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Chelate-Assisted Ring-Closing Metathesis: A Strategy for Accelerated Macrocyclization at Ambient Temperatures Carolyn S. Higman, Daniel Luis do Nascimento, Benjamin J. Ireland, Stephan Audörsch, Gwendolyn A Bailey, Robert McDonald, and Deryn Elizabeth Fogg J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13257 • Publication Date (Web): 18 Jan 2018 Downloaded from http://pubs.acs.org on January 18, 2018
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Journal of the American Chemical Society
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 Supporting Information Placeholder 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.
One 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 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 co-product 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 gen-
eral,6 reduced concentrations retard metathesis, permitting catalyst decomposition to compete with RCM.
Chart 1. Leading Ru metathesis catalysts and (inset) intermediates discussed. Ph Cl H2IMes Ru GII
Ph Cl H2IMes Ru
PCy3
GIII
Cl R
py
py Cl
Key intermediates
Cl H2IMes Ru A
Cl
Cl Cl H2IMes Ru
OiPr Cl
R = H: HII R = NO2: nG
H2IMes B
Ru Cl
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 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 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
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uncovering new capabilities that promote conformational preorganization of substrates bearing polar groups.
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enabled complete RCM, but the Grela catalyst nG performed best, with ca. 90% 1’. O
Scheme 1. Ring-chain equilibrium in RCM of conformationally mobile dienes exemplified by 1.
8 O
4
1
O
RT, 5 mM 1 1 mol% Ru C6H6
(b)
8 O
O
16
4
1
O
O
5 mM 1 + GII
1’
16
O
(a) (c)
O
1’ 8 O
[Ru]
4
n
As a prime objective, we sought to identify a bidentate, hemilabile ligand (Scheme 2) that could permit facile entry into the catalytic cycle, while impeding decomposition of intermediates A and B. To prevent ligand-induced decomposition, we further stipulated that this ancillary ligand should possess limited nucleophilicity,15 and low Brønsted basicity.16 o-Dianiline (ODA) meets each of these criteria.17,18 Treating GIII with ODA at RT resulted in immediate formation of the target catalyst Ru-1, in 40% equilibrium yield. Ligand exchange was forced to completion by repeated azeotropic removal of pyridine, after which Ru-1 was isolated in ca. 80% yield by reprecipitating from CH2Cl2hexanes. The IMes analog Ru-1’ was prepared likewise from GIII’. The analytical data are consistent with the structure shown. This assignment is further supported by crystallographic analysis of Ru-1’, X-ray quality crystals of which deposited from toluene-hexanes at –30 °C.
Scheme 2. Synthesis of o-dianiline (ODA) catalysts, and ORTEP plot showing perspective view of Ru-1’.a NH2 Ligand Design Criteria
Ph Cl NHC Ru GIII; GIII’
py
py + Cl
H 2N
ODA
• high donor ability • high (hemi)lability • low nucleophilicity • low Bronsted basicity
1. C 6H6, 15 min 2. Evaporate 3. Repeat
Cl NHC Ru H2N NHC Ru-1 H 2IMes Ru-1’ IMes
Figure 1. Assessing catalyst performance in RCM of diene 1 to yield lactone 1’. (Final E:Z = 78:22 in all cases). 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 isopropoxystyrene20 or PCy36,19a (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.; Katarzyna; Urbaniak; 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, 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.; Doherty, G. A.; Woodard, B. T.; Lemieux, C.; Geck Do, M.; Zhang, H.; Ballard, J.; Vigers, G.; Brandhuber, B. J.; Stengel, P.; Josey, J. A.; Beigelman, L.; Blatt, L.; Seiwert, S. D. 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.; Keiĵ, 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., RutheniumCatalyzed 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, 1951–1960. (f) Marhold, M.; Stillig, C.; Fröhlich, R.; Haufe, G. Eur. J.
Org. Chem. 2014, 5777–5785. (g) Schmidt, B. Eur. J. Org. Chem. 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, 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) Örnskov, 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 re-uptake 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 inter-ligand 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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O 8 O
4
Ph Cl NHC Ru H2N
NH2
O
Cl
FAST RT
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