Letter pubs.acs.org/OrgLett
Catalytic Asymmetric Cascade Using Spiro-Pyrrolidine Organocatalyst: Efficient Construction of Hydrophenanthridine Derivatives Jin-Miao Tian,† Yong-Hai Yuan,‡ Yu-Yang Xie,† Shu-Yu Zhang,† Wen-Qiang Ma,‡ Fu-Min Zhang,‡ Shao-Hua Wang,‡ Xiao-Ming Zhang,‡ and Yong-Qiang Tu*,†,‡ †
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China State Key Laboratory of Applied Organic Chemistry, School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
‡
S Supporting Information *
ABSTRACT: A newly developed SPD (spiro-pyrrolidine) organocatalyst has been demonstrated to enable an asymmetric aza-Michael/Michael/aldol cyclization cascade, in which two six-membered rings (B/C) and three stereocenters have been constructed in a catalytic one-step process. It is so far the most efficient method for construction of hydrophenanthridine derivatives featuring high enantioselectivity. The trans- or cis-fused B/C-rings can be selectively assembled in a substrate-controlled manner. Moreover, this cascade could magnify to gram scale without loss of enanioselectivity.
C
available to access the 5N-type frameworks (Scheme 1, 1a and 1b).4 These methods involve a multistep process or start from a
hiral spiro-cycloalkanes, as a privileged scaffold, have displayed powerful stereocontrolling ability in asymmetric transition-metal catalysis.1 In contrast, asymmetric organocatalysis with the spiro-heterocyclic backbone catalysts is rarely reported.2 Recently, our group has developed an organocatalyst based on the 1-azaspiro[4.4]nonane silylether,3 which could catalyze the asymmetric Michael reaction in high enantioselectivity.3a It is promising to use this organocatalyst in a cascade reaction to construct more complicated polycyclic systems, such as the tricyclic hydrophenanthridine. The tricyclic hydrophenanthridine framework exists widely in a number of biologically important molecules, such as those in Figure 1.4 As is well-known, tetrahydrocannabinol (THC) with
Scheme 1. Strategies Accessing Hydrophenanthridine-Type Compounds
Figure 1. Bioactive molecules containing the hydrophenanthridine framework.
chiral substrate, and all generate only the C6a,C10a-trans-fused products. Therefore, development of a generally efficient asymmetric method to synthesize the structurally diverse hydrophenanthridines is still in high demand. Development of novel and efficient cascade reactions has been an attractive and widely used strategy for organic synthesis
the 5O-motif has already been widely studied and utilized in clinics for a long time.5 It was recently discovered that the 5Nhydrophenanthridine derivatives exhibit even much better bioactivities than their 5O-congeners in some aspects. For example, CP 50 is 30 times stronger than THC in activating the CB2 receptors and also possesses analgesic and antiemetic properties with 9−14 times greater potency than morphine.4d At present, however, only two asymmetric synthetic strategies are © 2017 American Chemical Society
Received: October 25, 2017 Published: November 28, 2017 6618
DOI: 10.1021/acs.orglett.7b03330 Org. Lett. 2017, 19, 6618−6621
Letter
Organic Letters
was obtained (entry 8). When the temperature was lowered to −5 °C, the enantioselectivity was dramatically enhanced to 96% ee (entry 9). Furthermore, several other organocatalysts were tested under similar conditions. For example, sterically less hindered catalyst 2 or nonspirocyclic catalysts 3 and 4 all gave unsatisfactory results, indicating that using our explored bulky catalyst 1 was necessary for this transformation (entries 10−12). As a result, entry 9 was chosen as the standard condition for the following substrate scope expansion. With the optimized conditions in hand (Table 1, entry 9), the scope of substrate 2 was first investigated. The results obtained (Scheme 2) showed that all aldehydes 2a−2m with various R3
because they can access the structurally more complex and diverse molecules with less transformations.6 In connection with the synthesis of the hydrophenanthridine framework mentioned above, we envisioned that a cascade aza-Michael/Michael addition and aldol cyclization between appropriate α,βunsaturated β-aminophenyl ketone and α,β-unsaturated aldehyde under certain organocatalytic conditions could asymmetrically construct such a framework in a single catalytic step (Scheme 1, 1c). Here, we present our successfully explored cascade by using our newly developed and powerful spiropyrrolidine (SPD) silylether-type aminocatalyst.7 To realize the above designed cascade, a potential challenge, that a competitive intra- or intermolecular condensation of the primary NH2 of 1a with the carbonyls would prohibit the expected initial catalytic step, would have to be overcome (Table 1).8 Therefore, the Ts-protected amino substrates 1a1 and
Scheme 2. Scope of α,β-Unsaturated Aldehydes 2a
Table 1. Optimization of Aza-Michael/Michael/Aldol Cascadea
entry
catalyst
additive
temp (°C)
yieldb (%)
eec (%)
1d 2 3 4 5 6e 7f 8 9g 10 11 12
1 1 1 1 1 1 1 1 1 2 3 4
PhCO2H PhCO2H NaOAc Et3N Na2CO3 NaOAc/4 Å MS NaOAc/H2O DMAP DMAP DMAP DMAP DMAP
rt rt rt rt rt rt rt rt −5 rt rt rt
ND 6 30 ND 8 11 12 36 46 48 18 42
ND 60 78 ND 72 80 81 82 96 66 −40 38
a
Unless otherwise noted, reactions were performed (also see Supporting Information): 2a−2m (1.5 equiv) and catalyst 1 (0.2 equiv) were added at −5 °C to toluene (2 mL), then DMAP (1 equiv) and 1a (0.20 mmol, 1 equiv) were added and stirred for 3 days. b1.127 g of 1a was used.
