Published on Web 03/24/2006
Enantioselective Synthesis of Cyclic Enol Ethers and All-Carbon Quaternary Stereogenic Centers Through Catalytic Asymmetric Ring-Closing Metathesis Ai-Lan Lee,† Steven J. Malcolmson,† Alessandra Puglisi,† Richard R. Schrock,‡ and Amir H. Hoveyda*,† Contribution from the Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received December 12, 2005; E-mail:
[email protected] Abstract: The first examples of catalytic asymmetric ring-closing metathesis (ARCM) reactions of enol ethers are reported. To identify the most effective catalysts, various chiral Mo- and Ru-based catalysts were screened. Although chiral Ru catalysts (those that do not bear a phosphine ligand) promote ARCM in some cases, such transformations proceed in 98%).
Introduction
Research in these laboratories has, in recent years, led to the development of an assortment of Mo-1 and Ru-based2 precatalysts that can be used to promote olefin metathesis reactions; several examples of such complexes are illustrated in Scheme 1. One noteworthy aspect of our programs relates to chiral complexes that give rise to efficient enantioselective transformations. Within this context, the higher oxidation state (vs Rubased) systems have proven to be particularly effective for asymmetric ring-closing metathesis (ARCM).1,3,4 Mo-based complexes exhibit high reactivity (1-5 mol % loading) with reactions that involve substrates bearing allylic or homoallylic ethers or amines to deliver optically enriched unsaturated heterocycles (>90% ee).1,3 Enol ethers, a versatile class of compounds in organic chemistry, can participate in olefin metathesis reactions.1,2 Nonetheless, particularly for electronic reasons, the reactivity of the derived Mo-alkylidenes and Ru-based carbenes can be significantly different than those derived from allylic or ho† ‡
Boston College. Massachusetts Institute of Technology.
(1) For a review on achiral and chiral Mo-based complexes and their related olefin metathesis reactions, see: Schrock; R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (2) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 81688179. For a comprehensive review on achiral and chiral Ru-based complexes developed in these laboratories and their related olefin metathesis reactions, see: (c) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8-23. 10.1021/ja058428r CCC: $33.50 © 2006 American Chemical Society
moallylic ethers.5 Metal-catalyzed ring-closing metathesis (RCM) has been used to access small and medium ring cyclic enol ethers,6 and such protocols have been applied to the preparation of natural products.7 In all the studies disclosed thus far, however, optically enriched enol ethers are obtained by treatment of a nonracemic substrate with an achiral Mo- or Ru-based (3) For examples of Mo-catalyzed ARCM, see: (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041-4042. (b) La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 97209721. (c) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 82518259. (d) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553-9559. (e) Cefalo, D. R.; Keily, A. F.; Wuchrer, M.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139-3140. (f) Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868-2869. (g) Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5, 4899-4902. (h) Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron 2004, 60, 7345-7351. (i) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526-8533. (4) For examples of Ru-catalyzed ARCM, see: (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228. (b) Van Veldhuizen, J. J.; Kingsbury, J. S.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954-4955. (c) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502-12508. (d) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840-1846. (5) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164. (6) For representative examples of cyclic enol ether synthesis through olefin metathesis reactions, see: (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029-4031. (b) Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623-9626. (c) Clark, J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231-8248. (d) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380-1386. (e) Liu, L.; Postema, M. H. D. J. Am. Chem. Soc. 2001, 123, 8602-8603. (f) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 1339013391. (g) Hekking, K. F. W.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron 2003, 59, 6751-6758. J. AM. CHEM. SOC. 2006, 128, 5153-5157
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ARTICLES Scheme 1. Representative Achiral and Chiral Metal Complexes
of the desired 10 in 89% yield after silica gel chromatography (eluted with 1% Et3N).
