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Abstract

Enantioselective synthesis of α-amino esters have been achieved through the Petasis borono-Mannich multicomponent reaction using (R)-BINOL-derived catalysts with stable heteroaryl and alkenyl trifluoroborate salts under mild conditions. The reaction provides direct access to optically active α-amino esters with moderate to good yields and enantioselectivities.

Keywords

α-amino esters enantioselective synthesis Petasis borono-Mannich reaction trifluoroborate salts

Introduction

α-Amino acids are widely found in bioactive natural products and medicinal compounds.^1,2 Since α-amino esters were recognized as main precursors of α-amino acid derivatives, much efforts have been devoted to the synthesis of α-amino esters including organometallics addition^3–5 or metal-catalyzed addition reactions,^6–9 Friedel–Crafts reactions,^10–13 Mannich reactions,^14,15 Michael additions,¹⁶ hydrogenations,^17,18 [4+2] cycloadditions,^19–22 and so on. Among them, Petasis borono-Mannich (PBM) reaction highlighted the prominence toward the facile synthesis of α-amino esters in which highly functionalized products were obtained from simple aldehydes, amines, and boronic acid precursors.²³

Besides excellent functional group compatibility with the great tolerance of air and moisture, PBM multicomponent reaction usually requires aldehydes with an adjacent heteroatom directing group to form a boron “ate” complex where the boronic acid nucleophiles were likely activated for further addition.²⁴ Recently, Carrera’s group²⁵ reported acid-promoted addition of organotrifluoroborate salts to imines and enamines with the elimination of pendant heteroatom on the iminium intermediate (Scheme 1(a)). Pioneered by Lou and Schaus,²⁶ catalytic asymmetric PBM reaction provides direct access to induce the enantioenriched α-amino esters by employing alkenyl boronates and biphenol-derived catalysts (Scheme 1(b)). Muncipinto et al.²⁷ established catalytic diastereoselective PBM reaction of α-hydroxyaldehydes with secondary amines. Although several groups including Yamaoka et al.,²⁸ Han et al.,²⁹ and Au and Pyne³⁰ have been involved in the development of catalytic asymmetric PBM reaction, poor activity of these reaction systems with modest enantioselectivity was often observed between boronic acids or their esters with corresponding reaction partners.

Scheme 1.

(a) Acid-promoted Petasis borono-Mannich reactions of trifluoroborate salts. (b) Catalytic asymmetric Petasis borono-Mannich reactions of boronate esters. (c) This work: enantioselective synthesis of α-amino esters via Petasis borono-Mannich reaction of trifluoroborate salts.

To address the continued lack of such methods, we envisioned the application of chiral biphenol catalysts and trifluoroborate salts would overcome the above-mentioned limitations by taking advantage of the multicomponent strategy of the PBM reaction. The use of trifluoroborate salts would be preferred to boronic acids or boronate esters from a practical standpoint for ease of use and long-term stability. Here, we describe the successful implementation of this concept for the synthesis of optical active α-amino esters by the one-pot strategy of the PBM reaction in the presence of trifluoroborate salts, ethyl glyoxylates in combination with aromatic or aliphatic amines.

Results and discussion

Encouraged by Lou et al.³¹ and Jiang et al.’s work,³² our research was initiated with amine 1b, ethyl glyoxylate 2a, and trifluoroborate salts 3a in the presence of 4 Å MS and chiral ligand L4. The initial attempt afforded the desired product α-amino ester 4a in 14% yield and 64% ee (Table 1, entry 1). It was indicated by thin-layer chromatography (TLC) that the imine intermediate was not completely consumed during the reaction. Various additives such as BF₃·OEt₂,^33–37 LiBr,³⁸ (nBu)₄NHSO₄,³⁹ and (nBu)₄NBr⁴⁰ were carefully screened for the activation of trifluoroborate salts.^41–49 In general, the addition of additives indeed provided the desired products with moderate yields, albeit in low enantioselectivity (Table 1, entries 2–5). The full consumption of imine intermediate was achieved to provide 4a in a higher yield (55%) with promising enantiomeric excess (ee) of 70% where 4 Å MS and LiBr were employed as additives (Table 1, entry 6). Subsequently, different lithium salts³⁸ were examined (Table 1, entries 7–13). It was found that 3 equiv of LiBr in combination with solvent such as PhCF₃ was the best choice regarding the yield and enantioselectivity of the reaction. May also reported the use of lithium salts such as LiBr which promoted the rate of addition by driving the fluoride dissociation of trifluoroborate salts. Based on the above condition, a series of (R)-BINOL derivatives^41–49 were also evaluated in order to improve the yield and enantioselectivity of PBM reaction. Electron-withdrawing substituents at 3,3′-positions of chiral ligand did not result in higher enantioselectivity (Table 1, entries 15–17). Diminished enantioselectivity was also observed from ligand L5 which possess large substituents at the 3,3′-positions (Table 1, entry 17).

