Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalyst- and Substituent-Controlled Switching of Chemoselectivity for the Enantioselective Synthesis of Fully Substituted Cyclobutane Derivatives via 2 + 2 Annulation of Vinylogous Ketone Enolates and Nitroalkene Pavan Sudheer Akula,† Bor-Cherng Hong,* and Gene-Hsiang Lee‡ †
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, Republic of China Instrumentation Center, National Taiwan University, Taipei 106, Taiwan, Republic of China
Org. Lett. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 12/10/18. For personal use only.
‡
S Supporting Information *
ABSTRACT: The first regioselective, diastereoselective, and enantioselective organocatalyzed Michael−Michael cascade of vinylogous ketone enolates and nitroalkenes for the construction of fully substituted cyclobutanes is achieved by the deployment of the appropriate chiral squaramide catalyst and the pertinent substituent on the substrate. The domino reaction provided cyclobutanes with four contiguous stereocenters, including a quaternary center in good yields with diastereomeric ratio of >20:1 and with enantioselectivities of mostly up to 98% enantiomeric excess (ee). The structures and the absolute configurations of the adducts were confirmed by single-crystal X-ray crystallographic analyses of the appropriate products.
C
with iminium catalysis for the synthesis of chiral cyclobutanes with subsequent ring expansion to give cyclopentanone derivatives.5 In mechanistic studies of the organocatalytic Michael addition of aldehydes to nitroalkenes, the research groups of Blackmond, Seebach, and Hayashi revealed a restingstate cyclobutane intermediate. These findings led to thoughtprovoking questions that encouraged the development of new methods in the synthesis of cyclobutanes.6,7 Later, Jørgensen and co-workers designed a bifunctional hydrogen-bonding catalyst for the double activation of α,β-unsaturated aldehydes and nitroalkenes to give cyclobutanes as the products, rather than as reaction intermediates (Scheme 1a).8 Independently, Vicario et al. reported a cooperative catalyzed enantioselective formal [2 + 2] cycloaddition of enal and α-hydroxymethyl nitroalkene, with the catalyst cocktail of arylprolinol ether and thiourea (Scheme 1b).9 To achieve this reaction, two types of catalysts produced a synergistic catalysis, with the driving force arising from the hemiacetal formation. Extending the discoveries from these early investigations, a series of ingenious examples of enantioselective synthesis have been presented.10 However, attempts to apply these strategies to other reactant analogues afforded acyclic products instead of cyclobutanes. For example, the reaction of allylic ketone and cinnamaldehyde
yclobutane derivatives stand out for their unique scaffolds in naturally occurring compounds1 and have long been of interest to chemists, especially as a molecular building block for subsequent transformations (Figure 1).2
Figure 1. Selected natural products and therapeutic agents containing chiral cyclobutanes.
While most of the direct synthetic methods give rise to racemic cyclobutanes, only a few instances of metal-catalyzed3 or photochemical4 enantioselective approaches have been realized. The pioneering work of Ishihara and his co-workers described the organocatalytic enantioselective [2 + 2] cycloaddition of unactivated alkenes and α-acyloxyacroleins © XXXX American Chemical Society
Received: October 18, 2018
A
DOI: 10.1021/acs.orglett.8b03335 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Table 1. Screening of Conditions for the Reactionsa
Scheme 1. Organocatalytic α/γ-Alkylations
entry
1, 2
catalyst
time, t (h)
1 2 3 4 5 6 7 8 9 10 11j 12k 13l 14m
1a, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2b 1b, 2a 1a, 2a 1a, 2a 1a, 2a 1a, 2a
A B C D E F G H F F F F F F
24 24 22 14 20 8 10 20 8 30 12 13 18 48
3:4
yield of 3 (%)c
yield of 4c (%)
ee of 4d (%)
nde naf 39:61 28:72 36:64 6:94 9:91 19:81 25:75 80:(20)i 12:82 11:89 11:89 9:91
20:1, and only one diastereomer in each reaction was observed. The structures of (+)-4a, (+)-4e, (+)-4i, and (+)-4j, including their absolute stereochemistry, were explicitly revealed by their single-crystal X-ray diffraction analyses and the stereo plots of the X-ray crystal analyses are illustrated in Figure 2.18 To account for the regioselectivity and stereoselectivity, we propose a plausible mechanism (Scheme 2). The initial
