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Construction of Enantioenriched [3.1.0] Bicycles via a RutheniumCatalyzed Asymmetric Redox Bicycloisomerization Reaction Barry M. Trost, Michael C. Ryan, Meera Rao, and Tim Z. Markovic J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Nov 2014 Downloaded from http://pubs.acs.org on December 1, 2014
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Construction of Enantioenriched [3.1.0] Bicycles via a Ruthenium-Catalyzed Asymmetric Redox Bicycloisomerization Reaction Barry M. Trost,* Michael C. Ryan, Meera Rao, and Tim Z. Markovic Department of Chemistry, Stanford University, Stanford, California 94305-5580 Supporting Information Placeholder
ABSTRACT: Enantiomerically enriched [3.1.0] bicycles containing vicinal quaternary centers were synthesized from [1,6]-enynes using a cyclopentadienylruthenium (CpRu) catalyst containing a tethered chiral sulfoxide. The reaction was complicated by the fact that the substrates contained a racemic propargyl alcohol that could affect the selectivity of the process. Nonetheless, high levels of enantioinduction were observed, despite complications arising from the use of racemic substrates. Mechanistic studies showed that while the utilization of either enantiomer of propargyl alcohol led to high product e.r. when conducted in acetone, a significant matched/mismatched effect is observed in THF.
O
(a) TsN
5 mol% CpRu(PPh 3)2Cl
Me
OH
3 mol% CSA, 5 mol% In(OTf) 3 Acetone, 0.25 M, 16 h 85% yield
Me
Chiral sulfoxides are a relatively unexplored ligand class for transition metals.14 Very recently, we have
N Ts
alcohol coordination
reductive elimination
[Ru]
Me TsN
Me
[Ru]
Me
O H N Ts
H Me
redox isomerization
Me
TsN
In recent years, transition metal-catalyzed asymmetric cycloisomerization reactions1 are an important class of reactions for the construction of enantiomerically enriched complex molecules in an atom,2 step,3 and redox4 economical fashion. Examples of gold,5 platinum,6 palladium,7 and rhodium8-catalyzed simple asymmetric cycloisomerization reactions have been reported in the literature. While there has been progress in utilizing chiral ruthenium catalysts for asymmetric cycloaddition,9 cyclopropanation,10 and allylic alkylation reactions,11 there have been no reported examples of using a chiral ruthenium catalyst for cycloisomerization reactions, to the best of our knowledge. Ruthenium-catalyzed reactions have distinguished themselves as an important class of transformations that can construct complex organic molecules quickly and efficiently.12 Previously, we reported the cyclopentadienylruthenium (CpRu)catalyzed redox bicycloisomerization of [1,6] and [1,7] enynes to form structurally complex [3.1.0] and [4.1.0] bicycles that contain vicinal, quaternary stereocenters (Figure 1a).13 Intrigued by the possibility of making this process enantioselective, we hoped that an appropriate choice of ruthenium catalyst would deliver high levels of enantioinduction.
Me
Me
[Ru]
[2+2] cycloaddition
Me O
TsN
O
[Ru]
O
Me
Me
PF 6MeCN (b)
R
Ru S
MeCN
O
Ru HO
L*
(c)
OH R'
H
Ru L*
R' H
R
MeO 1
Chiral-at-Ru Complexes L *= chiral ligand
Figure 1. (a) Ruthenium-catalyzed redox bicycloisomerization reaction reported by Trost. (b) Ruthenium catalyst 1 containing a tethered chiral sulfoxide. (c) Possible diastereomeric complexes formed from propargyl alcohol coordination.
described the conveniently synthesized CpRu complex 1 which does not resort to a resolution of an intermediate CpRu complex15 and its application towards asymmetric allylic substitution reactions (Figure 1b).16 It also has the added advantage of having its asymmetry-inducing element, the chiral sulfoxide, in close proximity to the metal center. This increases the possibility of asymmetric induction during the enantiodetermining step. Our hope was that the application of 1 would provide a means by which one could access enantioenriched [3.1.0] and [4.1.0] bicycles.
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Table 1. Asymmetric Redox Bicycloisomerization with Tris-Substituted Nitrogen PF 6-
R
TrisN
OH
MeCN 3 mol% MeCN
O
Ru
S O
Acetone, 40 °C,
0.25 M, 16 h
N Tris 2b-9b
R' MeO
2a-9a O
O
Me
Me
O
O
O
Me
Me N Tris
6b 48% yield, 90.0:10.0 e.rc
c
i-Pr
p-tolyl
N Tris
a
N Tris 5b 57% yield, 93.0:7.0 e.r
4b 88% yield, 92.0:8.0 e.rb
4
Me
8
Me N Tris
3b 47% yield, 64.0:36.0 e.ra 75% yield, 98.5:1.5 e.r.
O
O
Ph
Me N Tris
2b 78% yield, 56.0:44.0 e.ra 85% yield, 90.5:9.5 e.r.
b
O
i-Pr
Me N Tris
R'
R
N Tris
N Tris 8b 75% yield, 90.0:10.0 e.r
7b 42% yield, 94.0:6.0 e.r
9b 50% yield, 82.5:17.5 e.r
Reaction conducted in THF. 5 mol% of catalyst used. 8.5 mol% of catalyst used.