Table 1.

Optimization of the reaction conditions.^a


Entry	Catalyst	Additive (s)	Solvent	Yield (%)^b	ee (%)^c
1	L4	4 Å MS (125 mg)	PhCF₃	14	64
2	L4	LiClO₄ (0.5 equiv), (nBu)₄NHSO₄ (0.5 equiv)	PhCF₃	50	0
3	L4	LiClO₄ (0.5 equiv), (nBu)₄NBr (0.5 equiv)	PhCF₃	47	1
4	L4	4 Å MS (125 mg), LiBr (3.0 equiv), BF₃·Et₂O (3.0 equiv)	PhCF₃	41	6
5	L4	4 Å MS (125 mg), BF₃·Et₂O (1.0 equiv)	PhCF₃	41	5
6	L4	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCF₃	55	70
7	L4	4 Å MS (125 mg), LiI (3.0 equiv)	PhCF₃	23	13
8	L4	4 Å MS (125 mg), LiCl (3.0 equiv)	PhCF₃	50	45
9	L4	4 Å MS (125 mg), LiClO₄ (3.0 equiv)	PhCF₃	33	50
10	L4	4 Å MS (125 mg), LiBr (3.0 equiv)	THF	20	2
11	L4	4 Å MS (125 mg), LiBr (3.0 equiv)	CH₂Cl₂	27	20
12	L4	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCH₃	29	73
13	L4	4 Å MS (125 mg), LiBr (3.0 equiv)	MTBE	35	51
14	L1	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCF₃	NR	–
15	L2	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCF₃	23	39
16	L3	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCF₃	52	50
17	L5	4 Å MS (125 mg), LiBr (3.0 equiv)	PhCF₃	52	52

MTBE: methyl tert-butyl ether; HPLC: high-performance liquid chromatography; NR: no reaction.

General reaction conditions: 1b:2a:3a = 1:1.2:2, solvent (0.1 M), 12 h, 35°C, under air.

Determined by integration of ¹H NMR signals relative to triphenylmethane as an internal standard.

Ratio determined by HPLC with a Daicel Chiralpak column.

With the optimized reaction conditions in hand, the scope of the heteroaryl trifluoroborate salts^50–53 was then examined (Table 2). Electron-rich heteroaryl trifluoroborate salts such as thiophene, furan, pyrrole, and indole underwent the direct addition, providing the products with good levels of enantioselectivities. It was found that the 5-substituted-2-heteroaryl trifluoroborate salts resulted in products 4b and 4d with diminished enantioselectivities (Table 2, entries 2 and 4). When we switched to pyrrole-2-trifluoroborate salts as nucleophiles, only racemic products of such reaction were accessed in reasonable yields (Table 2, entries 5–6). Benzo-fused heterocycles provided products in moderate enantioselectivities (entries 7–8). In the case of N-Boc-indoles-derived potassium trifluoroborate salts, the corresponding products were accomplished with low enantiose-lectivities (entries 9 and 10).

Table 2.

