Letter Cite This: Org. Lett. 2018, 20, 5319−5322
pubs.acs.org/OrgLett
Organocatalytic Enantioselective Cycloetherifications Using a Cooperative Cation-Binding Catalyst Amol P. Jadhav,†,§ Jeong-A Oh,†,§ In-Soo Hwang,† Hailong Yan,‡ and Choong Eui Song*,† †
Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea Innovative Drug Research Centre (IDRC), School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
‡
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S Supporting Information *
ABSTRACT: A highly enantioselective cycloetherification strategy for the straightforward synthesis of enantioenriched tetrahydrofurans, tetrahydropyrans, and oxepanes using Song’s cation-binding oligoEG catalyst and KF as the base is demonstrated. A wide range of ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones were cyclized to the corresponding five-, six-, and seven-membered chiral oxacycles with high enantiopurity. This remarkably successful catalysis can be ascribed to systematic cooperative cation-binding catalysis in a densely confined supramolecular chiral cage generated in situ from the chiral catalyst, substrate, and KF.
O
THP rings.9 The catalytic asymmetric intramolecular haloetherification strategy has been used to effectively access halogencontaining chiral THF and THP rings.10 However, the synthesis of chiral oxacycles through the direct cyclization of α,βunsaturated carbonyl substrates bearing a pendant nucleophilic hydroxyl group (i.e., intramolecular oxa-Michael reactions) has been rarely explored.11 For five- and six-membered cyclic ethers, the rapid nature of a noncatalyzed intramolecular cyclization event makes asymmetric oxycyclization reactions highly challenging. For example, all attempts for the intramolecular oxa-Michael reactions for the synthesis of chiral THFs with chiral NHC catalysts have afforded almost racemic products (0− 11% ee) (Scheme 1, eq 1).11d Furthermore, the direct construction of chiral large ring ethers such as seven- and eight-membered cyclic ethers from acyclic precursors remains a more challenging problem mainly because of the unfavorable entropic factor. The probability of meeting both reactive sites for the reaction would decrease as the chains get longer.12 Given the importance of chiral oxacyclic compounds of various ring sizes, developing a general and direct synthetic method to access them is highly desirable. In order to effectively transfer the chiral information from the catalyst during an oxycyclization event, simultaneous activation of a pendant hydroxyl group of terminal hydroxy-α,β-unsaturated ketones (nucleophilic site) and their electrophilic β-carbon is an essential condition. Thus, the use of catalysts capable of
xacyclic frameworks are prominent scaffolds and have attracted immense attention due to their widespread presence in natural products and bioactive compounds. Chiral tetrahydrofuran (THF) and tetrahydropyran (THP) subunits in particular are abundant in several macrodiolides,1 acetogenins,2 C-glycosides,3 lignans4 and ionophores,5 macrolides,6 and salinomycin and its derivatives.7 In addition, many polycyclic marine natural products and terpenoids possess chiral sevenmembered oxepane moieties8 (Figure 1). Several methods have been developed for the enantioselective synthesis of THF and
Figure 1. Some natural and bioactive compounds containing chiral five-, six-, and seven-membered oxacyclic frameworks. © 2018 American Chemical Society
Received: July 18, 2018 Published: August 14, 2018 5319
DOI: 10.1021/acs.orglett.8b02240 Org. Lett. 2018, 20, 5319−5322
Letter
Organic Letters
respectively. Excellent yields and enantioselectivity were obtained with a variety of 2-substituted THFs and THPs. Furthermore, this protocol was also successfully extended for use in synthesizing more challenging highly enantioenriched 2substituted seven-membered oxacycles. We initiated our investigation of the asymmetric cycloetherification of (E)-6-hydroxy-1-phenylhex-2-en-1-one (2a) with catalyst (R)-1a (15 mol %) in toluene at 0 °C to form the chiral THF product 3a. In the absence of KF loading, the reaction did not take place (Table 1, entry 1). However, in the presence of KF (3 equiv), the desired intramolecular cyclization proceeded smoothly, providing the desired product 3a in good yield and good enantioselectivity (Table 1, entry 2). These results strongly indicate that KF is necessary not only to promote the cyclization of 2a but also to cooperate with Song’s chiral oligoEG catalyst (R)-1 to generate a well-organized chiral
