Enantioselective Nucleophilic Aromatic Substitution Reaction of Azlactones to Synthesize Quaternary α-Amino Acid Derivatives

Abstract

An asymmetric organocatalytic nucleophilic aromatic substitution reaction of azlactones with electron-deficient aryls was established. A variety of α-aryl α-alkyl α-amino acid esters and peptides were obtained in decent yields and stereoselectivities. A new bifunctional catalytic mode involving charge-transfer interaction and hydrogen bonding is proposed to explain the enantioselectivity.

Quaternary amino acid derivatives are important in biochemistry, drug discovery, and synthetic chemistry.[1] A wide variety of stereoselective methods, including diastereoselective derivations, self-regenerations, and enantioselective syntheses, have been developed to construct quaternary stereocenters from natural amino acid derivatives.[2] Enantio­selective α-substitutions of racemic aldimine Schiff bases or azlactones are the most usual and effective of these methods. Nevertheless, reporting of the direct introduction of an aryl substituent at the α-carbon has been sporadic compared with that of various alkylation reactions.[3] Intramolecular α-arylation through N-to-Cα migration from optically active N-aryl amino acid derivatives provides an alternative route in which a chiral memory effect plays an important role.[4] The typical intermolecular asymmetric catalytic nucleophilic aromatic substitution (S_NAr) reaction is challenging due to the dearomatization process involved in the addition–elimination mechanism.[5] The Maruoka group reported that chiral phase-transfer catalysts promoted an asymmetric S_NAr reaction of aldimine Schiff bases with electron-deficient aryl fluorides or arene chromium complexes (Scheme [1a]).[6] The Wang group used a formal α-arylation of an azlactone for this purpose (Scheme [1b]).[7] As another useful type of amino acid template, azlactones undergo enantioselective S_NAr reactions to provide ready access to both α-aryl α-alkyl α-amino acid derivatives and their related peptide derivatives.[8] We are interested in enantioselective S_NAr reactions of azlactones with nitro-group-bearing fluoroarenes, with the aim of expanding the range of suitable substrates.

Chiral phase-transfer catalysts, especially those based on cinchona alkaloids, are popular in asymmetric S_NAr reaction,[6] [9] delivering enantiocontrol through electrostatic interactions in ion pairs between the quaternary ammonium or phosphonium ion and the nucleophile. Our research group has achieved good results in chiral guanidine amide-mediated asymmetric catalytic transformations of azlactones through bifunctional hydrogen-bond activation.[10] However, the requirement for excess base to neutralize the HF generated in the S_NAr reaction of fluoroarenes can hamper the effective interaction between the chiral guanidine catalyst and the azlactone, leading to poor enantiocontrol. In addition, the ready formation of molecular electron donor–acceptor (EDA) complexes between the electron-­deficient arene and the nucleophilic partners through noncovalent bonding can weaken interactions between the ­catalyst unit and the reactants.

Here, we report the use of a type of polyaryl-substituted chiral guanidine amide organocatalyst in the presence of K₃PO₄·H₂O as a base for the title reaction. This catalytic system permits efficient enantioselective S_NAr reactions of azlactones with aryl fluorides, leading to rapid construction of α-aryl α-alkyl α-amino acid derivatives and peptides. A new catalytic mode in which the electron-rich guanidine unit of the catalyst interacts with the electron-deficient electrophile, in combination with a hydrogen-bonding interaction, delivers stereoselectivity.