Scope of the heteroaryl trifluoroborate salts.^a


Entry	Nucleophile	Product	Time (h)	Yield (%)^b	ee (%)^c
1 2		4a 4b	8 48	50 54	70 8
3 4		4c 4d	5 4	69 52	52 3
5 6		4e 4f	10 4	60 54	5 0
7 8		4g 4h	24 24	15 52	71 71
9 10		4i 4j	5 8	80 55	44 38

HPLC: high-performance liquid chromatography.

General reaction conditions: 1b:2a:3 = 1:1.2:2, 4 Å MS (125 mg), PhCF₃ (0.1 M), LiBr (3 equiv), 35°C, under air.

Isolated yield.

Ratio determined by HPLC using a Daicel Chiralpak column.

A diverse and representative scope of amines with heteroaryl and alkenyl trifluoroborate salts was well tolerated for this process (Table 3). Good yields and enantioselectivities were obtained when the alkenyl trifluoroborate salts were employed (Table 3, entries 1 and 2). The functional group tolerance of primary amines was also investigated in which oxygen-, nitrogen-, and sulfur-containing heterocyclic trifluoroborates served as nucleophiles and exhibited similar yields and different enantioselectivities (Table 3, entries 3–5). Notably, only trace amount of desired product 4p was formed when 3-methoxyaniline was applied as primary amine under optimized conditions (Table 3, entry 6). The effect of varying into 2-furaldehyde was then examined where the reaction may not be acidic enough to proceed further (Table 3, entry 7). It was suspected that the group of ethyl glyoxylate still imposes strong effect for the activation of trifluoroborate salts in the reaction.^54,55

Table 3.

Scope of various amines with heteroaryl or alkenyl trifluoroborate salts.^a


Entry	Amine	Aldehyde	Nucleophile	Product	Time (h)	Yield (%)^b	ee (%)^c
1	1a	2a		4k	15	65	82
2	1b	2a		4l	24	60	80
3	1c	2a		4m	8	82	69
4	1c	2a		4n	8	82	17
5	1c	2a		4o	12	54	7
6	1d	2a		4p	8	6	54
7	1b			4q	48	NR	–

HPLC: high-performance liquid chromatography.

General reaction conditions: 1:2:3 = 1:1.2:2, 4 Å MS (125 mg), PhCF₃ (0.1 M), LiBr (3 equiv), 35°C, under air.

Isolated yield.

Ratio determined by HPLC with a Daicel Chiralpak column.

Conclusion

In conclusion, α-amino esters as precursors of unnatural amino acid derivatives play a pivotal role in both medicinal chemistry and chemical biology. We developed an efficient method toward the enantioselective synthesis of heterocyclic-derived α-amino esters through BINOL-catalyzed PBM multicomponent reaction under mild conditions. The reaction performs well for both stable alkenyl and heteroaryl trifluoroborate salts, in addition with a series of aromatic and aliphatic amines. The synthetic applications of such method will be further explored in our laboratory.

Experimental

General

Melting points were determined using a Büchi B-540 capillary melting point apparatus. NMR data including ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were recorded on Bruker 400 MHz or 600 MHz. All of the ¹³C NMR spectra were broad band proton-decoupled. ¹H NMR Chemical shifts were reported in ppm relative to residual signals of the solvents (CDCl₃: 7.26 ppm; (CD₃)₂SO: 2.50 ppm). ¹³C NMR chemical shifts were reported in ppm relative to the solvent (CDCl₃: 77.16 ppm; (CD₃)₂SO: 39.52 ppm). Hexafluor-obenzene (δ = –164.9 ppm) was employed as an external standard in ¹⁹F NMR spectra. Coupling constants J are given in Hertz (Hz). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet or as a combination of them. High-resolution mass spectra (HRMS) were recorded on an Agilent 6210 TOF LC/MS using electron spray ionization (ESI) as ion source. Optical rotations were determined using an AUTOPOL V automatic polarimeter. Enantiomeric excess (ee) was determined by high-performance liquid chromatography (HPLC) analysis using Agilent 1100 HPLC equipped with Daicel Chiralpak IA, IB, IC, IF, IG, and AS-H columns.

