Letter pubs.acs.org/OrgLett
Enantioselective Synthesis of 4H‑Pyran via Amine-Catalyzed Formal (3 + 3) Annulation of δ‑Acetoxy Allenoate Weiping Zhou,† Chunjie Ni,‡ Jiangfei Chen,‡ Dong Wang,‡ and Xiaofeng Tong*,†,‡ †
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China ‡ Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, 1 Gehu Road, Changzhou, 213164, China S Supporting Information *
ABSTRACT: The formal (3 + 3) annulations of δ-acetoxy allenoates and 1C,3O-bisnucleophiles are reported with the use of 6′-deoxy-6′-perfluorobenzamido-quinine (4g) as a catalyst, which provide rapid access to 4H-pyrans with excellent enantioselectivity. The reaction features a wide reaction scope and mild reaction conditions. The crucial roles of amide NH of 4g as a H-bond donor have also been elucidated, which not only activates allenoate to facilitate formation of cationic intermediate A but also enhances the electrophilicity of its δ-position for nucleophilic 1,6-addition.
T
Scheme 1. Amine-Catalyzed Asymmetric Annulations of Allenoates (E = CO2R)
he Lewis-base-catalyzed annulations have evolved into one of the most fascinating fields in organic chemistry.1 Specifically, the phosphine-catalyzed asymmetric annulation of allenoate has come to be a powerful tool for the construction of structurally divergent enantioenriched cycles2 since the first report3 from the group of Zhang in 1997. In contrast, the amine-catalyzed analogues are still scarce.4 It was not until 2011 that the Masson and Zhu group reported the first aminecatalyzed asymmetric (2 + 2) annulation of allenoate with imine (Scheme 1a).5 After that, the asymmetric allenoate (4 + 2) annulation with oxadiene under amine catalysis has also been developed.6 Among them, cinchona alkaloid-based bifunctional catalysts are commonly employed to guide the reaction stereochemistry via H-bonding such as transition state A. An advance has also been made toward the asymmetric (3 + 3) annulation of β′-acetoxy allenoate and 3-oxo-nitrile by using a trifunctional amine catalyst (Scheme 1b).7 Similarly, the interaction of the functional groups of the catalyst with a nitrile substrate is also pivotal for excellent enantioselectivity (transition state B). However, γ-substituted allenoate has not yet been explored in this arena, which can be partly attributed to its steric hindrance, especially in the case of a sterically congested amine catalyst.8 Thus, a new strategy is required to circumvent this hurdle. Herein, we report the asymmetric (3 + 3) annulation of δ-acetoxy allenoate 1 and 1C,3O-bisnucleophile 2 using a bifunctional amine catalyst. Alternatively, a Hbonding interaction of the catalyst with allenoate is suggested (transition state C), which enables 4H-pyran to be obtained with excellent enantioselectivity (Scheme 1c). Our study commenced with the evaluation of cinchona alkaloid-based catalysts9 for the reaction of 1a and 2a (Scheme 2). To our surprise, quinine-derived 4a was completely inactive and 2a was recovered in 95% yield (entry 1).8 Delightedly, (S)3aa was obtained in 35% yield and 54% ee when catalyst 4b © XXXX American Chemical Society
bearing a 6′-OH group was used (entry 2). Moreover, catalyst 4c bearing a stronger H-bond donor (HNBz)10 increased the yield and ee to 86% and 60%, respectively (entry 3). Lowering the reaction temperature (0 °C) was benificial, giving 3aa in Received: March 3, 2017
A
DOI: 10.1021/acs.orglett.7b00658 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Nitriles 2f−2h with a heteroaryl group, such as furan, thiophene, and pyridine, also worked well under these reaction conditions, giving products in good yields and with excellent ee. In addition, 3-alkyl-nitriles 2i and 2j were compatible and excellent reaction performances were still achieved. Then, the scope of the allenaote partner was briefly investigated. A variety of allenates 1 with different types of substituents at the δposition, including an aromatic ring (1a−1e), alkene (1f), and alkyl group (1g), were applicable to the reaction. Finally, product 3hh was obtained in 90% yield and 96% ee, whose structure was established on the X-ray crystallographic analysis.11 Thus, its absolute configuration was assigned to be S, and other products were determined by analogy. Then, this process was extended to 1,3-dicarbonyl compounds 5 (Scheme 4). Cyclohexane-1,3-dione 5a was found to
