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Diastereo- and Enantioselective Formal [3+2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-catalyzed Radical Redox Relay Wei Hao, Johannes H. Harenberg, Xiangyu Wu, Samantha N. MacMillan, and Song Lin J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Feb 2018 Downloaded from http://pubs.acs.org on February 21, 2018
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Diastereo- and Enantioselective Formal [3+2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay Wei Hao1, Johannes H. Harenberg1,2, Xiangyu Wu1, Samantha N. MacMillan1, Song Lin1,3* 1
2
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853. Department Chemie, 3 Ludwig-Maximilians-Universität München, Munich, Germany 81377. Atkinson Center for a Sustainable Future, Cornell University, Ithaca, NY 14853
Supporting Information Placeholder ABSTRACT: We report a stereoselective formal [3+2]
cycloaddition of cyclopropyl ketones and radicalacceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C–C bonds and two contiguous stereogenic centers with generally excellent diastereoand enantioselectivity.
Owing to the high reactivity and unique selectivity of organic radicals, the discovery of new reactions mediated by these open-shell intermediates continues to provide solutions to synthetic problems challenging in traditional two-electron chemistry.1 In this context, new catalyst-controlled stereoselective reactions involving free radical intermediates remain highly desirable.2 Since early reports of the use of Lewis acids, transition metals, and organocatalysts,3 innovative catalytic strategies that regulate the absolute stereochemistry of radical addition reactions have provided powerful synthetic methods and accelerated understanding of open-shell reaction pathways.4 Because they can adopt multiple continuous oxidation states, Ti complexes are highly versatile catalysts for redox radical organic transformations.5 Although chiral Ti complexes can engage radical pathways to catalyze enantioselective C–C formation,6 such reactions have been primarily limited to pinacol-type couplings,7 Barbier reactions,8 and ring-opening functionalizations of epoxides.9 Recently, we disclosed a new strategy in
which a TiIII catalyst triggers a series of tandem radical redox processes leading to the [3+2] cycloaddition of N-acylaziridines and alkenes to furnish substituted pyrrolidine products (Scheme 1A).10 This approach exploits several unique characteristics of Ti, including the oxophilicity of TiIV, the capability of TiIII to induce bond weakening,11 and the biradical character of TiIV azaenolates.12 Although it resembles dual-catalytic photoredox chemistry,13 our strategy is distinct in that it integrates a redox mediator and a substrateactivating cocatalyst into one molecular scaffold,14 thereby allowing us to control reactivity and stereoselectivity by tuning the structure of a single ligand. We hypothesized that this radical redox-relay strategy could be applied to the [3+2] cycloaddition of cyclopropyl ketones—structural analogues of Nacylaziridines—and alkenes (Scheme 1C) to produce highly substituted cyclopentanes. These carbocyclic structures are ubiquitous in bioactive compounds and frequently used as analogs to pyrrolidines in medicinal chemistry studies.15 SCHEME 1. [3+2] Cycloaddition via Ti-catalyzed radical redox relay and its related literature precedents.
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Journal of the American Chemical Society A. Titanium-catalyzed radical redox relay (ref. 10)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
R4 R5
O R3 R2 R1
N
R5
+
Cp*TiCl3 (cat.), Zn (cat.)
O +
TiIII
TiIV R3
N
alkene
R
O
5 4R
N
R2 R1
O
N
R2 R1
R4
R3
TiIV - TiIII R3
R2 R1
B. Related literature on enantioselective cyclopentane synthesis via [3+2] cycloadditions (ref. 15) R1O2C
R2 R2
CO2R1
CO2R1
[Pd] or [Cu] or Ar–SH (cat.)