General procedure for the enantioselective synthesis of α-amino ester derivatives (4a-p) through PBM reaction

To a 25-mL vial equipped with a stir bar, 4 Å powdered molecular sieves (125 mg) was added. The amine 1 (0.1 mmol, 1.0 equiv), ethyl glyoxylate 2a (0.12 mmol, 1.2 equiv), L4 (0.02 mmol, 0.2 equiv), trifluoroborate salts 3 (0.2 mmol, 2.0 equiv), and LiBr (0.3 mmol, 3.0 equiv) were then added. PhCF₃ (2 mL, 0.05 M) was added. The reaction was heated to 35°C and monitored by TLC analysis. After the reaction is complete, the solution was filtered through a short celite pad. The combined organic layer was concentrated under reduced pressure and purified via flash column chromatography on silica gel to afford the corresponding products 4.

Ethyl 2-((4-methoxyphenyl)amino)-2-(thiophen-2-yl)acetate (4a)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 50% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.22 (dd, J = 5.1, 1.2 Hz, 1H), 7.14–7.10 (m, 1H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 6.74 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 5.26 (s, 1H), 4.33–4.14 (m, 2H), 3.70 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) (Supplemental material, S24). ¹³C NMR (101 MHz, CDCl₃): δ 171.2, 153.0, 141.7, 140.1, 127.1, 125.6, 125.5, 115.3, 114.9, 62.1, 58.0, 55.7, 14.1 ppm. HRMS (ESI) m/z calcd. for C₁₅H₁₈NO₃S [M+H]⁺: 292.1102; found 292.1104 (Supplemental material, S24). [α]_D20 = −5.0 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 70% (n-Hexane/ethanol = 70/30, flow rate 1 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 14.212 min, t_r (minor) = 16.317 min).

Ethyl 2-(5-bromothiophen-2-yl)-2-((4-methoxyphenyl)amino)acetate (4b)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 54% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 6.95–6.86 (m, 2H), 6.76 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 5.14 (s, 1H), 4.31–4.17 (m, 2H), 3.73 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) (Supplemental material, S25). ¹³C NMR (101 MHz, CDCl₃): δ 170.5, 153.3, 143.6, 139.7, 130.1, 125.9, 115.4, 115.0, 112.3, 62.5, 58.3, 55.8, 14.2 ppm (Supplemental material, S25). HRMS (ESI) m/z calcd. for C₁₅H₁₇BrNO₃S [M+H]⁺: 370.0107; found 370.0091. [α]_D20 = −1.4 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 8% (n-Hexane/ethanol = 80/20, flow rate 0.8 mL min⁻¹, λ = 254 nm, T = 20°C, t_r (major) = 21.206 min, t_r (minor) = 23.235 min).

Ethyl 2-(furan-2-yl)-2-((4-methoxyphenyl)amino)acetate (4c)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 69% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (dd, J = 1.8, 0.9 Hz, 1H), 6.83–6.70 (m, 2H), 6.69–6.59 (m, 2H), 6.40–6.26 (m, 2H), 5.13 (s, 1H), 4.29–4.13 (m, 2H), 3.73 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) (Supplemental material, S26). ¹³C NMR (101 MHz, CDCl₃): δ 170.3, 153.1, 150.5, 142.8, 140.0, 115.5, 114.9, 110.7, 108.2, 62.1, 56.4, 55.8, 14.2 ppm (Supplemental material, S26). HRMS (ESI) m/z calcd. for C₁₅H₁₇NNaO₄ [M+Na]⁺: 298.1050; found 298.1060. [α]_D20 = −37.6 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IF column, ee = 52% (n-Hexane/ethanol = 95/5, flow rate 0.7 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 25.185 min, t_r (minor) = 23.940 min).

