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FULL PAPER Shuji Ikeda et al. Hybridization-sensitive fluorescent DNA probe with self-avoidance ability
PERSPECTIVE Laurel K. Mydock and Alexei V. Demchenko Mechanism of chemical O-glycosylation: from early studies to recent discoveries
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DOI: 10.1039/C3OB42068J
Diastereoselective synthesis of epoxide-fused benzoquinolizidine derivatives using intramolecular domino aza-Michael addition/Darzens reaction Jiajia Guo,a Xiaoyang Suna and Shouyun Yu*a 5
10
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x An efficient and diastereoselective strategy based on intramolecular domino aza-Michael/Darzens reaction to synthesis epoxide-fused benzoquinolizidine has been described. Three bonds (1 C-C, 1 C-N and 1 C-O), three rings and three chiral centers can be constructed in single pot under very mild condition. All the products were isolated in only one diastereomer with 40-80% yields.
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15
20
25
30
Benzoquinolizidine alkaloids are abundant in natural products and pharceuticals, such as tetrabenazine,1 emetine,2 butaciamol3 and tetrahydroberberie4. And many of them exhibit interesting biological activity. For example, tetrabenazine is an orphan drug for the symptomatic treatment of hyperkinetic movement disorder.1, 5 Emetine is a drug used as both an antiprotozoal6 and antimalarial7. Butaciamol acts as a dopamine receptor antagonist.8 And tetrahydroberberie has significant potential as Anti-microbials drug.9 Accordingly, much attention has focused on the development of general approaches to these alkaloids.10 The aza-Michael addition represents one of the most powerful strategies for the formation of carbon–nitrogen bonds in the preparation of amines and nitrogen heterocyclic compounds.11,12 Its intramoleccular variants or related domino reactions13 are efficient strategies for preparation of chiral nitrogen heterocycles and show great synthetic potential in total synthesis of alkaloids11i,12a,12f,14,15a.
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Figure 1 Benzoquinolizidine alkaloids
This journal is © The Royal Society of Chemistry [year]
Recently, we have succeeded in the development of the enantioselective intramolecular aza-Michael additions and their appliactions in synthesis of alkaloids,15 which prompted us to design aza-Michael addition-triggered domino reactions14b,16 to achieve more complex and useful motifs. Due to the importance of tetrahydroisoquinoline skeleton,17 we designed aza-Michaeal triggered domino reactions of the amino α,β-unsaturated ketone 1a to achieve this motif as shown in Scheme 1. We envisage that Michael adduct I can be generated by treatment of 1a with base. There are two competitive pathways when Michael adduct I is upon base. In pathway A, pyrrolidinoisoquinoline 2 is provided
by intramolecular alkylation. And in pathway B, intramolecular Darzens reaction18 leads to formation of benzoquinolizidine 3a. When ketone 1a was treated with tBuOK (1.2 equiv.) at room temperature in THF, no pyrrolidinoisoquinoline 2 was observed. Instead, epoxidefused benzoquinolizidine 3a was isolated with 24% chemical yield in one diastereomer.
Scheme 1 Aza-Michael-triggered domino reactions The intriguing and promising result prompted us to screen the reaction conditions further as shown in Table 1. Firstly, temperature screening showed that the best yield was obtained (44%) at 0 °C (entry 2). Both of higher and lower temperature gave the decreasing yield (entries 1 and 3). Various bases were then evaluated at 0 °C. Potasium, sodium and cesium-based bases, such as t-BuOK, KHMDS, NaH, MeONa and CsOH•H2O, could promote this transformation in 26-61% yield while lithium-based bases, such as t-BuOLi, LiHMDS and n-BuLi, did not work at all. CsOH•H2O proved to be the best base, which could give the desired product 3a in 61% yield (entry 10). The quantity of the base could affect this reaction significantly. When 1.5 equiv. of
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Table 2 Substrate scope of domino aza-Micheal/Darzens reaction.a,b
30
Entry
1
3
Yield/%c
1
80
2
64
3
56
4d
40
5
72
6d
55
7
52
8
61
9d
52
10d
57
Table 1 Condition screening.a,b
15
Entry
Base(equiv.)