Scheme 1. Asymmetric Synthesis of Chiral Cyclic Ethers via Catalytic Intramolecular Oxa-Michael Reactions
Table 1. Optimization of Reaction Conditionsa
multipoint interactions in the reaction transition state via hydrogen bonding and steric interactions would help ensure the high enantioselectivity of resultant oxacycles. In this context, Asano and Matsubara have reported the successful use of bifunctional cinchona-derived thiourea catalysts for the synthesis of five- and six-membered chiral cyclic ethers (THFs and THPs) from ε- and ζ-hydroxy-α,β-unsaturated ketones, respectively (Scheme 1, eq 2).13a,b Soon after, Zou and Zhao also reported the successful intramolecular oxa-Michael reactions to chiral THFs and THPs catalyzed by chiral primary-secondary diamines (Scheme 1, eq 2).13c Less than a decade ago, we developed easily accessible and efficient multifunctional 1,1′-bi-2-naphthol (BINOL)-based organocatalysts (Song’s oligoEGs 1, Scheme 1, eq 3)14,15 bearing polyether-tethered free phenol groups for asymmetric cation-binding catalysis. Metal ions such as K+ coordinate with the Lewis basic ether oxygen sites to generate a soluble chiral anion in a confined chiral space. Moreover, terminal phenol groups are capable of simultaneously activating the electrophile by hydrogen bonding interaction, resulting in a well-organized transition state. Several challenging catalytic asymmetric reactions have been successfully accomplished using Song’s chiral oligoEGs as an evolved cation-binding catalytic system based on the above-described ambiphilic activation mechanism.15 The ease of modulation and vast application potential of this systematic cooperative hydrogen-bonding catalytic system led us to explore challenging intramolecular cycloetherification reactions using Song’s oligoEGs for the synthesis of enantioenriched 2-substituted oxacycles. Herein, we describe a Song chiral oligoEG catalyzed highly enantioselective cycloetherification method for the synthesis of chiral 2-substituted tetrahydrofurans and tetrahydropyrans from the corresponding ε- and ζ-hydroxy-α,β-unsaturated ketones,
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
cat. (mol %) (R)-1a (15) (R)-1a (15) (R)-1b (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (15) (R)-1a (10) (R)-1a (5) (R)-1a (1)
KF (equiv)
time (h)
yield (%)b
ee (%)c
toluene
−
24
n.r.
−
toluene
3
24
91
80
toluene
3
15
96
55
o-xylene
3
24
96
78
m-xylene
3
24
95
80
anisole
3
20
97
90
MTBE
3
20
96
80
THF
3
168
96
91
2-methyl THF CH2Cl2
3
72
96
90
3
16
96
91
CH2Cl2
1.2
20
96
96
CH2Cl2
0.5
24
97
97
CH2Cl2
0.3
28
96
96
CH2Cl2
0.5
25
95
97
CH2Cl2 CH2Cl2
0.5 0.5
26 100
98 96
97 95
solvent
The reactions were performed on a 0.2 mmol scale of 2a at 0 °C. Isolated yield. cEnantiomeric excess (ee) was determined through HPLC analysis (see the Supporting Information). Anisole: methoxybenzene. MTBE: methyl-tert-butylether. THF: tetrahydrofuran. 2Methyl THF: 2-methyl-tetrahydrofuran. n.r.: no reaction. a
b
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DOI: 10.1021/acs.orglett.8b02240 Org. Lett. 2018, 20, 5319−5322
Letter
Organic Letters Scheme 2. Substrate Scopea
pocket for stereoinduction. Under the same conditions as those of entry 2, the CF3-substituted catalyst (R)-1b provided only moderate enantioselectivity (Table 1, entry 3). In further experiments, different solvents were examined with catalyst (R)1a (15 mol %) and KF (3 equiv) (Table 1, entries 4−10). In nonpolar solvents such as o-xylene and m-xylene, although we observed almost quantitative formation of the cyclized product 3a, the enantioselectivity obtained was still unsatisfactory (Table 1, entries 4 and 5). Comparatively higher enantioselectivity (ee = 90%) for 3a was observed when anisole was used as a solvent (Table 1, entry 6). Using ethereal solvents such as THF and 2methyl THF for the cyclization of 2a also resulted in high enantioselectivity (ee = up to 91%), but the reactions proceeded too slowly (72−168 h, Table 1, entries 8−9). Dichloromethane proved to be the optimal choice in terms of reaction time (16 h) and enantioselectivity (ee = 91%) (Table 1, entry 10). Thus, for the further optimization of reaction conditions on KF loading, CH2Cl2 was used as a solvent (Table 1, entries 11−13). It was evident that a substoichiometric