z
Catalysis
Asymmetric Synthesis of Chiral γ- and δ-Amino Esters
Using Trichlorosilane Activated with a Lewis Base Catalyst
Belma Hasdemir,* Hasniye Yaşa, Tülay Yıldız, Hatice Başpınar Küçük, and Hülya Çelik Onar
[a]Novel chiral γ- and δ- amino esters 2 a–k were synthesized by enantioselective reduction of N-aryl γ- and δ-imino esters with aryl, substituted aryl, and heteroaryl groups 1 a–k using trichlorosilane activated with optically active N-pivaloyl L-pro-line I in high yields (50%–98%) with enantioselectivities (10%– 84% enantiomeric excess). The structures of the chiral amino
esters 2 a–k were clarified by infrared, nuclear magnetic resonance (1
H and 13
C) and gas chromatography-mass spec-trometry. The enantiomeric excess of these compounds were identified by chiral high-performance liquid chromatography using a Chiralpak AD H column. The highest ee of 84% and highest yield of 98% were found for 2 d.
Introduction
Chiral amino acid and amino esters are important compounds used as precursors in the preparation of various pharmaceutical and agrochemical molecules,[1–3]
particularly chiral γ-amino acids, γ-lactams, and δ-amino alcohols, which are building blocks for pharmaceutical substances in the chemical industry.[4–11]
Moreover, amino acids have important applica-tions in various organic syntheses as chiral starting materials, auxiliaries,[12]
polymer sources,[13,14]
and catalysts. All the above-mentioned compounds can easily be obtained by enantiose-lective reduction of imino esters.[15]
Therefore, the development of effective methods for the synthesis of chiral γ- and δ-amino esters is of great value for drug discovery and organic synthesis. In recent years, although many catalysts have been developed in the enantioselective hydrogenation of ketimines using Lewis base organocatalyst-activated trichlorosilane,[16]
there are still a few reports of asymmetric synthesis of γ- and δ-amino esters.[17] In these studies, N-substituted proline amide, N-substituted proline, and carboxyamide-type Lewis-base
cata-lysts have been developed, and have been used successfully in the asymmetric reduction of N-aryl ketimines,[18] α-imino
esters,[19] β-enamino esters,[20] β-nitroenamines,[21] and
indoles.[22]
In a study on the enantioselective reduction of amino esters, Malkov et al. accomplished an asymmetric reduction of
N-aryl α-, β-, and γ-imino esters with trichlorosilane by the
valine-derived Lewis basic.[17a]In another study, the
enantiose-lective synthesis of γ-amino esters by trichlorosilane was achieved using chiral picolinamide catalysts.[17c] In further
research, amino esters were obtained by hydrogenation of
δ-imino esters under high hydrogen pressure in the presence of chiral iridium complexes.[17b]
In our own previous work, we reported the synthesis of isomeric amino acid methyl esters, oximino alcohols, and amino alcohols by reduction of aliphatic oximino esters.[23]
In addition, our working group has carried out successful studies on the asymmetric reduction of ketone, diketone and keto esters.[24,25]
In this study, 11 novel chiral γ- and δ-amino esters with aryl, substituted aryl, and heteroaryl groups 2a–k were obtained from their corresponding imino esters 1a–k using trichlorosilane activated by the chiral Lewis base catalyst I (Scheme 1). Trichlorosilane, chosen as a reducing agent, was preferred due to its reactivity, low cost, and wide availability. Moreover, the use of chiral Lewis bases provided control of the absolute stereochemistry of the reaction. All chiral amino esters 2a–k were identified by infrared (IR), nuclear magnetic resonance (1H and 13C NMR) and gas chromatography-mass
spectrometry (GC-MS). The enantiomeric excess of these compounds was determined by chiral high-performance liquid chromatography (HPLC) and measurement of their optical rotations. We used ten different chiral organocatalysts for asymmetric reduction of imino esters (Figure 1). Among these, we synthesized four new catalysts derived from (S)-2-amino-2-phenylacetic acid, VII–X. According to our literature research, catalysts IV and V are commercially available, but there are no data on their optical rotation and spectroscopic analysis. The spectroscopic data and optical rotation signs of these catalysts were determined in this study.
