Letter Cite This: Org. Lett. 2018, 20, 236−239
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Regio- and Diastereodivergent [4 + 2] Cycloadditions with Cyclic 2,4‑Dienones Wei Xiao,† Qian-Qian Yang,† Zhi Chen,† Qin Ouyang,*,‡ Wei Du,† and Ying-Chun Chen*,†,‡ †
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
‡
S Supporting Information *
ABSTRACT: By employing activated alkenes with bulky αfunctional groups, such as α-cyano-α,β-unsaturated ketones and Meldrum’s acid−based alkenes, a previously unreported crosstrienamine pathway of cyclic 2,4-dienones is adopted to deliver γ′,δregioselective [4 + 2] cycloadducts catalyzed by cinchona-derived amines. In addition, a diastereodivergent [4 + 2] cycloaddition reaction is realized with Z-configured 4-alkylideneisoxazol-5(4H)ones under similar catalytic conditions, even through a three- or four-component cascade process with simple starting materials.
B
Scheme 1. Regiodivergent Cycloaddition Pathways of Cyclic 2,4-Dienones via Aminocatalysis
uilding chiral compound libraries with skeletal diversity or stereodiversity from identical or analogous sets of starting materials has received increased attention in asymmetric catalysis, as biological activities are essentially correlated to the molecular structures.1 An array of synthetic strategies, including employing different catalysts or synergistic catalysts, changing additives or other reaction parameters, modifying the functional groups of substrates, etc., have been developed.2 Nevertheless, the simultaneous accomplishment of regio- and diastereodivergence under similar catalytic conditions, which can construct chiral substances with both structural diversity and stereodiversity, still remains as a challenging task.3 Cyclic enone substrates can possess multiple reactive sites through diverse aminocatalytic modes,4 thus providing opportunities for divergent synthesis. Moreover, the introduction of an exo-β-vinyl substituent to cyclic enones may provide even more potential. They commonly engaged in δregioselective 1,6-addition reactions by the formation of vinylogous iminium ions I,5 and a few cascade γ,δ-[3 + 2], γ′,δ-[4 + 2], and β,δ-[3 + 3] annulations with specifically designed nucleophiles have also been developed (Scheme 1, a).6 On the other hand, such vinylogous iminium ions can preferably isomerize to HOMO-raised cross-trienamine species II, and subsequent α′,β-regioselective [4 + 2] cycloaddition reactions with activated alkenes would deliver bicyclo[2.2.2]octane skeletons (Scheme 1, b).7 As a previous mechanism study suggested that the α′,β-[4 + 2] reaction might proceed in a stepwise cascade manner rather than a concerted Diels−Alder cycloaddition pathway,7 the application of the activated alkenes with bulky α-functional groups might change this inherent preference due to the steric hindrance in the final formation of the bridged ring systems (Scheme 1, c). Here we disclose another type of unprecedented cross-trienamine intermediates © 2017 American Chemical Society
III,8 rendering γ′,δ-regiodivergent [4 + 2] functionalizations to access fused frameworks, which are ubiquitous in many natural products and bioactive compounds (Scheme 1, d).9 The initial reaction of cyclic 2,4-dienone 1a and activated alkene 2 bearing a bulky electron-withdrawing 1,2-benzoisothiazole-1,1-dioxide motif10 showed exclusive α′,β-regioselectivity, catalyzed by 9-amino-9-deoxyepicinchonine C1 and salicylic acid A1 (Table 1) in toluene at 50 °C, affording the bridged product 3 in excellent stereoselectivity (Scheme 2).11 The reaction pathway also did not change when benzylideneReceived: November 20, 2017 Published: December 14, 2017 236