Solvent
Temp./°C
Yield/%c
1
t-BuOK(1.2)
THF
rt
24
2
t-BuOK(1.2)
THF
0
44
3
t-BuOK(1.2)
THF
-20
29
4
KHMDS (1.2)
THF
0
53
5
LiHMDS(1.2)
THF
0
0
6
t-BuOLi(1.2)
THF
0
0
7
NaH(1.2)
THF
0
26
8
n-BuLi(1.2)
THF
0
0
9
MeONa(1.2)
THF
0
45
10
CsOH•H2O(1.2)
THF
0
61
11
CsOH•H2O(1.5)
THF
0
66
12
CsOH•H2O(2.0)
THF
0
53
d
CsOH•H2O(1.5)
THF
0
72
14e
CsOH•H2O(1.5)
THF
0
57
d
CsOH•H2O(1.5)
DMF
0
0
16d
CsOH•H2O(1.5)
DMSO
rt
0
17
d
CsOH•H2O(1.5)
1,4-dioxane
rt
80
18
d
CsOH•H2O(1.5)
MeOH
0
0
19d
CsOH•H2O(1.5)
toluene
0
trace
20d
CsOH•H2O(1.5)
CH3CN
0
19
21d
CsOH•H2O(1.5)
DCE
0
trace
d
CsOH•H2O(1.5)
DME
0
49
13
15
22 a
20
25
A solution of 1a (0.1 mmol) and base in the indicated solvent (2 mL) was stirred for 2-4 h. b3a was isolated in one diastereomer in all cases. c Isolated yield. dIn 1 mL of solvent. eIn 5 mL of solvent.
With optimal conditions established, we explored the generality of this transformation. As shown in Table 2, a variety of amino α, β-unsaturated ketones were evaluated. To our delight, aliphatic α, β-unsaturated ketones worked quite well to provide the desired benzoquinolizidine 3a-k in only one diastereomer with 40-80% yields. The amino chalcone derivatives, such as 1l, could not go through this reaction (entry 12).
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CsOH•H2O was used, slightly higher yield (66%) was obtained (entry 11). However, the yield dropped to 53% when 2.0 equiv. of CsOH•H2O was used (entry 12). Concentration of the reaction mixture could also affect this transformation. Higher concentration gave better yield (entry 13) while lower yield was obtained in diluted reaction mixture (entry 14). Finally, different solvents were tested (entries 15-22). 1,4-Dioxane proved to be the best solvent (80% yield, entry 17). Due to high melting point of the solvent, the reaction carried out at room temperature in 1,4dioxane. It is noteworthy that epoxide-fused benzoquinolizidine 3a was isolated exclusively as one diastereomer in all cases based on NMR analysis.
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11
80
12
0
25
Notes and references 30
a
A solution of 1 (0.1 mmol) and CsOH•H2O(0.15 mmol) in dioxane (1 mL) at room temperature was stirred for 2-4 h. bAll the products were isolated in one diastereomer. cIsolated yield. dThe reaction carried out in the mixture of dioxane/THF (2/1) at 0 °C. 5
10
The possible mechanism has been proposed for this domino reaction as shown in Figure 2. The amino α, β-unsaturated ketone 1 goes through intramolecular aza-Michael addition assisted by base to give enolate 4. After protonation of enolated 4, the resultant keto-amide 5 is deprotonated and then intramolecularly attacks the ketone to generate the oxygen anion 6. The anion 6 attacks back to chloride to give the epoxide 3. The structure and stereochemistry of 3a was established ambiguously by single crystal X-ray diffraction analysis.19
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‡ Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. 1
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State Key Laboratory of Analytical Chemistry for Life Science, Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China. Fax: 86-25- 83317761; Tel: 86-25-83594717; E-mail: [email protected] † Electronic Supplementary Information (ESI) available: Full experimental procedures, characterization data for all the compounds. See DOI: 10.1039/b000000x/
55
Figure 2 Proposed mechanism for domino aza-Michael/Darzens reaction.
