English

• 1.   Introduction

  Chemoselectivity, which refers to the ability of a given reagent to react with one particular group in a molecule in preference to another group, is of vital importance for a given reaction.^[1] Reactions that proceed in highly chemoselective manner require minimal reliance on protecting groups^[2] and improve both atom^[3] and step economy.^[4] Optically active non-natural amino acids are basic subunits for a broad range of important molecules in medicine and biology.^[5-6] In particular, optically pure β, γ-alkynyl α-amino acids and their derivatives, which allow for further synthetic elaboration, represent a special class of these compounds.^[7] Although continuous attention has been paid to explore the efficient methodologies for their synthesis, asymmetric synthesis of β, γ-alkynyl α-amino acids and their derivatives has remained challenging.^[8-9] The enantioselective addition of terminal alkynes to α-imino esters represents a straightforward strategy.^[8] However, the methods suffered from narrow scope of the alkyne component. Asymmetric reduction of imines has emerged as a powerful tool for amines synthesis, ^[10] and therefore selective reduction of β, γ-alkynyl α-imino esters represents the other ideal strategy.^[9] However, chemo- and enantioselective reduction of the imine moiety with the alkyne intact proved to be difficult (Scheme 1, A). You group^[9a] reported a chiral phosphoric acid (CPA) catalyzed asymmetric transfer hydrogenation process using Hantzsch ester as reducing agent, giving β, γ-alkenyl α-amino esters through concurrent reduction of both C≡C bond and C＝N bond. Zhou group^[9b] demonstrated that the chemoselective reduction of the C＝N bond over C≡C bond could be achieved by using 5, 6-dihydrophenanthri- dine as the hydrogen source. However, the expected β, γ-alkynyl α-amino ester was isolated in only 26% yield with 36% ee. Recently, we reported a non-enzymatic redox deracemization of β, γ-alkynyl α-amino esters consisting of a copper mediated aerobic oxidation and CPA catalyzed asymmetric transfer hydrogenation (Scheme 1, B).^[11] β, γ-Alkynyl α-imino esters were identified as oxidized intermediates for subsequent asymmetric reduction using benzothiazoline as hydride donor with exclusive chemoselectivity at the imine moiety over alkyne.^[12] Given the ready availability of β, γ-alkynyl α-imino esters, we herein report the direct asymmetric transfer hydrogenation method using benzothiazoline as hydride donor to prepare optical pure β, γ-alkynyl α-amino esters with excellent chemo- and enantioselectivity (Scheme 1, C).

  Scheme 1

  

  Scheme 1.  Overview of chemo- and enantioselective reduction of β, γ-alkynyl α-imino esters

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  2.   Results and discussion

  The synthetic route of compound 1 is shown in Scheme 2. Initially, asymmetric transfer hydrogenation of aliphatic alkynyl substituted α-imino ester 1a was selected as a model reaction using CPA 3 as the catalyst and 1.2 equiv. of benzothiazoline 4 as reducing agent in the presence of 3Å molecular sieves (Table 1). CPA 3a catalyzed reaction with 4a proceeded smoothly affording the expected (S)-2a in 71% yield with 70% ee (Entry 1, Table 1). Notably, no unexpected alkyne reduction product was observed. An extensive investigation of CPA catalysts suggested 3e was the best choice, ^[13] and (S)-2a was obtained in 72% yield with 76% ee (Entries 2~8, Table 1). Further optimization of benzothiazolines identified 4d to be optimal (Entries 9~13, Table 1). The solvents were found to be crucial to the yields and enantioselectivity, and when asymmetric reduction was performed in a 1:1 mixture of decane and mesitylene, the asymmetric transfer hydrogen provided (S)-2a in 89% yield with 90% ee (Entries 14~24, Table 1). The reaction was found to be sensitive to the moisture, and 3Å molecular sieves was identified as the best choice (Entries 25~27, Table 1).

  Scheme 2

  

  Scheme 2.  Synthetic route of compound 1

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  Table 1

  