DOI: 10.1021/acs.orglett.7b03598 Org. Lett. 2018, 20, 236−239
Letter
Organic Letters
with excellent diastereo- and enantioselectivity. Therefore, the inherent α′,β-regioselective reaction pathway was completely prohibited, probably due to the higher reaction barrier in the formation of vicinal quaternary stereocenters. Further screenings indicated that the combination of 9amino-9-deoxyepiquinidine C2 and 2-mercaptobenzoic acid A2 improved the yield with retained enantioselectivity (Table 1, entry 1).12 Subsequently, we explored the substrate scope and limitations of the γ′,δ-[4 + 2] cycloadditions. The results are summarized in Table 1. An array of α-cyano-α,β-unsaturated ketones 6 were tested in the reactions with 2,4-dienone 1a. Substrates 6 with different substituents at the β-position, including electron-rich and -poor aryl, 2-furyl or 2-styryl groups, smoothly gave the corresponding products 7b−e in moderate to good yields with excellent enantioselectivity (Table 1, entries 2−5). Similarly good results were produced for substrates 6 with diverse α′-aroyl groups (entries 6−9). On the other hand, 2,4-dienones 1 with a substituted phenyl group or an ester group were compatible in the reactions with alkene 6a (entries 10−12). Unfortunately, neither substrates 1 nor 6 possessing alkyl substituents produced the desired cycloadducts. The alkenes 8 derived from Meldrum’s acid also showed exclusive γ′,δ-regioselectivity in the reactions with 2,4-dienones 1. The combination of amine C3 (Table 1) and acid A1 exhibited better catalytic efficiency.12 As summarized in Table 2, the expected tricyclic products 9 were generally isolated in
Table 1. Substrate Scope and Limitations of [4 + 2] Cycloadditions with 2,4-Dienones 1 and Activated Alkenes 6a
entry
R
R1, R2
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12
Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeOC6H4 4-BrC6H4 CO2Et
Ph, Ph 4-MeOC6H4, Ph 4-BrC6H4, Ph 2-furyl, Ph 2-styryl, Ph Ph, 4-MeC6H4 Ph, 4-BrC6H4 Ph, 2-furyl Ph, 1-naphthyl Ph, Ph Ph, Ph Ph, Ph
7a, 75 7b, 77 7c, 70 7d, 78 7e, 66 7f, 65 7g, 72 7h, 64 7i, 67 7j, 71 7k, 63 7l, 52
97 98 98 95d 96 96 96 96 95 97 97 98
a
Table 2. [4 + 2] Cycloadditions of 2,4-Dienones 1 and Meldrum’s Acid-Based Alkenes 8a
Reactions were performed with 2,4-dienone 1 (0.2 mmol), alkene 6 (0.1 mmol), catalyst C2 (20 mol %), and acid A2 (40 mol %) in toluene (1.0 mL) at 50 °C for 12 h. bYield of the isolated product. c Determined by HPLC analysis on a chiral stationary phase; dr >19:1 by 1H NMR analysis. dThe absolute configuration of 7d was determined by X-ray analysis (CCDC 1570505). The other products were assigned by analogy.
Scheme 2. Activated Alkenes-Controlled Switchable Regiodivergent [4 + 2] Cycloadditions of Cyclic 2,4Dienones
entry
R, R1
t (h)
drb
yield (%)c
ee (%)d
1 2 3 4 5 6
Ph, Ph Ph, 4-MeC6H4 Ph, 4-ClC6H4 Ph, 2-thienyl 2-MeC6H4, Ph 4-BrC6H4, Ph
48 55 53 57 39 56
10:1 8:1 10:1 7:1 8:1 12:1
9a, 72 9b, 73 9c, 65 9d, 62 9e, 68 9f, 64
90e 92 92 87 90 91
a
Reactions were performed with 2,4-dienone 1 (0.15 mmol), alkene 8 (0.1 mmol), catalyst C3 (20 mol %) and acid A1 (40 mol %) in toluene (2.0 mL) at rt. bDetermined by 1H NMR analysis of the crude product. cYield of the isolated pure diastereomer. dDetermined by HPLC analysis on a chiral stationary phase. eThe absolute configuration of 9a was determined by X-ray analysis (CCDC 1570506). The other products were assigned by analogy.