Supporting Information).18 However, when these conditions were applied to [1,6]-enynes, only low levels of enantioinduction were observed for substrates 2a and 3a (Table 1). Switching to acetone, a more coordinating solvent, had a profound effect on the selectivity of the reaction, boosting the e.r. to 90.5:9.5 and 98.5:1.5 for 2b and 3b, respectively. Encouraged by these results, substrates containing aromatic (4a), olefinic (5a), and alkynyl (6a) groups were prepared in an effort to probe steric and coordinative effects in the redox bicycloisomerization reaction. This series of substrates showcased the chemoselectivity of the redox bicycloisomerization reaction, which can tolerate both isolated alkenes and alkynes without significantly impacting the reactivity or enantioselectivity, a degree of chemoselectivity not reported for any previous metalcatalyzed asymmetric cycloisomerization to our knowledge.19 Substrate 7a, which contains a more bulky cyclopentyl group at the internal position of its
However, the fact that substrates of this type contain a chiral, racemic stereocenter presents a complicating aspect to this reaction. One can envision that coordination of the propargyl alcohol to the metal center can occur with either one of two possible diastereochemical outcomes, thus creating a stereocenter at ruthenium (Figure 1c). While the aforementioned stereocenter is destroyed concomitant with redox isomerization, it is unclear whether this transfer of stereochemical information to the metal would have an adventitious, detrimental, or inconsequential impact on the selectivity. Initial optimization efforts were made on [1,7]enynes containing racemic propargyl alcohols due to their product’s similarity to triple-uptake inhibitors developed by GlaxoSmithKline®.17 From these initial studies, the use of a 2,4,6-triisopropylbenzenesulfonyl (Tris) group and THF as the solvent were determined to be optimal for enantioinduction and yield (see
Table 2. Impact of Enyne Backbone on Enantioselectivity PF 6-
X
n
R
OH
3 mol%
MeCN MeCN
O
Ru
S O
Acetone, 40 °C,
R'
R
0.25 M, 16 h
n
X
R' MeO
10a-19a O
O
Me
Me
O
Ph
Me N Ts
O
11b 84% yield, 95.0:5.0 e.ra
i-Pr
N P(O)(OPh) 2
15b 64% yield, 96.0:4.0 e.r a b
O
16b 51% yield, 96.0:4.0 e.r.
Ph
Me
13b 84% yield, 98.0:2.0 e.r.
O
Me
Ph
N P(O)(OPh) 2
O
Me
N P(O)(OPh) 2
N Ts
12b 56% yield, 91.0:9.0 e.r
O Me
O
i-Pr Me
N Ts
10b 81% yield, 94.0:6.0 e.r.
10b-19b
i-Pr
N P(O)(OPh) 2
14b 61% yield, 97.0:3.0 e.ra
O
H
Me
Me N P(O)(OPh) 2
17b 69% yield, 88.0:12.0 e.r.
BnO 2C
CO2Bn
18b 49% yield, 92.0:8.0 e.r.b
N Tris 19b 56% yield, 85.0:15.0 e.r.c
5 mol% of catalyst used. 7.5 mol% of catalyst used. performed in THF.
c Reaction
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alkene, also exhibits excellent enantioselectivity. Vinylcyclopropane 8a, a type of substrate prone to metal-catalyzed reactions, is tolerated under these conditions, as the corresponding [3.1.0] bicycle 8b can be obtained in a 75% yield and 90:10 e.r.. Finally, 9a, which contains an aromatic moiety at the internal position of its olefin, was obtained in a slightly diminished e.r. (82.5:17.5). During the course of our mechanistic studies (vide infra), it was observed that less bulky paratoluenesulfonamides 10a and 11a gave slightly improved enantiomeric ratios than the analogous Trisbased substrates 2a and 4a (Table 2). A dependence of the nature of the nitrogen substituent was noted in comparing the two sulfonamides; we were intrigued by the notion that alternate groups on nitrogen may improve the enantioselectivity of the bicycloisomerization reaction. Indeed, we discovered that the diphenylphosphoramidate backbone gave even higher selectivities when compared to the two sulfonamide backbones as well as improve the yield in some cases. Thus, bicyclic products 13b through 16b were all obtained in good yield and greater than 96:4 e.r.. Even the most challenging substrate for the sulfonamides, 9a, displayed an improved selectivity of 88.0:12.0 when exchanged for a diphenylphosphoramidate backbone (17a). We have also shown that this chemistry can be extended beyond pyrrolidine products, as [3.1.0] carbocycle 18b can be isolated in a 49 percent yield and a 92.0:8.0 e.r.. Finally, [4.1.0] bicyclic piperidine 19b could be obtained in a 56% yield and 85.0:15.0 e.r. when the Tris functional group is utilized and when the reaction is run in THF. Intrigued by the high levels of asymmetry induced by chiral ruthenium catalyst 1, we wondered if the observed enantioselectivity was at all influenced by the stereochemistry of the starting alcohol even though the stereocenter is destroyed in the process. To test this, we synthesized tosyl-substituted [1,6]enynes 10a containing an enantiomerically enriched