Scheme 2. Optimization of the Reaction Conditions
Scheme 4. Reaction Scope of Allenoate 1 and 1,3-Dicarbonyl Compound 5
95% yield and 85% ee (entry 4). However, the reaction became sluggish without ee improvement when the temperature was further decreased to −20 °C (entry 5). Surprisingly, a significant decrease in yield was observed when 4d bearing a 6′-HNTs group was employed as the catalyst (entry 6). These results clearly indicated that both of the reaction efficiency and enantioselectivity would closely interrelate with the donating ability of the H-bond of the catalyst. Accordingly, we focused our attention on catalysts 4e−4g. The H-bond donors were optimized by subtly tuning the electronic property of the benzoyl moiety. Screening of these three catalysts rapidly disclosed that catalyst 4g with a perfluorobenzamido group (HNCOC6F5) is the best one, affording 3aa in 94% yield and 99% ee (entry 9). Then, the reaction scope of the asymmetric (3 + 3) annulations of allenoates 1 and 3-oxo-nitriles 2 was examined (Scheme 3). Various 3-aryl-nitriles 2a−2e, including a substituent such as −OMe, −F, −I, and −NO2, reacted well with 1a, giving the corresponding products with excellent ee. Scheme 3. Reaction Scope of Allenoate 1 and Nitrile 2
be capable of engaging in the (3 + 3) annulations with various allenoates, as illustrated by the isolation of products 6aa, 6ga, and 6ia−6oa with excellent ee. 5-Substituted cyclohexane-1,3diones 5b and 5c exhibited similar activity as 5a. Tolerance of the medium cycle was demonstrated by the conversion of cycloheptane-1,3-dione 5d to 6ad. Additionally, acyclic 1,3dicarconyl compounds 5e and 5f were found to be suitable substrates and similar levels of reaction performance were observed. Notably, β-carbonyl esters 5g and 5h also reacted well with allenoate 1a, delivering 6ag and 6ah with excellent ee. The compatibility of a 1,3-dicarbonyl substrate was further illustrated by the reactions of lactone 5i with allenoates 1a and B
DOI: 10.1021/acs.orglett.7b00658 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 1p. Although acyclic 3-oxo-amide was inert under the standard conditions, piperidine-2,4-dione 5j was able to react with 1a, affording 6aj in 73% yield and 94% ee. It was noteworthy that allenoate 7 was alternatively obtained when dimethyl malonate was used as a substrate (eq 1). Due to
Scheme 6. Roles of Catalyst 4g (E = CO2Et)
the lower activity of dimethyl malonate, an elevated reaction temperature (30 °C) was required. Remarkably, this reaction still maintained good enantioselectivity. Upon treatment of aqueous KOH (20 mol %), compound 7 could be converted into 4H-pyran 8 in 90% yield and with 76% ee (eq 1). On the basis of these results and our previous work,12 we proposed a possible mechanism as outlined in Scheme 5. The
Scheme 7. Synthetic Application
Scheme 5. Proposed Mechanism (E = CO2Et)
reaction is initiated by an addition−elimination process between allenoate 1a and an amine catalyst, leading to cationic intermediate A. Then, with the help of a base additive, 1,6addition of 2 to A results in the generation of intermediate B, which is followed by 1,2-elimination of the amine catalyst to generate allenoate C. With the assistance of a base, intramolecular oxa-Michael addition occurs in a 6-trig-exo manner to give 4H-pyran 3, thus furnishing a formal (3 + 3) annulation. To probe the underlying role of H-bond donor of catalyst 4g, we conducted the reactions of 1k with CD3CO2D in the presence of different amine catalysts (Scheme 6a). The use of 4g (20 mol %) offered compound 1k-D with 30% acetoxy group exchange. This result strongly implied that the addition− elimination process toward the formation of cationic intermediate A is reversible. In sharp contrast, this event did not happen in the case of either DABCO or 4a. These results clearly revealed the unique role of amide NH group of 4g (Scheme 6b). The amide NH would interact with allenoate 1 via H-bonding, which not only activates allenoate but also enables the attack of the amine catalyst in a pseudointramolecular manner,13 thus facilitating the generation of cationic intermediate A. This may be the reason for the high activity of catalyst 4g. Moreover, the H-bonding would be also able to significantly enhance the electrophilicity of δC of C. This effect eventually makes the attack of AcO− operative, which accounts for the reversible reaction of 1k and 4g. To demonstrate the synthetic utility of this (3 + 3) annulation, we targeted compound 12, a tricyclic core of calyxin I (Scheme 7). This natural product has attractive
