highly valuable. XiMo offers catalysts that are not only highly efficient but afford products with high degrees of stereoselectivity that are otherwise simply out of reach.

Through the use of XiMo catalysts, you can readily prepare a large variety of acyclic or cyclic alkenes with exceptional selectivity and efficiency. Our catalysts can be easily used in large scale (kilogram or higher); in fact, the larger the scale, the better XiMo catalysts perform.

XiMo catalysts contain the highly abundant and inexpensive metals molybdenum and tungsten; thus, XiMo catalysts offer processes that are substantially more sustainable in the long term than those that involve relatively precious and rapidly depleting metals. XiMo catalysts have already been used in highly efficient and stereoselective preparation of important molecules such as anti-oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer’s disease, the potent immunostimulant KRN7000, anti-cancer agents epothilones A and C, as well as potent anti-microbial and anti-cancer nakadomarin A.

See the recent publication by Richard Schrock and Amir Hoveyda:
Molybdenum-Based Complexes with Two Aryloxides and a Pentafluoroimido Ligand: Catalysts for Efficient Z-Selective Synthesis of a Macrocyclic Trisubstituted Alkene by Ring-Closing Metathesis

8 January 2013

 

New Homogeneous Catalysts

The early olefin metathesis catalysts that are present in "classical" homogeneous and heterogeneous molybdenum and tungsten catalyst systems, e.g. WCl6, are likely to be oxo alkylidene complexes. Tungsten oxo alkylidene complexes can now be prepared in many variations as well-defined homogeneous compounds. These new homogeneous catalysts show highly promising activity and selectivity for a large variety of olefin metathesis reactions.

See the recent publication by Richard Schrock and Amir Hoveyda:
Z-Selective Olefin Metathesis Reactions Promoted by Tungsten Oxo Alkylidene Complexes

8 January 2013

 

XiMo has recently licensed two patents from the Max Planck Institute

Catalysts for the alkyne metathesis
Patent in English | Patent in German
See the corresponding publication:
Practical New Silyoxy-based alkyne metathesis catalysts with optimized activity and selectivity profiles

Molybdenum and Tungsten metal complexes and use thereof as precatalysts for olefin metathesis
Patent in German
See the corresponding publication:
Rendering Schrock-type Molybdenum alkylidene complexes air stable: user friendly precatalysts for alkene Metathesis

3 January 2013

Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

 

A transformative advance in chemistry has been the development of catalyst-controlled stereoselective olefin metathesis reactions; the original discovery, disclosed in 2009, and many of the subsequent related breakthroughs have been the result of research carried out in the laboratories of Professor Amir Hoveyda. During the past eight years the BC team has shown that incorporation of appropriate ligands within molybdenum-, tungsten (in collaboration with Professor Richard Schrock and co-workers at MIT) as well as ruthenium-based complexes has made formerly inaccessible reactivity and selectivity levels feasible. Now, graduate students Ming Joo Koh and Thach Nguyen and senior research fellow, Dr. Sebastian Torker, from the Hoveyda group together with postdoctoral fellows Dr. Jonathan Lam and Dr. Jakob Hyvl of the Schrock laboratories report in a Letter published in Nature (doi:10.1038/nature21043). that molybdenum monoaryloxide chloride (MAC) complexes furnish higher energy Z isomers of trifluoromethyl-substituted alkenes through cross-metathesis with commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. The latter reagent is an inexpensive, non-flammable widely used commercially as foam blowing agent and; additionally, it has zero ozone depleting potential and minimal global warming potential. Otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloro- and 1,2- dibromoethene can also be effected with substantially improved efficiency and Z selectivity. The importance of the new advance is highlighted through synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. With the aid of DFT calculations, a logical basis for the origins of activity and selectivity levels, which contradict the previously proposed principles, has been provided.

 

See the recent publication by Richard Schrock and Amir Hoveyda:

Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

(Ming Joo Koh, Thach T. Nguyen, Jonathan K. Lam, Sebastian Torker, Jakub Hyvl, Richard R. Schrock & Amir H. Hoveyda, Nature, doi:10.1038/nature21043)

 

23 January 2017

Ximo provides highly selective olefin metathesis catalysts that enable synthetic efficiency.

XiMo partners with selected leading companies, providing access to its intellectual property and technical expertise, to solve important industrial chemistry problems.

XiMo was founded in 2010 by MIT Professor Richard Schrock and Boston College Professor Amir Hoveyda, along with a small group of other investors and co-founders.

www.camellia.plc.uk