Scheme 1. Reductive Removal of the Sulfonyl and Phosphoryl Groups on Nitrogen Me
Me
i
RN
Me
ii if R= -Ts or -Tris
RN
O
O
O Me
Me
HN
O
iii
O Me
if R= -P(O)(OPh)2
23 20 R= -Tris, 83% yield 21 R= -Ts, 75% yield 22 R= -P(O)(OPh)2, 70% yield
R= -Tris, 91% yield R= -Ts, 85% yield R= -P(O)(OPh)2, 78% yield
i) TsOH•H 2O, (MeO) 3CH, (CH 2OH)2, r.t., 3h; ii) sodium naphthalide, THF, -78 °C to r.t., 5 min; iii) LiAlH 4, Et 2O, r.t., 17 h
propargyl alcohol in both the R and S configurations, conveniently made utilizing our Prophenol chemistry (see Supporting Information).20 When these propargyl alcohols were applied to the standard reaction conditions in acetone, a very slight matched/mistmatched effect was observed (entries 13). However, when run in THF, a less coordinating solvent, a much more substantial effect was observed; a 92.0:8.0 e.r. was obtained with the (R) propargyl alcohol and a 68.0:32.0 e.r. obtained with the (S) propargyl alcohol. The origin of this effect is currently unclear, but these mechanistic experiments suggest that acetone’s ability to compete with the coordination of the chiral alcohol to the metal center during the course of the reaction is an important factor for obtaining high enantioselectivities. Both sulfonamides can be deprotected to the free pyrrolidine by using sodium naphthalide in THF after protection of the ketone as the ketal (Figure 2). The diphenylphosphoramidate group can also be removed under reductive conditions with lithium aluminum hydride in ether. The direction of optical rotation of pyrrolidine 23 did not depend on the starting protected pyrrolidine, indicating that 20-22 have the same absolute configuration. The absolute configuration of ketal 20 was confirmed to be (R,R) based on single crystal x-ray crystallography (Figure 2).
Table 3. Effect of Propargylic Stereocenter on Enantioselectivity PF 6-
TsN
Me
OH
∗
MeCN 3 mol% MeCN
O
Ru
Solvent, 40 °C,
S O 0.25 M, 16 h
N Ts 10b
Me MeO
10a
alcohol configuration
yield (%)
e.r.
entry
solvent
1
Acetone
rac
81
94.0:6.0
2
Acetone
(R)a
84
93.5:6.5
3
Acetone
(S)a
81
96.5:3.5
4
THF
rac
52
80.0:20.0
5
THF
(R)a
61
92.0:8.0
THF
(S)a
52
68.0:32.0
6 a Starting
Me
Me
Figure 2. X-ray crystal structure of 20
In conclusion, we have developed the first asymmetric ruthenium-catalyzed redox cycloisomerization reaction known to date. This
alcohol has a 97:3 e.r.
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process exhibits a degree of chemoselectivity not reported for any other metal-catalyzed cycloisomerization. It is also important to note that this new chiral catalyst is effective for two very different types of processes, allylic alkylation and redox bicycloisomerization. Such a feature encourages examination of this new chiral catalyst for other ruthenium-catalyzed reactions. Ongoing studies are currently being performed to elucidate the mechanism of this transformation. ASSOCIATED CONTENT
Supporting Information. Experimental Details, crystallographic data, and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author
[email protected] ACKNOWLEDGMENT
We would like to thank the NSF for their generous support (NSF-CHE-1145236), Dr. Allen Oliver (X-Ray Crystallographic Laboratory, Notre Dame University) is gratefully acknowledged for assistance in growing crystals and XRD analysis. REFERENCES (1) (a) Fairlamb, I. J. S. Angew. Chem. Int. Ed. 2004, 43, 1048– 1052. (b) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3, 2899–2919. (c) For a review of achiral cycloisomerization reactions see: Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem. Int. Ed. 2008, 47, 4268–4315. (2) Trost, B. M. Science 1991, 254, 1471–1477. (3) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40–49. (4) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem. Int. Ed. 2009, 48, 2854–2867. (5) (a) Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. Chem. Eur. J. 2009, 15, 1319–1323. (b) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464–3465. (c) Martínez, A.; García-García, P.; Fernández-Rodríguez, M. A.; Rodríguez, F.; Sanz, R. Angew. Chem. Int. Ed. 2010, 49, 4633–4637. (d) Teller, H.; Fürstner, A. Chem. Eur. J. 2011, 17, 7764–7767. (6) (a) Feducia, J. A.; Campbell, A. N.; Doherty, M. Q.; Gagné, M. R. J. Am. Chem. Soc. 2006, 128, 13290–13297. (b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801–3804. (c) Brissy, D.; Skander, M.; Jullien, H.; Retailleau, P.; Marinetti, A. Org. Lett. 2009, 11, 2137–2139. (7) (a) Goeke, A.; Kuwano, R.; Ito, Y.; Sawamura, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 662–663. (b) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676–7684. (c) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem. Int. Ed. 2001, 40, 249– 253. (d) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704–4705. (8) (a) Cao, P.; Zhang, X. Angew. Chem. Int. Ed. 2000, 39, 4104–4106. (b) Wender, P. A.; Haustedt, L. O.; Lim, J.; Love, J. A.; Williams, T. J.; Yoon, J.-Y. J. Am. Chem. Soc. 2006, 128, 6302–6303. (c) Shintani, R.; Nakatsu, H.; Takatsu, K.; Hayashi,