amount of KF was sufficient to achieve both excellent conversion and enantioselectivity for the cyclization of 2a (Table 1, entries 11−13). Enantioselectivity was significantly increased up to 97% ee when reducing the KF loading. Furthermore, we were also able to reduce the catalyst loading of (R)-1a up to 5 mol % without compromising the reaction time, yield, or enantioselectivity (Table 1, entry 15). Excellent enantioselectivity (ee = 95%) was also obtained even with a 1 mol % catalyst loading (Table 1, entry 16). With the optimized reaction conditions in hand (0.5 equiv of KF and 5 mol % catalyst (R)-1a in CH2Cl2 at 0 °C), the generality of our catalytic protocol was evaluated through enantioselective cyclization of a range of enones (2, 4, and 6), and these results are summarized in Scheme 2. Regardless of the electronic and steric nature of the substituents on the aromatic ring, the ε-hydroxy-α,β-unsaturated ketones 2b−2i were smoothly cyclized to the corresponding 2-substituted THF products 3b−3i with high yields and excellent ee’s (ee = up to 97%). An enone substituted by an alkyl group 2j was also cyclized with excellent yield, but the enantioselectivity obtained was moderate.16 Although the reactions were comparatively slower, ζ-hydroxy-α,β-unsaturated ketones 4a−4c of varied electronic nature also underwent the cycloetherification reaction, producing the corresponding 2-substituted THPs 5a−5c with excellent yield and high enantioselectivity (ee = 87− 93%).16 To our delight, with increased catalytic loading of (R)1a (20 mol %) and by carrying out the reaction at room temperature, the scope of the present protocol was successfully extended to the synthesis of highly challenging seven-membered 2-substituted oxepanes 7a−7c with moderate yields and moderate to good enantioselectivities from η-hydroxy-α,βunsaturated ketones 6a−6c.16 To the best of our knowledge, this is the first successful preparation of chiral oxepane derivatives via direct catalytic cyclization from the acyclic precursors 6.17 However, an intramolecular oxa-Michael reaction for the synthesis of eight-membered chiral cyclic ethers did not occur. Perhaps, the high degree of ring strain and unfavorable entropic factor precluded the formation of the ring. Based on our previous reports regarding cation-binding catalysis,15 a plausible reaction mechanism is illustrated in Figure 2. First, the binding of catalyst (R)-1a to KF generates a soluble chiral fluoride anion, which enhances the nucleophilicity of terminal alcohols, 2, 4, and 6 through H---F hydrogen bonding. Simultaneously, the acidic phenol moiety of the BINOL backbone of (R)-1a activates the carbonyl group of α,β-
a The reactions were carried out on a 0.25 mmol scale. bThe reaction was carried out at 1 mmol scale. c20 mol % loading of catalyst (R)-1a and reactions were run at 25 °C.
Figure 2. Plausible catalytic cycle.
unsaturated ketones. Subsequently, intramolecular oxa-Michael addition proceeds with high enantioselectivity in the confined chiral cage generated in situ through the coordination of KF with the catalyst. In conclusion, we have successfully developed an efficient catalytic asymmetric method for the direct cycloetherification of 5321
DOI: 10.1021/acs.orglett.8b02240 Org. Lett. 2018, 20, 5319−5322
Letter
Organic Letters ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones using Song’s chiral oligoEG as a cation-binding catalyst and KF as a base. Highly useful cyclic ether skeletons such as 2-substituted THFs, THPs, and oxepanes were obtained with excellent yields and enantioselectivities via asymmetric intramolecular oxa-Michael addition reactions. This remarkably successful catalysis can be ascribed to systematic cooperative cation-binding catalysis in a densely confined supramolecular chiral cage generated in situ from the chiral catalyst, substrate, and KF. In a confined chiral cage, both reaction centers (nucleophilic terminal hydroxyl group and electrophilic β-carbon) of terminal-hydroxy-α,βunsaturated ketones are activated through double hydrogen bonding in a manner similar to real enzymes. The resultant close proximity of the reactive sites enhances the reactivity and facilitates efficient transfer of the stereochemical information. The extension of this strategy for constructing a challenging chiral macrocyclic ether system (≥8-membered) is currently being investigated in our laboratory.