In summary, an efficient and diastereoselective strategy to synthesis epoxide-fused benzoquinolizidine has been described. This strategy is relied on intramolecular domino azaMichael/Darzens reaction of amino α, β-unsaturated ketones. Three bonds (1 C-C, 1 C-N and 1 C-O), three rings and three chiral centers can be constructed in single pot under very mild condition. All the products were isolated exclusively as one diastereomer with 40-80% yields.
a
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50
15
This work was financially supported by 863 program (2013AA092903), National Natural Science Foundation of China (21102072, 21272113) and Research Fund for the Doctoral Program of Higher Education of China (20110091120008).
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A. Brossi, H. Lindlar, M. Walter and O. Schnider, Helv. Chim. Acta., 1958, 41, 119-139. 2 (a) G. H. Mahran, S. H. Hilal and T. S. El-Alfy, Planta. Med., 1975, 27, 127-132; (b) N. Sakurai, K. Nakagawa-Goto, J. Ito, Y. Sakurai, Y. Nakanishi, K. F. Bastow, G. Cragg and K.-H. Lee, Phytochemistry, 2006, 67, 894-897. 3 F. T. Bruderlein, L. G. Humber and K. Voith, J. Med. Chem., 1975, 18, 185-188. 4 J. S. Buck and R. M. Davis, J. Am. Chem. Soc., 1930, 52, 660-664. 5 (a) E. T. McNeal, G. A. Lewandowski, J. W. Daly and C. R. Creveling, J. Med. Chem., 1985, 28, 381-388; (b) Q. Yu, W. Luo, J. Deschamps, H. W. Holloway, T. Kopajtic, J. L. Katz, A. Brossi and N. H. Greig, ACS Med. Chem. Lett., 2010, 1, 105-109. 6 K. Merschjohann, F. Sporer, D. Steverding and M. Wink, Planta. Med., 2001, 67, 623-627. 7 I. Muhammad, D. C. Dunbar, S. I. Khan, B. L. Tekwani, E. Bedir, S. Takamatsu, D. Ferreira and L. A. Walker, J. Nat. Prod., 2003, 66, 962-967. 8 (a) D. A. Hall and P. G. Strange, Br. J. Pharmacol., 1997, 121, 731736; (b) P. J. Pauwels, S. Tardif, T. Wurch and F. C. Colpaert, Br. J. Pharmacol., 2001, 134, 88-97. 9 R. Perumal Samy and P. Gopalakrishnakone, Evid. Based. Complement. Alternat. Med., 2010, 7, 283-294. 10 (a) K. Orito, Y. Satoh, H. Nishizawa, R. Harada and M. Tokuda, Org. Lett., 2000, 2, 2535-2537; (b) T. Itoh, M. Miyazaki, H. Fukuoka, K. Nagata and A. Ohsawa, Org. Lett., 2006, 8, 1295-1297; (c) M. J. Rishel, K. K. D. Amarasinghe, S. R. Dinn and B. F. Johnson, J. Org.Chem., 2009, 74, 4001-4004; (d) M. Johannes and K.-H. Altmann, Org. Lett., 2012, 14, 3752-3755; (e) S. Lin, L. Deiana, A. Tseggai and A. Córdova, Eur. J. Org. Chem., 2012, 2012, 398-408. 11 For recent reviews on asymmetric aza-Michael addition, see: (a) M. Liu and M. P. Sibi, Tetrahedron, 2002, 58, 7991-8035; (b) J. L. Vicario, D. Badía, L. Carrillo, J. Etxebarria, E. Reyes and N. Ruiz, Org. Prep. Proced. Int., 2005, 37, 513-538; (c) L.-W. Xu and C.-G. Xia, Eur. J. Org. Chem., 2005, 2005, 633-639; (d) J. L. Vicario, D. Badía and L. Carrillo, Synthesis, 2007, 14, 2065-2092; (e) D. Enders, C. Wang and J. X. Liebich, Chem. Eur. J., 2009, 15, 11058-11076; (f)