bioactivities, but no total synthesis has been reported to date.14 We believe that the development of an efficient approach to calyxin I analogues would be useful for structure−activity relationship studies.15 Treatment of 6mg with Pd/C in H2 (1 atm) led to pyran 9 as a single isomer in 80% yield. After deprotection of the MOMO group, compound 1011 was obtained via lactonization with the help of TFA. While the configuration of C3 is opposite to that of calyxin I, the epimerization was achieved via the isomerization/lactone opening and relactonization processes, giving compound 12 in 95% yield (over two steps) and 90% ee (Scheme 7). In summary, we have developed the 4g-catalyzed formal (3 + 3) annulation of δ-acetoxy allenoate 1 with a 1C,3Obisnucleophile, which provides a facile access to 4H-pyran with excellent enantioselectivity. The crucial roles of amide NH of 4g as a H-bond donor have been elucidated, which not only facilitate the formation of cationic intermediate A but also enhance the electrophilicty of its δ-position. We anticipate that the findings presented in this work will foster further exploration of the Lewis base catalyzed allenoate annulation via a cationic intermediate.16
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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.7b00658. C
DOI: 10.1021/acs.orglett.7b00658 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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J. Am. Chem. Soc. 2008, 130, 12596. (c) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (11) The crystallographic coordinates of 3hh and 10 have been deposited with the deposition numbers CCDC 1533837 and 1533840, respectively. These data can be obtained from the Cambridge Crystallographic Data Centre, at
[email protected]. (12) (a) Hu, J.; Dong, W.; Wu, X.-Y.; Tong, X. Org. Lett. 2012, 14, 5530. (b) Gu, Y.; Li, F.; Hu, P.; Liao, D.; Tong, X. Org. Lett. 2015, 17, 1106. (c) Zhao, H.; Meng, X.; Huang, Y. Chem. Commun. 2013, 49, 10513. (13) Mbofana, C. T.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 3285. (14) (a) Gewali, M. B.; Tezuka, Y.; Banskota, A. H.; Ali, M. S.; Saiki, I.; Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733. (b) Ali, M. S.; Banskota, A. H.; Tezuka, Y.; Saiki, I.; Kadota, S. Biol. Pharm. Bull. 2001, 24, 525. (15) (a) Ackrill, T. D.; Sparkes, H. A.; Willis, C. L. Org. Lett. 2015, 17, 3884. (b) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912. (c) Reddy, B. V. S.; Reddy, M. R.; Reddy, S. G.; Sridhar, B.; Kumar, S. K. Eur. J. Org. Chem. 2015, 2015, 3103. (d) Cakir, S. P.; Stokes, S.; Sygula, A.; Mead, K. T. J. Org. Chem. 2009, 74, 7529. (16) (a) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550. (b) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 5643. (c) Ziegler, D. T.; Riesgo, L.; Ikeda, T.; Fujiwara, Y.; Fu, G. C. Angew. Chem., Int. Ed. 2014, 53, 13183. (d) Kramer, S.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 3803. (e) Li, K.; Hu, J.; Liu, H.; Tong, X. Chem. Commun. 2012, 48, 2900. (f) Gu, Y.; Hu, P.; Ni, C.; Tong, X. J. Am. Chem. Soc. 2015, 137, 6400.
General procedures, data and NMR spectra of products (PDF) X-ray data for compound 3hh (CIF) X-ray data for compound 10 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xiaofeng Tong: 0000-0002-6789-1691 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is supported by the NSF (21472042), Jiangsu Province Funds for Distinguished Young Scientists (BK20160005), and Qing-Lan Project. We are also grateful to Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00658 Org. Lett. XXXX, XXX, XXX−XXX