and R4 substituents performed well to generate the expected products 3a−3m in moderate to good yields and high enantioselectivities (up to 98% ee). Either aromatic/heteroaromatic (furan, thiofuran) or aliphatic (Me, CO2Et) substitutions were well tolerated, regardless of the electronical difference of the substituents at the aromatic ring. When the substituents R3/R4 were single methyl or dimethyl groups, both reactions proceeded well to give the products 3l and 3m in high enantioselectivities. These products were precursors for the synthesis of antiemetic/analgesic drug CP 50 and CB2 receptor agonists (Figure 1). To demonstrate the practical utility of this method, a gram scale of 1a (1.127g, 7 mmol) was used, and the reaction still proceeded smoothly to afford 3a in maintained 95% ee, albeit at a slightly lower 42% yield. The absolute and relative configurations of products 3a−3m were unambiguously assigned by X-ray analysis of 3f. Subsequently, the scope of substrates 1b−1j was investigated, which indicated that substitution at any of the C2−C4 positions could be tolerable for this reaction and gave moderate to good yields and high enatioselectivities (Scheme 3). For example, substitutions with electron-withdrawing Br, Cl, or F could give good yields and up to 99% ee (4b−4f, 4h−4j). The substitution could be further extended to the stronger electron-withdrawing NO2, which afforded product 4g in up to 99% ee. In particular, an ethyl ketone 1j (R5 = Me) could also react well with 2a and
a
Unless otherwise noted, reactions were performed (also see Supporting Information): cinnamaldehyde 2a (1.5 equiv) and catalyst (0.2 equiv) were added at rt to toluene (2 mL). Then additives (1 equiv) and substrate 1a (0.20 mmol, 1 equiv) were added and stirred for 1.5 day. bIsolated yield. cDetermined by chiral HPLC analysis. dTsprotected 1a1 used. e100 mg of 4 Å MS added. f3 equiv of H2O added. g Stirred for 3 days at −5 °C.
cinnamaldehyde 2a were used initially to test the cascade reaction using catalyst 1 in an acid environment of PhCO2H. Unfortunately, the expected product 3a could not be detected (Table 1, entry 1). To our delight, however, when unprotected amine 1a was subjected to the same conditions, a trace amount of 3a was formed with 60% ee, albeit in only 6% yield (entry 2). It was later found that a basic NaOAc additive rather than the acidic one could increase both the yield and enantioselectivity of the reaction (entry 3). More basic additives Et3N and Na2CO3 (entries 4 and 5) were next examined, but inferior results were obtained. Either removal (entry 6) or addition of H2O (entry 7) in the reaction system resulted in better enantioselectivities of 80 and 81% ee, but with lower yields of 11 and 12%, respectively. Pleasingly, when DMAP (dimethylaminopyridine) was used as a basic additive, a better yield with maintained enantioselectivity 6619
DOI: 10.1021/acs.orglett.7b03330 Org. Lett. 2017, 19, 6618−6621
Letter
Organic Letters Scheme 3. Scope of α,β-Unsaturated β-Aminophenyl Ketone 1a
Scheme 4. Scope of C1-Substituted 5 Forming C6a,C10a-cisProductsa
a Unless otherwise noted, reactions were performed (see Supporting Information): 2 (0.30 mmol, 1.5 equiv) and catalyst 1 (0.2 equiv) were added at −5 °C to the solvent (2 mL), then DMAP (1 equiv) and substrates 5a−5d (0.20 mmol) were added and stirred for 5 days.