moderate yields with excellent enantioselectivity from diversely substituted substrates, though some minor diastereomers were also observed (Table 2, entries 1−6). As outlined in Scheme 3, by treatment with PPA, highly regioselective intramolecular Friedel−Crafts acylation reactions were conducted for adducts 9 with different electronic groups, delivering tetracyclic frameworks9 10 and 11, respectively, in moderate yields with complete diastereoselectivity. The realization of diastereodivergence is quite challenging, especially for products with multiple stereogenic centers. When the assembly of Z-configured 4-benylideneisoxazol-5(4H)one13 12a and 2,4-dienone 1a was explored under the catalysis
malononitrile 4 was applied, and product 5 with vicinal quaternary centers was formed in moderate yield and enantiocontrol. Interestingly, the regioselectivity was changed by using the analogous alkene 6a with a bulkier benzoyl group, giving the γ′,δ-regioselective [4 + 2] product 7a with the fused framework, rather than the bridged 7a′, in a moderate yield 237
DOI: 10.1021/acs.orglett.7b03598 Org. Lett. 2018, 20, 236−239
Letter
Organic Letters
A3 was the optimal catalytic system,12 producing better results (entry 2). As summarized in Table 3, the substrate scope was generally substantial. Alkylidene isoxazol-5(4H)-one 12 derived from a variety of aromatic aldehydes, as well as the one with a heteroaryl or 2-styryl group, smoothly engaged in the reactions with 2,4-dienone 1a (entries 3−10). Although an alkene from an aliphatic aldehyde showed lower reactivity, the expected product 13j was obtained in a moderate yield with good enantioselectivity (entry 11). In addition, a 4-benzylideneisoxazol-5(4H)-one with a 2-phenyl group delivered cycloadduct 13k with good results (entry 12). On the other hand, 2,4-dienones 1 with diverse aryl groups, and even with an alkyl or an ester group, successfully produced the corresponding cycloadducts in fair to good yields with high enantioselectivity (entries 13−19). Unfortunately, a β-styryl 2-cyclopentenone exhibited poor reactivity and enantioselectivity (entry 20). The reaction still proceeded smoothly at a 1.0 mmol scale, whereas a slightly lower yield and ee value were attained (entry 21). The three-component reaction of 2,4-dienone 1a, 3methylisoxazol-5(4H)-one 14, and benzaldehyde 15a could be efficiently promoted under the catalysis of bifunctional C4 and acid A3, through a cascade14 Knoevenagel condensation/[4 + 2] cycloaddition process. Adding 4 Å molecular sieves (MS) was beneficial for the enantioselectivity (Scheme 4). These
Scheme 3. Construction of Polycyclic Architectures
of amine C1 and acid A1, the same γ′,δ-regioselective [4 + 2] cycloadduct 13a was obtained in exclusive diastereoselectivity and moderate enantiocontrol; surprisingly, the absolute configuration at 4a,5-carbons was switched, but that at the 7carbon remained unchanged (Table 3, entry 1). It suggested that the current [4 + 2] reaction should not proceed in a concerted Diels−Alder pathway, as trans-structure was observed at 4a,7-sites. Moreover, the enantioselectivity of the initial γ′-regioselective Michael addition was switched, though the same catalytic conditions were applied. Subsequent screenings identified that a combination of bifunctional substance C4 and benzoic acid Table 3. Diastereodivergent [4 + 2] Cycloadditions of 2,4Dienones 1 and Z-Configured Alkenes 12a