  Table 1.  Reaction condition optimization^a

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  Entry	Solvent	R (3)	Ar (4)	Yieldb/%	eec/%
  1	Hexane	4-CF3C6H4 (3a)	Ph (4a)	71	70
  2	Hexane	3, 5-(CF3)2C6H3 (3b)	Ph (4a)	74	53
  3	Hexane	1-Naphthyl (3c)	Ph (4a)	65	33
  4	Hexane	2-Naphthyl (3d)	Ph (4a)	68	50
  5	Hexane	2, 4, 6-iPr3C6H2 (3e)	Ph (4a)	72	76
  6	Hexane	2, 4, 6-(cyclo-C6H11)3C6H2 (3f)	Ph (4a)	62	71
  7	Hexane	SiPh3 (3g)	Ph (4a)	< 5	n.d.
  8	Hexane	9-Anthryl (3h)	Ph (4a)	53	50
  9	Hexane	2, 4, 6-iPr3C6H2 (3e)	4-ClC6H4 (4b)	60	70
  10	Hexane	2, 4, 6-iPr3C6H2 (3e)	4-MeOC6H4 (4c)	64	47
  11	Hexane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	67	79
  12	Hexane	2, 4, 6-iPr3C6H2 (3e)	2-Naphthyl (4e)	47	65
  13	Hexane	2, 4, 6-iPr3C6H2 (3e)	9-Anthryl (4f)	< 5	n.d.
  14	Cyclohexane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	73	69
  15	CH2Cl2	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	89	7
  16	THF	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	< 5	n.d.
  17	Ethyl acetate	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	76	55
  18	Toluene	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	85	71
  19	Mesitylene	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	92	85
  20	Pentane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	52	68
  21	Decane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	78	86
  22	Decane/mesitylene (V:V＝8:2)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	80	86
  23	Decane/mesitylene (V:V＝7:3)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	84	87
  24	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	89	90
  25d	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	75	68
  26e	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	80	79
  27f	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	82	81
  a Reaction conditions: 1a (0.1 mmol), 3 (5 mol%), 4 (0.12 mmol), and 3Å molecular sieves (40 mg) in solvent (2.0 mL) at room temperature for 4 h. b Yield of the isolated product. c Determined by chiral HPLC analysis. d Reaction without molecular sieves. e 4Å molecular sieves was used. f 5Å molecular sieves. n.d.＝not determined.

  With the optimized conditions in hand, the scope of asymmetric transfer hydrogenation of β, γ-alkynyl α-imino esters was investigated (Table 2). The reaction was found to be fairly general for substrates bearing a wide range of aliphatic alkynes with varied chain lengths, affording corresponding optically pure 2a~2c in good yields with excellent ee (90%~98%). The method had good functional group compatibility and good tolerance to aryl (2d), benzyl ether (2e), acetal (2f), alkenyl (2g) and silyl ether (2h). Substrates containing electronically varied heteroaryl (2i) and aryl acetylenes (2j~2l) were also suitable candidates. In addition, the method was found to be insensitive to the variant of the ester moiety, as demonstrated by effective reduction of 2m and 2n.

  Table 2

  

  Table 2.  Scope of β, γ-alkynyl α-imino esters

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  3.   Conclusions

  In summary, an effective chemo- and enantioselective transfer hydrogenation of β, γ-alkynyl α-imino esters to afford optically pure β, γ-alkynyl α-amino esters has been described. The excellent chemoselectivity was achieved by chiral phosphoric acid catalyzed asymmetric reduction with benzothiazoline as hydride donor. The reaction exhibited good functional group tolerance, providing a range of optically active non-natural α-amino esters with excellent enantioselectivity.

  4.   Experimental section

  4.1   General information

  All reactions were carried out with dry solvents under anhydrous conditions. Standard syringe techniques were applied for transfer of dry solvents and some air-sensitive reagents and were introduced into reaction vessels through a rubber septum. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AVANCE Ⅲ 500 NMR Spectrometer at 500 MHz and 125 MHz, respectively. CDCl₃ was used as solvent and reference (δ_H＝7.26, δ_C＝77.23). Analytical thin layer chromatography (TLC) was performed on precoated silica gel GF254 plates. Column chromatography was carried out on silica gel (200~300 mesh). HRMS were carried out on an Orbitrap analyzer. UV spectra were obtained with an Agilent 8453E UV- Visible spectroscopy system. Optical rotations were measured using a 2.5 mL cell with a 10 cm path length on a Hanon P850 Automatic Polarimeter. Enantiomeric excesses were determined by HPLC using a Daicel Chiralpak AD-H or IB column with hexane/i-PrOH as the eluent.

  4.2   Substrate preparation

  p-Anisidine (5 mmol) was dissolved in toluene (10 mL), and anhydrous sodium sulfate (10 mmol) was added with stirring. Ethyl glyoxalate (6 mmol) was added slowly and the mixture was allowed to stir for 1 h. After completion of the reaction, sodium sulfate was removed by filtration and toluene was removed under vacuum to yield the crude S1 which was used for the next step without purification.^[14-15]