a
Unless otherwise noted, reactions were performed: 2a or 2m (1.5 equiv) and catalyst 1 (0.2 equiv) were added at −5 °C to the solvent (2 mL), then DMAP (1 equiv) and substrates 1b−1j (0.20 mmol, 1 equiv) were added and stirred for 3 days (also see Supporting Information). b2m used at −10 to −5 °C for 4 days.
generated the even more complex product 4k in 94% ee. The absolute and relative configurations of products 4b−4k were unambiguously assigned by X-ray analysis of 4c. It should be noted that substrates 1 with electron-donating R2 were not accessible due to the preferable intramolecular condensation of the active NH2 with the carbonyl generating undesired quinolines during preparation.9 Having constructed the C6a,C10a-trans-fused hydrophenanthridines above, we turned to assemble the C6a,C10a-cis-fused systems, as they also possess some important biological activities in bioactive studies, such as BK Ca agonist (Figure 1). After a widespread investigation of both substrate structure and reaction conditions, fortunately we found that just a simple introduction of a non-hydrogen substituent R1 at C1 of ring A could thoroughly change the fusing pattern to afford the complete cisproduct with excellent enantioselectivity under the standard conditions. As presented in Scheme 4, all substrates 5a−5d bearing C1−Cl, Br, or Me unexceptionally reacted to give the cisfused products 6a−6g; when the R1 was Me in 6e, a low 30% ee was observed. Even changing the substitution at C3 and/or C6 still gave the cis-fused products 6f and 6g. The absolute and relative configurations of 6a−6g were unambiguously confirmed by X-ray analysis of 6a, 6e, and 6f. A stepwise aza-Michael/Michael cyclization rather than the hetero-Diels−Alder reaction was suggested as a key mechanism in the first annulation.6e,8 Furthermore, the trans or cis annulation process could be rationalized by considering two possible transition states A and B (Figure 2). When C1 hydrogensubstituted substrate 1a was used, a trans-conformer A would be adopted, where a A1,3 strain between the small H atom and the vinyl could be negligible and thus the trans-product 3a was formed.10 If a bulkier Br was located at C1 such as in 5a, a strong A1,3 interaction between Br and the vinyl occurred, and favorable cis-conformer B′ rather than the trans-conformer B was dominant, which would generate the cis-product 6a after further annulation. To further demonstrate the utility of the above cascade, several hydrophenanthridine derivatives 7−9 corresponding to the bioactive hydrocannabinols have been synthesized (Scheme 5).5
Figure 2. Proposed transition state for trans or cis annulation selection.
Scheme 5. Synthesis of Hydrophenanthridine Derivatives 7−9
Thus, reduction of 3m followed by treatment with MeMgBr gave 9a-hydroxy product 7 in 74% yield over two steps. Dehydration of 7 produced the THC analogue 8 in 85% yield. Final reduction of 8 with BH3·Me2S generated hexahydrocannabinol analogues 9 and 9′ as isolated isomers.11 In conclusion, a highly efficient cascade aza-Michael/Michael/ aldol cyclization has been realized by the use of our newly developed SPD-type aminocatalyst. This cascade is so far the most expeditious approach for the construction of hydrophenanthridine derivatives and features high enantioselectivities, a wide substrate scope, and potential application on a preparative scale. These results further demonstrate the particular, powerful, and promising properties of the SPD-type organocatalysts. Further investigation of this SPD organocatalyst and the biological activity of the hydrophenanthridine derivatives is ongoing in our group.
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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.7b03330. 6620
DOI: 10.1021/acs.orglett.7b03330 Org. Lett. 2017, 19, 6618−6621
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Organic Letters
Rissanen, K.; Enders, D. Org. Lett. 2017, 19, 3025−3028. (g) Zhu, L.; Chen, Q.; Shen, D.; Zhang, W.; Shen, C.; Zeng, X.; Zhong, G. Org. Lett. 2016, 18, 2387−2390. (h) Lee, Y.; Heo, S.; Kim, S.-G. Adv. Synth. Catal. 2015, 357, 1545−1550. (i) Pantaine, L.; Coeffard, V.; Moreau, X.; Greck, C. Org. Lett. 2015, 17, 3674−3677. (j) Ren, L.; Lei, T.; Ye, J.-X.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51, 771−774. (7) Selected aminocatalysis examples reported by other groups: (a) Kano, T.; Shirozu, F.; Maruoka, K. J. Am. Chem. Soc. 2013, 135, 18036−18039. (b) Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 7516−7520. (c) Jones, S. B.; Simmons, B.; Mastracchio, A.; Macmillan, D. W. C. Nature 2011, 475, 183−188. (d) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304−1307. (e) Michrowska, A.; List, B. Nat. Chem. 2009, 1, 225−228. (f) Kang, Y.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2010, 132, 11847− 11849. (g) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem. - Eur. J. 2008, 14, 4788−4791. (h) Wang, W.; Li, H.; Wang, J.; Zu, L.-S. J. Am. Chem. Soc. 2006, 128, 10354−10355. (i) Chen, X.-H.; Yu, J.; Gong, L.-Z. Chem. Commun. 2010, 46, 6437−6448. (8) Leth, L. A.; Glaus, F.; Meazza, M.; Fu, L.; Thogersen, M. K.; Bitsch, E. A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 15272−12576. (9) (a) Cheng, C.-C.; Yan, S.-J. In Organic Reaactions; Dauben, W. D., Ed. Wiley-VCH: Weinheim, 1982; Chapter 2, pp 37−201. (b) Liu, C.Y.; Yang, D.-Q.; Huang, C.-H. Chin. J. Synth. Chem. 2001, 6, 567−569. (10) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841−1860. (11) Klotter, F.; Studer, A. Angew. Chem., Int. Ed. 2015, 54, 8547− 8550.
