DOI: 10.1002/chem.201703479

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Organocatalytic Highly Regio- and Enantioselective Umpolung Michael Addition Reaction of a-Imino Esters Yasushi Yoshida,* Takashi Mino, and Masami Sakamoto[a] Abstract: The catalytic asymmetric umpolung reaction of ketimines is of great importance, because it can easily provide chiral amines bearing a tetrasubstituted carbon atom on its asymmetric center. Because amino acids with a tetrasubstituted carbon center are useful due to their wide applicability as pharmaceuticals and chiral building blocks, their enantioselective synthesis has great significance in organic synthesis. Herein, we demonstrate a metal-free novel phase-transfer-catalyzed highly regio- and enantioselective umpolung Michael reaction of a-imino esters, which provides amino acid derivatives in high yields with up to 98 % ee. The products are successfully converted into chiral amino acid derivative and d-lactone with high enantiopurity.

An umpolung strategy, which can increase the number of possible chemical combinations by inversing the innate reactivity of a functional group, facilitates efficient molecular transformations; therefore, umpolung reactions have been extensively studied in organic chemistry.[1, 2] The benzoin reaction and Stetter reaction, which utilize an electrophilic formyl group as a nucleophilic acyl anion equivalent, are among the most successful examples of C@C bond-forming umpolung reactions (Figure 1).[3] The asymmetric versions of such reactions have also been eagerly investigated in the last decades by Enders, Rovis, Bode, and others using chiral N-heterocyclic carbene (NHC) catalysts.[4] On the other hand, the organocatalytic asymmetric umpolung reaction of imines, which can provide important chiral amine scaffolds, have rarely been reported.[5] In 2015, Deng et al. reported the cinchona alkaloid-derived chiral phase-transfer-catalyzed highly regio-, enantio-, and diastereoselective Michael addition reactions of aldimines and trifluoromethyl ketimines with enals to give the corresponding iminals in up to 96 % ee, with a diastereomeric ratio of more than 95:5.[5a] Recently, they successfully extended the substrate scope from enals to enones by developing novel chiral catalysts to generate the corresponding imino ketones in up to

99 % ee. This method was utilized for the preparation of a potent nonopiate antinociceptive agent for pain relief.[5b] On the other hand, Zhang et al. reported the chiral phosphine catalyzed highly enantioselective umpolung addition of trifluoromethyl ketimines with Morita–Baylis–Hillman adduct to produce g-amino acid derivatives in up to 99 % ee.[5c] To the best of our knowledge, only these three examples of organocatalytic asymmetric umpolung reaction of imines exist to date. The preparation of chiral amino acids in high enantiopurity is of great importance because of their wide application in pharmaceuticals, fine chemicals, and chiral building blocks.[6] Although their organocatalytic enantioselective syntheses have strenuously been researched through phase-transfer-catalyzed reactions[6] and asymmetric Strecker reactions,[7] the synthesis of amino acids with a tetrasubstituted carbon center on its aposition is still challenging. For example, Maruoka et al. reported a phase-transfer-catalyzed enantioselective alkylation reaction of glycine-derived imines bearing an alkyl group on the asymmetric center, with alkyl halides. This reaction provided atetrasubstituted a-amino acid derivatives in high yields with

[a] Prof. Dr. Y. Yoshida, Prof. Dr. T. Mino, Prof. Dr. M. Sakamoto Molecular Chirality Research Center Graduate School of Engineering, Chiba University 1–33, Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522 (Japan) E-mail: [email protected] Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/ chem.201703479. Chem. Eur. J. 2017, 23, 12749 – 12753

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Table 1. Optimization of reaction conditions.[a]

Entry

Base

X

Conc. [M]

t [h]

Yield [%]

ee [%]

1 2 3 4 5 6[b] 7[b] 8[b] 9[b]

KOH (aq.) CsOH Cs2CO3 K2CO3 (aq.) K2CO3 (aq.) K2CO3 (aq.) K2CO3 (aq.) K2CO3 (aq.) K2CO3 (aq.)