[a] Dr. B. Hasdemir, Dr. H. Yaşa, Dr. T. Yıldız, Dr. H. B. Küçük, Dr. H. Ç. Onar Istanbul University-Cerrahpaşa, Department of Chemistry, Faculty of Engineering, 34320 Avcılar, Istanbul, Turkey
E-mail: karaefe@istanbul.edu.tr
Supporting information for this article is available on the WWW under
Results and Discussion
In this work, we aimed to synthesize biologically important γ-and δ- amino acid methyl esters that are not available in the literature in high enantiomeric purity. For this purpose, we carried out asymmetric reduction of aryl, substituted aryl, and heteroaryl prochiral imino esters 1 a–k by trichlorosilane in the presence of chiral Lewis base organocatalyst (Scheme 1). The novel N-aryl γ- and δ- imino esters 1 a–k selected as starting material were synthesized before by our group.[26,27]
In the literature research, we found that high enantioselec-tivity was obtained in the asymmetric reduction of ketimines with trichlorosilane-activated N-substituted L-proline anilides.[18]
Among these L-proline anilides, it was found that a high ee value (88%) was obtained when N-pivaloyl L-proline anilide was used as catalyst.[18d] In another study, N-substituted L-proline
was used as catalyst and an ee of 60%–77% was
determined.[18e]
As a result of these observations, we focused on the synthesis of structurally different new chiral catalysts to examine the effect of the catalyst on enantioselectivity in the asymmetric reduction of imino esters with trichlorosilane. For this purpose, we synthesized N- pivaloyl L-proline I, containing free acid group, N-pivaloyl L-proline amides II–V and (S)-2-amino-2-phenylacetic acid derivatives VI–X. Among these catalysts, four catalysts VII–X were synthesized for the first time in this study (Figure 1).
The methyl 5-(4-methoxyphenylimino)-5-phenylpentanoate 1 d was selected as a model substrate for determining the best catalyst, solvent, temperature, and time. Therefore, many differ-ent experimdiffer-ental conditions have been studied. First, synthe-sized chiral catalysts I–X (Figure 1) were investigated for their capacity for enantioselective reduction of 1 d in dichloro-methane (CH2Cl2) at 0°C. The results are shown in Table 1.
Under these conditions, treatment of δ-imino ester 1 d with trichlorosilane in the presence of 10 mol% of catalyst II gave the corresponding aryl δ-amino ester 2 d in high conversion
(95%) with moderate enantioselectivity (62% ee) (Table 1, entry 2).
However, other N-pivaloyl L-proline amide derivatives III–V led to poor enantioselectivity in 25%–84% conversions (Table 1, entries 3–5). In addition, catalyst I, containing a free acid group, afforded high conversion (99%) and high enantioselectivity (84% ee) (Table 1, entry 1).
By using N-pivaloyl (S)-2-amino-2-phenylacetic acid VI and amides VII–X, amino ester 2 d was obtained with high conversion (60%–95%) and poor enantioselectivity or rasemic form (Table 1, entries 6–10).
The reduction reactions with Lewis base catalysts II–X containing bulky groups used in our study were expected to result in higher ee, but the observed reactions produced the opposite result. However, in the presence of Lewis base catalyst I, which has a smaller structure than other catalysts, higher reduction yield and ee were obtained. Stereoselectivity ob-served with catalyst I, containing a free acid group, can be explained by the transition state for the reduction of imino esters (Figure 2). Malkov et al. showed the transition state for the reduction of ketimines with a valine-derived catalyst.[28]We
suggested a transition state for the asymmetric reduction reaction of imino esters performed with catalyst I. In this model, we propose that the coordination between catalyst I and trichlorosilane is more stable and hydride transfer is easier. In addition, the catalyst can more easily interact with the imino ester compound for asymmetric reduction.
As a result of these interactions, the expected optically active amino esters can be obtained.
Based on these experimental results, we found catalyst I to be the most effective, and we then researched the reduction of imino ester 1 d in various solvents in order to increase enantiomeric selectivity and determine the best reaction conditions in the presence of catalyst I. The optimization studies are summarized in Table 2. Using toluene, acetonitrile Figure 1. Catalysts synthesized in this work
Table 1. Catalyst screening for the imino ester 1 d.