entry
product
1 2
4a: R1 = H; R2 = H; R3 = Ph; R4 = Me 4d: R1 = H; R2 = H; R3 = 4-BrC6H4; R4 = Me 4e: R1 = H; R2 = H; R3 = 4-FC6H4; R4 = Me 4f: R1 = H; R2 = H; R3 = 3-BrC6H4; R4 = Me 4g: R1 = H; R2 = H; R3 = 4-ClC6H4; R4 = Me 4h: R1 = H; R2 = H; R3 = 4-MeOC6H4; R4 = Me 4i: R1 = H; R2 = H; R3 = 2-ClC6H4; R4 = Me 4j: R1 = H; R2 = H; R3 = 2-BrC6H4; R4 = Me 4k: R1 = H; R2 = H; R3 = 4-NO2C6H4; R4 = Me 4l: R1 = Br; R2 = H; R3 = Ph; R4 = Me 4m: R1 = Cl; R2 = H; R3 = 4-NO2C6H4; R4 = Me 4n: R1 = H; R2 = H; R3 = PhCH2CH2; R4 = Me 4o: R1 = H; R2 = H; R3 = n-Bu; R4 = Me 4p: R1 = H; R2 = OMe; R3 = Ph; R4 = Me 4q: R1 = H; R2 = F; R3 = Ph; R4 = Me 4r: R1 = H; R2 = H; R3 = Ph; R4 = Et
3 4 5 6 7 8 9 10 11 12 13 14 15 16
time, t (h)
yieldb,c (%)
eed (%)
8 12
93 89
98 98
10
90
98
10
90
98
10
92
98
14
89
98
10
92
98
10
93
96e
10
93
98
14 14
87 93
93e 98e
16
66
98e
16
54
99e
10
95
98
10 12
89 87
98 98
a
Unless otherwise noted, the reactions were performed on a 0.45 M scale of 1 (1.5 equiv) and 2 (1.0 equiv) in CH2Cl2 at rt (25−30 °C) and in the indicated time. bIsolated yields of 4. cdr >20:1, determined by 1H NMR of the crude reaction mixture. dUnless otherwise addressed, the ee of 4 was analyzed by HPLC with Chiralpak IC. eThe ee was analyzed with Chiralpak IA.
Figure 2. Stereo plots of the X-ray analyses of (+)-4a, (+)-4e, (+)-4i, and (+)-4j. [Legend: C, gray; O, red; N, blue; F, chartreuse; Cl, green; Br, purple.]
enolization of enone 1a with catalyst F occurs through the squaramide hydrogen-bonding activation and the protonation process of the quinuclidine moiety (TS A). Subsequent conjugate addition of enolized 1a to nitroalkene 2a occurs via the squaramide-amine-activated process (TS B), in which the γ-alkylation of 1a occurs. It is noteworthy that replacing the substituent on the nitroolefin, from 2b to 2a (where H was replaced by Me), altered the nature of the electrophile 2 and governed the γ-alkylation of 1a toward 2a to render the intermediate C, instead of the α-alkylation of 1a to produce the α-branched ketone 3a, as well as the subsequent intramolecular nitro-Michael cyclization of C. The stereomodel presented in the frame above TS B invoked an alternative view to elucidate C
DOI: 10.1021/acs.orglett.8b03335 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
52% yields, respectively, with high diastereoselectivity (>20:1) and enantioselectivity (98% ee) of 4s obtained. (See Figure 3.) In summary, the efficient organocatalytic enantioselective [2 + 2] cycloaddition of enones to nitroolefins was realized with high diastereoselectivities (>20:1), enantioselectivities (93%− 99% ee), and excellent yields. Unlike the previous examples of enantioselective [2 + 2] cycloaddition of enals and nitroolefins with the usage of secondary amine organocatalysts, this current enantioselective [2 + 2] cycloaddition of enone and nitroalkene occurred with the aid of the hydrogen-bonding process and the bifunctional squaramide catalyst. Our study revealed that the dichotomous regioselectivity (α vs γ) of vinylogous ketone to nitroolefin was governed by a few factors, including the organocatalysts, the substituents on the nitroolefin, and the substituents on the vinylogous carbonyl compounds. With the appropriate and dexterous arrangement of these elements, the γ-alkylation of the vinylogous ketone to nitroolefin becomes feasible, as does the subsequent cyclization to render the [2 + 2] cycloaddition adducts. This domino reaction not only contributes a concise method for the synthesis of highly substituted cyclobutanes, but also manifests an example of deploying suitable catalysts and substituents in cascade reactions that would be otherwise unattainable. The cyclobutanes prepared are relatively stable and are adequate for further transformation, even at elevated temperatures, e.g., with SeO2 at 100 °C for prolonged reaction times. The structures of some products were explicitly determined by X-ray crystallographic analyses. Furthermore, an unprecedented isomerization of (E)-nitrostyrene 2a to (Z)-2a with a household compact fluorescent light in the absence of catalyst has been revealed in this study. Given the limited examples of the highly enantioselective synthesis of highly substituted cyclobutanes,21 this cascade asymmetric reaction method could provide a valuable contribution to chemical synthesis.