We initially chose azlactone 1a and 1-fluoro-2,4-dinitrobenzene (2a) as model substrates to optimize the reaction conditions (Table [1]). To reduce the base-initiated racemic background reaction, the weak base K₃PO₄ was added to neutralize HF. Due to the predisposition of the arylated azlactone product to undergo ring opening,[8] methanol was added to yield the quaternary amino acid ester as the isolated product. Firstly, several chiral guanidine amide catalysts were examined in CHCl₃ at –20 °C. We found that each subunit of the catalyst, including the amide substituent, the amidine substituents, and the amino acid backbone, had a marked influence on the enantioselectivity (Table [1], entries 1–7). Among the N,N′-diphenyl-substituted guanidines G-1 to G-4 with various amide units, the enantiomerically enriched product 3a was obtained only in the presence of the bulkier (triphenylmethyl)amine-based guanidine amide catalyst G-3 (entry 3). Almost no enantiocontrol was found with the aniline, (diphenylmethyl)amine-, or tert-butylamine-based analogues G-1, G-2, and G-4 respectively (entries 1, 2, and 4). Also, an N-aryl substituent on the guanidine subunit was critical, as the dialkyl-substituted catalysts G-5 and G-6 gave poor enantioselectivity, whereas guanidine G-7 containing a phenyl and a cyclohexyl substituent on the amidine unit afforded the product with acceptable enantioselectivity (entries 5–7). Switching the catalyst to the l-piperidine-2-carboxylic acid derived catalyst G-8 led to the formation of a racemic product. To improve the enantioselectivity and yield, we carefully examined the reaction temperature, inorganic base additive, solvent, and concentration of substrates [see the Supporting Information (SI) for details]. To our delight, after a slight modification of reaction conditions by decreasing the reaction temperature and increasing the amount of azlactone and the concentration, we obtained the desired product 3a in 94% yield and 82% ee (entry 9). Next, we examined the effects of various substituents on the C5-phenyl group of the azlactone (see the SI for details), and in the presence of azlactone 1b as the nucleophile, the desired product 3b was obtained in 82% yield and 87% ee (entry 10). When the reaction temperature was further decreased to –60 °C, product 3b was obtained in 82% yield and 89% ee in the presence of 15 mol% of G-3 (entry 11). The use of K₃PO₄·H₂O resulted in a slight improvement in the yield (entry 12). To further test the utility of this organocatalytic asymmetric S_NAr reaction, the enantiomer of guanidine G-3 was tested under the standard conditions, and the amino acid derivative ent-3b was obtained in 87% yield and 89% ee (entry 13).

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst	Temp (°C)	Yieldb (%)	eec (%)
1	G-1	–20	74 (3a)	0
2	G-2	–20	66 (3a)	0
3	G-3	–20	82 (3a)	70
4	G-4	–20	43 (3a)	3
5d	G-5	–20	86 (3a)	20
6d	G-6	–20	82 (3a)	13
7	G-7	–20	85 (3a)	66
8	G-8	–20	55 (3a)	0
9e	G-3	–50	94 (3a)	82
10e,f	G-3	–50	82 (3b)	87
11e–g	G-3	–60	82 (3b)	89
12e–h	G-3	–60	85 (3b)	89
13e–h	ent-G-3	–60	87 (ent-3b)	89

^a Unless otherwise noted, the first step of the reaction was carried out with 1a (0.1 mmol), 2a (1.0 equiv), K₃PO₄ (5.0 equiv.), G (10 mol%) in CHCl₃ (0.1 M) at –20 °C.

^b Isolated yields after derivation.

^c Determined by Waters UltraPerformance Convergence Chromatography (UPC²).

^d 48 h.

^e 2a (2.0 equiv) and 1a (0.1 mmol) in CHCl₃ (0.33 M).

^f 1b instead of 1a.

^g G-3 (15 mol%) was used at –60 °C.

^h K₃PO₄·H₂O instead of K₃PO₄.