Entry[a] Catalyst Conversion [%][b] ee[%][c]
1 I 98 84 2 II 95 62 3 III 84 6 4 IV 25 16 5 V 35 6 6 VI 69 6 7 VII 95 rac 8 VIII 80 rac 9 IX 60 16 10 X 95 rac
[a] The reactions were carried out using 0.29 mmol of imino ester 1 d and 0.43 mmol of HSiCl3with 0.029 mmol of catalyst. [b] Determined
and tetrahydrofuran as the solvents resulted in high yields with poor enantioselectivities (Table 2, entries 1, 3 and 4). When the reaction was performed in benzene and 1, 2-dichloroethane, the enantioselectivities significantly improved (Table 2, en-tries 2 and 5). In the case of chloroform, the reduction reaction did not occur (Table 2, entry 6). The best enantioselectivities of 81%–84% ee were achieved when dichloromethane was used (Table 2, entries 7–11). It was observed that the best conversion (99%) and enantioselectivity (84% ee) were obtained at 0°C and 20 hours, when we examined the reaction temperature and time using dichloromethane as the solvent (Table 2, entry 7).
With this optimum reaction condition, asymmetric reduc-tion of various imino esters 1a–k was carried out using trichlorosilane activated with catalyst I in CH2Cl2 at 0°C for
20 hours (Table 3). The substituent and C=N position effects in the reduction N-aryl γ- and δ-imino esters with chloro- (1a), methyl- (1b), and methoxy- (1c) groups were examined. The
results are summarized in Table 3. Aryl substituted N-aryl γ-amino esters 2a–c compounds showed lower yield and enantioselectivity than δ-amino esters 2d–g (Table 3, entries 1– 3). Chloro and methyl phenyl substituted δ-amino esters 2e and 2 f had the same ee values (80% ee). When the reduction of δ-imino ester 1 g, having methoxy phenyl substitution on a phenyl ring, was achieved, the yield and enantioselectivity were lower (Table 3, entry 7) than 1e and 1 f. In the case of phenyl substituted δ-imino ester 1d, the reaction gave excellent yield (98%) with high enantioselectivities (84% ee) (Table 3, entry 4).
Heteroaryl substituted amino esters 2 h–k were synthesized with moderate yields (64%–86%) and low enantioselectivities (10%–60% ee and racemic) compared with amino esters 2 a–g (Table 3, entries 8–11).
Conclusion
In this paper, ten chiral Lewis bases, directly derived from commercially present enantiomerically pure L-proline or (S)-2-amino-2-phenylacetic acid, were synthesized and the effects on enantioselectivity in the asymmetric reduction of imino esters investigated. Catalysts VII–X were first synthesized in this study. A total of 11 original γ- and δ-amino acid methyl esters with aryl, substituted aryl, and heteroaryl groups 2a–k were successfully obtained using trichlorosilane activated with catalyst I. The highest enantioselectivity (84% ee) was deter-mined for 2d.
In the present work, the synthesized chiral amino ester compounds can be converted into corresponding optically active amino acids and extensively used as chiral starting materials, auxiliaries, and as a chiral catalyst in organic synthesis.
Figure 2. Proposed transition state for asymmetric reduction of 2 d by Cl3SiH
activated catalyst I.
Table 2. Reaction condition studies for the asymmetric reduction of 1 d.
Entry[a] Solvent T [°C] Time (h) Conversion [%][b] ee[c][%]
1 Toluene 0 20 95 18 2 Benzene 0 20 79 72 3 MeCN 0 20 93 22 4 THF 0 20 94 14 5 (CH2)2Cl2 0 20 92 74 6 CHCl3 0 20 NR[d] -7 CH2Cl2 0 20 99 84 8 CH2Cl2 0 2 40 82 9 CH2Cl2 0 5 80 82 10 CH2Cl2 rt 20 90 81 11 CH2Cl2 -10 20 88 83
[a] The reactions were carried out using 0.29 mmol of imino ester 1 d and 0.43 mmol of Cl3SiH with 0.029 mmol of catalyst I. [b] Determined by GC-MS. [c]
Supporting Information Summary
Experimental section, data of chiral compounds with relevant references, HPLC chromatograms, 1
H and 13
C NMR spectra of products are in supporting information (SI).
Acknowledgements
This study was supported by Turkey Scientific and Technological Research Center Project (TÜBİTAK) with Project number 115Z761.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Asymmetric synthesis · Lewis bases · Optically active amino esters · Organocatalyst
[1] a) G. C. Barrett, Amino Acids, Peptides and Proteins, Vol. 27, R. S. C. Publications, London, 1996, p. 1–101; b) G. C. Barrett, Chemistry and Biochemistry of the Amino Acids, Chapman and Hall, London, 1985, p. 684; c) J. H. Jones, Amino Acids and Peptides, Vol. 23, The Royal Society of Chemistry, London, 1992 (Specialist Periodical Report).
