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Dianionic Phase-Transfer Catalyst for Asymmetric Fluorocyclization Hiromichi Egami, Tomoki Niwa, Hitomi Sato, Ryo Hotta, Daiki Rouno, Yuji Kawato, and Yoshitaka Hamashima J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13690 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 9, 2018
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Journal of the American Chemical Society
Hiromichi Egami,† Tomoki Niwa,† Hitomi Sato,† Ryo Hotta,† Daiki Rouno,† Yuji Kawato,† and Yoshitaka Hamashima*† †
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Supporting Information Placeholder ABSTRACT: Inspired by the dicationic nature of the
electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of di-carboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluorocyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic tri-substituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear di-substituted alkenes. Results suggest that the reaction proceeds via a fluorocarbocation intermediate.
a. Asymmetric fluorolactonization precatalyst Selectfluor (1) Na 3PO 4, Na 2SO 4 R1
R2
cyclohexane, rt
CO2H
Ar
F R2 R1
Cl N+ 2BF 4– N+ F Selectfluor (1)
OH
O
CO 2H
O Ar up to 94% ee
precatalyst
b. Active complex and the basic design of di-anion catalysts R
O– Ar
R
O
H
O
O CO2 – Ar
Cl
F N+ + N
–O
O CO2 – N+
Cl
2C
N+ F R
R
Phase-transfer activity mono-anion < formal di-anion
Forming two ionic pairs between the designed catalyst and Selectfluor
c. This work: 6-endo fluorocyclization of allylic amides
Fluorinated compounds have found extensive applications in pharmaceutical, agrochemical, and materials sciences.1 Many methods for the introduction of fluorine atoms into organic frameworks have been reported.2 In particular, asymmetric fluorofunctionalization of alkenes has attracted much attention, because it is a powerful approach to obtain structurally diverse fluorinated compounds.3 However, stereoselective fluorination of alkenes is still challenging, although cinchona alkaloidderived chiral fluorinating reagents4 and chiral hypervalent iodine reagents5 have been studied. Following Toste’s pioneering work,6,7 we became interested in anionic phase-transfer catalysis for enantioselective fluorination. We recently reported the first successful example of enantioselective fluorolactonization of ene-carboxylic acids with a carefully designed hydroxyl-carboxylic acid precatalyst (Figure 1a).8 Upon deprotonation in-situ, the carboxylate ion of the active catalyst acts as a phase-transfer unit to form an ion pair with Selectfluor (1), whilst the hydroxyl group interacts with the anionic substrate to define its position (Figure 1b, left).
O R1
R2 Ph
R3
N H
n O O CO 2H HO 2C
Ph
Ph
2a: n = 1 2b: n = 2 2c: n = 3
O
N up to 99% ee
toluene
Ph
R3
precatalyst 2 Selectfluor (1) base R1
R2 F R1
R1
O O CO 2H HO 2C R2
R2
2d: R1 = H, R 2 = Ph 2e: R1 = H, R 2 = H
Figure 1. Background and our design strategy for novel dicarboxylate catalysts
Mechanistic studies of the fluorolactonization8 strongly indicated that a binary complex between the catalyst and the substrate anion is responsible for bringing 1 into the organic phase (Figure 1b, left). This observation prompted us to think that the cooperative action of two carboxylate anions located at an appropriate separation distance would achieve high reaction efficiency.9 Based on this hypothesis, we designed dicarboxylic acid precatalysts 2 (Figure 1c), which would form a series of linked dicarboxylate catalysts (Figure 1b, right). Even
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though the designed catalysts are conformationally flexible, we envisaged that the two-point ionic pairing of the catalyst with 1 would form a well-defined chiral environment. Based on our halogenation project regarding bromocyclization reactions of allylic amides,10 we selected fluorocyclization of ene-amides as a model reaction, since the amide has a hydrogen-bonding donor for interaction with a catalyst carboxylate and asymmetric 6-endo-fluorocyclization is unprecedented in the literature.11 Herein, we disclose a highly enantioselective fluorocyclization of allylic amides using designed and novel dianionic phase-transfer catalysts (Figure 1c). The precatalyst 2a was readily synthesized in 5 steps from compound 3 (Scheme 1). Thus, monoprotection of 3,3’-dibromo-BINOL (3) and etherification with 1,3propanediol-ditosylate, followed by acidic hydrolysis, provided linked-BINOL derivative 4 in 64% yield over 2 steps. After the introduction of phosphate groups, all bromine atoms were replaced with phenyl groups. Finally, reductive carboxylation with lithium-naphthalenide12 furnished the desired diacid 2a in 69% yield.
