Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

Higman, Carolyn S.; Lummiss, Justin A. M.; Fogg, Deryn E.

doi:10.1002/anie.201506846

Cited by 261 publications

(192 citation statements)

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“…26,27 These complexes are of central importance in olefin metathesis, a highly topical area of modern catalytic chemistry, 28 but serve more broadly as models for reactive, coordinatively unsaturated transition-metal complexes. They are characterized by widely differing susceptibilities to fragmentation, a key asset in gauging the importance of the experimental parameters discussed below.…”

Section: Resultsmentioning

confidence: 99%

Confronting Neutrality: Maximizing Success in the Analysis of Transition-Metal Catalysts by MALDI Mass Spectrometry

Bailey

Fogg

2016

ACS Catal.

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The elucidation of molecular identity is a central challenge in homogeneous transition-metal catalysis. Most exacting, despite advances in electrospray-ionization mass spectrometry (ESI-MS), are neutral complexes, which encompass the vast majority of metal catalysts. Insight into molecular constitution, readily achieved in other areas of the chemical sciences, is commonly thwarted by decomposition of inorganic and organometallic compounds, particularly for highly reactive species. MALDI-MS, where coupled with charge-transfer ionization, stands out from all other current MS methods in its unique capacity to report on the molecular identity of metal complexes irrespective of their initial charge state. Identified in the present work are methods that enable routine, unambiguous identification of such complexes across a wide range of standard MALDI mass spectrometers. The origin of fragmentation during MALDI-MS analysis is explored on 13 different instruments at nine facilities, and across a range of mass analyzers, from TOF, TOF-TOF, and Q-TOF to Orbitrap. Selected as test analytes were the second-generation Hoveyda and Grubbs metathesis catalysts, and the Grubbs resting-state methylidene complex, which span a very broad range in terms of ligand lability, and hence susceptibility to fragmentation. Three critical parameters emerge: (1) Using the minimum applied laser energy necessary for sample volatilization; (2) Minimizing the absorption cross-section of the analyte at the laser wavelength: (a) by appropriate laser choice, where options exist; (b) by using a matrix that absorbs as strongly as possible at the laser wavelength, in significant excess relative to the analyte (e.g. 500-fold); (c) by prompt analysis, to limit matrix sublimation in the ion source; (3) Using a charge-transfer matrix devoid of reactive protic or donor sites. A final, forward-looking section highlights relevant advances in state-of-the-art instrumentation, and instrumental features that would contribute to the optimization of next-generation MALDI spectrometers for this emerging application. These include fast-firing, contoured-profile and, potentially, wavelength-tunable lasers; high-resolution mass analyzers; automatic plate rastering with software to support retroactive compilation of spectra from optimal sampling locations, and soft-vacuum or atmospheric-pressure sources, in conjunction with a standardized anaerobic interface.

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Section: Resultsmentioning

confidence: 99%

Confronting Neutrality: Maximizing Success in the Analysis of Transition-Metal Catalysts by MALDI Mass Spectrometry

Bailey

Fogg

2016

ACS Catal.

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“…Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms) 5 . 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 6 ).…”

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Kinetically E-selective macrocyclic ring-closing metathesis

Shen

Nguyen

Koh

et al. 2017

Nature

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Macrocyclic compounds 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 precursor1. Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms)5. 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., dihydroxylation6). Still, while kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, the only available olefin metathesis approach for accessing macrocyclic E olefins entails selective removal of the Z component of a stereoisomeric mixture by ethenolysis10, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization, a particularly serious problem when the E alkene is energetically less favored. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. Reactions are 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 twelve-membered ring antibiotic recifeiolide12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib14,15 the Z isomer of which has lower potency than the E16. 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 (0.02 vs. 0.001 M; 73% yield, 92% E).

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“…1 It is widely used in the synthesis of pharmaceuticals as well as in the production of pheromones and musks as replacements for toxic, synthetic polycyclic and nitroarene musks. 2 The stereochemistry of the alkene, E or Z , in these cyclic structures is often crucial to the biological activity of a molecule or its olfactory characteristics, and small amounts of impurity of the other stereoisomer in chemical mixtures can drastically decrease their potency. It is often particularly difficult to separate E - and Z -isomers as techniques for their separation are not general.…”

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confidence: 99%

“…One year later, Z -selective cyclometallated ruthenium-based catalyst 4 (7.5 mol %) was reported to generate macrocyclic lactones, lactams, and ketones (75 – 94% Z ) with the purpose of synthesizing pheromones and fragrances. 2f This method was limited by long reaction times, required the use of high boiling solvents and elevated temperatures, and delivered most products with ca. 85% Z -selectivity.…”

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confidence: 99%

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A Highly Efficient Synthesis of Z‐Macrocycles Using Stereoretentive, Ruthenium‐Based Metathesis Catalysts

Ahmed

Grubbs

2017

Angew Chem Int Ed

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A highly efficient, Z-selective ring-closing metathesis system for the formation of macrocycles using a stereoretentive, ruthenium-based catalyst supported by a dithiolate ligand is reported. This catalyst is demonstrated to be remarkably active as observed in initiation experiments showing complete catalyst initiation at –20 °C within 10 min. Macrocyclization reactions generated Z-products from easily accessible diene starting materials bearing a Z-olefin moiety. This stereoretentive approach provides a more efficient and selective route to Z-macrocyles than in previously reported systems. Reactions were completed in appreciably shorter reaction times, and turnover numbers of up to 100 could be achieved. Macrocyclic lactones ranging in size from twelve-membered to seventeen-membered rings are synthesized in moderate to high yields (68 – 79% yield) with excellent Z-selectivity (95% – 99% Z).

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Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty‐Chemicals Manufacturing

Abstract: The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.

Cited by 261 publications

References 50 publications

Confronting Neutrality: Maximizing Success in the Analysis of Transition-Metal Catalysts by MALDI Mass Spectrometry

Confronting Neutrality: Maximizing Success in the Analysis of Transition-Metal Catalysts by MALDI Mass Spectrometry

Kinetically E-selective macrocyclic ring-closing metathesis

A Highly Efficient Synthesis of Z‐Macrocycles Using Stereoretentive, Ruthenium‐Based Metathesis Catalysts

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