[2] S. L. Manjinder, K. R. Yeeman, N. G. J. Michael, C. V. John, J. Org. Chem.
2002, 67, 1536–1547.
[3] V. K. Tandon, D. B. Yadav, R. V. Singh, A. K. Chaturvedi, P. K. Shukla, Bioorg. Med. Chem. Lett. 2005, 15, 5324–5328.
[4] D. Seebach, A. K. Beck, D. J. Bierbaum, Chem. Biodiversity 2004, 1, 1111– 1239.
[5] S. Han-Essian, X. H. Luo, R. Schaum, S. Michnick, J. Am. Chem. Soc. 1998, 120, 8569–8570.
[6] M. G. Woll, J. R. Lai, I. A. Guzei, S. J. C. Taylor, M. E. B. Smith, S. H. Gellman, J. Am. Chem. Soc. 2001, 123, 11077–11078.
[7] D. Seebach, M. Brenner, M. Rueping, B. Schweizer, B. Jaun, Chem. Commun. 2001, 207–208.
[8] D. Seebach, M. Brenner, M. Rueping, B. Jaun, Chem. Eur. J. 2002, 8, 573– 584.
[9] H. Ren, R. Liu, L. Chen, T. J. Zhu, W. M. Zhu, Q. Q. Gu, Arch. Pharmacal Res. 2010, 33, 499–502.
[10] R. L. Elliott, K. B. Ryther, D. J. Anderson, M. Piattoni-Ka-plan, T. A. Kuntzweiler, D. Donnelly-Roberts, S. P. Arneric, M. W. Holladay, Bioorg. Med. Chem. Lett. 1997, 7, 2703–2708.
[11] C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46, 8748–8758; Angew. Chem. 2007, 119, 8902–8912.
[12] a) J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric Synthesis, Wiley, New York, 1995; b) Z. Tomasz, A. Michał, J. Janusz, Tetrahedron: Asymmetry 2002, 13, 2053–2059; c) J.-K. Kim, J. Kim, S. Song, O. Jung, H. Suh, J. Inclusion Phenom. Macrocyclic Chem. 2007, 58, 187–192; d) C. Somlai, A. Peter, P. Forgo, B. Penke, Synthetic Commun.
2003, 33, 1815–1820; e) G. Pollini, N. Baricordi, S. Benetti, C. De Risi, V.
Zanirato, Tetrahedron Lett. 2005, 46, 3699–3701.
[13] N. Atsushi, M. Toyoharu, K. Hiroto, E. Takeshi, Macromolecules 2003, 36, 9335–9339.
[14] S. Fumio, E. Takeshi, Macromol. Chem. Phys. 1999, 200, 2651–2661. [15] a) J. Chen, F. Li, F. Wang, Y. Hu, Z. Zhang, M. Zhao, W. Zhang, Org. Lett.
2019, 21, 9060–9065; b) Y. Xiong, H. Mei, L. Wu, J. Han, Y. Pan, G. Li, Beilstein J. Org. Chem. 2014, 10, 653–659; c) X-H. Hu, X-P. Hu, Adv. Synth. Catal. 2019, 5063–5068; d) J. Mazuela, T. Antonsson, M. J. Johansson, L. Knerr, S. P. Marsden, Org. Lett. 2017, 19, 5541–5544; e) H. Almahli, F. Hendra, C. Troufflard, C. Cavé, D. Joseph, S. Delarue-Cochin, Chirality,
2011, 23, 265–271; f) Q. Dai, W. Yang, X. Zhang, Org. Lett. 2005, 7, 5343–
5345.
[16] a) S. Jones, C. J. A. Warner, Org. Biomol. Chem. 2012, 10, 2189–2200; b) M. Figlus, S. T. Caldwell, D. Walas, G. Yesilbag, G. Cooke, P. Kocovsky, A. V. Malkov, A. Sanyal, Org. Biomol. Chem. 2010, 8, 137–141; c) A. V. Malkov, K. Vranková, R. C. Sigerson, S. Stončius, P. Kočovský, Tetrahedron
2009, 65, 9481–9486; d) Z. Wang, C. Wang, L. Zhou, J. Sun, Org. Biomol. Chem. 2013, 11, 787–797; e) F. Iwasaki, O. Onomura, K. Mishima, T. Kanematsu, T. Maki, Y. Matsumura, Tetrahedron Lett. 2001, 42, 2525– 2527.