  To a stirred mixture of the corresponding alkyne (0.4 mmol, 2.0 equiv.) and AgOTf (0.02 mmol, 10 mol%) in CH₂Cl₂ (2 mL) was the added S1 (0.2 mmol, 1.0 equiv.), the mixture was stirred overnight at room temperature. After all the S1 disappeared monitored by TLC, Cu(OAc)₂ (0.02 mmol, 10 mol%) was added. The mixture was stirred at room temperature under dioxygen atmosphere (dioxygen balloon, 101 kPa) for 3 h and then was purified by flash chromatography to give the desired product 1 by using solution of EtOAc in petroleum ether as eluent.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)dec-3-ynoate (1a): Using 10% solution of EtOAc in petroleum ether as eluent (54.8 mg, 87% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.44~7.40 (m, 2H), 6.91~6.87 (m, 2H), 4.41 (q, J＝7.1 Hz, 2H), 3.82 (s, 3H), 2.39 (t, J＝7.0 Hz, 2H), 1.55~1.50 (m, 2H), 1.40 (t, J＝7.1 Hz, 3H), 1.32~1.24 (m, 6H), 0.88~0.86 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.27, 159.19, 141.79, 140.14, 124.45, 113.81, 102.12, 75.35, 62.81, 55.58, 31.46, 28.67, 27.86, 22.69, 19.89, 14.37, 14.22; HRMS (ESI) calcd for C₁₉H₂₆NO₃ [M+H]⁺ 316.1907, found 316.1925.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)dodec-3-ynoate (1b): Using 10% solution of EtOAc in petroleum ether as eluent (61.1 mg, 89% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.44~7.40 (m, 2H), 6.91~6.87 (m, 2H), 4.40 (q, J＝7.1 Hz, 2H), 3.82 (s, 3H), 2.39 (t, J＝7.0 Hz, 2H), 1.55~1.50 (m, 2H), 1.40 (t, J＝7.1 Hz, 3H), 1.30~1.23 (m, 10H), 0.88~0.85 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.26, 159.18, 141.77, 140.08, 124.46, 113.79, 102.07, 75.34, 62.78, 55.55, 31.99, 29.33, 29.23, 28.99, 27.88, 22.82, 19.87, 14.36, 14.26; HRMS (ESI) calcd for C₂₁H₃₀NO₃ [M+H]⁺ 344.2220, found 344.2244.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)oct-3-ynoate (1c): Using 10% solution of EtOAc in petroleum ether as eluent (49.4 mg, 86% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.44~7.38 (m, 2H), 6.91~6.87 (m, 2H), 4.40 (q, J＝7.1 Hz, 2H), 3.81 (s, 3H), 2.39 (t, J＝7.0 Hz, 2H), 1.51 (dt, J＝14.9, 7.0 Hz, 2H), 1.41~1.33 (m, 5H), 0.88 (t, J＝7.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.23, 159.15, 141.77, 140.08, 124.41, 113.78, 102.01, 75.32, 62.77, 55.56, 29.87, 22.01, 19.51, 14.33, 13.67; HRMS (ESI) calcd for C₁₇H₂₂NO₃ [M+H]⁺ 288.1594, found 288.1588.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)-5-phenylpent-3- ynoate (1d): Using 10% solution of EtOAc in petroleum ether as eluent (57.1 mg, 89% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.38~7.34 (m, 2H), 7.31~7.26 (m, 1H), 7.24~7.21 (m, 1H), 7.19~7.15 (m, 2H), 6.86~6.82 (m, 2H), 4.41 (q, J＝7.1 Hz, 2H), 3.83 (s, 3H), 2.87 (t, J＝7.3 Hz, 2H), 2.71 (t, J＝7.3 Hz, 2H), 1.41 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.27, 159.30, 141.64, 140.02, 128.70, 128.59, 126.74, 124.58, 113.87, 100.67, 75.87, 62.85, 55.63, 34.10, 21.94, 14.41; HRMS (ESI) calcd for C₂₀H₂₀NO₃ [M+H]⁺ 322.1438, found 322.1441.

  (Z)-Ethyl 6-(benzyloxy)-2-((4-methoxyphenyl)imino)hex- 3-ynoate (1e): Using 10% solution of EtOAc in petroleum ether as eluent (69.2 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.45~7.39 (m, 2H), 7.36~7.28 (m, 5H), 6.91~6.88 (m, 2H), 4.49 (s, 2H), 4.40 (q, J＝7.1 Hz, 2H), 3.81 (s, 3H), 3.44 (t, J＝6.5 Hz, 2H), 2.41 (t, J＝7.0 Hz, 2H), 1.64~1.54 (m, 5H), 1.46~1.38 (m, 5H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.26, 159.20, 141.80, 140.10, 138.73, 128.57, 127.81, 127.74, 124.45, 113.84, 101.75, 75.45, 73.13, 70.29, 62.83, 55.60, 29.42, 27.77, 25.67, 19.85, 14.39; HRMS (ESI) calcd for C₂₅H₃₀NO₄ [M+H]⁺ 408.2169, found 408.2185.

  (Z)-Ethyl 8-(1, 3-dioxolan-2-yl)-2-((4-methoxyphenyl)- imino)oct-3-ynoate (1f): Using 20% solution of EtOAc in petroleum ether as eluent (60.3 mg, 84% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.45~7.39 (m, 2H), 6.93~6.88 (m, 2H), 4.81 (t, J＝4.7 Hz, 1H), 4.41 (q, J＝7.1 Hz, 2H), 3.97~3.93 (m, 2H), 3.85~3.82 (m, 5H), 2.41 (t, J＝6.9 Hz, 2H), 1.68~1.57 (m, 5H), 1.52~1.46 (m, 2H), 1.40 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.25, 159.24, 141.80, 140.04, 124.47, 113.87, 104.49, 101.53, 75.51, 65.05, 62.80, 55.60, 33.47, 27.84, 23.49, 19.85, 14.37; HRMS (ESI) calcd for C₂₀H₂₆NO₅ [M+H]⁺ 360.1805, found 360.1811.