Scheme 4. Multicomponent Cascade Reactions
entry
R
R1, R2
t (h)
yield (%)b
ee (%)c
d
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 2-MeC6H4 3-MeOC6H4 4-MeOC6H4 3-BrC6H4 4-BrC6H4 c-hexyl CO2Et Ph Ph
Ph, CH3 Ph, CH3 2-MeC6H4, CH3 3-MeC6H4, CH3 4-MeOC6H4, CH3 2-ClC6H4, CH3 3-ClC6H4, CH3 4-BrC6H4, CH3 2-thienyl, CH3 2-styryl, CH3 c-hexyl, CH3 Ph, Ph Ph, CH3 Ph,CH3 Ph, CH3 Ph, CH3 Ph, CH3 Ph, CH3 Ph, CH3 Ph, CH3 Ph, CH3
36 36 38 28 29 31 42 47 30 30 52 24 24 33 30 32 40 50 36 96 36
13a, 55 13a, 78 13b, 72 13c, 79 13d, 82 13e, 84 13f, 68 13g, 63 13h, 86 13i, 71 13j, 52 13k, 82 13l, 83 13m, 78 13n, 80 13o, 81 13p, 63 13q, 56 13r, 58 13s, 41 13a, 70
68 90 90 87 87 80 88 93 88 84 80 84 88 92 87e 86 91 93 87 −44 88
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20f 21g
results inspired us to explore the more challenging and complicated four-component cascade reaction process, involving condensations of simple 3-methyl-2-cyclohexenone 16 and 3-methyl-isoxazol-5(4H)-one 14 with aldehydes 15, respectively, followed by the [4 + 2] cycloaddition. While bifunctional amine-thiourea C4 failed to deliver the desired product probably because it might not be effective for the formation of dienone 1, finally we uncovered that adding 10 mol % of cinchona-based amine C3, in combination with catalyst C5, could afford the cycloadducts ent-13 in modest yields with high enantioselectivity, probably proceeding in a relay aminocatalytic manner.12 In conclusion, we reported that the inherent cross-trienamine-mediated α′,β-regioselective [4 + 2] cycloadditions of cyclic 2,4-dienones could be switched. A γ′,δ-regioselective [4 + 2] cycloaddition pathway was developed by assembling cyclic 2,4-dienones with α-cyano-α,β-unsaturated ketones or Meldrum’s acid based alkenes, through forming previously
a
Unless noted otherwise, reactions were performed with 2,4-dienone 1 (0.15 mmol, n = 1), alkene 12 (0.1 mmol), catalyst C4 (20 mol %), and acid A3 (40 mol %) in toluene (1.0 mL) at 50 °C. bYield of isolated product. cDetermined by HPLC analysis on a chiral stationary phase; dr >19:1 by 1H NMR analysis. dWith amine C1 and acid A1. e The absolute configuration of 13n was determined by X-ray analysis (CCDC 1570507). The other products were assigned by analogy. fn = 0, with C3 and A1. gAt a 1.0 mmol scale. 238
DOI: 10.1021/acs.orglett.7b03598 Org. Lett. 2018, 20, 236−239
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Organic Letters
S.; Tur, F.; Mønsted, S. M. N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2015, 54, 10193. (4) For selected reviews, see: (a) Jurberg, I. D.; Chatterjee, I.; Tannert, R.; Melchiorre, P. Chem. Commun. 2013, 49, 4869. (b) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986. (c) Afewerki, S.; Córdova, A. Chem. Rev. 2016, 116, 13512. (5) Tian, X.; Liu, Y.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 6439. (6) (a) Tian, X.; Melchiorre, P. Angew. Chem., Int. Ed. 2013, 52, 5360. (b) Gu, X.; Guo, T.; Dai, Y.; Franchino, A.; Fei, J.; Zou, C.; Dixon, D. J.; Ye, J. Angew. Chem., Int. Ed. 2015, 54, 10249. (c) Sun, X.; Fei, J.; Zou, C.; Lu, M.; Ye, J. RSC Adv. 2016, 6, 106676. (7) Feng, X.; Zhou, Z.; Zhou, R.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. J. Am. Chem. Soc. 2012, 134, 19942. (8) (a) Halskov, K. S.; Johansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 12943. (b) Dieckmann, A.; Breugst, M.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 3237. (c) Zhou, Z.; Wang, Z.