Ethyl 2-((4-methoxyphenyl)amino)-2-(5-methylfuran-2-yl)acetate (4d)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 52% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 6.82–6.69 (m, 2H), 6.68–6.59 (m, 2H), 6.22 (d, J = 3.1 Hz, 1H), 5.91 (m, 1H), 5.06 (s, 1H), 4.34–4.06 (m, 2H), 3.72 (s, 3H), 2.27 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) (Supplemental material, S27). ¹³C NMR (101 MHz, CDCl₃): δ 170.6, 153.0, 152.6, 148.4, 140.2, 115.5, 114.9, 109.0, 106.6, 61.9, 56.5, 55.7, 14.2, 13.7 ppm (Supplemental material, S27). HRMS (ESI) m/z calcd. for C₁₆H₂₀NO₄ [M+H]⁺: 290.1387; found 290.1385. [α]_D20 = −1.8 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 3% (n-Hexane/ethanol = 80/20, flow rate 0.8 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 18.173 min, t_r (minor) = 19.782 min).

tert-Butyl-2-(2-ethoxy-1-((4-methoxyphenyl)amino)-2-oxoethyl)-1H-pyrrole-1-carboxylate (4e)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 60% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.24–7.18 (m, 1H), 6.78–6.71 (m, 2H), 6.71–6.63 (m, 2H), 6.28 (dd, J = 3.5, 1.8 Hz, 1H), 6.09 (t, J = 3.4 Hz, 1H), 5.67 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 1.58 (s, 9H), 1.26 – 1.17 (m, 3H) (Supplemental material, S28). ¹³C NMR (101 MHz, CDCl₃): δ 171.4, 152.8, 149.4, 140.7, 131.1, 122.6, 115.7, 114.8, 114.2, 110.2, 84.3, 77.4, 61.7, 56.1, 55.7, 28.1, 14.3 ppm (Supplemental material, S28). HRMS (ESI) m/z calcd. for C₂₀H₂₇N₂O₅ [M+H]⁺: 375.1914; found 375.1903. [α]_D20 = −11.6 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IF column, ee = 5% (n-Hexane/ethanol = 80/20, flow rate 0.8 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 8.238 min, t_r (minor) = 9.124 min).

Ethyl 2-((4-methoxyphenyl)amino)-2-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)acetate (4f)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 20:1) to afford the yellow oil in 54% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (dd, J = 8.6, 1.3 Hz, 2H), 7.56–7.50 (m, 1H), 7.40–7.34 (m, 3H), 6.78–6.72 (m, 2H), 6.55 (d, J = 8.9 Hz, 2H), 6.29–6.24 (m, 2H), 5.71 (s, 1H), 4.14 (m, J = 7.1, 3.2 Hz, 2H), 3.75 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) (Supplemental material, S29). ¹³C NMR (101 MHz, CDCl₃): δ 171.6, 153.2, 140.1, 139.3, 133.8, 131.2, 129.1, 127.4, 124.4, 115.7, 114.8, 114.6, 111.6, 61.8, 55.8, 54.4, 14.2 ppm (Supplemental material, S29). HRMS (ESI) m/z calcd. for C₂₁H₂₂N₂NaO₅S [M+Na]⁺: 437.1142; found 437.1132. [α]_D20 = −2.2 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IF column, ee = 0% (n-Hexane/ethanol = 90/10, flow rate 1 mL min⁻¹, λ = 254 nm, T = 20°C, t_r = 16.789 min, t_r = 19.107 min).

Ethyl 2-(benzo[b]thiophen-2-yl)-2-((4-methoxyphenyl)amino)acetate (4g)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 15% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.84–7.66 (m, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.31 (pd, J = 7.2, 1.4 Hz, 1H), 6.77–6.71 (m, 2H), 6.69–6.62 (m, 2H), 5.32 (d, J = 1.0 Hz, 2H), 4.50–4.01 (m, 3H), 3.71 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) (Supplemental material, S30). ¹³C NMR (101 MHz, CDCl₃): δ 170.7, 153.1, 142.8, 139.8, 139.7, 124.5, 124.5, 123.7, 122.5, 122.5, 115.4, 115.0, 62.5, 58.6, 55.8, 14.2, 1.2 ppm (Supplemental material, S30). HRMS (ESI) m/z calcd. for C₁₉H₂₀NO₃S [M+H]⁺: 342.1158; found 342.1154. [α]_D20 = −3.4 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 71% (n-Hexane/ethanol = 80/20, flow rate 0.8 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 47.504 min, t_r (minor) = 51.387 min).