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T. Chem. Eur. J. 2009, 15, 8692–8694. (d) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J. Angew. Chem. Int. Ed. 2009, 48, 6293–6295. (e) Nishimura, T.; Maeda, Y.; Hayashi, T. Org. Lett. 2011, 13, 3674–3677. (f) Nishimura, T.; Takiguchi, Y.; Maeda, Y.; Hayashi, T. Adv. Synth. Catal. 2013, 355, 1374– 1382. (9) (a) Kündig, E. P.; Saudan, C. M.; Bernardinelli, G. Angew. Chem. Int. Ed. 1999, 38, 1219–1223. (b) Brinkmann, Y.; Madhushaw, R. J.; Jazzar, R.; Bernardinelli, G.; Kündig, E. P. Tetrahedron 2007, 63, 8413–8419. (c) Bădoiu, A.; Bernardinelli, G.; Mareda, J.; Kündig, E. P.; Viton, F. Chemistry – An Asian Journal 2008, 3, 1298–1311. (10) (a) Maas, G. Chem. Soc. Rev. 2004, 33, 183–190. (b) Nishiyama, H. In Ruthenium Catalysts and Fine Chemistry; Bruneau, C.; Dixneuf, P. H., Eds.; Topics in Organometallic Chemistry; Springer Berlin Heidelberg, 2004; pp. 81–92 and references therein. (11) (a) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem. Soc. 2001, 123, 10405–10406. (b) Onitsuka, K.; Matsushima, Y.; Takahashi, S. Organometallics 2005, 24, 6472–6474. (c) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008, 47, 1454–1457. (d) Kanbayashi, N.; Onitsuka, K. J. Am. Chem. Soc. 2010, 132, 1206–1207. (e) Kanbayashi, N.; Onitsuka, K. Angew. Chem. Int. Ed. 2011, 50, 5197–5199. (f) Kanbayashi, N.; Takenaka, K.; Okamura, T.; Onitsuka, K. Angew. Chem. Int. Ed. 2013, 52, 4897–4901. (12) For Reviews see: (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879–5918. (b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067– 2096. (c) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem. Int. Ed. 2005, 44, 6630–6666. (13) Trost, B. M.; Breder, A.; O’Keefe, B. M.; Rao, M.; Franz, A. W. J. Am. Chem. Soc. 2011, 133, 4766–4769. (14) (a) Hiroi, K. Curr. Org. Synth. 2008, 5, 305-320. (b) Mariz, R.; Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172–2173. (c) Chen, Q.-A.; Dong, X.; Chen, M.W.; Wang, D.-S.; Zhou, Y.-G.; Li, Y.-X. Org. Lett. 2010, 12, 1928–1931. (d) Mariz, R.; Poater, A.; Gatti, M.; Drinkel, E.; Bürgi, J. J.; Luan, X.; Blumentritt, S.; Linden, A.; Cavallo, L.; Dorta, R. Chem. Eur. J. 2010, 16, 14335–14347. (e) Baker, R. W.; Radzey, H.; Lucas, N. T.; Turner, P. Organometallics 2012, 31, 5622–5633. (15) See for example: (a) Komatsuzaki, N.; Uno, M.; Kikuchi, H.; Takahashi, S. Chemistry Letters 1996, 25, 677–678. (b) Dodo, N.; Matsushima, Y.; Uno, M.; Onitsuka, K.; Takahashi, S. J. Chem. Soc., Dalton Trans. 2000, 35–41. (16) Trost, B. M.; Rao, M.; Dieskau, A. P. J. Am. Chem. Soc. 2013, 135, 18697–18704. (17) (a) Bertani, B., Di Fabio, R., Micheli, F., Tedesco, G., & Terreni, S., WO 2008031772A1, 2008. (b) Micheli, F.; Cavanni, P.; Andreotti, D.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Carletti, R.; Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.; Marchioro, C.; Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K. D.; Roscic, M.; Sartori, I.; Spada, S.; Tedesco, G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L.; Di Fabio, R. J. Med. Chem. 2010, 53, 4989–5001. (18) Other catalyst systems were tried, but catalyst 1 proved to be the most reactive and enantioselective for the transformation. See Supporting Information for details. (19) All of the redox bicycloisomerization reactions presented proceed to full conversion. The remaining mass balance is a mixture of acyclic redox isomerization and β-hydride elimination products. For more information, see ref. 13. (20) Trost, B. M.; Quintard, A. Angew. Chem. Int. Ed. 2012, 51, 6704–6708.
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Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications. PF 6-
X
n
R
OH
MeCN 3 - 7.5 mol% MeCN
O
Ru
Acetone, 0.25 M,
S O 40 °C, 16 h
R'
R n
X
R' MeO
n =1-2 X = -NTris, -NTs, -NP(O)(OPh)2, -C(CO2Bn) 2
Vicinal, quaternary all-carbon stereocenters, 18 examples, 82.5:17.5 to 98.5:1.5 e.r.