CO2R1
donor-acceptor cyclopropanes
C. Radical [3+2] cycloaddition of cyclopropyl ketones and alkenes R4 R3
O Ar R1 R2
R4
+
cat. R3
R1 R2
O Ar
Precedent (ref. 16): cat. = Ru(bpy)3(PF6)2 (2.5 mol%), Gd(OTf)3 (10–20 mol%), PyBOX (20–30 mol%); demonstrated for electron-neutral and -rich alkenes This work: cat. = Ti(salen) complex (2.5–10 mol%); demonstrated for electronneutral and -deficient alkenes
To date, the intermolecular cycloaddition strategy for enantioenriched cyclopentanes has been largely limited to the use of donor-acceptor-type cyclopropanes. These substrates readily undergo ring opening in the presence of a catalyst to form 1,3dipolar intermediates before alkene addition (Scheme 1B).16 Yoon et al.17 reported an elegant combination of photoredox chemistry and chiral Lewis acid catalysis to expand the scope of the [3+2] cycloaddition (see Scheme 1C). Despite its excellent enantioselectivity, the reaction generally required high loadings of the chiral Lewis acid and was primarily demonstrated for electron-neutral and rich alkenes. We studied radical [3+2] cycloaddition using 2,2dimethylcyclopropyl phenyl ketone (1) and styrene as substrates. In principle, the coordination of TiIII to the carbonyl group in 1 would trigger radical relay from the metal center to the quaternary carbon, leading to the homolytic cleavage of a C–C bond in the cyclopropane to form a carbon-centered radical tethered to a TiIV enolate. Similar to the mechanism of our previous aziridine-alkene reaction,10 this intermediate would engage styrene in a stepwise radical cycloaddition to furnish cyclopentane 2, during which TiIV would regain an electron from the reactant assembly and return to TiIII, achieving catalytic turnover. TABLE 1. Reaction Optimization.
A survey of reaction parameters revealed that salen-supported complex 3 bearing phenylene-1,2diamine and 3-adamantyl-5-methyl salicylaldehyde was the optimal catalyst (Table 1, entry 1). With Mn as the reductant and Et3N·HCl18 as an additive in ethyl acetate at room temperature, the reaction delivered a nearly quantitative yield of cycloadduct 2 in the trans configuration as effectively a single stereoisomer (>19:1 dr, 97% ee). Altering the salicylaldehyde (4) or the diamine backbone (5) on the ligand substantially decreased both diastereoand enantioselectivity (entries 2, 3). Half-titanocene CpTiCl3 (6), an effective catalyst in our previous aziridine cycloaddition reactions, was also competent. Notably, the cis isomer was the major product in a 3:1 dr with acetonitrile as the solvent (entry 4). As such, both diastereomeric products could be obtained by changing the catalyst identity. Similar results were obtained using catalyst 7 with 1,3-diaminopropane as the ligand backbone (entry 5). The cycloaddition was equally efficient and marginally less enantioselective when Mn was replaced with Zn (entry 6). The loading of Et3N·HCl could be reduced to 50 mol% with marginal decrease in yield (entry 7). In theory, the overall redox-neutral transformation requires only a catalytic amount of reductant to activate the catalyst. Decreasing the loading of Mn to 20 mol%, however, led to
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substantially lower product yield (entry 8). The interplay between 3, Mn, and Et3N·HCl in initiating and maintaining the radical redox catalytic cycle is intriguing,19 and mechanistic understanding of such a process is currently underway. Finally, replacing ethyl acetate with tetrahydrofuran or acetonitrile as the solvent led to diminished stereoselectivity (entries 9, 10). We then explored the substrate scope of the radical [3+2] cycloaddition under the trans selective conditions using catalyst 3 (Scheme 2). A variety of styrene derivatives proved excellent coupling partners, yielding the corresponding products (2, 8– 15) in high dr and ee. Functional groups such as pinacolborate (9) and N-heterocycles (14, 15) were compatible. We noted that reactions using electrondeficient styrenes (e.g., 9, 10) were less enantioselective and required lower temperatures for reaching high levels of ee. Cycloadduct 16 with Nmethylimidazol-2-yl group was isolated in high yield, good dr, and excellent ee from the corresponding heterocyclic substrate. 3-Vinyl-3-deoxyestrone was converted to 17 as nearly a single stereoisomer. We obtained crystal structures of 2 and 17 and determined their absolute and relative stereochemistries. Stereochemical assignments for structurally similar products were made by analogy. 1,1-Disubstituted alkenes were also suitable substrates. Products 18–20, each with a quaternary stereogenic centers, were isolated in high stereochemical purity. Ethyl 2-phenylacrylate was also converted to 21 in 9:1 dr and 80% ee. In all cases, the aryl substituent from the alkene substrate adopted a trans relationship with the benzoyl group in the major diastereomeric product.20 Both isoprene and acrylamide underwent the desired transformation to furnish products 22 and 23, respectively, in moderate to high dr and excellent ee.