70 70 70 70 70 140 140 170 200

0.1 0.1 0.1 0.1 0.1 0.2 0.05 0.05 0.05

2 2 2 2 15 15 15 15 15

25 37 28 14 24 51 68 73 81

60 47 51 55 n.d. 51 51 51 51

[a] Conditions: 1 a (1.0 equiv), 3 (2.0 equiv), 4 a (2 mol %), base (X mol %), toluene (conc.), @20 8C, time. [b] Performed at 0 8C. All yields were determined by NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard; ee values were determined by HPLC analysis after NaBH4 reduction; n.d.: not determined. T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication

Figure 1. Catalytic umpolung reaction of carbonyl compounds and imines.

up to 99 % ee.[6b] To achieve more general enantioselective preparations, the development of an enantioselective ketimine umpolung strategy considered to be effective. Herein, we describe a novel chiral phase-transfer-catalyzed asymmetric umpolung Michael addition reaction of a-imino esters with enals for the highly enantioselective synthesis of a-tetrasubstituted d-hydroxy a-amino acid derivatives, which is utilized for the preparations of chiral amino alcohol and d-lactone. Chiral amino alcohol compounds are often observed as the core units of pharmaceuticals and agrochemicals.[8] We first examined the enantioselective umpolung Michael addition reaction of methyl ester 1 a with acrolein (3) at 2 mol % loading of chiral phase-transfer catalyst 4 a in toluene at @20 8C for the optimization of the reaction conditions (Table 1). The use of strong bases, such as 50 wt % KOH (aq.), CsOH, and Cs2CO3 resulted in a low yield of the product despite the high conversion, because of the decomposition of both the substrate and the product (Table 1, entries 1–3). The Chem. Eur. J. 2017, 23, 12749 – 12753

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use of 33 % K2CO3 (aq.) as a weaker base provided iminal 5 a in only 14 % yield, but it gave clean reaction outcome due to the inhibition of the side reactions (Table 1, entry 4). Hence, further reaction optimizations were carried out by using K2CO3 (Table 1, entries 5–9). Increasing the amount of K2CO3 to 140 mol % and the reaction temperature to 0 8C increased the product yield to 51 % (Table 1, entry 6). Upon reducing the reaction concentration to 0.05 m, the yield increased to 68 % (Table 1, entry 7). The best result was obtained by further increasing the base loading for 200 mol % to give the corresponding product in 81 % yield (Table 1, entry 9). Interestingly, in every cases products were obtained in > 20:1 regioisomeric ratio. Next, screening of the catalysts was carried out (Table 2). Although 3,5-dimethoxyphenyl substituted cinchonium salt 4 a gave the product in only 51 % ee, Deng’s catalyst 4 b provided the chiral imine product in 91 % yield with 77 % ee. Because good results were obtained with catalyst 4 b, its optimization

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Communication Table 2. Optimization of the catalyst.[a]

Table 3. Asymmetric umpolung Michael reaction of a-imino esters 1.[a]

Entry

1

R1

R2

Yield [%]

ee [%]

1 2 3[b] 4 5 6 7

1a 1b 1c 1d 1e 1f 1g

Me iPr tBu tBu tBu tBu tBu

C6 H 5 C6 H 5 C6 H 5 2-MeC6H4 3-MeC6H4 4-MeC6H4 4-MeOC6H4

63 73 76 76 77 65 52

82 85 93 79 93 94 96

8

1h

tBu

74

94

9 10 11 12 13[c] 14[c]

1i 1j 1k 1l 1m 1n

tBu tBu tBu tBu tBu tBu

63 60 73 75 58 48

90 84 85 63 90 98 (98)[d]

2-naphthyl 4-BrC6H4 4-ClC6H4 4-CF3C6H4 iPr tBu

[a] Conditions: 1 (1.0 equiv), 3 (2.0 equiv), 4 e (2 mol %), K2CO3 (200 mol %), toluene (0.05 m), 0 8C, 4–17 h. [b] On 0.5 mmol scale with 1 mol % catalyst loading. [c] Reaction time was 72 h. [d] 4 e’ was used instead of 4 e. Opposite enantiomer was obtained as major one. All yields were isolated product’s yields; ee values were determined by HPLC analysis.

Entry

4

Yield [%]

ee [%]

1 2 3 4 5 6

4a 4b 4c 4d 4e 4 e’

81 91 96 97 87 85

51 77 76 78 82 79[b]

[a] Conditions: 1 a (1.0 equiv), 3 (2.0 equiv), 4 (2 mol %), K2CO3 (200 mol %), toluene (0.05 m), 0 8C, 15 h. [b] Opposite enantiomer was obtained as major one. All yields were determined by NMR spectroscopy by using 1,3,5-trimethoxybenzene as an internal standard; ee values of 5 a were determined by HPLC analysis after NaBH4 reduction.