With the optimized conditions in hand, we investigated the substrate scope for the synthesis of various amino acid derivatives (Table [2]). We initially focused on the azlactone, which provides various amino acid scaffolds for the α-aryl α-alkyl α-amino acid derivatives. Azlactones 1b–e bearing electron-donating or electron-withdrawing aryl groups R¹ were smoothly converted into the corresponding products 3b–e in yields of 69–94% and 80–89% ee (Table [2], entries 2–5). The absolute configuration of product 3d was determined to be R by X-ray crystal-diffraction analysis.[11] Next, azlactones derived from phenylalanine analogues were employed. The electronic properties and position of the substituents on the aromatic ring of the benzyl substituent of azlactones 1f–k had little influence on the enantioselectivity and reactivity, and the corresponding amino acid esters 3f–k were obtained in excellent yields (85–99%) and enantioselectivities (87–93% ee) (entries 6–11). The reaction could also be extended to the alkyl-substituted azlactones 1l–o; when a longer reaction time was employed, the corresponding products 3l–o were obtained in medium yields and ee values (entries 12–15). Additionally, 1,5-difluoro-2,4-dinitrobenzene (2b) as the aryl fluoride was subjected to the S_NAr reaction to give, after the treatment with methanol, the methoxy-substituted product 3p in 89% yield and 93% ee (entry 16).

Table 2 Substrate Scope^a

Entry	R1	R2	Yieldb (%)	eec (%)
1	Ph	Bn	86 (3a)	84
2	4-FC6H4	Bn	85 (3b)	89
3	4-ClC6H4	Bn	70 (3c)	85
4	4-BrC6H4	Bn	69 (3d)	84 (R)
5	4-MeOC6H4	Bn	94 (3e)	80
6	4-FC6H4	4-fluorobenzyl	92 (3f)	87
7	4-FC6H4	4-chlorobenzyl	85 (3g)	87
8	4-FC6H4	4-bromobenzyl	97 (3h)	89
9	4-FC6H4	4-methylbenzyl	99 (3i)	91
10	4-FC6H4	3-fluorobenzyl	89 (3j)	93
11	4-FC6H4	3-methylbenzyl	99 (3k)	89
12d	4-FC6H4	Me	67 (3l)	45
13d	4-FC6H4	Et	71 (3m)	64
14d	Ph	Pr	70 (3n)	49
15d	4-FC6H4	CH2Cy	83 (3o)	56
16e	4-FC6H4	3-fluorobenzyl	89 (3p)	93

^a Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), K₃PO₄·H₂O (5 equiv), G-3 (15 mol%), CHCl₃ (0.33 M), –60 °C, 3 d.

^b Isolated yield.

^c Determined by UPC².

^d 4 d.

^e 2b was used.

Next, to explore the utility of S_NAr reaction of azlactone further, we investigated a series of amino acid esters as nucleophiles to achieve a direct synthesis of peptides. Transformations of azlactone 1j are summarized in Scheme [2]. Representative nonnatural chiral peptides containing a quaternary stereocenter were obtained smoothly, which is beneficial to biochemistry and medicinal chemistry. With methyl glycinate, the reaction proceeded smoothly in the presence of DMAP (1 equiv) to give the desired dipeptide 3q in 92% yield and 93% ee. The transformations of phenylmethanol and methyl glycylglycinate similarly gave the corresponding derivatives 3u and 3v with good enantioselectivities. When optically pure methyl l-leucinate, methyl l-phenylalaninate, and methyl (S)-2-aminopentanoate were added as nucleophiles, the diastereomers of the corresponding dipeptides 3r–t were obtained through the use of the enantiomer of the chiral catalyst. (R,S)-Dipeptides and the related (S,S)-dipeptides with quaternary carbon centers of opposite configuration were directly obtained from the azlactone by using G-3 and ent-G-3, respectively, as catalysts. The scalability of this method was demonstrated by the scaled-up reaction of 1j (2.7 mmol) with 2a (2.0 equiv), which gave the desired chiral amino acid ester 3j in 85% yield (1.12 g) and 87% ee.