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SCHEME 2. Substrate scope of Ti-catalyzed [3+2] cycloadditions.* Cl
B(pin)
CN
F
OMe
Ph O Me Me
O
Ph Me Me
2 (XRD) 98%, dr > 19:1, 97% ee
O Me Me
Ph
O Me Me
Ph
8a
9b
10b
75%, dr = 12:1, 96% ee
91%, dr > 19:1, 97% ee
53%, dr > 19:1, 89% ee
Ph
O
13 92%, dr > 19:1, 94% ee
Me Me
Me Me
O
Ph
Me Me
14 87%, dr > 19:1, 79% ee
CO2tBu O Me Me
Ph 24d
91%, dr > 19:1, 73% ee
Me Me
N N
Me Me
19 82%, dr > 19:1, 96% ee
Ph
25 95%, dr > 19:1, 65% ee
Ph
20 81%, dr > 19:1, 90% ee SO2Ph O
Me CO2tBu O Me Me
Me Me
Me Me
Ph
Ph
Me Me
21 87%, dr = 9:1, 80% ee B(pin) O
Me Me
Ph
17 (XRD) 92%, trans/cis > 19:1, 95% de O
Me Me
O
Ph
H
O Ph
16 92%, dr = 6:1, 88% ee
Ph CO2Et O Me Me
H
Ph
15 91%, dr > 19:1, 98% ee (83%, dr > 19:1, 92% ee)c
O
18 96%, dr > 19:1, 96% ee
H Me
O Ph
Ph
12 89%, dr > 19:1, 96% ee
O
Me Ph Me Me
11 85%, dr = 12:1, 94% ee
Ph
NTs
O
O Me Me
Ph
Me O
N
Me Me
O Me Me
Ph
Me Me
Ph
Ph
23 91%, dr = 11:1, 96% ee
Ph O
Me Me
O
22 90%, dr = 4:1, 96% ee
Ph Ph Ph
26b
27b
28b
81%, dr > 19:1, 51% ee
79%, dr > 19:1, 46% ee
90%, 45% ee
Ph 2
O Me Me
NMe2
O
Me
29 82%, dr = 5:1, 13% ee
4
Ph
O 1
Ph
30e 93%, dr = 2:1, 79% ee (major), 93% ee (minor)
*Reactions conducted on 0.1 mmol scale with 1 equiv cyclopropyl ketone, 1.2 equiv alkene, 10 mol% 3, 1.5 equiv Mn, 1.5 equiv Et3N·HCl in EtOAc at 22 °C for 12 h. Isolated yields reported. aWith 5 mol% 3. bAt –25 °C for 48 h. c On 1.0 mmol scale with 2.5 mol% 3 and 1.05 equiv alkene for 60 h. dAt –35 °C for 50 h. eAt 0 °C for 48 h. Electron-deficient alkenes were also investigated as radical acceptors in the [3+2] cycloaddition. Acrylates (24, 25), phenyl vinyl sulfone (26), and vinyl pinacolborane (27) underwent the radical cascade to yield the corresponding products in nearly complete diastereoselectivity favoring the configuration in which the electron-withdrawing substituent is placed trans to the benzoyl group. Achieving high enantioselectivity was challenging with these alkene under the standard conditions. Lowering the temperature, however, improved selectivity with the expense of longer reaction times. 1-Phenylstyrene was also converted to the desired product (28) in moderate ee. We hypothesize that in these cases, the greater stability of the carboncentered radicals resulting from the first C–C bond formation might alter the position of the selectivitydetermining transition state on the reaction coordinate, thus influencing enantioinduction by the chiral catalyst. Mechanistic studies of the origin of enantioselectivity and its dependence on the electronic properties of the alkene are underway. Methyl 2,2-dimethylcyclopropyl ketone was converted to cycloadduct 29 in synthetically useful
dr, albeit with low ee. 2-Phenylcyclopropyl phenyl ketone reacted to furnish 30 in 2:1 dr with respect to the stereochemistry at position 4; both diastereomers were formed in high ee. We also demonstrated the scalability of the reaction. On a 1 mmol scale with only 2.5 mol% catalyst 3, product 15 was obtained in 83% yield, complete trans selectivity, and 92% ee.21 The Lewis acid catalyzed 1,3-dipolar cycloaddition of donor−acceptor cyclopropanes with 2π coupling partners has been reported.22 Compared with our system, this canonical two-electron mode of activation is usually applied to different cyclopropane derivatives and dipolarophiles, giving rise to different product structures. To further support the radical intermediacy in our Ti-catalyzed cycloaddition, we conducted a spin trapping experiment using 5,5-dimethyl-pyrroline N-oxide (DMPO) and observed the formation of persistent nitroxide radical adduct 31 with ESR spectrometry and mass spectrometry (see Scheme 3 and SI). SCHEME 3. Spin trapping experiment.