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base depends on the nature of the substrate, since Na2HPO4 gave slightly better results for 5a (entry 9). Table 1. Catalyst Screeninga
precatalyst
yield (%)b
ee (%)c
1
2a
87
93
2
2b
75
64
3
2c
76
87
4
2d
84
33
5
entry
2e
37
40
6
9
48
–17
7
10
44
–55
8
11
84
–68
d
2a
95
95
10
2a
58e
89 / 96f
11
9
5g
–9 / - f
12
10
6g
–20 / –40 f
13
11
trace
-
14h
2a
76e
93 / 98 f
9
Scheme 1. Preparation of 2a
In order to identify the optimum catalyst, fluorination reactions of chromene derivative 5a were carried out in toluene using Na3PO4 as an insoluble base (Table 1). To our delight, 2a promoted the desired reaction smoothly to give 6a in 87% yield with 93% ee as a single diastereomer (entry 1). The length of the methylene linker affected the reaction efficiency, revealing that the C3 linker gave the best results (entries 2 and 3). Both the chemical yield and the enantioselectivity decreased significantly when 2d and 2e were used, revealing that full substitution at the 3,3’-positions of the catalyst is essential for this reaction (entries 4 and 5). Interestingly, previously known precatalysts7,8 were less effective. Binaphthyl dicarboxylic acid 9 provided the product with only 17% ee (entry 6). Hydroxyl-carboxylic acid 10 and phosphoric acid 11 were also examined, and again, lower enantioselectivities were observed (entries 7 and 8). These control experiments supported our working hypothesis regarding the optimum ionic valency within the catalyst as well as the distance between the ionic parts. Further optimization13 revealed that the optimum
a
The reactions were carried out with precatalyst, 1, Na3PO4 in toluene (1 mL) on a 0.1 mmol scale, unless otherwise mentioned. b Yields were determined by 1H NMR analysis using 1,1,2,2,-tetrabromoethane as an internal standard. c Ee values were determined by chiral HPLC analysis. d Run with Na2HPO4 instead of Na3PO4. e Diastereomer ratio was 1:1. f Ee values of each diastereomers. g Diastereomer ratio was 2:1. h Run with Na2SO4.
Notably, reactions of less reactive acyclic substrate 7a clearly demonstrated that 2a is superior to other known catalysts (entries 10-13). For example, phosphoric acid 11 was totally ineffective (entry 13). As found in our previous study,8 the addition of Na2SO4 was effective for accelerating the fluorination of 7a (entry 14). Although the diastere-
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Journal of the American Chemical Society omer ratio was almost 1:1, the enantioselectivity was excellent for both diastereomers (vide infra).
Table 2. Fluorination of Cyclic Allylic Amidesa
applicable, and high asymmetric induction was observed (6k-6n). It should be noted that reactions generally gave complex mixtures when carried out without catalyst and in MeCN. This observation emphasizes the use of phasetransfer conditions as crucial for this type of fluorination reaction. Table 3. Fluorination of Acyclic Substratesa
a
Condition A: The reaction was carried out with 2a, 1, Na2HPO4 at 15 °C in toluene for 72 h. Condition B: The reaction was carried out with 2a, 1, Na3PO4 and Na2SO4 at 25 °C in toluene for 24 h. b Run with 20 mol % of 2a. c Run for 5 d. d Run with 3 equiv. of Na2HPO4.