was then conducted. From the plausible reaction mechanism (Figure 3), we thought that the p–p interaction between the electron-rich benzyl substituent on the nitrogen atom in the catalyst and the 4-NO2C6H4 moiety in the substrate could control the transition state conformation, which seems crucial for improving the enantioselectivity of the product. Therefore, catalysts bearing more p-electron-rich substituents were tested. When 2-naphthyl substituted 4 c and electron-rich catalyst 4 d Chem. Eur. J. 2017, 23, 12749 – 12753

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Figure 2. Single-crystal X-ray structure of (S)-(+ +)-2 f.

were employed, the products were obtained in 96 % yield with 76 % ee, and 97 % yield with 78 % ee, respectively. Finally, the best result was obtained with biphenyl-substituted cinchonium salt 4 e, which contains an expanded p-conjugated system,

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Communication and provided the chiral imine product 5 a in 87 % yield with 82 % ee. With the optimal conditions in hand, we evaluated the substrate scope for the a-imino ester umpolung reaction (Table 3). Methyl ester 1 a gave product 2 a in 82 % ee after NaBH4 reduction,[9] but the bulky isopropyl ester 1 b produced product 2 b in 73 % yield with higher enantioselectivity (85 %), probably due to the easier enantioface discrimination of the ketimine carbon atom (Table 3, entries 1 and 2). Finally, when the bulkier tert-butyl ester 1 c was reacted with acrolein, 2 c was isolated in 76 % yield with 93 % ee (Table 3, entry 3). Because the best enantioselectivity was obtained by using the tert-butyl ester derivative, the scope for R2 was investigated with substrates containing the tert-butoxy carbonyl moiety. Electronrich group substituted derivatives 1 d–h and 2-naphthyl substituted compound 1 i produced corresponding products 2 d–i in high yields with excellent enantioselectivities (Table 3, entries 4–9, 90–96 % ee); an exception was 1 d bearing an o-tolyl substituent, in which case the enantioselectivity was relatively lower Figure 3. Plausible asymmetric induction mechanism. (79 % ee). On the other hand, substrates 1 j–l with electronwithdrawing groups produced the desired amino alcohols with relatively lower enantioselectivities (Table 3, entries 10–12). Although 4-BrC6H4- and 4ClC6H4- substituted derivatives 1 j and k gave products 2 j and k with 84 and 85 % ee, respectively, the stronger electron-withdrawing 4-CF3C6H4- substituted product 2 l was isolated with only 63 % ee. Interestingly, bulky alkyl groups, such as iso-propyl substituted 1 m and tert-butyl substituted 1 n, were well toler- Scheme 1. Deuterium-incorporation experiment. ated under the reaction conditions and gave the desired products in 90 and 98 % ee, respectively. Importantly, both enantiomers of 2 n were easily and selectively synphiles in the Michael addition reaction with acrolein to form thesized in excellent enantiopurity when using 4 e and its iminal product 5 enantioselectively, and the regenerated catapseudo-enantiomer catalyst 4 e’. Absolute configuration of 2 f lyst. In this reaction mechanism, the enantioselectivity outwas unambiguously determined as (S)-(+ +)-2 f by X-ray crystalcome is affected by the asymmetric environment around the lographic analysis of its single crystal (Figure 2).[10] nucleophilic aza-allyl anion moiety. The chiral phase-transfer catalyst can interact with substrate-derived anion in two ways: To investigate the reaction mechanism for the present umpolung reaction, the deuterium-incorporation experiment was 1) via p–p interaction between the 4-NO2C6H4- moiety of the carried out (Scheme 1). When 1 c was treated with D2O solusubstrate and the electron-rich biphenyl-substituted aromatic tion of K2CO3 in the presence of catalyst 4 e at 0 8C, 1 c and its ring of the catalyst;[11] and 2) via cation–anion interaction of regioisomer 1 c’ were formed. Recovered 1 c bore almost no the chiral ion pair to create an effective asymmetric environdeuterium, however, isomerized 1 c’ contained around 50 % of ment.[12] The anionic character of the aza-allyl anion moiety is deuterium on its asymmetric center. This result suggests that enhanced by electron-donating substituents; thus, the cation once the 2-aza-allyl anion formed, then almost no re-protonaand anion of A pair tightly and a better asymmetric environtion on 4-nitrobenzylic position occurred. And a-position of ment is created around the nucleophilic ketimine carbon. On tert-butoxy carbonyl moiety almost predominantly protonated the other hand, electron-withdrawing substituents weaken the somehow because of its higher nucleophilicity. anionic character, so that the cation and anion of B pair loosely From the substrate scope results, a plausible asymmetric inand the enantioselectivity of the product decreases. A more duction model for the umpolung reaction of a-imino esters is detailed investigation of the reaction mechanism is ongoing. proposed (Figure 3). Counteranion exchange of the chiral Because amino alcohols 2 were obtained with high enantiophase-transfer catalyst with aza-allyl anion conjugated with selectivity, their derivatizations were conducted (Scheme 2). carbonyl moiety derived from substrate 1 takes place to form The tert-butyl group of 2 c was removed by treatment with chiral ion pairs A and B. These ion pairs act as chiral nucleoTfOH in CH2Cl2 at low temperature, and a tandem dehydrative Chem. Eur. J. 2017, 23, 12749 – 12753