  (Z)-Ethyl 4-(cyclohex-1-en-1-yl)-2-((4-methoxyphenyl)- imino)but-3-ynoate (1g): Using 10% solution of EtOAc in petroleum ether as eluent (53.5 mg, 86% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.50~7.45 (m, 2H), 6.92~6.87 (m, 2H), 6.30 (d, J＝1.1 Hz, 1H), 4.40 (q, J＝7.1 Hz, 2H), 3.81 (s, 3H), 2.13 (t, J＝5.1 Hz, 4H), 1.64~1.55 (m, 4H), 1.39 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.15, 159.32, 141.78, 141.12, 139.53, 124.88, 119.92, 113.73, 101.00, 81.58, 62.71, 55.58, 28.20, 26.20, 22.08, 21.30, 14.32; HRMS (ESI) calcd for C₁₉H₂₂NO₃ [M+H]⁺ 312.1594, found 312.1596.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)-4-(trimethylsilyl)- but-3-ynoate (1h): Using 5% solution of EtOAc in petroleum ether as eluent (48.5 mg, 80% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.57~7.51 (m, 2H), 6.92~6.87 (m, 2H), 4.41 (q, J＝7.1 Hz, 2H), 3.84 (s, 3H), 1.41 (t, J＝7.1 Hz, 3H), 0.21 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 162.94, 159.83, 141.30, 138.60, 125.31, 113.76, 106.89, 97.51, 62.85, 55.67, 14.34, －0.58; HRMS (ESI) calcd for C₁₆H₂₂NO₃Si [M+H]⁺ 304.1363, found 304.1378.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)-4-(thiophen-3- yl)but-3-ynoate (1i): Using 15% solution of EtOAc in petroleum ether as eluent (52.6 mg, 84% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.60 (dd, J＝3.0, 1.1 Hz, 1H), 7.55~7.51 (m, 2H), 7.31 (dd, J＝5.0, 3.0 Hz, 1H), 7.14 (dd, J＝5.0, 1.1 Hz, 1H), 6.97~6.93 (m, 2H), 4.46 (q, J＝7.1 Hz, 2H), 3.85 (s, 3H), 1.44 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.08, 159.62, 141.85, 139.33, 132.54, 130.06, 126.20, 124.93, 120.49, 113.95, 93.98, 83.58, 62.95, 55.69, 14.43; HRMS (ESI) calcd for C₁₇H16NO₃S [M+H]⁺ 314.0845, found 314.0844.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)-4-phenylbut-3- ynoate (1j): Using 15% solution of EtOAc in petroleum ether as eluent (55.9 mg, 91% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.59~7.53 (m, 2H), 7.50~7.45 (m, 2H), 7.43~7.39 (m, 1H), 7.38~7.33 (m, 2H), 6.98~6.94 (m, 2H), 4.47 (q, J＝7.1 Hz, 2H), 3.86 (s, 3H), 1.45 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.07, 159.66, 141.84, 139.31, 132.72, 130.35, 128.76, 125.02, 121.28, 113.96, 98.51, 83.57, 62.93, 55.70, 14.43; HRMS (ESI) calcd for C₁₉H₁₈NO₃ [M+H]⁺ 308.1281, found 308.1288.

  (Z)-Ethyl 2-((4-methoxyphenyl)imino)-4-(p-tolyl)but-3- ynoate (1k): Using 15% solution of EtOAc in petroleum ether as eluent (55.2 mg, 86% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.57~7.54 (m, 2H), 7.38~7.34 (m, 2H), 7.17~7.13 (m, 2H), 6.98~6.93 (m, 2H), 4.46 (q, J＝7.1 Hz, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.44 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.10, 159.53, 141.85, 140.94, 139.42, 132.64, 129.51, 124.96, 118.14, 113.89, 99.11, 83.29, 62.84, 55.63, 21.86, 14.38; HRMS (ESI) calcd for C₂₀H₂₀NO₃ [M+H]⁺ 322.1438, found 322.1443.

  (Z)-Ethyl 4-(4-fluorophenyl)-2-((4-methoxyphenyl)- imino)but-3-ynoate (1l): Using 15% solution of EtOAc in petroleum ether as eluent (55.3 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.55~7.50 (m, 2H), 7.49~7.43 (m, 2H), 7.08~7.04 (m, 2H), 6.98~6.94 (m, 2H), 4.46 (q, J＝7.1 Hz, 2H), 3.86 (s, 3H), 1.45 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.82, 163.02, 162.85, 159.67, 141.82, 139.25, 134.89 (d, J＝8.8 Hz), 124.91, 116.28 (d, J＝22.3 Hz), 113.97, 97.38, 83.42, 62.99, 55.71, 14.44; HRMS (ESI) calcd for C₁₉H₁₇FNO₃ [M+H]⁺ 328.1187, found 328.1196.

  (Z)-Methyl 2-((4-methoxyphenyl)imino)dec-3-ynoate (1m): Using 10% solution of EtOAc in petroleum ether as eluent (52.4 mg, 87% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.52~7.38 (m, 2H), 6.94~6.87 (m, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 2.40 (t, J＝7.0 Hz, 2H), 1.53 (dd, J＝14.9, 7.2 Hz, 2H), 1.37~1.27 (m, 6H), 0.88 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.79, 159.37, 141.63, 139.55, 124.61, 113.88, 102.28, 75.34, 55.62, 53.65, 31.47, 28.72, 27.88, 22.71, 19.93, 14.23; HRMS (ESI) calcd for C₁₈H₂₄NO₃ [M+H]⁺ 302.1751, found 302.1755.