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Communication
Construction of Enantioenriched [3.1.0] Bicycles via a RutheniumCatalyzed Asymmetric Redox Bicycloisomerization Reaction Barry M. Trost, Michael C. Ryan, Meera Rao, and Tim Z. Markovic J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Nov 2014 Downloaded from http://pubs.acs.org on December 1, 2014
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Construction of Enantioenriched [3.1.0] Bicycles via a Ruthenium-Catalyzed Asymmetric Redox Bicycloisomerization Reaction Barry M. Trost,* Michael C. Ryan, Meera Rao, and Tim Z. Markovic Department of Chemistry, Stanford University, Stanford, California 94305-5580 Supporting Information Placeholder
ABSTRACT: Enantiomerically enriched [3.1.0] bicycles containing vicinal quaternary centers were synthesized from [1,6]-enynes using a cyclopentadienylruthenium (CpRu) catalyst containing a tethered chiral sulfoxide. The reaction was complicated by the fact that the substrates contained a racemic propargyl alcohol that could affect the selectivity of the process. Nonetheless, high levels of enantioinduction were observed, despite complications arising from the use of racemic substrates. Mechanistic studies showed that while the utilization of either enantiomer of propargyl alcohol led to high product e.r. when conducted in acetone, a significant matched/mismatched effect is observed in THF.
O
(a) TsN
5 mol% CpRu(PPh 3)2Cl
Me
OH
3 mol% CSA, 5 mol% In(OTf) 3 Acetone, 0.25 M, 16 h 85% yield
Me
Chiral sulfoxides are a relatively unexplored ligand class for transition metals.14 Very recently, we have
N Ts
alcohol coordination
reductive elimination
[Ru]
Me TsN
Me
[Ru]
Me
O H N Ts
H Me
redox isomerization
Me
TsN
In recent years, transition metal-catalyzed asymmetric cycloisomerization reactions1 are an important class of reactions for the construction of enantiomerically enriched complex molecules in an atom,2 step,3 and redox4 economical fashion. Examples of gold,5 platinum,6 palladium,7 and rhodium8-catalyzed simple asymmetric cycloisomerization reactions have been reported in the literature. While there has been progress in utilizing chiral ruthenium catalysts for asymmetric cycloaddition,9 cyclopropanation,10 and allylic alkylation reactions,11 there have been no reported examples of using a chiral ruthenium catalyst for cycloisomerization reactions, to the best of our knowledge. Ruthenium-catalyzed reactions have distinguished themselves as an important class of transformations that can construct complex organic molecules quickly and efficiently.12 Previously, we reported the cyclopentadienylruthenium (CpRu)catalyzed redox bicycloisomerization of [1,6] and [1,7] enynes to form structurally complex [3.1.0] and [4.1.0] bicycles that contain vicinal, quaternary stereocenters (Figure 1a).13 Intrigued by the possibility of making this process enantioselective, we hoped that an appropriate choice of ruthenium catalyst would deliver high levels of enantioinduction.
Me
Me
[Ru]
[2+2] cycloaddition
Me O
TsN
O
[Ru]
O
Me
Me
PF 6MeCN (b)
R
Ru S
MeCN
O
Ru HO
L*
(c)
OH R'
H
Ru L*
R' H
R
MeO 1
Chiral-at-Ru Complexes L *= chiral ligand
Figure 1. (a) Ruthenium-catalyzed redox bicycloisomerization reaction reported by Trost. (b) Ruthenium catalyst 1 containing a tethered chiral sulfoxide. (c) Possible diastereomeric complexes formed from propargyl alcohol coordination.
described the conveniently synthesized CpRu complex 1 which does not resort to a resolution of an intermediate CpRu complex15 and its application towards asymmetric allylic substitution reactions (Figure 1b).16 It also has the added advantage of having its asymmetry-inducing element, the chiral sulfoxide, in close proximity to the metal center. This increases the possibility of asymmetric induction during the enantiodetermining step. Our hope was that the application of 1 would provide a means by which one could access enantioenriched [3.1.0] and [4.1.0] bicycles.
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Table 1. Asymmetric Redox Bicycloisomerization with Tris-Substituted Nitrogen PF 6-
R
TrisN
OH
MeCN 3 mol% MeCN
O
Ru
S O
Acetone, 40 °C,
0.25 M, 16 h
N Tris 2b-9b
R' MeO
2a-9a O
O
Me
Me
O
O
O
Me
Me N Tris
6b 48% yield, 90.0:10.0 e.rc
c
i-Pr
p-tolyl
N Tris
a
N Tris 5b 57% yield, 93.0:7.0 e.r
4b 88% yield, 92.0:8.0 e.rb
4
Me
8
Me N Tris
3b 47% yield, 64.0:36.0 e.ra 75% yield, 98.5:1.5 e.r.
O
O
Ph
Me N Tris
2b 78% yield, 56.0:44.0 e.ra 85% yield, 90.5:9.5 e.r.
b
O
i-Pr
Me N Tris
R'
R
N Tris
N Tris 8b 75% yield, 90.0:10.0 e.r
7b 42% yield, 94.0:6.0 e.r
9b 50% yield, 82.5:17.5 e.r
Reaction conducted in THF. 5 mol% of catalyst used. 8.5 mol% of catalyst used.