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(8) (a) Levine, S. D.; Adams, R. E.; Chen, R.; Cotter, M. L.; Hirsch, A. F.; Kane, V. V.; Kanojia, R. M.; Shaw, C.; Wachter, P.; Chin, E.; Huettemann, R.; Ostrowski, P.; Mateos, J. L.; Noriega, L.; Guzmán, A.; Mijarez, A.; Tovar, L. J. Am. Chem. Soc. 1979, 101, 3404. (b) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7. (c) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1. (d) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1. (9) (a) Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 2096. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. (c) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (d) Cox, N.; Uehling, M. R.; Haelsig, K. T.; Lalic, G. Angew. Chem., Int. Ed. 2013, 52, 4878. (e) Adint, T. T.; Wong, G. W.; Landis, C. R. J. Org. Chem. 2013, 78, 4231. (f) Liu, L.; Kaib, P. S. J.; Tap, A.; List, B. J. Am. Chem. Soc. 2016, 138, 10822. (g) Lee, S.; Kaib, P. S. J.; List, B. J. Am. Chem. Soc. 2017, 139, 2156. (10) (a) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003, 125, 15748. (b) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256. (c) Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun. 2013, 49, 2418. (d) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627. (e) Zhou, P.; Cai, Y.; Zhong, X.; Luo, W.; Kang, T.; Li, J.; Liu, X.; Lin, L.; Feng, X. ACS Catal. 2016, 6, 7778. (11) (a) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (b) Díez, D.; Núñez, M. G.; Benéitez, A.; Moro, R. F.; Marcos, I. S.; Basabe, P.; Broughton, H. B.; Urones, J. G. Synlett 2009, 2009, 390. (c) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225. (d) Phillips, E. M.; Riedrich, M.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 13179. (12) (a) Carreno, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladie, G. Org. Lett. 2004, 6, 297. (b) Pavlik, C.; Onorato, A.; Castro, S.; Morton, M.; Peczuh, M.; Smith, M. B. Org. Lett. 2009, 11, 3722. (13) (a) Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711. (b) Fukata, Y.; Miyaji, R.; Okamura, T.; Asano, K.; Matsubara, S. Synthesis 2013, 45, 1627. (c) Lu, Y.; Zou, G.; Zhao, G. ACS Catal. 2013, 3, 1356. (14) Lee, J. W.; Yan, H.; Jang, H. B.; Kim, H. K.; Park, S. W.; Lee, S.; Chi, D. Y.; Song, C. E. Angew. Chem., Int. Ed. 2009, 48, 7683. (15) (a) For a review, see: Oliveira, M. T.; Lee, J.-W. ChemCatChem 2017, 9, 377. (b) Yan, H.; Jang, H. B.; Lee, J.-W.; Kim, H. K.; Lee, S. W.; Yang, J. W.; Song, C. E. Angew. Chem., Int. Ed. 2010, 49, 8915. (c) Yan, H.; Oh, J. S.; Lee, J.-W.; Song, C. E. Nat. Commun. 2012, 3, 1212. (d) Park, S. Y.; Lee, J. W.; Song, C. E. Nat. Commun. 2015, 6, 7512. (e) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Angew. Chem., Int. Ed. 2016, 55, 331. (f) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2016, 138, 16486. (g) Vaithiyanathan, V.; Kim, M. J.; Liu, Y.; Yan, H.; Song, C. E. Chem. - Eur. J. 2017, 23, 1268. (h) Kim, M. J.; Xue, L.; Liu, Y.; Paladhi, S.; Park, S. J.; Yan, H.; Song, C. E. Adv. Synth. Catal. 2017, 359, 811. (i) Yu, L.; Wu, X.; Kim, M. J.; Vaithiyanathan, V.; Liu, Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Adv. Synth. Catal. 2017, 359, 1879. (j) Park, S. Y.; Hwang, I.-S.; Lee, H. J.; Song, C. E. Nat. Commun. 2017, 8, 14877. (k) Tan, Y.; Luo, S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2017, 139, 6431. (l) Duan, M.; Liu, Y.; Ao, J.; Xue, L.; Luo, S.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Org. Lett. 2017, 19, 2298. (m) Paladhi, S.; Liu, Y.; Kumar, B. S.; Jung, M.-J.; Park, S. Y.; Yan, H.; Song, C. E. Org. Lett. 2017, 19, 3279. (n) Park, S. Y.; Liu, Y.; Oh, J. S.; Kweon, Y. K.; Jeong, Y. B.; Duan, M.; Tan, Y.; Lee, J.-W.; Yan, H.; Song, C. E. Chem. - Eur. J. 2018, 24, 1020. (o) Paladhi, S.; Hwang, I.-S.; Yoo, E. J.; Ryu, D. H.; Song, C. E. Org. Lett. 2018, 20, 2003. (16) The absolute configurations of 3a,13a 5a,13a and 7a10e were determined by comparison of their retention times of HPLC with those reported in the literature,13a and the configurations for all other adducts were assigned analogously. (17) Attempts to synthesize seven-membered chiral cyclic ethers by the intramolecular oxa-Michael reaction using metal complexes of chiral N,N-dioxides as the catalysts were made by Feng and co-workers, but no Michael adducts were obtained.10e
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02240.
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Experimental details and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hailong Yan: 0000-0003-3378-0237 Choong Eui Song: 0000-0001-9221-6789 Author Contributions §
A.P.J. and J.-A.O. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Korean Research Foundation (Grant No: NRF-2017R1A2A1A05001214 and NRF-2016R1A4A1011451).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02240 Org. Lett. 2018, 20, 5319−5322
