Chelate-Assisted Ring-Closing Metathesis: A Strategy for Accelerating

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Cite This: J. Am. Chem. Soc. 2018, 140, 1604−1607

Chelate-Assisted Ring-Closing Metathesis: A Strategy for Accelerating Macrocyclization at Ambient Temperatures Carolyn S. Higman,§,† Daniel L. Nascimento,§,† Benjamin J. Ireland,† Stephan Audörsch,† Gwendolyn A. Bailey,† Robert McDonald,‡ and Deryn E. Fogg*,† †

Center for Catalysis Research & Innovation, and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada K1N 6N5 ‡ X-Ray Crystallography Laboratory, University of Alberta, Edmonton, Canada T6G 2G2 S Supporting Information *

demanding reactions is limited by decomposition of Ru intermediates, particularly active species A and the unsubstituted metallacyclobutane B. Exacerbating factors include high temperatures and the presence of ethylene (the usual coproduct of metathesis, which increases the proportion of vulnerable, unproductive B). Also problematic are the high dilutions required to favor macrocyclic products.1,3,5 In general,6 reduced concentrations retard metathesis, permitting catalyst decomposition to compete with RCM. Competing catalyst decomposition is a particular challenge in macrocyclization of flexible dienes. For such substrates (e.g., 1, Scheme 1; precursor to a leading synthetic musk),7 the kinetic

ABSTRACT: Ring-closing metathesis (RCM) offers versatile catalytic routes to macrocycles, with applications ranging from perfumery to production of antiviral drugs. Unwanted oligomerization, however, is a long-standing challenge. Oligomers can be converted into the cyclic targets by catalysts that are sufficiently reactive to promote backbiting (e.g., Ru complexes of N-heterocyclic carbenes; NHCs), but catalyst decomposition limits yields and selectivity. Incorporation of a hemilabile o-dianiline (ODA) chelate into new catalysts of the form RuCl2(NHC)(ODA)(=CHPh) accelerates macrocyclization, particularly for dienes bearing polar sites capable of H-bonding: it may also inhibit catalyst decomposition during metathesis. Significant improvements relative to prior Ru-NHC catalysts result, with fast macrocyclization of conformationally flexible dienes at room temperature.

Scheme 1. Ring−Chain Equilibrium in RCM of Conformationally Mobile Dienes Exemplified by 1

O

ne of the most prominent advances enabled by olefin metathesis is the assembly of macrocyclic rings via ringclosing metathesis (RCM).1 RCM is among the most versatile catalytic methodologies developed to date for the synthesis of diverse macrocyclic structures, entities of keen interest in the medicinal and fine-chemicals sectors.1,2 Pioneering advances in total synthesis3 demonstrated its power, and laid the foundation for widespread adoption. RCM macrocyclization has recently been exploited as a pivotal step in the assembly of several active pharmaceutical ingredients (APIs).1 Catalyst efficiency, however, remains a challenge.4 While the Ru precatalysts (Chart 1) are often robust, productivity in

products are oligomers rather than the desired macrocycles (Scheme 1a vs 1b).8 The macrocycles can be liberated via backbiting, if the catalyst is sufficiently active and long-lived, and if dilutions are high enough for the ring−chain equilibrium to favor the cyclic product8 (5 mM, in the case of 1; Scheme 1c). However, metathesis at internal, chiefly trans-configured olefinic sites typically requires high temperatures or long reaction times. Either promotes catalyst decomposition, trapping a proportion of the potential product as oligomers. To date, high productivity has been attained only where decomposition is restrained by aggressively removing ethylene,9,10 adding the catalyst slowly or in several doses, and, in the extreme, stringently purifying reagents and solvent.11 Barring such measures, catalyst loadings of 3−5 mol % are the norm for quantitative RCM of 1.5,8,12,13 Such loadings increase process costs, impede product isolation, and can degrade selectivity, owing to double-bond isomerization

Chart 1. Leading Ru Metathesis Catalysts and (inset) Intermediates Discussed

Received: December 15, 2017 Published: January 18, 2018 © 2018 American Chemical Society

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DOI: 10.1021/jacs.7b13257 J. Am. Chem. Soc. 2018, 140, 1604−1607