b. Preliminary Screening of Achiral Mo- and Ru-Based Olefin Metathesis Catalysts. We investigated the ability of Moand Ru-based complexes (e.g., Scheme 1) to promote RCM. These preliminary investigations (Table 1) indicated that Ruand Mo-based catalysts efficiently initiate the reaction; however, studies involving some of the less facile RCM (e.g., 12) suggested that Mo alkylidenes are somewhat more effective (compare entries 1-3, Table 1) and that phosphine-free 22b promotes RCM significantly more readily than the PCy3-bearing second-generation Grubbs complex 1110 (compare entries 2-5 and 8-10, Table 1). Accordingly, we included the available chiral Mo-based alkylidenes as well as phosphine-free Ru-based carbenes (Scheme 1) in our investigations of catalytic ARCM of enol ethers.
c. Mo-Catalyzed Enantioselective Synthesis of Tertiary Stereogenic Centers Through ARCM of Enol Ethers. As the data summarized in entries 1-2 of Table 2 indicate, secondary acyclic enol ethers 12 and 10, in the presence of 5-10 mol % binaphthyl-based chiral Mo complex 4a (see below for catalyst complex. A strategically unique and valuable, but thus far unexplored, alternative would be to access optically enriched cyclic enol ethers through ARCM of achiral substrates. Herein, we report the first examples of catalytic enantioselective olefin metathesis reactions of enol ethers, leading to the formation of five- and six-membered ring heterocycles in up to 94% ee. The present disclosure also contains the first instances of enantioselective syntheses of all-carbon quaternary stereogenic centers8 through olefin metathesis.
Table 1. Preliminary Examination of the Reactivity of Achiral Moand Ru-Based Complexesa
Results and Discussion
a. Synthesis of Acyclic Enol Ether Substrates. To initiate our investigations, we prepared various acyclic unsaturated enol ethers (see Tables 1-3). A representative procedure is depicted in eq 1.9 Treatment of bis(homoallylic) alcohol 9 with 0.5 mol % of commercially available Pd(OCOCF3)2 and 4,7-diphenyl1,10-phenanthroline in the presence of 0.75 equiv Et3N and 20 equiv n-butyl vinyl ether (75 °C, 24 h) leads to the formation (7) For an example of enol ether RCM in natural product total synthesis, see: Oliver, S. F.; Hogenauer, K.; Simic, O.; Antonello, A.; Smith, M. D.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5996-6000. (8) For recent reviews of catalytic asymmetric methods for the formation of all-carbon quaternary stereogenic centers, see: (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. 2004, 101, 5363-5367. (9) Bosch, M.; Schlaf, M. J. Org. Chem. 2003, 68, 5225-5227. 5154 J. AM. CHEM. SOC.
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entry
catalyst
temp (°C)
time (h)
conv (%)b
1 2 3 4 5 7 8 9 10
1 2 2 11 11 1 2 11 11
22 22 65 22 65 22 22 22 65
3 14 1 14 1 1 1 17 1
>98 98
a All reactions carried out under an atmosphere of N . b Conversions 2 determined by 400 MHz 1H NMR analysis of the unpurified product mixture. c 57% conv. after 4.5 h and 94% conv. after 14 h.
Enantioselective Synthesis Through Catalytic ARCM
ARTICLES
Table 2. Enantioselective Synthesis of Tertiary Carbon Stereogenic Centers by Mo-Catalyzed ARCM of Enol Ethersa
a All reactions performed under N atmosphere. b Conversions determined by analysis of the 400 MHz 1H NMR spectra of unpurified mixtures. c Isolated 2 yields after silica gel chromatography. d Enantioselectivities determined by chiral GLC analysis (see the Supporting Information for details). e Lower isolated f yields are due to product volatility. Lower conversion (68%) but identical ee is observed at 22 °C.
Table 3. Representative Data from Catalyst Screening Studiesa
entry
catalyst
conv (%)b
ee (%)c
1 2 3 4 5 6
3a 3b 3c 4a 5 6
62 72
