Catalytic Enantioselective Decarboxylative Mannich-Type Reaction of

Letter Cite This: Org. Lett. 2018, 20, 5393−5397

pubs.acs.org/OrgLett

Catalytic Enantioselective Decarboxylative Mannich-Type Reaction of N‑Unprotected Isatin-Derived Ketimines Masanao Sawa, Shotaro Miyazaki, Ryohei Yonesaki, Hiroyuki Morimoto,* and Takashi Ohshima* Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Org. Lett. 2018.20:5393-5397. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/08/18. For personal use only.

S Supporting Information *

ABSTRACT: The first catalytic enantioselective decarboxylative Mannich-type reaction of N-unprotected ketimines is reported, directly providing N-unprotected 3-tetrasubstituted 3-aminooxindoles in high yield and ee without protection/deprotection steps. The utility of this reaction is demonstrated in the short step synthesis of (+)-AG-041R.

C

A promising approach to streamlining the synthesis is to use Nunprotected ketimines,5−7 which can directly provide Nunprotected amines without additional protection/deprotection steps (Scheme 1, eq 2).8 Nevertheless, reported catalytic enantioselective Mannich-type reactions of N-unprotected ketimines are limited to N-unprotected trifluoromethyl ketimines,9 and, to the best of our knowledge, no application to nonfluorinated N-unprotected ketimines has been reported, presumably due to the limited reactivity of N-unprotected ketimines. To overcome these limitations, we envisioned using a decarboxylative Mannich-type reaction because excluding carbon dioxide could make the addition process irreversible to give the desired products. Although decarboxylative Mannichtype reactions have been reported with N-protected ketimines,10,11 to the best of our knowledge, there are no examples using N-unprotected ketimines as the electrophile. Herein, we report the first catalytic enantioselective decarboxylative Mannich-type reaction of N-unprotected ketimines with β-keto acids and malonic acid half thioesters as the nucleophile, directly affording N-unprotected 3-tetrasubstituted 3-aminooxindoles in high yield and ee (Scheme 1, eq 3). We demonstrated the utility of this method in a short-step synthesis of the gastrin/CCK-B receptor antagonist (+)-AG-041R.12 We selected N-unprotected isatin-derived ketimine 113 as the electrophile because the 3-aminooxindole moiety is important in pharmaceutical chemistry.14 Although the reaction of 1a with βketo acid 2a did not proceed without a catalyst (Table 1, entry 1), the combination of a Lewis acidic metal catalyst and a chiral bis(oxazoline) ligand effectively promoted the decarboxylative

hiral nitrogen-containing compounds are widely distributed in natural products and biologically active molecules.1 One of the most straightforward methods for the synthesis of these compounds is the application of catalytic enantioselective Mannich-type reactions to imines.2 Applying these reactions to ketimines provide optically active amines with tetrasubstituted carbon stereocenters.3 Although many catalytic enantioselective Mannich-type reactions are reported, the use of N-protected imines is necessary in most cases to accommodate the desired reaction pathways with optimal reactivity and selectivity (Scheme 1, eq 1). Therefore, protection/deprotection steps are inevitably required to obtain synthetically useful Nunprotected amines,4 which impedes the more straightforward synthesis of the target molecules. Scheme 1. Catalytic Enantioselective Mannich-Type Reactions of Ketimines

Received: July 23, 2018 Published: August 14, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b02306 Org. Lett. 2018, 20, 5393−5397

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Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Scope of β-Keto Acids

entry

cat.

lig.

solvent

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9e 10 11 12 13 14 15e,g

none Zn(OTf)2 Sc(OTf)3 Fe(OTf)3 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2

none L1 L1 L1 L1 L2 L3 L4 L5 L1 L1 L1 L1 L1 L1

PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl toluene Et2O THF CHCl3 CH2Cl2 CH2Cl2

0 82 78 76 74 67 68 67 70 71 61 63 75 66 (63)f >99 (98)f

− 8 4 0 78 75d 0 66d 65d 32 11 87 84 91 91

a

PhCl was used as a solvent.