Supporting Information).18 However, when these conditions were applied to [1,6]-enynes, only low levels of enantioinduction were observed for substrates 2a and 3a (Table 1). Switching to acetone, a more coordinating solvent, had a profound effect on the selectivity of the reaction, boosting the e.r. to 90.5:9.5 and 98.5:1.5 for 2b and 3b, respectively. Encouraged by these results, substrates containing aromatic (4a), olefinic (5a), and alkynyl (6a) groups were prepared in an effort to probe steric and coordinative effects in the redox bicycloisomerization reaction. This series of substrates showcased the chemoselectivity of the redox bicycloisomerization reaction, which can tolerate both isolated alkenes and alkynes without significantly impacting the reactivity or enantioselectivity, a degree of chemoselectivity not reported for any previous metalcatalyzed asymmetric cycloisomerization to our knowledge.19 Substrate 7a, which contains a more bulky cyclopentyl group at the internal position of its
However, the fact that substrates of this type contain a chiral, racemic stereocenter presents a complicating aspect to this reaction. One can envision that coordination of the propargyl alcohol to the metal center can occur with either one of two possible diastereochemical outcomes, thus creating a stereocenter at ruthenium (Figure 1c). While the aforementioned stereocenter is destroyed concomitant with redox isomerization, it is unclear whether this transfer of stereochemical information to the metal would have an adventitious, detrimental, or inconsequential impact on the selectivity. Initial optimization efforts were made on [1,7]enynes containing racemic propargyl alcohols due to their product’s similarity to triple-uptake inhibitors developed by GlaxoSmithKline®.17 From these initial studies, the use of a 2,4,6-triisopropylbenzenesulfonyl (Tris) group and THF as the solvent were determined to be optimal for enantioinduction and yield (see
Table 2. Impact of Enyne Backbone on Enantioselectivity PF 6-
X
n
R
OH
3 mol%
MeCN MeCN
O
Ru
S O
Acetone, 40 °C,
R'
R
0.25 M, 16 h
n
X
R' MeO
10a-19a O
O
Me
Me
O
Ph
Me N Ts
O
11b 84% yield, 95.0:5.0 e.ra
i-Pr
N P(O)(OPh) 2
15b 64% yield, 96.0:4.0 e.r a b
O
16b 51% yield, 96.0:4.0 e.r.
Ph
Me
13b 84% yield, 98.0:2.0 e.r.
O
Me
Ph
N P(O)(OPh) 2
O
Me
N P(O)(OPh) 2
N Ts
12b 56% yield, 91.0:9.0 e.r
O Me
O
i-Pr Me
N Ts
10b 81% yield, 94.0:6.0 e.r.
10b-19b
i-Pr
N P(O)(OPh) 2
14b 61% yield, 97.0:3.0 e.ra
O
H
Me
Me N P(O)(OPh) 2
17b 69% yield, 88.0:12.0 e.r.
BnO 2C
CO2Bn
18b 49% yield, 92.0:8.0 e.r.b
N Tris 19b 56% yield, 85.0:15.0 e.r.c
5 mol% of catalyst used. 7.5 mol% of catalyst used. performed in THF.
c Reaction
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alkene, also exhibits excellent enantioselectivity. Vinylcyclopropane 8a, a type of substrate prone to metal-catalyzed reactions, is tolerated under these conditions, as the corresponding [3.1.0] bicycle 8b can be obtained in a 75% yield and 90:10 e.r.. Finally, 9a, which contains an aromatic moiety at the internal position of its olefin, was obtained in a slightly diminished e.r. (82.5:17.5). During the course of our mechanistic studies (vide infra), it was observed that less bulky paratoluenesulfonamides 10a and 11a gave slightly improved enantiomeric ratios than the analogous Trisbased substrates 2a and 4a (Table 2). A dependence of the nature of the nitrogen substituent was noted in comparing the two sulfonamides; we were intrigued by the notion that alternate groups on nitrogen may improve the enantioselectivity of the bicycloisomerization reaction. Indeed, we discovered that the diphenylphosphoramidate backbone gave even higher selectivities when compared to the two sulfonamide backbones as well as improve the yield in some cases. Thus, bicyclic products 13b through 16b were all obtained in good yield and greater than 96:4 e.r.. Even the most challenging substrate for the sulfonamides, 9a, displayed an improved selectivity of 88.0:12.0 when exchanged for a diphenylphosphoramidate backbone (17a). We have also shown that this chemistry can be extended beyond pyrrolidine products, as [3.1.0] carbocycle 18b can be isolated in a 49 percent yield and a 92.0:8.0 e.r.. Finally, [4.1.0] bicyclic piperidine 19b could be obtained in a 56% yield and 85.0:15.0 e.r. when the Tris functional group is utilized and when the reaction is run in THF. Intrigued by the high levels of asymmetry induced by chiral ruthenium catalyst 1, we wondered if the observed enantioselectivity was at all influenced by the stereochemistry of the starting alcohol even though the stereocenter is destroyed in the process. To test this, we synthesized tosyl-substituted [1,6]enynes 10a containing an enantiomerically enriched