  (Z)-Propyl 2-((4-methoxyphenyl)imino)dec-3-ynoate (1n): Using 10% solution of EtOAc in petroleum ether as eluent (55.9 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃) δ: 7.46~7.40 (m, 2H), 6.92~6.88 (m, 2H), 4.30 (t, J＝6.8 Hz, 2H), 3.83 (s, 3H), 2.39 (t, J＝7.0 Hz, 2H), 1.81 (dt, J＝14.4, 7.2 Hz, 2H), 1.56~1.50 (m, 2H), 1.35~ 1.24 (m, 6H), 1.01 (t, J＝7.4 Hz, 3H), 0.87 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.28, 159.19, 141.86, 140.10, 124.48, 113.81, 101.96, 75.41, 68.20, 55.58, 31.47, 28.69, 27.89, 22.69, 22.12, 19.87, 14.22, 10.50; HRMS (ESI) calcd for C₂H₂₈NO₃ [M+H]⁺ 330.2064, found 330.2081.

  4.3   General procedure for the enantioselective transfer hydrogenation of 1

  A mixture of 1 (0.1 mmol, 1.0 equiv.), 3e (0.01 mmol, 5 mol%), 3Å MS (40 mg), and 4d (0.12 mmol, 1.2 equiv.) in the mixture of decane (1.0 mL) and mesitylene (1.0 mL) was stirred at room temperature under N₂ for 4 h, and then directly purified by flash chromatography to give the desired product 2 by using solution of EtOAc in petroleum ether as eluent.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)dec-3-ynoate (2a): Using 5% solution of EtOAc in petroleum ether as eluent (28.4 mg, 89% yield). [α]_D²⁵+36.71 (c 1.28, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.81~6.76 (m, 2H), 6.69~6.65 (m, 2H), 4.70 (t, J＝2.1 Hz, 1H), 4.26 (q, J＝7.1 Hz, 2H), 3.74 (s, 3H), 2.17 (td, J＝7.0, 2.1 Hz, 2H), 1.49~1.43 (m, 2H), 1.33~1.23 (m, 8H), 0.87 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.68, 153.42, 139.77, 116.12, 114.87, 85.59, 75.25, 62.29, 55.80, 50.34, 31.46, 28.57, 28.49, 22.71, 18.87, 14.24, 14.21; HRMS (ESI) calcd for C₁₉H₂₈NO₃ [M+H]⁺ 318.2064, found 318.2072. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane, V:V＝25/75, 1.0 mL/ min, 249 nm), retention time: t_minor＝6.477 min, t_major＝9.070 min, ee＝90%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)dodec-3-ynoate (2b): Using 5% solution of EtOAc in petroleum ether as eluent (29.7 mg, 86% yield). [α]_D²⁵+32.51 (c 1.18, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.81~6.75 (m, 2H), 6.69~6.65 (m, 2H), 4.70 (t, J＝2.2 Hz, 1H), 4.26 (q, J＝7.1 Hz, 2H), 3.74 (s, 3H), 2.17 (td, J＝7.1, 2.2 Hz, 2H), 1.49~1.43 (m, 2H), 1.33~1.23 (m, 13H), 0.88 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.75, 153.43, 139.87, 116.11, 114.92, 85.61, 75.30, 62.31, 55.85, 50.37, 32.04, 29.39, 29.27, 28.95, 28.57, 22.86, 18.91, 14.30, 14.28; HRMS (ESI) calcd for C₂₁H₃₂NO₃ [M+H]⁺ 346.2377, found 346.2388. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ hexane, V:V＝25/75, 1.0 mL/min, 256 nm), retention time: t_rminor＝5.617 min, t_major＝7.633 min, ee＝98%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)oct-3-ynoate (2c): Using 5% solution of EtOAc in petroleum ether as eluent (24.5 mg, 85% yield). [α]_D²⁵+49.62 (c 1.12, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.81~6.76 (m, 2H), 6.70~6.65 (m, 2H), 4.70 (t, J＝2.2 Hz, 1H), 4.26 (qd, J＝7.1, 1.2 Hz, 2H), 3.74 (s, 3H), 2.18 (td, J＝7.0, 2.2 Hz, 2H), 1.49~1.41 (m, 2H), 1.39~1.32 (m, 2H), 1.29 (t, J＝7.1 Hz, 3H), 0.87 (t, J＝7.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.70, 153.42, 139.79, 116.14, 114.88, 85.55, 75.25, 62.29, 55.82, 50.37, 30.58, 21.97, 18.55, 14.23, 13.71; HRMS (ESI) calcd for C₁₇H₂₄NO₃ [M+H]⁺ 290.1751, found 290.1764. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/he- xane, V:V＝25/75, 1.0 mL/min, 241 nm), retention time: t_rminor＝7.163 min, t_major＝10.507 min, ee＝94%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)-6-phenylhex-3- ynoate (2d): Using 5% solution of EtOAc in petroleum ether as eluent (29.3 mg, 87% yield). [α]_D²⁵+36.7 (c 1.01, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.39~7.32 (m, 2H), 7.31~7.26 (m, 2H), 7.25~7.20 (m, 1H), 7.20~7.14 (m, 2H), 6.87~6.82 (m, 2H), 4.41 (q, J＝7.1 Hz, 2H), 3.82 (s, 3H), 2.87 (t, J＝7.3 Hz, 2H), 2.71 (t, J＝7.3 Hz, 2H), 1.41 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.26, 159.29, 141.61, 140.01, 139.68, 128.69, 128.59, 126.73, 124.58, 113.86, 100.67, 75.85, 62.85, 55.62, 34.09, 21.93, 14.40; HRMS (ESI) calcd for C₂₀H₂₂NO₃ [M+H]⁺ 338.1751, found 338.1767. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ hexane, V:V＝25/75, 1.0 mL/min, 308 nm), retention time: t_rminor＝11.233 min, t_major＝15.010 min, ee＝95%.