Scheme 3. Scope of N-Unprotected Isatin-Derived Ketimines

a

Reaction was carried out at 0.10 mmol scale unless otherwise noted. Determined by 1H NMR analysis of the crude reaction mixture. c Determined by chiral HPLC analysis. dEnantiomer was obtained. e Reaction time was 48 h. fIsolated yield. gReaction was carried out at 0.20 mmol scale. b

Mannich-type reaction. Among the metal catalysts investigated, Cu(OTf)2/L1, the catalyst system used in related decarboxylative aldol reactions,15 gave the desired product 3a with appreciable ee (Table 1, entries 2−5). Next, we screened various bis(oxazoline) ligands and found that phenyl-substituted bis(oxazoline) ligand L1 afforded optimal ee with 2a (Table 1, entries 5−9). We next screened various solvents and found that CH2Cl2 gave 3a with high ee (Table 1, entries 10−14). Finally, extending the reaction time provided 3a in 98% isolated yield and 91% ee (Table 1, entry 15). With the optimized conditions in hand, we examined the scope of β-keto acids 2 (Scheme 2). The reaction of β-keto acids having an electron-donating or -withdrawing group afforded the corresponding products 3b−d in high yield and high ee. βKeto acid having 2-furyl and 2-thienyl groups as well as a 2naphthyl group also gave the products 3e−g in high yield and good ee. In addition, the reaction was applicable to β-keto acids with various alkyl substituents (e.g., methyl, isopropyl, tert-butyl, phenylethyl, cyclohexyl, and cyclopropyl groups), and the corresponding products 3h−m were obtained in good to excellent yield and ee (up to 99% yield and up to 96% ee). We next explored the substrate scope of N-unprotected isatinderived ketimines 1 (Scheme 3). First, we investigated the reaction of N-unprotected ketimines bearing substituents at the 5-position. The reactions proceeded smoothly with not only electron-rich ketimines but also electron-deficient ketimines to give the corresponding products 3n−q in high yield and ee. We then examined ketimines having a chloro substituent at other positions. A chloro substituent was tolerated at the 4-position

a

The result at 0.50 mmol scale. bReaction time was 96 h.

and the 6-position, affording products 3r and 3s in high yield and high ee. Although a longer reaction time was required, ketimine bearing a chloro substituent at the 7-position gave the corresponding product 3t in good yield and ee. The absolute configuration of product 3p was unambiguously determined to be (S) by single-crystal X-ray diffraction analysis after derivatization.16 To demonstrate the utility of this reaction, we performed a short-step synthesis of (+)-AG-041R, a gastrin/CCK-B receptor antagonist (Scheme 4). Although previous enantioselective approaches toward (+)-AG-041R demonstrated the effectiveness of their catalytic methodologies,17 longer synthetic steps were often required due to the protecting group manipulations of the amino group. To streamline the synthesis, we envisioned that (+)-AG-041R would be accessible from Mannich adduct 5, which could be prepared from N-unprotected ketimine 1a and malonic acid half thioester 4, a donor of an acetic acid equivalent.15 To our delight, malonic acid half thioester 4a (R4 = Ph) and 4b (R4 = Bn) gave the desired product 5a and 5b in good yield and ee under the reaction conditions with a slight modification of the ligand and solvent, and the reaction of 5a could be scaled up to 1 mmol.16 Transformation of 5a with p-tolyl 5394

DOI: 10.1021/acs.orglett.8b02306 Org. Lett. 2018, 20, 5393−5397

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Organic Letters Scheme 4. Short-Step Synthesis of (+)-AG-041R

Scheme 5. Preliminary Mechanistic Studies

a

The result at 1.0 mmol scale.

isocyanate gave urea 6, which is a known intermediate for the synthesis of (+)-AG-041R,17d in 94% yield. Following the three additional steps reported in the literature, (+)-AG-041R was obtained in only five steps from known 1a with 37% overall yield (82% average yield per step). The absolute configuration was determined to be (R) by comparing the obtained optical rotation value with the value in the literature {AG-041R; [α]27D +27.2 (c 1.02, CHCl3), lit.12a [α]25D +27.9 (c 3.05, CHCl3)}. The above synthetic route was the shortest catalytic enantioselective synthesis of (+)-AG-041R to date from commercially available compounds, due to the strategic use of N-unprotected ketimines established in this study. Finally, preliminary mechanistic studies were performed to elucidate the reaction pathway. The reaction did not proceed either with acetophenone or its trimethylsilyl enol ether under the reaction conditions (Scheme 5, eqs 1 and 2), suggesting that the acid moiety of β-keto acids 2 is indispensable for promoting the reaction and that the addition of 2 to N-unprotected ketimines 1 precedes the decarboxylation process.18 In addition, the retro-reaction of the product 5a was not detected under the reaction conditions (Scheme 5, eq 3), suggesting that the reaction is irreversible after decarboxylation. These results are consistent with the reaction pathway shown in Scheme 5, eq 4, as well as the proposed mechanisms in related decarboxylative reactions.11a,15 Further clarification of the reaction mechanism is ongoing.19 In summary, we developed a catalytic enantioselective decarboxylative Mannich-type reaction of N-unprotected isatin-derived ketimines. With not only β-keto acids, but also malonic acid half thioesters as the nucleophile, the reaction directly afforded N-unprotected 3-tetrasubstituted 3-aminooxindoles in high yield and ee without requiring protection/ deprotection steps. To the best of our knowledge, this is the first example of a catalytic enantioselective decarboxylative addition to N-unprotected ketimines. In addition, we demonstrated the utility of this reaction in a short-step synthesis of (+)-AG-041R using a more straightforward process than previously reported. These results indicate that the substrate scope of N-unprotected ketimines could be expanded using related strategies, and further exploration of the chemistry of N-unprotected ketimines is ongoing in our laboratory.20