Scheme 1. Reductive Removal of the Sulfonyl and Phosphoryl Groups on Nitrogen Me
Me
i
RN
Me
ii if R= -Ts or -Tris
RN
O
O
O Me
Me
HN
O
iii
O Me
if R= -P(O)(OPh)2
23 20 R= -Tris, 83% yield 21 R= -Ts, 75% yield 22 R= -P(O)(OPh)2, 70% yield
R= -Tris, 91% yield R= -Ts, 85% yield R= -P(O)(OPh)2, 78% yield
i) TsOH•H 2O, (MeO) 3CH, (CH 2OH)2, r.t., 3h; ii) sodium naphthalide, THF, -78 °C to r.t., 5 min; iii) LiAlH 4, Et 2O, r.t., 17 h
propargyl alcohol in both the R and S configurations, conveniently made utilizing our Prophenol chemistry (see Supporting Information).20 When these propargyl alcohols were applied to the standard reaction conditions in acetone, a very slight matched/mistmatched effect was observed (entries 13). However, when run in THF, a less coordinating solvent, a much more substantial effect was observed; a 92.0:8.0 e.r. was obtained with the (R) propargyl alcohol and a 68.0:32.0 e.r. obtained with the (S) propargyl alcohol. The origin of this effect is currently unclear, but these mechanistic experiments suggest that acetone’s ability to compete with the coordination of the chiral alcohol to the metal center during the course of the reaction is an important factor for obtaining high enantioselectivities. Both sulfonamides can be deprotected to the free pyrrolidine by using sodium naphthalide in THF after protection of the ketone as the ketal (Figure 2). The diphenylphosphoramidate group can also be removed under reductive conditions with lithium aluminum hydride in ether. The direction of optical rotation of pyrrolidine 23 did not depend on the starting protected pyrrolidine, indicating that 20-22 have the same absolute configuration. The absolute configuration of ketal 20 was confirmed to be (R,R) based on single crystal x-ray crystallography (Figure 2).
Table 3. Effect of Propargylic Stereocenter on Enantioselectivity PF 6-
TsN
Me
OH
∗
MeCN 3 mol% MeCN
O
Ru
Solvent, 40 °C,
S O 0.25 M, 16 h
N Ts 10b
Me MeO
10a
alcohol configuration
yield (%)
e.r.
entry
solvent
1
Acetone
rac
81
94.0:6.0
2
Acetone
(R)a
84
93.5:6.5
3
Acetone
(S)a
81
96.5:3.5
4
THF
rac
52
80.0:20.0
5
THF
(R)a
61
92.0:8.0
THF
(S)a
52
68.0:32.0
6 a Starting
Me
Me
Figure 2. X-ray crystal structure of 20
In conclusion, we have developed the first asymmetric ruthenium-catalyzed redox cycloisomerization reaction known to date. This
alcohol has a 97:3 e.r.
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process exhibits a degree of chemoselectivity not reported for any other metal-catalyzed cycloisomerization. It is also important to note that this new chiral catalyst is effective for two very different types of processes, allylic alkylation and redox bicycloisomerization. Such a feature encourages examination of this new chiral catalyst for other ruthenium-catalyzed reactions. Ongoing studies are currently being performed to elucidate the mechanism of this transformation. ASSOCIATED CONTENT
Supporting Information. Experimental Details, crystallographic data, and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author
[email protected] ACKNOWLEDGMENT
We would like to thank the NSF for their generous support (NSF-CHE-1145236), Dr. Allen Oliver (X-Ray Crystallographic Laboratory, Notre Dame University) is gratefully acknowledged for assistance in growing crystals and XRD analysis. REFERENCES (1) (a) Fairlamb, I. J. S. Angew. Chem. Int. Ed. 2004, 43, 1048– 1052. (b) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3, 2899–2919. (c) For a review of achiral cycloisomerization reactions see: Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem. Int. Ed. 2008, 47, 4268–4315. (2) Trost, B. M. Science 1991, 254, 1471–1477. (3) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40–49. (4) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem. Int. Ed. 2009, 48, 2854–2867. (5) (a) Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. Chem. Eur. J. 2009, 15, 1319–1323. (b) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464–3465. (c) Martínez, A.; García-García, P.; Fernández-Rodríguez, M. A.; Rodríguez, F.; Sanz, R. Angew. Chem. Int. Ed. 2010, 49, 4633–4637. (d) Teller, H.; Fürstner, A. Chem. Eur. J. 2011, 17, 7764–7767. (6) (a) Feducia, J. A.; Campbell, A. N.; Doherty, M. Q.; Gagné, M. R. J. Am. Chem. Soc. 2006, 128, 13290–13297. (b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801–3804. (c) Brissy, D.; Skander, M.; Jullien, H.; Retailleau, P.; Marinetti, A. Org. Lett. 2009, 11, 2137–2139. (7) (a) Goeke, A.; Kuwano, R.; Ito, Y.; Sawamura, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 662–663. (b) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676–7684. (c) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem. Int. Ed. 2001, 40, 249– 253. (d) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704–4705. (8) (a) Cao, P.; Zhang, X. Angew. Chem. Int. Ed. 2000, 39, 4104–4106. (b) Wender, P. A.; Haustedt, L. O.; Lim, J.; Love, J. A.; Williams, T. J.; Yoon, J.-Y. J. Am. Chem. Soc. 2006, 128, 6302–6303. (c) Shintani, R.; Nakatsu, H.; Takatsu, K.; Hayashi,