[17] a) A. V. Malkov, K. Vrankovà, S. Stoncius, P. Kocovsky, J. Org. Chem. 2009, 74, 5839–5849; b) M. N. Cheemala, P. Knochel, Org. Lett. 2007, 9, 3089– 3092; c) Z.-Y. Xue, L.-X. Liu, Y. Jiang, W.-C. Yuan, X.-M. Zhang, Eur. J. Org. Chem. 2012, 251–255.
[18] a) Z. Y. Wang, M. N. Cheng, P. C. Wu, S. Y. Wei, J. Sun, Org. Lett. 2006, 8, 3045–3048; b) Y. Matsumura, K. Ogura, Y. Kouchi, F. Iwasaki, O. Onomura, Org. Lett. 2006, 8, 3789–3792; c) C. Baudequin, D. Chaturvedi, S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 2623–2629; d) T. Kanemitsu, A. Umehara, R. Haneji, K. Nagata, T. Itoh, Tetrahedron 2012, 68, 3893–3898;
Table 3. Asymmetric reduction of imino esters 1 a-k with trichlorosilane catalyzed by I.
Entry İmino ester R n Product Yield[a][%] ee[b][%]
1 1 a 4-ClC6H4 2 2 a 50 24 2 1 b 4-CH3C6H4 2 2 b 50 54 3 1 c 4-CH3OC6H4 2 2 c 50 63 4 1 d C6H5 3 2 d 98 84 5 1 e 4-ClC6H4 3 2 e 92 80 6 1 f 4-CH3C6H4 3 2 f 90 80 7 1 g 4-CH3OC6H4 3 2 g 54 62 8 1 h 2-Furyl 2 2 h 86 rac 9 1 i 2-Thienyl 2 2 i 45 60 10 1 j 2-Furyl 3 2 j 75 32 11 1 k 2-Thienyl 3 2 k 64 10
e) M. Bonsignore, M. Benaglia, L. Raimondi, M. Orlandi, G. Celentano, Beilstein J. Org. Chem. 2013, 9, 633–640.
[19] H. J. Zheng, W. B. Chen, Z. J. Wu, J. G. Deng, W. Q. Lin, W. C. Yuan, X. M. Zhang, Chem. Eur. J. 2008, 14, 9864–9867.
[20] a) X. Wu, Y. Li, C. Wang, L. Zhou, Lu, X. Sun, Chem. Eur. J. 2011, 17, 2842–2848; b) J. Ye, C. Wang, L. Chen, X. Wu, L. Zhou, J. Sun, Adv. Synth. Catal. 2016, 358, 1042–1047.
[21] X. W. Liu, Y. Yan, Y. Q. Wang, C. Wang, J. Sun, Chem. Eur. J. 2012, 18, 9204–9207.
[22] Y. C. Xiao, C. Wang, Y. Yao, J. Sun, Y. C. Chen, Angew. Chem. Int. Ed. 2011, 50, 1066–10664.
[23] H. Başpınar Küçük, H. Yaşa, T. Yildiz, A. S. Yusufoğlu, Synthetic Commun.
2017, 47, 2070–2077.
[24] a) T. Yildiz, A. Yusufoglu, Tetrahedron: Asymmetry 2010, 21, 2981–2987; b) T. Yildiz, A. Yusufoglu, Monatsh. Chem. 2013, 144, 183–190; c) T. Yildiz, Tetrahedron: Asymmetry 2015, 26, 497–504.
[25] a) B. Hasdemir, A. Yusufoğlu, Tetrahedron: Asymmetry 2004, 15, 65–68; b) H. Çelik Onar, B. Hasdemir, A. Yusufoğlu, J. Serb. Chem. Soc. 2007, 72, 421–427; c) B. Hasdemir, H. Çelik Onar, A. Yusufoğlu, Tetrahedron: Asymmetry 2012, 23, 1100–1105; d) B. Hasdemir, Synthetic Commun. 2015, 45, 1082–1088.
[26] B. Hasdemir, H. Yaşa, Y. Akkamış, J. Chinese Chem. Soc. 2019, 66, 197– 204.
[27] H. Yaşa, Turk. J. Chem. 2018, 42, 1105–1112.
[28] A. V. Malkov, A. Mariani, K. N. MacDougall, P. Kocovsky, Org. Lett. 2004, 6, 2253–2256.
Submitted: February 26, 2020 Accepted: May 13, 2020