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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.8b02306. Experimental details, characterization of compounds and their spectra (PDF) Accession Codes

CCDC 1823903 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.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (for T.O.) *E-mail: [email protected] (for H.M.) ORCID

Hiroyuki Morimoto: 0000-0003-4172-2598 Takashi Ohshima: 0000-0001-9817-6984 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (JSPS KAKENHI Grant Number JP15H05846 in Middle Molecular Strategy for T.O.) and Grant-in-Aid for Scientific Research (B) (JSPS KAKENHI Grant Number JP17H03972 for T.O.) and (C) (JSPS KAKENHI Grant Numbers JP15K07860 and JP18K06581 for H.M.) from JSPS, Basis for Supporting Innovative Drug Discovery and Life 5395

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Organic Letters

Zhao, P. Chem. - Eur. J. 2010, 16, 2619. (e) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8181. (f) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 11098. (g) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 10630. (h) Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int. Ed. 2013, 52, 6681. (i) Morisaki, K.; Morimoto, H.; Ohshima, T. Chem. Commun. 2017, 53, 6319. (j) Yonesaki, R.; Kondo, Y.; Akkad, W.; Sawa, M.; Morisaki, K.; Morimoto, H.; Ohshima, T. Chem. - Eur. J. 2018, DOI: 10.1002/chem.201804078. (8) Hoffmann, R. W. Synthesis 2006, 2006, 3531. (9) (a) Sukach, V. A.; Golovach, N. M.; Pirozhenko, V. V.; Rusanov, E. B.; Vovk, M. V. Tetrahedron: Asymmetry 2008, 19, 761. (b) Hara, N.; Tamura, R.; Funahashi, Y.; Nakamura, S. Org. Lett. 2011, 13, 1662. (c) Rassukana, Y. V.; Yelenich, I. P.; Vlasenko, Y. G.; Onys’ko, P. P. Tetrahedron: Asymmetry 2014, 25, 1234. (d) Sawa, M.; Morisaki, K.; Kondo, Y.; Morimoto, H.; Ohshima, T. Chem. - Eur. J. 2017, 23, 17022. (10) For selected examples of direct catalytic enantioselective decarboxylative Mannich-type reaction to N-protected ketimines, see: (a) Hara, N.; Nakamura, S.; Sano, M.; Tamura, R.; Funahashi, Y.; Shibata, N. Chem. - Eur. J. 2012, 18, 9276. (b) Yuan, H.-N.; Li, S.; Nie, J.; Zheng, Y.; Ma, J.-A. Chem. - Eur. J. 2013, 19, 15856. (c) Yuan, H.-N.; Wang, S.; Nie, J.; Meng, W.; Yao, Q.; Ma, J.-A. Angew. Chem., Int. Ed. 2013, 52, 3869. (d) Nakamura, S.; Sano, M.; Toda, A.; Nakane, D.; Masuda, H. Chem. - Eur. J. 2015, 21, 3929. (e) Kaur, J.; Kumari, A.; Bhardwaj, V. K.; Chimni, S. S. Adv. Synth. Catal. 2017, 359, 1725. For selected examples of direct catalytic enantioselective decarboxylative Mannich-type reaction to N-protected aldimines, see: (f) Ricci, A.; Pettersen, D.; Bernardi, L.; Fini, F.; Fochi, M.; Herrera, R. P.; Sgarzani, V. Adv. Synth. Catal. 2007, 349, 1037. (g) Yin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610. (h) Pan, Y.; Kee, C. W.; Jiang, Z.; Ma, T.; Zhao, Y.; Yang, Y.; Xue, H.; Tan, C.-H. Chem. - Eur. J. 2011, 17, 8363. (i) Yang, C.-F.; Shen, C.; Wang, J.-Y.; Tian, S.-K. Org. Lett. 2012, 14, 3092. (j) Hyodo, K.; Kondo, M.; Funahashi, Y.; Nakamura, S. Chem. Eur. J. 2013, 19, 4128. (k) Singjunla, Y.; Pigeaux, M.; Laporte, R.; Baudoux, J.; Rouden, J. Eur. J. Org. Chem. 2017, 2017, 4319. (11) For selected examples of direct catalytic enantioselective decarboxylative Mannich-type reactions of N-protected imines using related Cu/bis(oxazoline) catalysis, see: (a) Jia, C.