Ethyl 2-((4-methoxyphenyl)amino)-2-(5-methylfuran-2-yl)acetate (4h)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 52% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.50 (m, 2H), 7.29 (dd, J = 7.2, 1.3 Hz, 1H), 7.21 (td, J = 7.5, 1.1 Hz, 1H), 6.78–6.73 (m, 3H), 6.68 (d, J = 9.0 Hz, 2H), 5.25 (s, 1H), 4.38–4.15 (m, 2H), 3.72 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) (Supplemental material, S31). ¹³C NMR (101 MHz, CDCl₃): δ 169.8, 155.1, 153.3, 153.2, 139.5, 128.1, 124.6, 123.1, 121.3, 115.7, 114.9, 111.6, 105.3, 62.5, 56.9, 55.8, 29.8, 14.2 ppm (Supplemental material, S31). HRMS (ESI) m/z calcd. for C₁₉H₁₉NNaO₄ [M+Na]⁺: 348.1206; found 348.1198. [α]_D20 = −15.6 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 71% (n-Hexane/ethanol = 80/20, flow rate 0.8 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 31.296 min, t_r (minor) = 34.523 min).

tert-Butyl 3-(2-ethoxy-1-((4-methoxyphenyl)amino)-2-oxoethyl)-1H-indole-1-carboxylate (4i)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 20:1) to afford the yellow oil in 80% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 8.15 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 7.9, 1.2 Hz, 1H), 7.64 (s, 1H), 7.36–7.31 (m, 1H), 7.29–7.26 (m, 1H), 6.78–6.71 (m, 2H), 6.66–6.59 (m, 2H), 5.26 (s, 1H), 4.20 (ddq, J = 43.9, 10.7, 7.1 Hz, 2H), 3.72 (s, 3H), 1.65 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H) (Supplemental material, S32). ¹³C NMR (101 MHz, CDCl₃): δ 172.1, 152.8, 140.6, 136.4, 132.9, 128.7, 128.1, 126.8, 125.5, 121.5, 115.2, 115.0, 114.5, 61.9, 60.0, 55.9, 55.6, 29.8, 14.3 ppm (Supplemental material, S32). HRMS (ESI) m/z calcd. for C₂₄H₂₈N₂O₅ [M+H]⁺: 425.2071; found 425.2056. [α]_D20 = −17.2 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IB column, ee = 44% (n-Hexane/ethanol = 95/5, flow rate 1 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 9.787 min, t_r (minor) = 11.029 min).

tert-Butyl-5-bromo-3-(2-ethoxy-1-((4-methoxyphenyl)amino)-2-oxoethyl)-1H-indole-1-carboxylate (4j)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 20:1) to afford the white solid in 55% yield at 0.1 mmol scale. ¹H NMR (400 MHz, DMSO-d₆): δ 8.07 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.50 (dd, J = 8.9, 2.0 Hz, 1H), 6.72 (s, 3H), 6.06 (d, J = 8.9 Hz, 1H), 5.54–5.46 (m, 1H), 4.20–4.02 (m, 2H), 3.34 (s, 3H), 1.63 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H) (Supplemental material, S33). ¹³C NMR (101 MHz, DMSO-d₆): δ 172.1, 152.0, 149.1, 141.6, 134.1, 130.8, 127.7, 126.4, 123.4, 117.4, 117.1, 115.8, 114.9, 114.8, 85.1, 61.5, 55.7, 53.7, 28.1, 14.5 ppm (Supplemental material, S33). HRMS (ESI) m/z calcd. for C₂₄H₂₈BrN₂O₅ [M+H]⁺: 503.1176; found 503.1155. m.p.: 102.5–104.6°C. [α]_D20 = −6.8 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IB column, ee = 38% (n-Hexane/ethanol = 95/5, flow rate 0.8 mL min⁻¹, λ = 230 nm, T = 20°C, t_r (major) = 10.045 min, t_r (minor) = 11.153 min).

