New tools for olefin metathesis transformations Katarzyna Kaczanowska and Krzysztof Skowerski of Apeiron Synthesis present an approach towards robust and efficient olefin metathesis*
lefin metathesis has come a long way since its discovery and initial mechanistic studies, through to the Nobel Prize awarded to Yves Chauvin, Robert Grubbs and Richard Schrock for their work in this area.1 The enormous potential of this technology in fine chemical, polymers, pharmaceuticals, fragrances and flavours has been long recognised. Compared with non-catalytic processes, olefin metathesis typically offers a dramatic reduction in the number of manufacturing steps, the level of by-products and the quantities of solvents and waste, thereby significantly lowering capital and operating costs. However, despite many advantages and the increasing number of syntheses applying metathesis, the introduction of manufacturing processes exploring this technology to target complex chemical products has been rather slow. Recent review articles on olefin metathesis processes implemented to date, as well as related patent literature, have shed light on current trends and dynamics in the field.2, 3, 4 Since being founded in 2009, Apeiron Synthesis has developed a broad portfolio of catalysts that can satisfy nearly any approach or pathway employing olefin metathesis. The growing number of in-house and collaborative research projects has led company to identify three major recurring problems that limit the use of olefin metathesis, particularly on a large scale: 1. Unoptimised substrate structure 2. Impurities in solvents or substrates 3. Insufficient removal of gases (ethylene in the case of terminal olefin metathesis) Multiple examples of kilogram-scale processes described to date confirm that these issues can be successfully overcome with focused optimisation efforts.5,6 However, such attempts are often lengthy, resulting in increased costs. This article will summarise some of Apeiron’s work, the outcome of continuous efforts to develop customised catalysts and supportive technologies addressing encountered process difficulties.
Multiple ongoing studies continue to elucidate fine mechanistic details of the olefin metathesis catalytic cycle. In the case of chelating benzylidene-ether pre-catalysts (Hoveyda-type), the initiation mechanism that furnishes the active 14-electron species
Figure 1 – General structure of Hoveyda-type catalyst & ruthenium methylidene species (a) & designed analogues of ruthenium olefin metathesis catalysts (b) depends on the identity and concentration of the alkene substrate (Figure 1a). Most metathesis substrates contain terminal double bonds, which results in the formation of unstable methylidene complex and evolution of ethylene. It has been confirmed that the stability of methylidene species depends to a high degree on the structure of the remaining ligands.7 Additionally, ethylene can be associated by propagating species (ruthenium methylidene or alkylidene), resulting in unproductive cycles. Consequently, the optimisation of ancillary ligands should provide enhanced stability and selectivity of the catalyst, leading to improvements in process efficiency. For sterically non-demanding substrates, the pronounced effects of N-heterocyclic carbene (NHC) ligand enlargement on catalysts efficiency were confirmed. Easily accessible complexes containing the so-called SIPr ligand (Figure 1b, 2) can be extremely efficient, provided that substrates are rigorously purified. An excellent example is the synthesis of tetrahydro-1H-azepine derivative, which can be a starting point for the synthesis of Relacatib, a Cathepsin K inhibitor (Figure 2). This ring-closing metathesis (RCM) reaction was performed by scientists from Boehringer Ingelheim with 0.2 mol% of Apeiron’s classical nitro-Grela catalyst (Figure 1, 1).8 Two distillations of the substrate, each followed by treatment with activated alumina and replacement of metathesis initiator to nG-SIPr 2, allowed us to accomplish this reaction with only 0.004 mol% catalyst loading.
44 Speciality Chemicals Magazine July 2016
Nevertheless, in large-scale production or in the case of substrates which undergo fast ageing, such rigorous purification can cause operational and economic issues. We found that a further increase of NHC ligand size is rather problematic and this turned our attention to anionic ligands. We envisaged that the introduction of anionic ligands larger than chlorides can, for some substrates, bring similar benefits as replacing SIMes ligands with SIPr NHC. The exchange of chlorides with any other anionic ligands including bulky ones (i.e. –I) was reported to have a negative effect on initiation rates and/or the efficiency of Hoveyda-type complexes.9 We hypothesised that the negative effects of iodide on catalyst initiation would be balanced by the activating effects of a nitro group.10 Two new complexes containing SIMes or SIPr NHC ligands and iodides (Figure 1, 3 and 4) were synthesised in excellent yield and compared with parent catalysts bearing chlorides in standard olefin metathesis reactions. As expected, these new catalysts exhibited good initiation rates and were more efficient than 1 and 2 in the RCM of sterically non-demanding substrates purified by single distillation and activated alumina treatment. The most significant advantages of catalysts 3 and 4 were noted under challenging conditions which can cause fast catalyst deactivation. For example, RCM reactions carried out in ACS-grade solvents, such as toluene (which may contain traces of morpholine), 2-methyltetrahydrofuran (which coordinates to ruthenium and inhibits catalyst