In our previous study of chiral guanidine amide organocatalysis,[10] [12] we proposed a general bifunctional catalytic mode for the activation and enantiocontrol in the transformation of azlactones in which the guanidine unit acts as a base to promote the enolization of azlactone 1, and at the same time the electrophile is activated by hydrogen bonding to the amide unit. However, in the current reaction, the aryl substituents on both the amidine unit and the amide are critical in achieving enantioselectivity. In view of the electron-deficient nature of 1-fluoro-2,4-dinitrobenzene (2a) and the color changes that occurred during the reaction, we surmised that another important interaction might be present during the reaction. The UV/vis absorption spectrum of a mixture of 1-fluoro-2,4-dinitrobenzene (2a) with guanidine G-3 showed a clear red shift and the appearance of a yellowish color (Scheme [3a]), which is consistent with the action of 2a as an electron acceptor. In contrast, no signal or color changes occurred with the guanidine and the azlactone, or with 2a and the azlactone. When NMR titration experiments (see SI; S17) were carried out to probe into this interaction, the ¹H NMR signal for 1-fluoro-2,4-dinitrobenzene (2a) showed an obvious high-field shift on addition of guanidine G-3, whereas the protons of the phenyl substituent of the amidine unit of the catalyst showed a low-field shift, indicating the existence of a charge-transfer interaction between electron-deficient 2a and the electron-rich rings of guanidine. Moreover, the catalytic performance of G-3, G-4, and G-7 (Table [1]) indicates that steric hindrance by the amide unit also plays an important role in enantiocontrol. We suggest that hydrogen bonding of azlactone 1 occurs with the amide of the catalyst, blocking one side to attachment of the nucleophile.

Based on the absolute configuration of the product 3d,[11] as well as the interactions suggested by the above experiments, we propose a possible bifunctional catalytic mode (Scheme [3b]). When guanidine G-3 and 1-fluoro-2,4-dinitrobenzene (2a) are mixed, an unstable EDA complex is generated in which the electrophile is located near the amidine unit of the guanidine. The inorganic base accelerates the formation of an enol derivative of the azlactone, which can be bonded by the amide unit, and its Si-face is shielded by the nearby phenyl group of the amide of the catalyst. Next, an addition reaction occurs from the Re-face of the enolized azlactone to form a σ-complex intermediate, which then undergoes a rapid elimination process to yield the quaternary azlactone derivative (R)-3da. After treatment with methanol, the corresponding amino acetate (R)-3d is obtained as the final product.

In conclusion, we have established a catalytic asymmetric S_NAr reaction of azlactones with 1-fluoro-2,4-dinitrobenzene catalyzed by a chiral bifunctional guanidine organocatalyst.[13] A series of α-aryl α-alkyl α-amino acid esters and peptides were obtained in good yields and high stereoselectivities. The introduction of phenyl-based amidine and amide into the guanidine amide catalyst permits a new bifunctional catalytic mode in which the guanidine serves as an electron donor that interacts with the electron-deficient reactants. Studies on further applications of the chiral guanidine catalysts in asymmetric transformations are underway.

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• 13 Chiral Guanidine-Catalyzed Asymmetric S_NAr Reaction; General Procedure A dry tube was charged with G-3 (8.3 mg, 15 mol%), K₃PO₄·H₂O (116 mg, 0.5 mmol), and the appropriate fluoroarene 2 (0.2 mmol). Under a N₂ atmosphere, CHCl₃ (0.3 mL) was added, and the mixture was stirred at 35 °C for 30 min, then cooled to –60 °C for 10 min. The appropriate azlactone 1 (0.1 mmol) was added with stirring, and the mixture was stirred at –60 °C for about 72 h until 1 was fully consumed (TLC). MeOH (1 mL) and DAMP (1.2 mg, 10 mol%) were then added, and the mixture was stirred for about 15 mins at 35 °C. The product was purified by flash column chromatography [silica gel, PE–DCM (1:1)]. Methyl α-(2,4-dinitrophenyl)-N-(4-Fluorobenzoyl)-l-phenylalaninate (3b) White solid; yield: 39.7 mg (85%; 89% ee); mp 186–188 °C; [α]_D ¹⁶ –26.4 (c 0.664, CH₂Cl₂). UPC² (chiral IB-3 column, CO₂ /MeOH = 90:10, flow rate 1.5 mL/min, λ = 254 nm): t _R (minor) = 4.1 min; t _R (major) = 5.3 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.57–8.51 (m, 1 H), 8.46–8.40 (m, 1 H), 8.29–8.21 (m, 1 H), 7.60–7.51 (m, 2 H), 7.32–7.19 (m, 3 H), 7.14–6.93 (m, 5 H), 4.33 (d, J = 18.8 Hz, 1 H), 3.85 (s, 3 H), 3.75 (d, J = 18.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 166.4 (d, J = 251.7 Hz), 165.6, 148.3, 147.1, 140.3, 133.4, 130.8, 130.1, 129.4 (d, J = 9.1 Hz), 129.2 ( d, J = 3.2 Hz), 128.5, 128.0, 126.4, 119.8, 116.0 (d, J = 22.1 Hz), 64.0, 53.8, 40.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.6. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₃H₁₉FN₃O₇ = 468.1202; found: 468.1191.