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P. R. Krishna, A. Sreeshailam and R. Srinivas, Tetrahedron, 2009, 65, 9657-9672; (g) S. Fustero, M. Sánchez-Roselló, C. del Pozo, Pure. Appl. Chem., 2010, 82, 669-677; (h) J. Wang, P. Li, P. Y. Choy, A. S. C. Chan and F. Y. Kwong, ChemCatChem, 2012, 4, 917-925; (i) Z. Amara, J. Caron and D. Joseph, Nat. Prod. Rep., 2013, 30, 12111225. For organocatalytic exo-type aza-Michael additions, see: (a) S. Fustero, D. Jiménez, J. Moscardó, S. Catalán and C. del Pozo, Org. Lett., 2007, 9, 5283-5286; (b) E. C. Carlson, L. K. Rathbone, H. Yang, N. D. Collett and R. G. Carter, J. Org.Chem., 2008, 73, 51555158; (c) S. Fustero, J. Moscardó, D. Jiménez, M. D. Pérez-Carrión, M. Sánchez-Rosellóand C. del Pozo, Chem. Eur. J., 2008, 14, 98689872; (d) Q. Cai, C. Zheng and S.-L. You, Angew. Chem. Int. Ed., 2010, 49, 8666-8669; (e) S. Fustero , C. del Pozo, C. Mulet, R. Lazaro and M. Sánchez-Roselló, Chem. Eur. J., 2011, 17, 1426714272; (f) Q. Gu and S. You, Chem. Sci., 2011, 2, 1519-1522; (g) J.D. Liu, Y.-C. Chen, G.-B. Zhang, Z.-Q. Li, P. Chen, J.-Y. Du, Y.-Q. Tu and C.-A. Fan, Adv. Synth. Catal., 2011, 353, 2721-2730; (h) R. Miyaji, K. Asano and S. Matsubara, Org. Lett., 2013, 15, 3658-3661. (i) S. Fustero, J. Moscardó, M. Sánchez-Roselló, E. Rodríguez and P. Barrio, Org. Lett., 2010, 12, 5494–5497. (j) S. Fustero, E. Rodríguez, L. Herrera, A. Asensio, M. A. Maestro and P. Barrio, Org. Lett., 2011, 13, 6564–6567. (k) S. Fustero, L. Herrera, R. Lázaro, E. Rodríguez, M. A. Maestro, N. Mateu and P. Barrio, Chem. Eur. J., 2013, 19, 11776–11785. For recent reviews on domino reactions, see: (a) L. F. Tietze, Chem. Rev., 1996, 96, 115-136; (b) L. F. Tietze and A. Modi, Med. Res. Rev., 2000, 20, 304-322; (c) S. F. Mayer, W. Kroutil and K. Faber, Chem. Soc. Rev., 2001, 30, 332-339; (d) D. Enders, C. Grondal and M. R. M. Hüttl, Angew. Chem. Int. Ed., 2007, 46, 1570-1581; (e) A. Grossmann and D. Enders, Angew. Chem. Int. Ed., 2012, 51, 314-325; (f) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237-294. For selective papers on aza-Michael addition in total synthesis, see: (a) S. Fustero, S. Monteagudo, M. Sánchez-Roselló, S. Flores, P. Barrio and C. del Pozo, Chem. Eur. J., 2010, 16, 9835-9845; (b) X. Wang, J. An, X. Zhang, F. Tan, J. Chen and W. Xiao, Org. Lett., 2011, 13, 808-811; (c) B. Jiang, J. Wang and Z.-G. Huang, Org. Lett., 2012, 14, 2070-2073; (d) P. Radha Krishna and B. K. Reddy, Tetrahedron: Asymmetry, 2013, 24, 758-763. (a) C. Zeng, H. Liu, M. Zhang, J. Guo, S. Jiang and S. Yu, Synlett, 2012, 23, 2251-2254; (b) H. Liu, C. Zeng, J. Guo, M. Zhang and S. Yu, RSC Adv., 2013, 3, 1666-1668. For selective papers on aza-Michael addition-triggered domino reactions, see: (a) I. Ibrahem, R. Rios, J. Vesely, G.-L. Zhao and A. Cordova, Chem. Commun., 2007, 849-851; (b) H. Li, J. Wang, H. Xie, L. Zu, W. Jiang, E. N. Duesler and W. Wang, Org. Lett., 2007, 9, 965-968; (c) H. Sundén, R. Rios, I. Ibrahem, G.-L. Zhao, L. Eriksson and A. Córdova, Adv. Synth. Catal., 2007, 349, 827-832; (d) H. Li, J. Zhao, L. Zeng and W. Hu, J. Org. Chem., 2011, 76, 8064-8069; (e) Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen, P.-F. Xu and B. Wang, Chem. Eur. J., 2012, 18, 12958-12961; (f) H.-J. Lee and C.-W. Cho, J. Org. Chem., 2013, 78, 3306-3312; (g) Y. Yang, W.-M. Shu, S.-B. Yu, F. Ni, M. Gao and A.-X. Wu, Chem. Commun., 2013, 49, 17291731. For selective reviews on tetrahydroisoquinoline, see: (a) H. Rommelspacher, T. May and R. Susilo, Planta. Med., 1991, 57, 85-
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DOI: 10.1039/C3OB42068J