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[2]

[3]

[4]

Scheme 2. Derivatizations of amino alcohol 2 c. [5]

cyclization took place to form d-lactone 6 in quantitative yield. When the hydrogenolysis of 2 c was conducted in the presence of Pd/C, removal of the 4-nitrobenzyl group occurred to give the corresponding free amine 7 in 81 % yield. The enantiopurity of the products did not decrease under these transformations. In summary, we have demonstrated an efficient method for the enantioselective synthesis of a-tetrasubstituted a-amino acid derivatives through a catalytic asymmetric umpolung Michael addition reaction of a-imino esters with acrolein. Because known chiral catalysts produced the desired product in moderate enantioselectivity, novel chiral phase-transfer catalysts were developed to achieve the synthesis of amino alcohol products 2 with enantioselectivities up to 98 % ee.[13] Amino alcohol 2 c was successfully converted into a synthetically useful free chiral amino alcohol and a d-lactone. Further derivatizations of the chiral products and investigations into a more detailed reaction mechanism are ongoing in our group.

[6]

[7]

[8]

Acknowledgements We are grateful for the financial support from Research Promotion on SIS (the Society of Iodine Science), research grant from the General Sekiyu R & D Encouragement Assistance Foundation, and the Leading Research Promotion Program “Soft Molecular Activation” of Chiba University, Japan.

[9]

[10]

[11]

Conflict of interest The authors declare no conflict of interest.

[12]

Keywords: amino acids · asymmetric synthesis · imino esters · organocatalysis · umpolung [1] Recent reports on umpolung reaction, see: a) J. Liu, C.-G. Cao, H.-B. Sun, X. Zhang, D. Niu, J. Am. Chem. Soc. 2016, 138, 13103 – 13106; b) N. Chen, X.-J. Dai, H. Wang, C.-J. Li, Angew. Chem. Int. Ed. 2017, 56, 6260 – 6263; Angew. Chem. 2017, 129, 6356 – 6359; c) X.-J. Dai, H. Wang, C.-J. Chem. Eur. J. 2017, 23, 12749 – 12753

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[13]