Communication

Journal of the American Chemical Society catalyzed by decomposed catalyst.1,14 Here we describe a mechanistically guided catalyst design strategy. Redesign of the stabilizing ancillary ligand realized our initial goal of fast, efficient macrocyclization at room temperature, while uncovering new capabilities that promote conformational preorganization of substrates bearing polar groups. As a prime objective, we sought to identify a bidentate, hemilabile ligand (Scheme 2) that could permit facile entry into

as indicated by the similar performance of IMes complex Ru-1′. Of the benchmark catalysts in Chart 1, none enabled complete RCM, but the Grela catalyst nG performed best, with ca. 90% 1′. RCM by HII and GII is slower, consistent with retarded initiation vs the ODA catalysts or nG, as well as recapture of active species A by isopropoxystyrene 20 or PCy 3 6,19a (respectively). RCM by GIII terminates at 90%, 1′ achieved at 0.3−0.5 mol % Ru via slow catalyst addition (and, for NHC catalysts, ethylene removal), see: (a) Gawin, R.; Kozakiewicz, A.; Guńka, P. A.; Dąbrowski, P.; Skowerski, K. Angew. Chem., Int. Ed. 2017, 56, 981−986. (b) Gawin, R.; Tracz, A.; Chwalba, M.; Kozakiewicz, A.; Trzaskowski, B.; Skowerski, K. ACS Catal. 2017, 7, 5443−5449. (c) Tracz, A.; Matczak, M.; Urbaniak, K.; Skowerski, K. Beilstein J. Org. Chem. 2015, 11, 1823−1832. (d) Skowerski, K.; Kasprzycki, P.; Bieniek, M.; Olszewski, T. K. Tetrahedron 2013, 69, 7408−7415. (e) Monfette, S.; Eyholzer, M.; Roberge, D. M.; Fogg, D. E. Chem. - Eur. J. 2010, 16, 11720−11725. Rigorous purification of 1 and solvent, drying to 50 mM diene, enabling lower catalyst loadings. The effect is substrate-dependent, however. See, e.g.: (a) Sundararaju, B.; Sridhar, T.; Achard, M.; Sharma, G. V. M; Bruneau, C. Eur. J. Org. Chem. 2013, 2013, 6433−6442. (b) Jiang, Y.; Andrews, S. W.; Condroski, K. R.; Buckman, B.; Serebryany, V.; Wenglowsky, S.; Kennedy, A. L.; Madduru, M. R.; Wang, B.; Lyon, M.; et al. J. Med. Chem. 2014, 57, 1753−1769. A clever alternative means of suppressing oligomerization involves the imposition of spatial constraints via a mesoporous foam. See: (c) Jee, J.-E.; Cheong, J. L.; Lim, J.; Chen, C.; Hong, S. H.; Lee, S. S. J. Org. Chem. 2013, 78, 3048−3056. (13) For comparison, see: stereoselective Ru-catalyzed macrocyclization (7.5 mol % Ru; 60 °C): (a) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276−1279. (b) Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94−97. Mo-catalyzed (3− 10 mol %; RT): (c) Zhang, H.; Yu, E. C.; Torker, S.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 16493−16496. (14) (a) Larionov, E.; Li, H.; Mazet, C. Chem. Commun. 2014, 50, 9816−9826. (b) Nam, Y. H.; Snapper, M. L. Ruthenium-Catalyzed Tandem Metathesis/Non-Metathesis Processes. In Handbook of Metathesis; Grubbs, R. H., Wenzel, A. G., Eds.; Wiley-VCH: Weinheim, 2015; pp 311−380. (c) Fustero, S.; Simón-Fuentes, A.; Barrio, P.; Haufe, G. Chem. Rev. 2015, 115, 871−930. (d) Lampa, A.; Ehrenberg, A. E.; Vema, A.; Åkerblom, E.; Lindeberg, G.; Helena Danielson, U.; Karlén, A.; Sandström, A. Bioorg. Med. Chem. 2011, 19, 4917−4927. (e) Schmidt, B.; Hauke, S. Eur. J. Org. Chem. 2014, 2014, 1951−1960. (f) Marhold, M.; Stillig, C.; Fröhlich, R.; Haufe, G. Eur. J. Org. Chem. 2014, 2014, 5777−5785. (g) Schmidt, B. Eur. J. Org. Chem. 2004, 2004, 1865−1880. (15) Nucleophilic amines can abstract the alkylidene ligand: (a) Lummiss, J. A. M.; Botti, A. G. G.; Fogg, D. E. Catal. Sci. Technol. 2014, 4, 4210−4218. (b) Lummiss, J. A. M.; Ireland, B. J.; Sommers, J. M.; Fogg, D. E. ChemCatChem 2014, 6, 459−463. Nucleophilic phosphines can likewise attack the [Ru]CHR carbon: (c) Werner, H.; Stuer, W.; Weberndorfer, B.; Wolf, J. Eur. J. Inorg. Chem. 1999, 1999, 1707−1713. (d) Hansen, S. M.; Rominger, F.; Metz, M.; Hofmann, P. Chem. - Eur. J. 1999, 5, 557−566. (e) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961−7968. (f) Galan, B. R.; Pitak, M.; Keister, J. B.; Diver, S. T. Organometallics 2008, 27, 3630−3632. (g) Lummiss, J. A. M.; McClennan, W. L.; McDonald, R.; Fogg, D. E. Organometallics 2014, 33, 6738−6741. (h) McClennan, W. L.; Rufh, S.; Lummiss, J. A. M.; Fogg, D. E. J. Am. Chem. Soc. 2016, 138, 14668− 14677. (16) (a) Bailey, G. A.; Lummiss, J. A. M.; Foscato, M.; Occhipinti, G.; McDonald, R.; Jensen, V. R.; Fogg, D. E. J. Am. Chem. Soc. 2017, 139, 16446−16449. (b) Ireland, B. J.; Dobigny, B. T.; Fogg, D. E. ACS Catal. 2015, 5, 4690−4698.