Ethyl (E)-2-(dibenzylamino)-4-phenylbut-3-enoate (4k)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the colorless oil in 65% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.46–7.39 (m, 4H), 7.42–7.34 (m, 2H), 7.31 (td, J = 7.4, 3.1 Hz, 6H), 7.23 (ddd, J = 7.4, 5.6, 1.4 Hz, 3H), 6.57 (dd, J = 16.1, 1.2 Hz, 1H), 6.37 (dd, J = 16.1, 7.0 Hz, 1H), 4.33–4.17 (m, 2H), 4.10 (dd, J = 7.1, 1.3 Hz, 1H), 3.90–3.69 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H) (Supplemental material, S34). ¹³C NMR (101 MHz, CDCl₃): δ 172.1, 139.7, 136.7, 134.3, 128.8, 128.7, 128.4, 128.0, 127.1, 126.7, 124.6, 64.0, 60.8, 54.8, 14.6 ppm (Supplemental material, S34). HRMS (ESI) m/z calcd. for C₂₆H₂₈NO₂ [M+H]⁺: 386.2115; found 386.2129. [α]_D20 = −68.6 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 82% (n-Hexane/ethanol = 70/30, flow rate 1 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 4.640 min, t_r (minor) = 5.640 min).

Ethyl (E)-2-((4-methoxyphenyl)amino)-4-phenylbut-3-enoate (4l)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 60% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): 7.40–7.35 (m, 2H), 7.34–7.28 (m, 2H), 6.82–6.74 (m, 3H), 6.64 (d, J = 8.9 Hz, 2H), 6.29 (dd, J = 15.9, 5.9 Hz, 1H), 4.65 (dd, J = 5.9, 1.5 Hz, 1H), 4.24 (p, J = 7.2 Hz, 2H), 3.73 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H) (Supplemental material, S35). ¹³C NMR (101 MHz, CDCl₃): δ 172.1, 152.8, 140.6, 136.4, 132.9, 128.7, 128.1, 126.8, 125.5, 115.2, 115.0, 61.9, 60.0, 55.9, 14.3 ppm (Supplemental material, S35). HRMS (ESI) m/z calcd. for C₁₉H₂₂NO₃ [M+H]⁺: 312.1594; found 312.1604. [α]_D20 = −14.8 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 80% (n-Hexane/Ethanol = 70/30, flow rate 1 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 21.573 min, t_r (minor) = 31.569 min).

Ethyl 2-((2-bromo-4-methoxyphenyl)amino)-2-(thiophen-2-yl)acetate (4m)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 82% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.24 (dd, J = 5.1, 1.2 Hz, 1H), 7.14 (dt, J = 3.5, 0.9 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 6.69 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 5.28 (s, 1H), 4.33–4.14 (m, 2H), 3.69 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) (Supplemental material, S36). ¹³C NMR (101 MHz, CDCl₃): δ 170.5, 152.5, 141.1, 137.4, 127.2, 125.8, 125.7, 118.5, 114.4, 113.4, 110.9, 62.3, 57.7, 55.9, 14.1 ppm (Supplemental material, S36). HRMS (ESI) m/z calcd. for C₁₅H₁₆BrNNaO₃S [M+Na]⁺: 391.9926; found 391.9910. [α]_D20 = −4.8 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IB column, ee = 69% (n-Hexane/ethanol = 95/5, flow rate 0.8 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 9.029 min, t_r (minor) = 7.730 min).

Ethyl 2-((2-bromo-4-methoxyphenyl)amino)-2-(furan-2-yl)acetate (4n)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the colorless oil in 82% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.40 (dd, J = 1.8, 0.9 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.8 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.40–6.30 (m, 2H), 5.16 (s, 1H), 4.32–4.18 (m, 2H), 3.71 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) (Supplemental material, S37). ¹³C NMR (101 MHz, CDCl₃): δ 169.7, 152.6, 150.0, 142.9, 137.4, 118.5, 114.4, 113.4, 111.0, 110.8, 108.3, 62.3, 56.1, 56.0, 14.2 ppm (Supplemental material, S37). HRMS (ESI) m/z calcd. for C₁₅H₁₆BrNNaO₄ [M+Na]⁺: 376.0155; found 376.0147. [α]_D20 = −8.0 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak AS-H column, ee = 17% (n-Hexane/ethanol = 90/10, flow rate 0.7 mL min⁻¹, λ = 210 nm, T = 20°C, t_r (major) = 10.669 min, t_r (minor) = 9.456 min).