Scheme 2. Plausible Reaction Mechanism
the observed stereoselectivity. Accordingly, the succeeding nitro-Michael addition of the intermediate C delivered the cyclobutane product 4a and regenerated catalyst F to continue the reaction cycle. On the other hand, direct asymmetric addition of esters or the related carboxylic acid derivatives to π electrophiles persists to be a troublesome task; in this context, Palomo and his coworkers developed a method by using α-hydroxy ketones as the masked ester donors in the Brønsted-base-catalyzed conjugate additions to nitroalkenes.20 Here, we envisioned that the phenylethanonyl moiety in the cyclobutane 4 could be considered as the masked ester and the transformation process would be of interest. Accordingly, ketocyclobutane 4a was treated with SeO2 and acetic acid in dioxane−H2O (100 °C) for 18 h, affording diketone 5a in 57% yield (Figure 3).
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03335. Experimental procedures and characterization data for the new compounds (PDF) Figure 3. Other transformations of the cyclobutane products.
Accession Codes
CCDC 1868867, 1868868, 1868869, 1868870 contains 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 data_
[email protected],or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
Oxidation of 5a with Pb(OAc) 4 in MeOH at room temperature for 2 h provided ester 6a in 80% yield. In addition, some of the cyclobutane amino acids have been used for clinical trials. For example, mirogabalin is in Phase-III clinical trial for the treatment of diabetic peripheral neuropathic pain, renal impairment, postherpetic neuralgia, etc. Fluciclovine (18F) is being used for a Phase-III clinical trial in the treatment of prostate cancer (Figure 1). Accordingly, 4a and 6a were individually reduced with zinc powder in HOAc− H2O at room temperature for 24−15 h to give aminobutanes 7a and 8a in 78% and 73% yields, respectively. Lately, oxidation of 4a with m-CPBA and TFA in CH2Cl2 afforded 88% yield of ester 9a. For further extension of the functionality in the system, the reaction of the ester-substituted nitroolefin (2n) and 1e with catalyst F was scrutinized, and a ratio of 4s/ 3s was found to be 44:56 from the crude 1H NMR analysis (Figure 3). Compounds 4s and 3s were isolated in 34% and
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Bor-Cherng Hong: 0000-0002-4623-3366 Notes
The authors declare no competing financial interest. D
DOI: 10.1021/acs.orglett.8b03335 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
■
(15) Iriarte, I.; Olaizola, O.; Vera, S.; Gamboa, I.; Oiarbide, M.; Palomo, C. Angew. Chem., Int. Ed. 2017, 56, 8860. (16) (a) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253−281. (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. - Eur. J. 2011, 17, 6890. (c) Held, F. E.; Tsogoeva, S. B. Catal. Sci. Technol. 2016, 6, 645. (17) (Z)-2-Nitro-1-phenylpropene was reported to be obtained in a 1:1 ratio of (Z)- and (E)- isomeric mixtures from the UV irradiation of (E)-2-nitro-1-phenylpropene with a Hanau high-pressure mercury lamp (UV lamp) in petroleum ether; see: Pennings, M. L.; Reinhoudt, D. N. J. Org. Chem. 1982, 47, 1816−1823 Nevertheless, the isomerization of the nitroalkenes with the aid of household CFL has not been previously realized . (18) See the Supporting Information for details. (19) For recent examples of visible-light induced photoisomerization of alkenes, see: (a) Metternich, J. B.; Sagebiel, S.; Lueckener, A.; Lamping, S.; Ravoo, B. J.; Gilmour, R. Chem. - Eur. J. 2018, 24, 4228. (b) Cai, W.; Fan, H.; Ding, D.; Zhang, Y.; Wang, W. Chem. Commun. 2017, 53, 12918. (c) Metternich, J. B.; Gilmour, R. Synlett 2016, 27, 2541. (d) Zhan, K.; Li, Y. Catalysts 2017, 7, 337. (20) Olaizola, I.; Campano, T. E.; Iriarte, I.; Vera, S.; Mielgo, A.; García, J. M.; Odriozola, J. M.; Oiarbide, M.; Palomo, C. Chem. - Eur. J. 2018, 24, 3893. (21) For reviews, see: (a) Wang, M.; Lu, P. Org. Chem. Front. 2018, 5, 254. (b) Xu, Y.; Conner, M. L.; Brown, M. K. Angew. Chem., Int. Ed. 2015, 54, 11918. For recent examples, see: (c) Zhong, X.; Tang, Q.; Zhou, P.; Zhong, Z.; Dong, S.; Liu, X.; Feng, X. Chem. Commun. 2018, 54, 10511. (d) See ref 4d. (e) Kossler, D.; Cramer, N. Chem. Sci. 2017, 8, 1862.