  (S)-Ethyl 9-(benzyloxy)-2-((4-methoxyphenyl)amino)- non-3-ynoate (2e): Using 5% solution of EtOAc in petroleum ether as eluent (33.6 mg, 82% yield). [α]_D²⁵+32.71 (c 0.61, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.28~7.19 (m, 5H), 6.73~6.68 (m, 2H), 6.61~6.56 (m, 2H), 4.62 (t, J＝2.1 Hz, 1H), 4.42 (s, 2H), 4.18 (q, J＝7.1 Hz, 2H), 3.66 (s, 3H), 3.36 (t, J＝6.6 Hz, 2H), 2.11 (td, J＝7.0, 2.2 Hz, 2H), 1.55~1.49 (m, 2H), 1.45~1.39 (m, 2H), 1.37~1.30 (m, 2H), 1.21 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.69, 153.43, 139.84, 138.84, 128.56, 127.81, 127.71, 116.11, 114.91, 85.33, 75.47, 73.10, 70.44, 62.32, 55.84, 50.35, 29.44, 28.39, 25.57, 18.87, 14.27; HRMS (ESI) calcd for C₂₅H₃₂NO₄ [M+H]⁺ 410.2326, found 410.2329. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/he- xane, V:V＝25/75, 1.0 mL/min, 205 nm), retention time: t_rminor＝12.743 min, t_major＝18.110 min, ee＝93%.

  (S)-Ethyl 8-(1, 3-dioxolan-2-yl)-2-((4-methoxyphenyl)- amino)oct-3-ynoate (2f): Using 20% solution of EtOAc in petroleum ether as eluent (28.9 mg, 80% yield). [α]_D²⁵+49.71 (c 1.6, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.80~6.76 (m, 2H), 6.69~6.65 (m, 2H), 4.81 (t, J＝4.8 Hz, 1H), 4.69 (s, 1H), 4.26 (q, J＝7.1 Hz, 2H), 4.18 (s, 1H), 3.97~3.92 (m, 2H), 3.87~3.81 (m, 2H), 3.74 (s, 3H), 2.19 (td, J＝6.9, 2.1 Hz, 2H), 1.65~1.61 (m, 2H), 1.55~1.45 (m, 4H), 1.30 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.69, 153.42, 139.86, 116.11, 114.93, 104.64, 85.18, 75.55, 65.05, 62.34, 55.85, 50.36, 33.51, 28.45, 23.43, 18.86, 14.27; HRMS (ESI) calcd for C₂₀H₂₈NO₅ [M+H]⁺ 362.1962, found 362.1981; HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ hexane, V:V＝25/75, 1.0 mL/min, 241 nm), retention time: t_minor＝14.260 min, t_rmajor＝20.310 min, ee＝92%.