Li, Angew. Chem. Int. Ed. 2017, 56, 6302 – 6306; Angew. Chem. 2017, 129, 6399 – 6403. a) D. Seebach, E. J. Corey, J. Org. Chem. 1975, 40, 231 – 237. For reviews, see: b) B.-T. Grçbel, D. Seebach, Synthesis 1977, 357 – 402; c) D. Seebach, Angew. Chem. Int. Ed. Engl. 1979, 18, 239 – 258; Angew. Chem. 1979, 91, 259 – 278; d) R. Brehme, D. Enders, R. Fernandez, J. M. Lassaletta, Eur. J. Org. Chem. 2007, 5629 – 5660. a) R. S. Menon, A. T. Biju, V. Nair, Beilstein J. Org. Chem. 2016, 12, 444 – 461; b) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485 – 496; c) D. Enders, K. Breuer, Comprehensive Asymmetric Catalysis III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, Heidelberg, 2004. a) D. Enders, U. Kallfass, Angew. Chem. Int. Ed. 2002, 41, 1743 – 1745; Angew. Chem. 2002, 114, 1822 – 1824; b) M. S. Kerr, J. R. de Alaniz, T. Rovis, J. Am. Chem. Soc. 2002, 124, 10298 – 10299; c) M. S. Kerr, T. Rovis, J. Am. Chem. Soc. 2004, 126, 8876 – 8877; d) P.-C. Chiang, J. Kaeobamrung, J. W. Bode, J. Am. Chem. Soc. 2007, 129, 3520 – 3521. For reviews, see: e) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511 – 3522; f) D. M. Flanigan, F. R. Michailidis, N. A. White, T. Rovis, Chem. Rev. 2015, 115, 9307 – 9387. a) Y. Wu, L. Hu, Z. Li, L. Deng, Nature 2015, 523, 445 – 450; b) L. Hu, Y. Wu, Z. Li, L. Deng, J. Am. Chem. Soc. 2016, 138, 15817 – 15820; c) P. Chen, Z. Yue, J. Zhang, X. Lv, L. Wang, J. Zhang, Angew. Chem. Int. Ed. 2016, 55, 13316 – 13320; Angew. Chem. 2016, 128, 13510 – 13514. a) T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 1999, 121, 6519 – 6520; b) T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 2000, 122, 5228 – 5229; c) T. Ma, X. Fu, C. W. Kee, L. Zong, Y. Pan, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2011, 133, 2828 – 2831. For reviews, see: d) T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222 – 4266; Angew. Chem. 2007, 119, 4300 – 4345; e) S. Shirakawa, K. Maruoka, Angew. Chem. Int. Ed. 2013, 52, 4312 – 4348; Angew. Chem. 2013, 125, 4408 – 4445. a) M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996, 118, 4910 – 4911; b) S. J. Zuend, M. P. Coughlin, M. P. Lalonde, E. N. Jacobsen, Nature 2009, 461, 968 – 970; c) H.-Y. Wang, C.-W. Zheng, Z. Chai, J.-X. Zhang, G. Zhao, H. Y. Wang, C. W. Zheng, Z. Chai, J. X. Zhang, G. Zhao, Nat. Commun. 2016, 7, 12720 – 12728. For reviews, see: d) J. Wang, X. Liu, X. Feng, Chem. Rev. 2011, 111, 6947 – 6983; e) X.-H. Cai, B. Xie, ARKIVOC 2014, 1, 205 – 248. Recent reports for catalytic asymmetric synthesis of chiral amines, see: a) Y. Wu, L. Deng, J. Am. Chem. Soc. 2012, 134, 14334 – 14337; b) N. J. Oldenhuis, V. M. Dong, Z. Guan, J. Am. Chem. Soc. 2014, 136, 12548 – 12551; c) S.-L. Shi, Z. L. Wong, S. L. Buchwald, Nature 2016, 532, 353 – 356; d) X. Zhou, Y. Wu, L. Deng, J. Am. Chem. Soc. 2016, 138, 12297 – 12302; e) V. N. Wakchaure, B. List, Angew. Chem. Int. Ed. 2016, 55, 15775 – 15778; Angew. Chem. 2016, 128, 16007 – 16010; f) H. Huang, X. Liu, L. Zhou, M. Chang, X. Zhang, Angew. Chem. Int. Ed. 2016, 55, 5309 – 5312; Angew. Chem. 2016, 128, 5395 – 5398. For reviews, see: g) T. C. Nugenta, M. E. Shazly, Adv. Synth. Catal. 2010, 352, 753 – 819; h) Chiral Amine Synthesis: Methods, Developments and Applications (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010. Michael adduct 5 was partially decomposed during silica-gel column purification; therefore, more stable reduced amino alcohols were isolated. CCDC 1552783 (for compound (S)-(+ +)-2 f) contains the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. a) U. H. Dolling, P. Davis, E. J. J. Grabowski, J. Am. Chem. Soc. 1984, 106, 446 – 447; b) M. Bandini, A. Bottoni, A. Eichholzer, G. P. Miscione, M. Stenta, Chem. Eur. J. 2010, 16, 12462 – 12473; c) R. R. Knowles, S. Lin, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132, 5030 – 5032; d) A. J. Neel, M. J. Hilton, M. S. Sigman, F. D. Toste, Nature 2017, 543, 637 – 646. J. A. Raskatov, A. L. Thompson, A. R. Cowley, T. D. W. Claridge, J. M. Brown, Chem. Sci. 2013, 4, 3140 – 3147. Unfortunately, b-substituted unsaturated aldehydes, such as crotonaldehyde and cinnamaldehyde, did not give any Michael product.

Manuscript received: July 26, 2017 Accepted manuscript online: August 10, 2017 Version of record online: August 29, 2017

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Organocatalytic Highly Regio- and Enantioselective Umpolung Michael Addition Reaction of α-Imino Esters.

The catalytic asymmetric umpolung reaction of ketimines is of great importance, because it can easily provide chiral amines bearing a tetrasubstituted...
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