Detailed experimental procedures, spectra data for all newcompounds, copies of 1H, 13C, 19F NMR and HPLC spectra (PDF) Accession Codes
CCDC 1553534 and 1554885−1554888 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 Author
*E-mail:
[email protected]. ORCID
Shu-Yu Zhang: 0000-0002-1811-4159 Fu-Min Zhang: 0000-0001-5578-1148 Shao-Hua Wang: 0000-0002-4347-8245 Xiao-Ming Zhang: 0000-0002-9294-9672 Yong-Qiang Tu: 0000-0002-9784-4052 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support provided by the National Natural Science Foundation of China (Nos. 21502080, 21290180, 21372104, 21472077, and 21702136).
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REFERENCES
(1) (a) Zhu, S.-F.; Zhou, Q.-L. In Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, 2011; Chapter 4, pp 137−170. (b) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao 2014, 72, 778− 797. (2) (a) Jiang, M.; Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-G.; Zhou, Q.-L. Tetrahedron: Asymmetry 2006, 17, 384−387. (b) Xu, F.; Huang, D.; Han, C.; Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75, 8677− 8680. (c) Li, X.; Zhao, Y.; Qu, H.; Mao, Z.; Lin, X. Chem. Commun. 2013, 49, 1401−1403. (d) Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Angew. Chem., Int. Ed. 2013, 52, 2027−2031. (e) Cwiek, R.; Niedziejko, P.; Kaluza, Z. J. Org. Chem. 2014, 79, 1222−1234. (f) Li, S.; Zhang, J.-W.; Li, X.-L.; Cheng, D.-J.; Tan, B. J. Am. Chem. Soc. 2016, 138, 16561− 16566. (3) (a) Tian, J.-M.; Yuan, Y.-H.; Tu, Y.-Q.; Zhang, F.-M.; Zhang, X.-B.; Zhang, S.-H.; Wang, S.-H.; Zhang, X.-M. Chem. Commun. 2015, 51, 9979−9982. (b) Dou, Q.-Y.; Tu, Y.-Q.; Zhang, Y.; Tian, J.-M.; Zhang, F.-M.; Wang, S.-H. Adv. Synth. Catal. 2016, 358, 874−879. (c) Xu, M.H.; Tu, Y.-Q.; Tian, J.-M.; Zhang, F.-M.; Wang, S.-H.; Zhang, S.-H.; Zhang, X.-M. Tetrahedron: Asymmetry 2016, 27, 294−300. (4) (a) Migneault, D.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1995, 73, 1506−1513. (b) Lau, C. K. Patent Appl. CA 2170850 A1, 1996. (c) Travis, C. R. U.S. Patent Appl. US 20120122917 A1, 2012. (d) Sheshenev, A. E.; Boltukhina, E. V.; Hii, K. K. Chem. Commun. 2013, 49, 3685−3687. (5) Elsohly, M. A.; Radwan, M. M.; Gul, W.; Chandra, S. A. In Phytocannabinoids; Kinghorn, A. D., Falk, H., Gibbons, S., Kobayashi, J., Eds.; Springer: Switzerland, 2017; Chapter 1, pp 1−36. (6) (a) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993− 3009. (b) Catalytic Cascade Reactions; Xu, P.-F., Wang, W., Eds.; Wiley: Hoboken, NJ, 2014. (c) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390−2431. (d) Donslund, B. S.; Johansen, T. K.; Poulsen, P. H.; Halskov, K. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2015, 54, 13860−13874. (e) Raja, A.; Hong, B.-C.; Lee, G.-H. Org. Lett. 2014, 16, 5756−5759. (f) Kumar, M.; Chauhan, P.; Valkonen, A.; 6621
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