Having optimized the reaction conditions, we examined the generality for cyclic substrates (Table 2). Although minor tuning of the reaction conditions (conditions A or B) was needed depending on the substrate, the desired reaction occurred to give the corresponding fluorinated tricyclic compound as a single diastereomer. In these reactions, various functional groups including ester, ether, benzylic methyl group, and halogens were tolerated. Substituents on the chromene framework did not impact largely on the enantioselectivity (6b-6d). The dimethyl groups of the chromene core were not essential as a stereocontrolling element. Thus, sterically less hindered chromene and dihydronaphthalene substrates also underwent the fluorination reaction with excellent enantioselectivity (6e-6i). In addition to six-membered ring substrates, a five-membered indene derivative was also a good substrate, affording 6j in 63% yield with 93% ee. Furthermore, substituted aryl amide groups were also
a
The conditions were the same as in Table 2. b Determined by NMR analysis of the crude mixture. c Run at 15 °C. d Run for 4 d. e Run for 3 d. f Run for 2 d.
Next, we turned our attention to acyclic alkene substrates. First, di-substituted allylic amides were subjected to the reaction conditions (Table 3a). While the electronic nature of the substituents did not significantly affect the diastereoselectivity, the ee values of these reactions were generally excellent (8a-8e).14 To probe the stereochemistry of the products, Mosher’s ester method was applied after hydrolysis of the dihydrooxazine ring of 8a.13 This revealed that the diastereomers are derived from the stereoisomer at the benzylic position, while the facial selectivity of the fluorination step is well regulated. Coupled with findings in the literature,15 these results suggest that the fluorocyclization proceeds via the formation of a benzylic carbocation intermediate, which undergoes less stereoselective intramolecular C–O bond formation. Based on the above consideration, we expected the stereoselectivity of the cyclization step to be improved if the conformation of the carbocation intermediate was restricted sterically by additional substituents.16 Thus,
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we examined the fluorocyclization of acyclic trisubstituted allylic amides (Table 3b). Gratifyingly, the reactions proceeded with high diastereoselectivity, affording products 8f-8h with a fluorinated quaternary carbon center in up to 99% ee. The reaction was applicable to heteroaromatic compounds (8i-8k). Reduced diastereoselectivity observed for indole and benzofurane derivatives 8i and 8j is attributed to higher stability of the carbocation intermediate. In contrast, thiophene derivative was converted to the cyclized compound 8k with high diastereo- and almost perfect enantioselectivity (dr = 1:8.4, 99% ee). In summary, we have developed a new dianionic phase-transfer catalyst for highly enantioselective 6endo fluorocyclization of allylic amides with Selectfluor. The catalyst was able to control the fluorine-delivery step with high enantioselectivity in all the examples reported herein, indicating that the designed catalyst would be applicable to other types of fluorofunctionalization. Since the obtained compounds are highly functionalized, this method would be useful in synthesizing a variety of fluorinated compounds. Further investigations to expand the scope of the reaction and to elucidate the reaction mechanism are underway in our laboratory.
Supporting Information. Experimental procedures and spectroscopic data. This material is available free of charge via the Internet at http://pubs.acs.org.
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[email protected] The authors declare no competing financial interest.
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This work was supported by a Grant-in-Aid for Scientific Research (B) (No. 16H05077) from JSPS, Basis for Supporting Innovative Drug Discovering and Life Science Research (BINDS) from AMED, the Naito Foundation (Japan), The Research Foundation for Pharmaceutical Sciences, and The FUGAKU Trust for Medicinal Research. We thank Prof. Kenji Watanabe and Dr. Yuta Tsunematsu of University of Shizuoka for their kind help for mass spectrometry analysis.
