Solid olefin metathesis

To date a number of reactions have been carried out in ionic liquids [for examples, see Dell Anna et al. J Chem Soc, Chem Commun 434 2002 Nara, Harjani and Salunkhe Tetrahedron Lett 43 1127 2002 Semeril et al. J Chem Soc Chem Commun 146 2002 Buijsman, van Vuuren and Sterrenburg Org Lett 3 3785 2007]. These include Diels-Alder reactions, transition-metal mediated catalysis, e.g. Heck and Suzuki coupling reactions, and olefin metathesis reactions. An example of ionic liquid acceleration of reactions carried out on solid phase is given by Revell and Ganesan [Org Lett 4 3071 2002]. 

The synthesis and olefin metathesis activity in protic solvents of a phosphine-free ruthenium alkylidene bound to a hydrophilic solid support have been reported. This heterogeneous catalyst promotes relatively efficient ring-closing and cross-metathesis reactions in both methanol and water.200 The catalyst-catalyzed cross-metathesis of allyl alcohol in D20 gave 80% HOCH2CH=CHCH2OH. 

The epothilone synthesis in Scheme 13.49 has been used as the basis for a combinatorial approach to epothilone analogs. 167 The acyclic precursors were synthesized and attached to a solid support resin by steps A-E in Scheme 13.58. The cyclization and disconnection from the resin were then done by the olefin metathesis reaction. The aldol condensation in step D is not highly stereoselective. Similarly, olefin metathesis gives a mixture of E- and Z-stereoisomers so that the product of each combinatorial sequence is a mixture of four isomers. These were separated by thin-layer chromatography prior to bioassay. In this project, reactants A (3 variations), B (3 variations), and C (5 variations) were used, generating 45 possible combinations. The stereoisomeric products increase this to 180 (45 x 4). 

Since the discovery of ruthenium and molybdenum carbene complexes that efficiently catalyze olefin metathesis under mild reaction conditions and that are compatible with a broad range of functional groups, olefin metathesis has increasingly been used for the preparation of alkenes on insoluble supports. In particular, the ruthenium complexes Cl2(PCy3)2Ru=CHR, developed by Grubbs, show sufficient catalytic activity even in the presence of air and water [781] and are well suited for solid-phase synthesis. 

With the discovery by Grubbs of ruthenium carbene complexes such as Cl2(PCy3)2Ru=CHR, which mediate olefin metathesis under mild reaction conditions and which are compatible with a broad range of functional groups [111], the application of olefin metathesis to solid-phase synthesis became a realistic approach for the preparation of alkenes. Both ring-closing metathesis and cross-metathesis of alkenes and alkynes bound to insoluble supports have been realized (Figure 5.12). 

Figure 5.12. Main strategies for the application of olefin metathesis to solid-phase synthesis.

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

To examine the possibility of a more efficient catalytic olefin metathesis, we prepared chiral Mo-based catalysts, 4a and 4b [10]. This approach was not without precedence related chiral Mo complexes were initially synthesized in 1993 and were used to promote polymer synthesis [6]. We judged that these biphen-based complexes would be able to initiate olefin metathesis with high levels of asymmetric induction due to their rigidity and steric attributes. Chiral complexes 4a and 4b are orange solids, stable indefinitely when kept under inert atmosphere. 

The total synthesis proceeds in >10 steps on solid phase and includes various transformations, including an asymmetric Diels-Alder reaction, oxidation with singlet oxygen, and olefin metathesis. This synthesis sequence is among the most advanced and demanding solid-phase syntheses developed so far for chemical genomics experiments. It demonstrates that the total synthesis of complex natural products in multi-step sequences on solid phase is feasible. 

Recent examples of the first route have been described by Kobayashi and coworkers, who reported the synthesis and characterization of polymeric Pcs obtained through the olefin metathesis polymerization of terminal olefin groups in the side chains of unsymmetrical Pc monomers [159], X-ray analysis of the solid material indicates that the Pcs are ordered in stacks. 

Geert-Jan Boons et al. also synthesized peptidoglycan fragments such as the disaccharide repeating unit [51] and muramyl peptide derivatives containing Lys and DAP residues [52-55] obtained through cross olefin metathesis [56], The muramyl peptides, such as 48 prepared by solid-phase synthesis on Sieber amide resin (Scheme 14.6), were subjected to biological and structural analyses [50, 57, 58] of... 

Grafting (49) on a silica surface led to a well defined , highly active, heterogeneous olefin metathesis catalyst (51) fully characterized by solid-state NMR spectroscopy. ... 

Grubbs reported an unexpected reaction, which may be at play during the course of the synthesis of the second-generation olefin metathesis catalyst (264) (equation 46). The product (265), air stable both in solution and in the solid state, results from the C-H activation of one ortho methyl of the mesityl group. Unfortunately, no explanation was proposed for the mechanistic pathway leading to (265). 

Fully protected tumor-associated carbohydrate antigen Globo-H (50), a potential breast and prostate cancer vaccine [54, 55], was assembled by automated solid support synthesis using oct-4-ene-l,8-diol linker 49 and building blocks 51-56 (Scheme 20.15). The linker is stable to acid and base but is cleaved cleanly by olefin metathesis [56]. The octenediol linker performs best on Merrifield s PS resin, affording routinely loadings in a range of 0.1-0.3 mmol g 1. 

One of the areas garnering attention in catalysis research has been the development of green or environmentally benign catalytic systems. For olefin metathesis, the trend has been to develop catalytic systems that can be efficiently recycled. Success in this area has multiple implications for OM processes. First, a recyclable catalyst will give overall more turnovers per catalyst molecule, and thereby be more economical. Second, a catalyst that can be efficiently recycled (low loss of activity over repeated uses) leaches less Ruthenium into the product and thus less expensive processing costs. To this end immobilization of the olefin metathesis catalysts on a variety of solid supports and utilization of nonorganic solvent systems have been explored. 

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