92; (b) A. Couture, E. Deniau, P. Grandclaudon and P. Woisel, Tetrahedron, 1996, 52, 4433-4448; (c) J. D. Scott and R. M. Williams, Chem. Rev., 2002, 102, 1669-1730; (d) S. Aubry, S. PelletRostaing and M. Lemaire, Eur. J. Org. Chem., 2007, 2007, 52125225; (e) P. Siengalewicz, U. Rinner and J. Mulzer, Chem. Soc. Rev., 2008, 37, 2676-2690. 18 For selective reviews on Darzens reaction, see: (a) M. Ballester, Chem. Rev., 1955, 55, 283-300; (b) S. Arai, Y. Shirai, T. Ishida and T. Shioiri, Tetrahedron, 1999, 55, 6375-6386; (c) J. Y. Yuan, X. C. Liao, H. M. Wang and M. S. Tang, J. Stru. Chem., 2008, 49, 818-827; (d) J. Sweeney, Eur. J. Org. Chem., 2009, 2009, 4911-4919. 19 CCDC 954113 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk / data_request/cif.
Organic & Biomolecular Chemistry Accepted Manuscript
Organic & Biomolecular Chemistry
Organic & Biomolecular Chemistry Accepted Manuscript This article can be cited before page numbers have been issued, to do this please use: J. Guo, X. Sun and S. Yu, Org. Biomol. Chem., 2013, DOI: 10.1039/C3OB42068J.
This is an Accepted Manuscript, which has been through the RSC Publishing peer review process and has been accepted for publication.
Organic & Biomolecular Chemistry www.rsc.org/obc
Volume 8 | Number 3 | 7 February 2010 | Pages 481–716
Accepted Manuscripts are published online shortly after acceptance, which is prior to technical editing, formatting and proof reading. This free service from RSC Publishing allows authors to make their results available to the community, in citable form, before publication of the edited article. This Accepted Manuscript will be replaced by the edited and formatted Advance Article as soon as this is available. To cite this manuscript please use its permanent Digital Object Identifier (DOI®), which is identical for all formats of publication. More information about Accepted Manuscripts can be found in the Information for Authors.
ISSN 1477-0520
FULL PAPER Shuji Ikeda et al. Hybridization-sensitive fluorescent DNA probe with self-avoidance ability
PERSPECTIVE Laurel K. Mydock and Alexei V. Demchenko Mechanism of chemical O-glycosylation: from early studies to recent discoveries
1477-0520(2010)8:3;1-H
Please note that technical editing may introduce minor changes to the text and/or graphics contained in the manuscript submitted by the author(s) which may alter content, and that the standard Terms & Conditions and the ethical guidelines that apply to the journal are still applicable. In no event shall the RSC be held responsible for any errors or omissions in these Accepted Manuscript manuscripts or any consequences arising from the use of any information contained in them.
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DOI: 10.1039/C3OB42068J
Diastereoselective synthesis of epoxide-fused benzoquinolizidine derivatives using intramolecular domino aza-Michael addition/Darzens reaction Jiajia Guo,a Xiaoyang Suna and Shouyun Yu*a 5
10
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x An efficient and diastereoselective strategy based on intramolecular domino aza-Michael/Darzens reaction to synthesis epoxide-fused benzoquinolizidine has been described. Three bonds (1 C-C, 1 C-N and 1 C-O), three rings and three chiral centers can be constructed in single pot under very mild condition. All the products were isolated in only one diastereomer with 40-80% yields.