-M.; Zhang, H.-X.; Nie, J.; Ma, J.-A. J. Org. Chem. 2016, 81, 8561. (b) Lai, B.-N.; Qiu, J.-F.; Zhang, H.-X.; Nie, J.; Ma, J.-A. Org. Lett. 2016, 18, 520. (c) Jia, C.-M.; Zhang, H.-X.; Nie, J.; Ma, J.-A. J. Org. Chem. 2016, 81, 8561. (12) (a) Esaki, T.; Emura, T.; Hoshino, E. WO 9419322. (b) Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559. (13) Zari, S.; Kudrjashova, M.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett. 2014, 16, 1740. (14) For a leading review, see: (a) Chauhan, P.; Chimni, S. S. Tetrahedron: Asymmetry 2013, 24, 343. For selected examples, see: (b) Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005, 144, 1037. (c) Ghosh, A. K.; Schiltz, G.; Perali, R. S.; Leshchenko, S.; Kay, S.; Walters, D. E.; Koh, Y.; Maeda, K.; Mitsuya, H. Bioorg. Med. Chem. Lett. 2006, 16, 1869. (d) Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. J. Med. Chem. 2008, 51, 5731. (e) Vintonyak, V. V.; Warburg, K.; Kruse, H.; Grimme, S.; Hübel, K.; Rauh, D.; Waldmann, H. Angew. Chem., Int. Ed. 2010, 49, 5902. (f) Crosignani, S.; Jorand-Lebrun, C.; Page, P.; Campbell, G.; Colovray, V.; Missotten, M.; Humbert, Y.; Cleva, C.; Arrighi, J.-F.; Gaudet, M.; Johnson, Z.; Ferro, P.; Chollet, A. ACS Med. Chem. Lett. 2011, 2, 644. (15) (a) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852. (b) Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 1032. (16) See the Supporting Information for details. (17) (a) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. J. Org. Chem. 2009, 74, 7522. (b) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. (c) Zhao, K.; Shu, T.; Jia, J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2015, 21, 3933. (d) Hajra, S.; Bhosale, S. S.; Hazra, A. Org. Biomol. Chem. 2017, 15, 9217. See also refs 3i, 10a, and 12b. (18) In addition, the reaction did not proceed with acetone as nucleophile under the conditions used for direct catalytic Mannich-type

Science Research (BINDS) (Grant Number JP17am0101091) from AMED, Takeda Science Foundation, Uehara Memorial Foundation, and the Tokyo Biochemical Research Foundation. M.S. and R.Y. thank JSPS for Research Fellowships for Young Scientists. We thank Prof. Go Hirai’s group (Kyushu University) for the use of a polarimeter.

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REFERENCES

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Organic Letters reaction of N-unprotected trifluoromethyl ketimines,16 suggesting the importance of the use of β-keto acids as nucleophile. (19) We also found that a linear relationship was observed between the ee of ligand and the ee of product, implying that the catalyst works as monomeric species.16 Although we tried to observe the addition intermediates before decarboxylation, however, we were unable to observe such species, presumably due to the instability of the intermediates and limited solubilities of the starting materials under the reaction conditions. (20) We also tried the reaction with N-unprotected α-ketiminoester derived from ethyl benzoylformate (PhC(NH)CO2Et), but the desired Mannich adduct was not obtained under the current reaction conditions. Exploration to expand the scope of N-unprotected ketimines is ongoing.

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