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim, 2013. (b) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
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Wiley-Blackwell: Oxford, 2009. (c) Gouverneur, V.; Müller, K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications; Imperial College Press: London, 2012. (d) Müller, K.; Faeh, C.; Diederich, F. Science, 2007, 317, 1881-1886. (2) (a) Liang, T.; Neumann, C. N.; Ritter T. Angew. Chem. Int. Ed. 2013, 52, 8214-8264. (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826-870. (3) Wolstenhulme, J. R.; Gouverneur, V. Acc. Chem. Res. 2014, 47, 3560-3570. (4) (a) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001-7009. (b) Wang, M.; Wang, B. M.; Shi, L.; Tu, Y. Q.; Fan, C.-A.; Wang, S. H.; Hu, X. D.; Zhang, S. Y. Chem. Commun. 2005, 41, 5580-5582. (c) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed. 2008, 47, 4157-4161. (d) Wilkinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M. C.; Salmon, R., Gouverneur, V. Angew. Chem. Int. Ed. 2009, 48, 7083-7086. (e) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.; Ilupeji, J.; Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.; Gouverneur, V. Angew. Chem. Int. Ed. 2013, 52, 9796-9800. (5) (a) Kong, K.; Feige, P.; de Haro, T.; Nevado, C. Angew. Chem. Int. Ed. 2013, 52, 2469-2473. (b) Molnár, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 5004-5007. (c) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 5000-5003. (d) Woerly, E. M.; Banik, S. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 13858-13861. (6) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681-1684. (7) (a) Phipps, R. J.; Hiramatsu, K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 8376-8379. (b) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268-1271. (c) Wu, J.; Wang, Y.-M.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.; Toste, F. D. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 13729-13733. (d) Zi, W.; Wang, Y.-M.; Toste, F. D. J. Am. Chem. Soc. 2014, 136, 12864-12867. (e) Romanov-Michailidis, F., Guénée, L.; Alexakis, A. Angew. Chem. Int. Ed. 2013, 52, 92669270. (f) Liang, X.-W.; Liu, C.; Zhang, W.; You, S.-L. Chem. Commun. 2017, 53, 5531-5534. (8) Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.; Hamashima, Y. J. Am. Chem. Soc. 2015, 137, 10132-10135. (9) Toste proposed a 1:2 assembly between Selectfluor and chiral phosphate catalysts. See references 6 and 7. (10) (a) Kawato, Y.; Kubota, A.; Ono, H.; Egami, H.; Hamashima, Y. Org. Lett. 2015, 17, 1244-1247. (b) Kawato, Y.; Ono, H.; Kubota, A.; Nagao, Y.; Morita, N.; Egami, H.; Hamashima, Y. Chem. Eur. J. 2016, 22, 2127-2133. (c) Nagao, Y.; Hisanaga, T.; Egami, H.; Kawato, Y.; Hamashima, Y. Chem. Eur. J. 2017, 23, 16758-16762. (11) Shunatona, H. P.; Früh, N.; Wang, Y.-M.; Rauniyar, V.; Toste, F. D. Angew. Chem. Int. Ed. 2013, 52, 7724-7727. (12) Egami, H.; Sato, K.; Asada, J.; Kawato, Y.; Hamashima, Y. Tetrahedron 2015, 71, 6284-6388. (13) See Supporting Information. (14) The ee values between the diastereomers are generally different, probably because a kinetic resolution of the fluorocarbenium ion intermediate occurs during the cyclization step. (15) (a) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Bull. Chem. Soc. J. 1996, 69, 169-175. (b) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Tetrahedron 2000, 56, 1929-1936. (c) Zupan, M.; Skulj, P.; Stavber, S. Tetrahedron 2001, 57, 10027-10031. (d) Olah, G. A.; Prakash, G. K. S.; Rasul, G. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 8427-8430. (16) (a) Mühlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005, 127, 9348-9349. (b) Sparr, C.; Gilmour, R. Angew. Chem. Int. Ed. 2010, 49, 6520-6523.
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