Corresponding Author

Publication History

Received: 20 October 2020

Accepted after revision: 25 November 2020

Accepted Manuscript online:
25 November 2020

Article published online:
16 December 2020

© 2020. Thieme. All rights reserved

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• References and Notes

• 1a Venkatraman J, Shankaramma SC, Balaram P. Chem. Rev. 2001; 101: 3131
  CrossrefPubMedSearch in Google Scholar
• 1b Licini G, Prins LJ, Scrimin P. Eur. J. Org. Chem. 2005; 2005: 969
  CrossrefPubMedSearch in Google Scholar
• 1c Cardillo G, Gentilucci L, Tolomelli A. Mini-Rev. Med. Chem. 2006; 6: 293
  CrossrefPubMedSearch in Google Scholar
• 1d Hedges JB, Ryan KS. Chem. Rev. 2020; 120: 3161
  CrossrefPubMedSearch in Google Scholar
• 2 Cativiela C, Ordóñez M, Viveros-Ceballos JL. Tetrahedron 2020; 76: 130875
  CrossrefPubMedSearch in Google Scholar
• 3a Johansson CC. C, Colacot TJ. Angew. Chem. Int. Ed. 2010; 49: 676
  CrossrefPubMedSearch in Google Scholar
• 3b Hao Y.-J, Hu X.-S, Zhou Y, Zhou J, Yu J.-S. ACS Catal. 2020; 10: 955
  CrossrefSearch in Google Scholar