  (S)-Ethyl 4-(cyclohex-1-en-1-yl)-2-((4-methoxyphenyl)- amino)but-3-ynoate (2g): Using 5% solution of EtOAc in petroleum ether as eluent (28.5 mg, 91% yield). [α]_D²⁵+98.74 (c 0.66, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.81~6.77 (m, 2H), 6.71~6.65 (m, 2H), 6.10 (dt, J＝3.7, 2.0 Hz, 1H), 4.82 (s, 1H), 4.27 (q, J＝7.1 Hz, 2H), 3.75 (s, 3H), 2.10~2.00 (m, 4H), 1.63~1.53 (m, 4H), 1.30 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.46, 153.44, 139.80, 136.32, 120.00, 116.14, 114.92, 86.39, 81.51, 62.39, 55.85, 50.76, 29.09, 25.79, 22.36, 21.58, 14.27; HRMS (ESI) calcd for C₁₉H₂₄NO₃ [M+H]⁺ 314.1751, found 314.1761; HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ hexane, V:V＝25/75, 1.0 mL/min, 248 nm), retention time: t_minor＝8.183 min, t_major＝10.597 min, ee＝95%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)-4-(trimethylsilyl)- but-3-ynoate (2h): Using 3% solution of EtOAc in petroleum ether as eluent (25.0 mg, 82% yield). [α]_D²⁵+110.62 (c 1.16, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.80~6.77 (m, 2H), 6.70~6.66 (m, 2H), 4.72 (s, 1H), 4.33~4.24 (m, 2H), 4.19 (s, 1H), 3.75 (s, 3H), 1.30 (t, J＝7.1 Hz, 3H), 0.14 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.08, 153.57, 139.72, 116.26, 114.91, 100.19, 90.00, 62.47, 55.87, 51.17, 14.21, －0.09; HRMS (ESI) calcd for C₁₆H₂₄NO₃Si [M+H]⁺ 306.1520, found 306.1511; HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane, V:V＝25/75, 1.0 mL/min, 248 nm), retention time: t_minor＝4.683 min, t_rmajor＝5.693 min, ee＝91%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)-4-(thiophen-3- yl)but-3-ynoate (2i): Using 10% solution of EtOAc in petroleum ether as eluent (28.3 mg, 90% yield). [α]_D²⁵+108.71 (c 0.76, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.44 (dd, J＝3.0, 1.1 Hz, 1H), 7.23 (dd, J＝5.0, 3.0 Hz, 1H), 7.07 (dd, J＝5.0, 1.1 Hz, 1H), 6.83~6.79 (m, 2H), 6.75~6.71 (m, 2H), 4.93 (s, 1H), 4.36~4.20 (m, 3H), 3.75 (s, 3H), 1.32 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.13, 153.59, 139.66, 130.15, 129.81, 125.48, 121.38, 116.22, 115.00, 84.04, 79.75, 62.61, 55.86, 50.85, 14.29; HRMS (ESI) calcd for C₁₇H₁₈NO₃S [M+H]⁺ 316.1002, found 316.1020. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/he- xane, V:V＝25/75, 1.0 mL/min, 246 nm), retention time: t_minor＝15.287 min, t_major＝21.230 min, ee＝80%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)-4-phenylbut-3- ynoate (2j): Using 15% solution of EtOAc in petroleum ether as eluent (27.2 mg, 88% yield). [α]_D²⁵+107.82 (c 1.22, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.47~7.40 (m, 2H), 7.35~7.28 (m, 3H), 6.86~6.81 (m, 2H), 6.79~6.74 (m, 2H), 4.98 (s, 1H), 4.33 (q, J＝7.1 Hz, 2H), 3.77 (s, 3H), 1.35 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.14, 153.54, 139.61, 132.07, 128.83, 128.41, 122.32, 116.22, 114.95, 84.50, 84.36, 62.57, 55.81, 50.80, 14.26; HRMS (ESI) calcd for C₁₉H₂₀NO₃ [M+H]⁺ 310.1438, found 310.1442. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/he- xane, V:V＝25/75, 1.0 mL/min, 306 nm), retention time: t_minor＝11.110 min, t_major＝13.573 min, ee＝89%.

  (S)-Ethyl 2-((4-methoxyphenyl)amino)-4-(p-tolyl)but-3- ynoate (2k): Using 10% solution of EtOAc in petroleum ether as eluent (27.1 mg, 84% yield). [α]_D²⁵+104.8 (c 0.9, CHCl₃) ¹H NMR (500 MHz, CDCl₃) δ: 7.32 (d, J＝8.0 Hz, 2H), 7.10 (d, J＝7.9 Hz, 2H), 6.87~6.80 (m, 2H), 6.80~6.73 (m, 2H), 4.97 (s, 1H), 4.32 (q, J＝7.1 Hz, 2H), 3.75 (s, 3H), 2.34 (s, 3H), 1.33 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.19, 153.44, 139.64, 138.93, 131.90, 129.12, 119.19, 116.13, 114.88, 84.61, 83.63, 62.45, 55.73, 50.76, 21.59, 14.20; HRMS (ESI) calcd for C₂₀H₂₂NO₃ [M+H]⁺ 324.1594, found 324.1599. HPLC: the ee value was determined by HPLC analysis (Chiralcel IB, i-PrOH/hexane, V:V＝20/80, 1.0 mL/min, 255 nm), retention time: t_minor＝7.047 min, t_major＝8.553 min, ee＝86%.

  (S)-Ethyl 4-(4-fluorophenyl)-2-((4-methoxyphenyl)- amino)but-3-ynoate (2l): Using 15% solution of EtOAc in petroleum ether as eluent (28.4 mg, 87% yield). [α]_D²⁵+96.85 (c 0.96, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 7.41~7.32 (m, 2H), 7.01~6.96 (m, 2H), 6.83~6.78 (m, 2H), 6.77~6.72 (m, 2H), 4.94 (s, 1H), 4.31 (q, J＝7.1 Hz, 2H), 3.75 (s, 3H), 1.33 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.08, 162.91 (d, J＝250.1 Hz), 153.63, 139.56, 134.09, 134.02, 118.43, 116.27, 115.85, 115.67, 115.00, 84.13, 83.50, 62.65, 55.86, 50.80, 14.30; HRMS (ESI) calcd for C₁₉H₁₉FNO₃ [M+H]⁺ 328.1343, found 328.1359. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane, V:V＝25/75, 1.0 mL/min, 220 nm), retention time: t_minor＝11.970 min, t_major＝14.250 min, ee＝88%.