-X.; Ouyang, Q.; Xiao, W.; Du, W.; Chen, Y.-C. Chem. - Eur. J. 2017, 23, 2945. (9) For selected examples, see: (a) Chakrabarti, S.; Qian, M.; Krishnan, K.; Covey, D. F.; Mennerick, S.; Akk, G. Mol. Pharmacol. 2016, 89, 399. (b) Gao, J.; Aisa, H. A. J. Nat. Prod. 2017, 80, 1767. (c) Scaglione, J. B.; Manion, B. D.; Benz, A.; Taylor, A.; DeKoster, G. T.; Rath, N. P.; Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. J. Med. Chem. 2006, 49, 4595. (d) Tian, Y.; Xu, W.; Zhu, C.; Lin, S.; Guo, Y.; Shi, J. J. Nat. Prod. 2013, 76, 1039. (e) Roy, P. P.; Roy, K. J. Pharm. Pharmacol. 2010, 62, 1717. (10) Wang, K.-K.; Jin, T.; Huang, X.; Ouyang, Q.; Du, W.; Chen, Y.C. Org. Lett. 2016, 18, 872. (11) Zhou, R.; Xiao, W.; Yin, X.; Zhan, G.; Chen, Y.-C. Huaxue Xuebao 2014, 72, 862. (12) For more condition screening details, in addition to preliminary DFT calculations regarding regio- and diastereoselectivity of diverse [4 + 2] cycloadditions, see the Supporting Information. (13) (a) Cui, B.-D.; Li, S.-W.; Zuo, J.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2014, 70, 1895. (b) Capreti, N. M. R.; Jurberg, I. D. Org. Lett. 2015, 17, 2490. (14) (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390.
unreported cross-trienamine species with a primary amine catalyst. A spectrum of fused frameworks with high molecular complexity were produced in good to excellent diastereo- and enantioselectivity. Moreover, a diastereodivergent [4 + 2] cycloaddition pathway was furnished by combining cyclic 2,4dienones and Z-configured 4-alkylidene-isoxazol-5(4H)-ones under similar catalytic conditions, and a more challenging three- or even four-component cascade process with simple starting materials could be accomplished. The current substrate-controlled regio- and diastereodivergent asymmetric cycloaddition reactions provided versatile protocols to access chiral compound libraries with both structural diversity and stereodiversity, which might be valuable for drug discovery.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03598. Complete experimental procedures and characterization of new products, density functional theory (DFT) computational calculations, NMR spectra, and HPLC chromatograms (PDF) Accession Codes
CCDC 1570505−1570507 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Qin Ouyang: 0000-0002-1161-5102 Ying-Chun Chen: 0000-0003-1902-0979 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the NSFC (21772126 and 21372160). REFERENCES
(1) (a) Jozwiak, K.; Lough, W. J.; Wainer, I. W. Drug Stereochemistry: Analytical Methods and Pharmacology, 3rd ed.; CRC Press: 2012. (b) Wermuth, C. G. The Practice of Medicinal Chemistry, 3rd ed.; Elsevier: Amsterdam, 2008. (2) For selected recent reviews, see: (a) Bihani, M.; Zhao, J. C. G. Adv. Synth. Catal. 2017, 359, 534. (b) Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 5627. (c) Zhan, G.; Du, W.; Chen, Y.-C. Chem. Soc. Rev. 2017, 46, 1675. (d) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S.-g. Chem. Soc. Rev. 2017, 46, 4299. (e) Lin, L.; Feng, X. Chem. Eur. J. 2017, 23, 6464. (f) Funken, N.; Zhang, Y.; Gansäuer, A. Chem. Eur. J. 2017, 23, 19. (3) For limited examples, see: (a) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Angew. Chem., Int. Ed. 2016, 55, 2147. (b) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Angew. Chem., Int. Ed. 2016, 55, 9671. (c) Næsborg, L.; Halskov, K. 239
DOI: 10.1021/acs.orglett.7b03598 Org. Lett. 2018, 20, 236−239