For selected examples of asymmetric syntheses of quaternary amino acid derivatives from amino acid derivatives by ‘chiral memory’, see:
• 4a Tomohara K, Yoshimura T, Hyakutake R, Yang P, Kawabata T. J. Am. Chem. Soc. 2013; 135: 13294
  CrossrefPubMedSearch in Google Scholar
• 4b Atkinson RC, Fernández-Nieto F, Roselló MJ, Clayden J. Angew. Chem. Int. Ed. 2015; 54: 8961
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• 4c Kasamatsu K, Yoshimura T, Mandi A, Taniguchi T, Monde K, Furuta T, Kawabata T. Org. Lett. 2017; 19: 352
  CrossrefPubMedSearch in Google Scholar
• 4d Costil R, Fernández-Nieto F, Atkinson RC, Clayden J. Org. Biomol. Chem. 2018; 16: 2757
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• 4e Leonard DJ, Ward JW, Clayden J. Nature 2018; 562: 105
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• 4f Mambrini A, Gori D, Kouklovsky C, Kim H, Yoshida J.-i, Alezra V. Eur. J. Org. Chem. 2018; 6754
• 5a Bunnett JF, Zahler RE. Chem. Rev. 1951; 49: 273
  CrossrefSearch in Google Scholar
• 5b Terrier F. Modern Nucleophilic Aromatic Substitution . Wiley-VCH; Weinheim: 2013
  Search in Google Scholar
• 5c Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds. Mortier J. Wiley-VCH; Weinheim: 2016
  Search in Google Scholar
• 5d Asymmetric Dearomatization Reactions . You SL. Wiley-VCH; Weinheim: 2016
  Search in Google Scholar
• 6a Shirakawa S, Yamamoto K, Tokuda T, Maruoka K. Asian J. Org. Chem. 2014; 3: 433
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• 6b Shirakawa S, Yamamoto K, Maruoka K. Angew. Chem. Int. Ed. 2015; 54: 838
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• 7 Li G, Sun W, Li J, Jia F, Hong L, Wang R. Chem. Commun. 2015; 51: 11280
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• 8a D’Anello M, Erba E, Gelmi ML, Pocar D. Chem. Ber. 1988; 121: 67
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• 8b Teegardin KA, Weaver JD. Chem. Commun. 2017; 53: 4771
  CrossrefPubMedSearch in Google Scholar
• 8c Marra IF. S, de Castro PP, Amarante GW. Eur. J. Org. Chem. 2019; 5830
• 8d Wang Y.-N, Xiong Q, Lu LQ, Zhang Q.-L, Wang Y, Lan Y, Xiao W.-J. Angew. Chem. Int. Ed. 2019; 58: 11013
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  CrossrefPubMedSearch in Google Scholar
• 8f Xie M.-S, Huang B, Li N, Tian Y, Wu X.-X, Deng Y, Qu G.-R, Guo H.-M. J. Am. Chem. Soc. 2020; 142: 19226
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• 9a Bella M, Kobbelgaard S, Jørgensen KA. J. Am. Chem. Soc. 2005; 127: 3670
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• 9b Bella M, Kobbelgaard S, Jørgensen KA. J. Org. Chem. 2006; 71: 4980
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• 9c Armstrong RJ, Smith MD. Angew. Chem. Int. Ed. 2014; 53: 12822
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• 9d Shirakawa S, Koga K, Tokuda T, Yamamoto K, Maruoka K. Angew. Chem. Int. Ed. 2014; 53: 6220
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• 13 Chiral Guanidine-Catalyzed Asymmetric S_NAr Reaction; General Procedure A dry tube was charged with G-3 (8.3 mg, 15 mol%), K₃PO₄·H₂O (116 mg, 0.5 mmol), and the appropriate fluoroarene 2 (0.2 mmol). Under a N₂ atmosphere, CHCl₃ (0.3 mL) was added, and the mixture was stirred at 35 °C for 30 min, then cooled to –60 °C for 10 min. The appropriate azlactone 1 (0.1 mmol) was added with stirring, and the mixture was stirred at –60 °C for about 72 h until 1 was fully consumed (TLC). MeOH (1 mL) and DAMP (1.2 mg, 10 mol%) were then added, and the mixture was stirred for about 15 mins at 35 °C. The product was purified by flash column chromatography [silica gel, PE–DCM (1:1)]. Methyl α-(2,4-dinitrophenyl)-N-(4-Fluorobenzoyl)-l-phenylalaninate (3b) White solid; yield: 39.7 mg (85%; 89% ee); mp 186–188 °C; [α]_D ¹⁶ –26.4 (c 0.664, CH₂Cl₂). UPC² (chiral IB-3 column, CO₂ /MeOH = 90:10, flow rate 1.5 mL/min, λ = 254 nm): t _R (minor) = 4.1 min; t _R (major) = 5.3 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.57–8.51 (m, 1 H), 8.46–8.40 (m, 1 H), 8.29–8.21 (m, 1 H), 7.60–7.51 (m, 2 H), 7.32–7.19 (m, 3 H), 7.14–6.93 (m, 5 H), 4.33 (d, J = 18.8 Hz, 1 H), 3.85 (s, 3 H), 3.75 (d, J = 18.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 166.4 (d, J = 251.7 Hz), 165.6, 148.3, 147.1, 140.3, 133.4, 130.8, 130.1, 129.4 (d, J = 9.1 Hz), 129.2 ( d, J = 3.2 Hz), 128.5, 128.0, 126.4, 119.8, 116.0 (d, J = 22.1 Hz), 64.0, 53.8, 40.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.6. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₃H₁₉FN₃O₇ = 468.1202; found: 468.1191.

• Supplementary Material