35
40
15
20
25
30
Benzoquinolizidine alkaloids are abundant in natural products and pharceuticals, such as tetrabenazine,1 emetine,2 butaciamol3 and tetrahydroberberie4. And many of them exhibit interesting biological activity. For example, tetrabenazine is an orphan drug for the symptomatic treatment of hyperkinetic movement disorder.1, 5 Emetine is a drug used as both an antiprotozoal6 and antimalarial7. Butaciamol acts as a dopamine receptor antagonist.8 And tetrahydroberberie has significant potential as Anti-microbials drug.9 Accordingly, much attention has focused on the development of general approaches to these alkaloids.10 The aza-Michael addition represents one of the most powerful strategies for the formation of carbon–nitrogen bonds in the preparation of amines and nitrogen heterocyclic compounds.11,12 Its intramoleccular variants or related domino reactions13 are efficient strategies for preparation of chiral nitrogen heterocycles and show great synthetic potential in total synthesis of alkaloids11i,12a,12f,14,15a.
45
50
55
60
Figure 1 Benzoquinolizidine alkaloids
This journal is © The Royal Society of Chemistry [year]
Recently, we have succeeded in the development of the enantioselective intramolecular aza-Michael additions and their appliactions in synthesis of alkaloids,15 which prompted us to design aza-Michael addition-triggered domino reactions14b,16 to achieve more complex and useful motifs. Due to the importance of tetrahydroisoquinoline skeleton,17 we designed aza-Michaeal triggered domino reactions of the amino α,β-unsaturated ketone 1a to achieve this motif as shown in Scheme 1. We envisage that Michael adduct I can be generated by treatment of 1a with base. There are two competitive pathways when Michael adduct I is upon base. In pathway A, pyrrolidinoisoquinoline 2 is provided
by intramolecular alkylation. And in pathway B, intramolecular Darzens reaction18 leads to formation of benzoquinolizidine 3a. When ketone 1a was treated with tBuOK (1.2 equiv.) at room temperature in THF, no pyrrolidinoisoquinoline 2 was observed. Instead, epoxidefused benzoquinolizidine 3a was isolated with 24% chemical yield in one diastereomer.
Scheme 1 Aza-Michael-triggered domino reactions The intriguing and promising result prompted us to screen the reaction conditions further as shown in Table 1. Firstly, temperature screening showed that the best yield was obtained (44%) at 0 °C (entry 2). Both of higher and lower temperature gave the decreasing yield (entries 1 and 3). Various bases were then evaluated at 0 °C. Potasium, sodium and cesium-based bases, such as t-BuOK, KHMDS, NaH, MeONa and CsOH•H2O, could promote this transformation in 26-61% yield while lithium-based bases, such as t-BuOLi, LiHMDS and n-BuLi, did not work at all. CsOH•H2O proved to be the best base, which could give the desired product 3a in 61% yield (entry 10). The quantity of the base could affect this reaction significantly. When 1.5 equiv. of
[journal], [year], [vol], 00–00 | 1
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Page 2 of 4
Table 2 Substrate scope of domino aza-Micheal/Darzens reaction.a,b
30
Entry
1
3
Yield/%c
1
80
2
64
3
56
4d
40
5
72
6d
55
7
52
8
61
9d
52
10d
57
Table 1 Condition screening.a,b
15
Entry
Base(equiv.)