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In sum, we developed a stereoselective formal [3+2] cycloaddition of cyclopropyl ketones and alkenes using our previous reported radical redox relay strategy. With a Ti catalyst supported by a salen ligand, the reaction yielded highly substituted cyclopentanes in generally excellent diastereo- and enantioselectivity from readily accessible starting materials. We expect this radical redox catalysis to provide solutions to other challenging synthetic problems. ASSOCIATED CONTENT Supporting Information. Experimental procedures and characterization data (PDF). Crystallographic data were deposited in the Cambridge Structural Database (compound 2: CCDC1589640; compound 17: CCDC1589641). The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION Corresponding Author
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT This study made use of the Cornell Center for Materials Research Shared Facilities (DMR-1120296), the NMR facility (CHE-1531632) supported by the NSF, and the ESR facility supported by the NIGMS (P41GM103521). We thank Juno Siu for experimental assistance, Dr. Geoffrey Coates for kindly sharing salen ligands, Dr. Ivan Keresztes for help with NMR spectral analysis, and Dr. Boris Dzikovski for assistance with ESR data acquisition and analysis.
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Tetrahedron Lett. 1996, 37, 9123-9126. (g) Hamachi, K.; Irie, R.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4979-4982. (4) For representative recent examples, see: (a) Capacci, A. G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; MacMillan, D. W. C. Nat. Chem. 2017, 9, 1073-1077. (b) Miller, Z. D.; Lee, B. J.; Yoon, T. P. Angew. Chem., Int. Ed. 2017, 56, 11891-11895. (c) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681–684. (d) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P. Nature 2016, 532, 218-222. (e) Huang, X.; Quinn, T. R.; Harms, K.; Webster, R. D.; Zhang, L.; Wiest, O.; Meggers, E. J. Am. Chem. Soc. 2017, 139, 9120-9123. (f) Chen, B.; Fang, C.; Liu, P.; Ready, J. M. Angew. Chem., Int. Ed. 2017, 56, 8780-8784. (g) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 10141018. (h) Jiang, H.; Lang, K.; Lu, H.; Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc. 2017, 139, 9164-9167. (i) Milan, M.; Bietti, M.; Costas, M. ACS Cent. Sci. 2017, 3, 196-204. (5) For recent reviews, see: (a) Davis-Gilbert, Z. W.; Tonks, I. A. Dalton Trans. 2017, 46, 11522-11528. (b) Cuerva, J. M.; Juan, J. C.; Justicia, J.; Oller-Lòpez, J. L.; Oltra, J. E. Top. Curr. Chem. 2006, 264, 63–91. (c) Streuff, J. Chem. Rec. 2014, 14, 1100–1113. (d) Gansäuer, A.; Hildebrandt, S.; Vogelsang, E.; Flower II, R. A. Dalton Trans. 2016, 45, 448–452. (6) (a) Gansäuer, A.; Justicia, J.; Fan, C.-A.; Worgull, D.; Piestert, F. Top. Curr. Chem. 2007, 279, 25–52. (b) Streuff, J.; Gansäuer, A. Angew. Chem., Int. Ed. 2015, 54, 14232–14242. (7) For representative examples, see: (a) Bensari, A.; Renaud, J.-L.; Riant, O. Org. Lett. 2001, 3, 3863-3865. (b) Chatterjee, A.; Bennur, T. H.; Joshi, N. N. J. Org. Chem. 2003, 68, 5668–5671. (c) Li, Y-G.; Tian, Q-S.; Zhao, J.; Feng, Y.; Li, M. J.; You, T. P. Tetrahedron: Asymmetry 2004, 15, 1707–1710. For a mechanistically related carbonyl-nitrile reductive coupling, see: (d) Streuff, J.; Feurer, M.; Bichovski, P.; Frey, G.; Gellrich, U. Angew. Chem., Int. Ed. 2012, 51, 8661–8664. (8) For an examples, see: Estévez, R. E.; Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.; Choquesillo-Lazarte, D.; García-Ruiz, J. M.; Robles, R.; Gansäuer, A.; Cuerva, J. M.; Oltra, J. E. Chem. Eur. J. 2009, 15, 2774–2791. (9) For representative examples, see: (a) Gansäuer, A.; Bluhm, H.; Lauterbach, T. Adv. Synth. Catal. 