tert-Butyl-2-(1-((2-bromo-4-methoxyphenyl)amino)-2-ethoxy-2-oxoethyl)-1H-pyrrole-1-carboxylate (4o)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 54% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 7.21 (dd, J = 3.3, 1.8 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 8.9, 2.7 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 6.28 (dd, J = 3.4, 1.8 Hz, 1H), 6.09 (t, J = 3.4 Hz, 1H), 5.71 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 1.59 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H) (Supplemental material, S38). ¹³C NMR (101 MHz, CDCl₃): δ 170.8, 152.3, 149.4, 138.1, 130.6, 122.7, 118.3, 117.6, 116.8, 115.2, 114.5, 114.4, 113.8, 110.9, 110.3, 84.5, 61.8, 56.0, 55.8, 28.1, 14.3 ppm (Supplemental material, S38). HRMS (ESI) m/z calcd. for C₂₀H₂₅BrN₂O₅ [M+H]⁺: 453.1009; found 453.1020. [α]_D20 = −4.0 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IF column, ee = 7% (n-Hexane/ethanol = 95/5, flow rate 0.8 mL min⁻¹, λ = 254 nm, T = 20°C, t_r (major) = 9.368 min, t_r (minor) = 10.075 min).

tert-Butyl 3-(2-ethoxy-1-((3-methoxyphenyl)amino)-2-oxoethyl)-1H-indole-1-carboxylate (4p)

The product was purified via flash column chromatography (n-Hexane/EtOAc = 30:1) to afford the yellow oil in 6% yield at 0.1 mmol scale. ¹H NMR (400 MHz, CDCl₃): δ 8.15 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.31–7.23 (m, 3H), 7.06 (t, J = 7.8 Hz, 1H), 6.29 (dd, J = 17.9, 8.2 Hz, 3H), 6.21 (s, 1H), 5.31 (s, 1H), 4.34–4.09 (m, 2H), 3.73 (d, J = 2.3 Hz, 3H), 1.65 (s, 9H), 1.24–1.20 (t, J = 7.1 Hz, 3H) (Supplemental material, S39). ¹³C NMR (101 MHz, CDCl₃): δ 171.8, 160.8, 149.6, 147.8, 130.2, 128.6, 124.9, 124.5, 122.9, 119.9, 117.4, 115.5, 106.5, 103.8, 99.7, 84.2, 77.4, 62.1, 55.2, 54.1, 29.9, 28.3, 22.9, 14.2 ppm (Supplemental material, S39). HRMS (ESI) m/z calcd. for C₂₄H₂₈N₂O₅ [M+H]⁺: 425.2071; found 425.2051. [α]_D20 = −5.0 (c 1.0, CHCl₃). Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IG column, ee = 54% (n-Hexane/ethanol = 70/30, flow rate 1 mL min⁻¹, λ = 280 nm, T = 20°C, t_r (major) = 8.595 min, t_r (minor) = 9.883 min).

Supplemental Material

SUPPORTING_INFORMATION – Supplemental material for Enantioselective synthesis of α-amino esters through Petasis borono-Mannich multicomponent reaction of potassium trifluoroborate salts

Supplemental material, SUPPORTING_INFORMATION for Enantioselective synthesis of α-amino esters through Petasis borono-Mannich multicomponent reaction of potassium trifluoroborate salts by Mengnan Tong, Xiang Bai, Xin Meng, Jianfei Wang, Tao Wang, Xingyi Zhu and Bin Mao in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We thank the National Natural Science Foundation of China (No. 21606200) and Zhejiang Provincial Natural Science Foundation of China (LY19B020010) for financial support.

ORCID iD

Bin Mao

Supplemental material

Supplemental material for this article is available online.

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