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T. Chem. Eur. J. 2009, 15, 8692–8694. (d) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J. Angew. Chem. Int. Ed. 2009, 48, 6293–6295. (e) Nishimura, T.; Maeda, Y.; Hayashi, T. Org. Lett. 2011, 13, 3674–3677. (f) Nishimura, T.; Takiguchi, Y.; Maeda, Y.; Hayashi, T. Adv. Synth. Catal. 2013, 355, 1374– 1382. (9) (a) Kündig, E. P.; Saudan, C. M.; Bernardinelli, G. Angew. Chem. Int. Ed. 1999, 38, 1219–1223. (b) Brinkmann, Y.; Madhushaw, R. J.; Jazzar, R.; Bernardinelli, G.; Kündig, E. P. Tetrahedron 2007, 63, 8413–8419. (c) Bădoiu, A.; Bernardinelli, G.; Mareda, J.; Kündig, E. P.; Viton, F. Chemistry – An Asian Journal 2008, 3, 1298–1311. (10) (a) Maas, G. Chem. Soc. Rev. 2004, 33, 183–190. (b) Nishiyama, H. In Ruthenium Catalysts and Fine Chemistry; Bruneau, C.; Dixneuf, P. H., Eds.; Topics in Organometallic Chemistry; Springer Berlin Heidelberg, 2004; pp. 81–92 and references therein. (11) (a) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem. Soc. 2001, 123, 10405–10406. (b) Onitsuka, K.; Matsushima, Y.; Takahashi, S. Organometallics 2005, 24, 6472–6474. (c) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem. Int. Ed. 2008, 47, 1454–1457. (d) Kanbayashi, N.; Onitsuka, K. J. Am. Chem. Soc. 2010, 132, 1206–1207. (e) Kanbayashi, N.; Onitsuka, K. Angew. Chem. Int. Ed. 2011, 50, 5197–5199. (f) Kanbayashi, N.; Takenaka, K.; Okamura, T.; Onitsuka, K. Angew. Chem. Int. Ed. 2013, 52, 4897–4901. (12) For Reviews see: (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879–5918. (b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067– 2096. (c) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem. Int. Ed. 2005, 44, 6630–6666. (13) Trost, B. M.; Breder, A.; O’Keefe, B. M.; Rao, M.; Franz, A. W. J. Am. Chem. Soc. 2011, 133, 4766–4769. (14) (a) Hiroi, K. Curr. Org. Synth. 2008, 5, 305-320. (b) Mariz, R.; Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172–2173. (c) Chen, Q.-A.; Dong, X.; Chen, M.W.; Wang, D.-S.; Zhou, Y.-G.; Li, Y.-X. Org. Lett. 2010, 12, 1928–1931. (d) Mariz, R.; Poater, A.; Gatti, M.; Drinkel, E.; Bürgi, J. J.; Luan, X.; Blumentritt, S.; Linden, A.; Cavallo, L.; Dorta, R. Chem. Eur. J. 2010, 16, 14335–14347. (e) Baker, R. W.; Radzey, H.; Lucas, N. T.; Turner, P. Organometallics 2012, 31, 5622–5633. (15) See for example: (a) Komatsuzaki, N.; Uno, M.; Kikuchi, H.; Takahashi, S. Chemistry Letters 1996, 25, 677–678. (b) Dodo, N.; Matsushima, Y.; Uno, M.; Onitsuka, K.; Takahashi, S. J. Chem. Soc., Dalton Trans. 2000, 35–41. (16) Trost, B. M.; Rao, M.; Dieskau, A. P. J. Am. Chem. Soc. 2013, 135, 18697–18704. (17) (a) Bertani, B., Di Fabio, R., Micheli, F., Tedesco, G., & Terreni, S., WO 2008031772A1, 2008. (b) Micheli, F.; Cavanni, P.; Andreotti, D.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Carletti, R.; Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.; Marchioro, C.; Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K. D.; Roscic, M.; Sartori, I.; Spada, S.; Tedesco, G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L.; Di Fabio, R. J. Med. Chem. 2010, 53, 4989–5001. (18) Other catalyst systems were tried, but catalyst 1 proved to be the most reactive and enantioselective for the transformation. See Supporting Information for details. (19) All of the redox bicycloisomerization reactions presented proceed to full conversion. The remaining mass balance is a mixture of acyclic redox isomerization and β-hydride elimination products. For more information, see ref. 13. (20) Trost, B. M.; Quintard, A. Angew. Chem. Int. Ed. 2012, 51, 6704–6708.
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Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications. PF 6-
X
n
R
OH
MeCN 3 - 7.5 mol% MeCN
O
Ru
Acetone, 0.25 M,
S O 40 °C, 16 h
R'
R n
X
R' MeO
n =1-2 X = -NTris, -NTs, -NP(O)(OPh)2, -C(CO2Bn) 2
Vicinal, quaternary all-carbon stereocenters, 18 examples, 82.5:17.5 to 98.5:1.5 e.r.
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