Solvent
Temp./°C
Yield/%c
1
t-BuOK(1.2)
THF
rt
24
2
t-BuOK(1.2)
THF
0
44
3
t-BuOK(1.2)
THF
-20
29
4
KHMDS (1.2)
THF
0
53
5
LiHMDS(1.2)
THF
0
0
6
t-BuOLi(1.2)
THF
0
0
7
NaH(1.2)
THF
0
26
8
n-BuLi(1.2)
THF
0
0
9
MeONa(1.2)
THF
0
45
10
CsOH•H2O(1.2)
THF
0
61
11
CsOH•H2O(1.5)
THF
0
66
12
CsOH•H2O(2.0)
THF
0
53
d
CsOH•H2O(1.5)
THF
0
72
14e
CsOH•H2O(1.5)
THF
0
57
d
CsOH•H2O(1.5)
DMF
0
0
16d
CsOH•H2O(1.5)
DMSO
rt
0
17
d
CsOH•H2O(1.5)
1,4-dioxane
rt
80
18
d
CsOH•H2O(1.5)
MeOH
0
0
19d
CsOH•H2O(1.5)
toluene
0
trace
20d
CsOH•H2O(1.5)
CH3CN
0
19
21d
CsOH•H2O(1.5)
DCE
0
trace
d
CsOH•H2O(1.5)
DME
0
49
13
15
22 a
20
25
A solution of 1a (0.1 mmol) and base in the indicated solvent (2 mL) was stirred for 2-4 h. b3a was isolated in one diastereomer in all cases. c Isolated yield. dIn 1 mL of solvent. eIn 5 mL of solvent.
With optimal conditions established, we explored the generality of this transformation. As shown in Table 2, a variety of amino α, β-unsaturated ketones were evaluated. To our delight, aliphatic α, β-unsaturated ketones worked quite well to provide the desired benzoquinolizidine 3a-k in only one diastereomer with 40-80% yields. The amino chalcone derivatives, such as 1l, could not go through this reaction (entry 12).
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CsOH•H2O was used, slightly higher yield (66%) was obtained (entry 11). However, the yield dropped to 53% when 2.0 equiv. of CsOH•H2O was used (entry 12). Concentration of the reaction mixture could also affect this transformation. Higher concentration gave better yield (entry 13) while lower yield was obtained in diluted reaction mixture (entry 14). Finally, different solvents were tested (entries 15-22). 1,4-Dioxane proved to be the best solvent (80% yield, entry 17). Due to high melting point of the solvent, the reaction carried out at room temperature in 1,4dioxane. It is noteworthy that epoxide-fused benzoquinolizidine 3a was isolated exclusively as one diastereomer in all cases based on NMR analysis.
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DOI: 10.1039/C3OB42068J
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0
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Notes and references 30
a
A solution of 1 (0.1 mmol) and CsOH•H2O(0.15 mmol) in dioxane (1 mL) at room temperature was stirred for 2-4 h. bAll the products were isolated in one diastereomer. cIsolated yield. dThe reaction carried out in the mixture of dioxane/THF (2/1) at 0 °C. 5
10
The possible mechanism has been proposed for this domino reaction as shown in Figure 2. The amino α, β-unsaturated ketone 1 goes through intramolecular aza-Michael addition assisted by base to give enolate 4. After protonation of enolated 4, the resultant keto-amide 5 is deprotonated and then intramolecularly attacks the ketone to generate the oxygen anion 6. The anion 6 attacks back to chloride to give the epoxide 3. The structure and stereochemistry of 3a was established ambiguously by single crystal X-ray diffraction analysis.19
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‡ Footnotes should appear here. These might include comments relevant to but not central to the matter under discussion, limited experimental and spectral data, and crystallographic data. 1
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State Key Laboratory of Analytical Chemistry for Life Science, Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China. Fax: 86-25- 83317761; Tel: 86-25-83594717; E-mail: [email protected] † Electronic Supplementary Information (ESI) available: Full experimental procedures, characterization data for all the compounds. See DOI: 10.1039/b000000x/
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Figure 2 Proposed mechanism for domino aza-Michael/Darzens reaction.
In summary, an efficient and diastereoselective strategy to synthesis epoxide-fused benzoquinolizidine has been described. This strategy is relied on intramolecular domino azaMichael/Darzens reaction of amino α, β-unsaturated ketones. Three bonds (1 C-C, 1 C-N and 1 C-O), three rings and three chiral centers can be constructed in single pot under very mild condition. All the products were isolated exclusively as one diastereomer with 40-80% yields.
a
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This work was financially supported by 863 program (2013AA092903), National Natural Science Foundation of China (21102072, 21272113) and Research Fund for the Doctoral Program of Higher Education of China (20110091120008).
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Acknowledgments
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Organic & Biomolecular Chemistry