2001, 343, 785–787. (b) Gansäuer, A.; Shi, L.; Otte, M. J. Am. Chem. Soc. 2010, 132, 11858– 11859. (c) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 32373240. (10) Hao, W.; Wu, X.; Sun, J. Z.; Siu, J. C.; MacMillan, S. N.; Lin, S. J. Am. Chem. Soc. 2017, 139, 12141-12144. For a review on a similar strategy for epoxide cycloaddition reactions, see ref. 5d. (11) Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 6440-6443. (12) Studies describing the biradical character of structurally analogous TiIV enolates: (a) Beaumont, S.; Ilardi, E. A.; Monroe, L. R.; Zakarian, A. J. Am. Chem. Soc. 2010, 132, 1482-1483. (b) Cież, D.; Pałasz, A.; Trzewik, B. Eur. J. Org. Chem. 2016, 1476-1493. (c) Gu, Z.; Herrmann, A. T.; Zakarian, A. Angew. Chem. Int. Ed. 2011, 50, 7136-7139. (d) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc. 2012, 134, 6976-6979. (e) Mabe, P. J.; Zakarian, A. Org. Lett. 2014, 16, 516-519; (f) Alvarodo, J.; Herrmann, A. T.; Zakarian, A. J. Org. Chem. 2014, 79, 6206-6220. (13) For representative recent reviews, see: (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035-10074. (b) Twilton, J., Le, C., Zhang, P., Shaw, M. H., Evans, R. W. & MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 1-18. (14) Chiral catalysts integrating both the photoredox and enantioselective catalysts in the same molecular scaffold have recently developed. For a review, see: Zhang, L.; Meggers, E. Acc. Chem. Res. 2017, 50, 320−330. (15) For examples, see: (a) Defauw, J. M.; Murphy, M. M.; Jagdmann Jr., E.; Hu, H.; Lampe, J. W.; Hollinshead, S. P.;
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Mitchell, T. J.; Crane, H. M.; Heerding, J. N.; Mendoza, J. S.; Davis, J. E.; Darges, J. W.; Hubbard, F. R.; Hall, S. E. J. Med. Chem. 1996, 39, 5215–5227. (b) Hanessian, S.; Yun, H.; Hou, Y.; Yang, G.; Bayrakdarian, M.; Therrien, E.; Moitessier, N.; Roggo, S.; Veenstra, S.; Tintelnot-Blomley, M.; Rondeau, J.-M.; Ostermeier, C.; Strauss, A.; Ramage, P.; Paganetti, P.; Neumann, U.; Betschart, C. J. Med. Chem. 2005, 48, 5175–5190. (16) (a) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50, 6167–6170. (b) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851–7854. (c) Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nat. Chem. 2014, 6, 702–705. (17) (a) Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2016, 138, 4722–4725. For a closely related, racemic intramolecular [3+2] cycloaddition, see: (b) Lu, Z.; Shen, M.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162-1164. (18) ESR data suggested that Et3N·HCl promotes the reduction of TiIV to TiIII. See SI. Analogous pyridinium salts have been shown to stabilize TiIII catalysts in epoxide ring opening: (a) Gansäuer, A.; Behlendorf, M.; von Laufenberg, D.; Fleckhaus, A.; Kube, C.; Sadasivam, D. V.; Flowers II, R. A. Angew. Chem. Int. Ed. 2012, 51, 4739−4742. (b) Gausäuer, A.; Kube, C.; Daasbjerg, K.;
Sure, R.; Grimme, S.; Fianu, G. D.; Sadasivam, D. V.; Flowers II, R. A. J. Am. Chem. Soc. 2014, 136, 1633–1671. (c) Gansäuer, A.; von Laufenberg, D.; Kube, C.; Dahmen, T.; Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.; Grimme, S.; Sadasivam, D. V.; Fiana, G. D.; Flowers II, R. A. Chem. Eur. J. 2015, 21, 280– 289. (19) For mechanistic studies of related TiIII-catalyzed epoxide ring opening reactions, see ref. 18. (20) The relative stereochemistry of products 18–22 was determined using 2D NMR. See SI. (21) The lower enantioselectivity likely arose from the decreased catalyst loading. Under the standard conditions in Table 1, using 2.5 mol% 3 instead of 10 mol% gave the product in 91% ee. This concentration dependence of reaction ee is currently under investigation. (22) (a) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122−3123. (b) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688−9692. Also see ref. 15.
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Insert Table of Contents artwork here R4 R3
O R2 R1 R1
+
*
TiIII catalyst
R4
R1
R3
O
+ TiIII
TiIV R2
alkene
R3 R4
R1 R1
*
R1
O
O R2
TiIV
- TiIII R2
R1 R1
24 examples, 53–98% yield, 2:1 to >19:1 dr, 13–98% ee
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