  (S)-Methyl 2-((4-methoxyphenyl)amino)dec-3-ynoate (2m): Using 5% solution of EtOAc in petroleum ether as eluent (27.2 mg, 90% yield). [α]_D²⁵+45.78 (c 1.08, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.81~6.77 (m, 2H), 6.69~6.65 (m, 2H), 4.73 (t, J＝2.1 Hz, 1H), 4.17 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 2.17 (td, J＝7.1, 2.1 Hz, 2H), 1.50~1.43 (m, 2H), 1.34~1.23 (m, 6H), 0.88 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 170.22, 153.47, 139.77, 116.10, 114.92, 85.77, 75.13, 55.81, 53.21, 50.21, 31.45, 28.59, 28.48, 22.70, 18.88, 14.20; HRMS (ESI) calcd for C₁₈H₂₆NO₃ [M+H]⁺ 304.1907, found 304.1914. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane, V:V＝25/75, 1.0 mL/min, 206 nm), retention time: t_minor＝10.213 min, t_major＝14.787 min, ee＝93%.

  (S)-Propyl 2-((4-methoxyphenyl)amino)dec-3-ynoate (2n): Using 5% solution of EtOAc in petroleum ether as eluent (27.5 mg, 83% yield). [α]_D²⁵+21.88 (c 1.1, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ: 6.80~6.75 (m, 2H), 6.69~6.64 (m, 2H), 4.71 (t, J＝2.2 Hz, 1H), 4.20~4.13 (m, 2H), 3.73 (s, 3H), 2.17 (td, J＝7.1, 2.2 Hz, 2H), 1.72~1.65 (m, 2H), 1.49~1.43 (m, 2H), 1.34~1.22 (m, 6H), 0.94 (t, J＝7.4 Hz, 3H), 0.87 (t, J＝7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 169.77, 153.34, 139.84, 115.98, 114.84, 85.42, 75.34, 67.71, 55.74, 50.24, 31.44, 28.55, 28.47, 22.66, 22.06, 18.82, 14.17, 10.36; HRMS (ESI) calcd for C₂₀H₃₀NO₃ [M+H]⁺ 332.2220, found 332.2218. HPLC: the ee value was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/hexane, V:V＝25:75, 1.0 mL/min, 255 nm), retention time: t_minor＝7.093 min, t_major＝11.487 min, ee＝92%.

  Supporting Information  ¹H NMR and ¹³C NMR spectra and HPLC spectra of 1a~1n and 2a~2n. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
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• 

  Scheme 1  Overview of chemo- and enantioselective reduction of β, γ-alkynyl α-imino esters

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  Scheme 2  Synthetic route of compound 1

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  Table 1.  Reaction condition optimization^a

  Entry	Solvent	R (3)	Ar (4)	Yieldb/%	eec/%
  1	Hexane	4-CF3C6H4 (3a)	Ph (4a)	71	70
  2	Hexane	3, 5-(CF3)2C6H3 (3b)	Ph (4a)	74	53
  3	Hexane	1-Naphthyl (3c)	Ph (4a)	65	33
  4	Hexane	2-Naphthyl (3d)	Ph (4a)	68	50
  5	Hexane	2, 4, 6-iPr3C6H2 (3e)	Ph (4a)	72	76
  6	Hexane	2, 4, 6-(cyclo-C6H11)3C6H2 (3f)	Ph (4a)	62	71
  7	Hexane	SiPh3 (3g)	Ph (4a)	< 5	n.d.
  8	Hexane	9-Anthryl (3h)	Ph (4a)	53	50
  9	Hexane	2, 4, 6-iPr3C6H2 (3e)	4-ClC6H4 (4b)	60	70
  10	Hexane	2, 4, 6-iPr3C6H2 (3e)	4-MeOC6H4 (4c)	64	47
  11	Hexane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	67	79
  12	Hexane	2, 4, 6-iPr3C6H2 (3e)	2-Naphthyl (4e)	47	65
  13	Hexane	2, 4, 6-iPr3C6H2 (3e)	9-Anthryl (4f)	< 5	n.d.
  14	Cyclohexane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	73	69
  15	CH2Cl2	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	89	7
  16	THF	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	< 5	n.d.
  17	Ethyl acetate	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	76	55
  18	Toluene	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	85	71
  19	Mesitylene	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	92	85
  20	Pentane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	52	68
  21	Decane	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	78	86
  22	Decane/mesitylene (V:V＝8:2)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	80	86
  23	Decane/mesitylene (V:V＝7:3)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	84	87
  24	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	89	90
  25d	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	75	68
  26e	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	80	79
  27f	Decane/mesitylene (V:V＝1:1)	2, 4, 6-iPr3C6H2 (3e)	1-Naphthyl (4d)	82	81
  a Reaction conditions: 1a (0.1 mmol), 3 (5 mol%), 4 (0.12 mmol), and 3Å molecular sieves (40 mg) in solvent (2.0 mL) at room temperature for 4 h. b Yield of the isolated product. c Determined by chiral HPLC analysis. d Reaction without molecular sieves. e 4Å molecular sieves was used. f 5Å molecular sieves. n.d.＝not determined.

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  Table 2.  Scope of β, γ-alkynyl α-imino esters

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