(17) Aniline is significantly less nucleophilic than pyridine. Values on the Mayr nucleophilicity scale: 12.99 vs. 11.05; both in H2O. See: http://www.cup.lmu.de/oc/mayr/reaktionsdatenbank/. (18) The conjugate acid of ODA has a pKa value of 3.81 (cf. 5.25 for pyridine). See: (a) Grantham, P. H.; Weisburger, E. K.; Weisburger, J. H. J. Org. Chem. 1961, 26, 1008−1017. (b) Ö rnskov, E.; Linusson, A.; Folestad, S. J. Pharm. Biomed. Anal. 2003, 33, 379−391. (19) (a) Lummiss, J. A. M.; Higman, C. S.; Fyson, D. L.; McDonald, R.; Fogg, D. E. Chem. Sci. 2015, 6, 6739−6746. (b) Vummaleti, S. V. C.; Nelson, D. J.; Poater, A.; Gomez-Suarez, A.; Cordes, D. B.; Slawin, A. M. Z.; Nolan, S. P.; Cavallo, L. Chem. Sci. 2015, 6, 1895−1904. (c) Back, O.; Henry-Ellinger, M.; Martin, C. D.; Martin, D.; Bertrand, G. Angew. Chem., Int. Ed. 2013, 52, 2939−2943. (20) Facile reuptake of isopropoxystyrene (originally proposed in: (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791−799) was recently demonstrated. See: (b) Griffiths, J. R.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2016, 138, 5380−5391. (c) Bates, J. M.; Lummiss, J. A. M.; Bailey, G. A.; Fogg, D. E. ACS Catal. 2014, 4, 2387−2394. (21) Bailey, G. A.; Higman, C. S.; Day, C. S.; Foscato, M.; Jensen, V. R.; Fogg, D. E. J. Am. Chem. Soc., submitted. (22) Yield of 1′ at 2 h with 0.05 mol% GIII; other conditions as in Figure 1: 19%. With 2 equiv ODA added: 19%. At 6 h: no change. (23) For examples of interligand EHCl hydrogen bonding (E = N, O), and its impact on selectivity in catalysis, see: (a) Roşca, D.-A.; Radkowski, K.; Wolf, L. M.; Wagh, M.; Goddard, R.; Thiel, W.; Fürstner, A. J. Am. Chem. Soc. 2017, 139, 2443−2455. (b) Rummelt, S. M.; Cheng, G.-J.; Gupta, P.; Thiel, W.; Fürstner, A. Angew. Chem., Int. Ed. 2017, 56, 3599−3604. (c) Rummelt, S. M.; Radkowski, K.; Roşca, D.-A.; Fürstner, A. J. Am. Chem. Soc. 2015, 137, 5506−5519. (24) Conrad, J. C.; Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2005, 127, 11882−11883. (25) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130− 9136.

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DOI: 10.1021/jacs.7b13257 J. Am. Chem. Soc. 2018, 140, 1604−1607