ACKNOWLEDGMENTS We acknowledge financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the Instrument Center of MOST for analyses of the compounds.
■
REFERENCES
(1) (a) Beniddir, M. A.; Evanno, L.; Joseph, D.; Skiredj, A.; Poupon, E. Nat. Prod. Rep. 2016, 33, 820−842. (b) Dembitsky, V. M. Phytomedicine 2014, 21, 1559. (c) Hong, Y. J.; Tantillo, D. J. Chem. Soc. Rev. 2014, 43, 5042. (d) Dembitsky, V. M. J. Nat. Med. 2007, 62, 1. (2) (a) Poplata, S.; Tröster, A.; Zou, Y.-Q.; Bach, T. Chem. Rev. 2016, 116, 9748. (b) Xu, Y.; Conner, M. L.; Brown, M. K. Angew. Chem., Int. Ed. 2015, 54, 11918. (c) Secci, F.; Frongia, A.; Piras, P. P. Molecules 2013, 18, 15541. (d) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (e) The Chemistry of Cyclobutanes, Rappoport, Z.; Liebman, J. F., Eds.; Wiley: Chichester, U.K., 2005. (f) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (g) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (h) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003. (3) (a) Pagar, V. V.; RajanBabu, T. V. Science 2018, 361, 68. (b) Conner, M. L.; Xu, Y.; Brown, M. K. J. Am. Chem. Soc. 2015, 137, 3482. (c) Hu, J.-L.; Feng, L.-W.; Wang, L.; Xie, Z.; Tang, Y.; Li, X. J. Am. Chem. Soc. 2016, 138, 13151. (d) Panish, R.; Chintala, S. R.; Boruta, D. T.; Fang, Y.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2013, 135, 9283. (e) Suarez-Pantiga, S.; Hernandez-Díaz, C.; Rubio, E.; González, J. M. Angew. Chem., Int. Ed. 2012, 51, 11552. (f) Hayashi, Y.; Narasaka, K. Chem. Lett. 1989, 18, 793. (g) Hayashi, Y.; Niihata, S.; Narasaka, K. Chem. Lett. 1990, 19, 2091. (h) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am. Chem. Soc. 1992, 114, 8869. (4) (a) Yagishita, F.; Sakamoto, M.; Mino, T.; Fujita, T. Org. Lett. 2011, 13, 6168. (b) Müller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.; Miranda, M. A.; Bach, T. J. Am. Chem. Soc. 2011, 133, 16689. (c) Coote, S. C.; Pöthig, A.; Bach, T. Chem. - Eur. J. 2015, 21, 6906. (d) Miller, Z. D.; Lee, B. J.; Yoon, T. P. Angew. Chem., Int. Ed. 2017, 56, 11891. (5) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930. (6) (a) Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2011, 133, 8822. (b) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719. (c) Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 6741. (7) Parra, A.; Reboredo, S.; Alemán, J. Angew. Chem., Int. Ed. 2012, 51, 9734. (8) Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.; Davis, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543. (9) Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo, L. Angew. Chem., Int. Ed. 2012, 51, 4104. (10) (a) Nielsen, A. J.; Jenkins, H. A.; McNulty, J. Chem. - Eur. J. 2016, 22, 9111. (b) Duan, G.-J.; Ling, J.-B.; Wang, W.-P.; Luo, Y.-C.; Xu, P.-F. Chem. Commun. 2013, 49, 4625. (11) For review: (a) Yin, Y.; Jiang, Z. ChemCatChem 2017, 9, 4306. (b) Schneider, C.; Abels, F. Org. Biomol. Chem. 2014, 12, 3531. (c) Chauhan, P.; Kaya, U.; Enders, D. Adv. Synth. Catal. 2017, 359, 888. (12) (a) Rout, S. R.; Joshi, H.; Singh, V. K. Org. Lett. 2018, 20, 2199. (b) Mondal, S.; Mukherjee, S.; Yetra, S. R.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2017, 19, 4367. (c) Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D. J. Nat. Commun. 2014, 5, 4479. (d) Chen, X.-Y.; Liu, Q.; Chauhan, P.; Li, S.; Peuronen, A.; Rissanen, K.; Jafari, E.; Enders, D. Angew. Chem., Int. Ed. 2017, 56, 6241. (13) Gu, Y.; Wang, Y.; Yu, T.-Y.; Liang, Y.-M.; Xu, P.-F. Angew. Chem., Int. Ed. 2014, 53, 14128. (14) Guo, Q.; Fraboni, A. J.; Brenner-Moyer, S. E. Org. Lett. 2016, 18, 2628. E
DOI: 10.1021/acs.orglett.8b03335 Org. Lett. XXXX, XXX, XXX−XXX
