Supporting Information - PDF Free Download

Supporting Information Iridium-Catalyzed Highly Regioselective Azide-Ynamide Cycloaddition to Access 5-Amido-Fully-Substituted 1,2,3-Triazoles under Mild, Air, Aqueous and Bioorthogonal Conditions Wangze Song,,,* an Zheng, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, PR China School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, 116024, PR China * wzsong@dlut.edu.cn 1. General Remarks... 2 2. General procedure for the preparation of substrates:... 2 3. ptimization of Reaction Conditions a... 4 4. Representative procedures for Ir-catalyzed cycloaddition... 5 5. Gram-scale preparation for Ir-catalyzed cycloaddition... 5 6. Characterization data of products... 6 7. Reference:... 12 8. MR Spectra... 13 S1

1. General Remarks Unless otherwise noted, all commercially available reagents and solvents were used without further additional purification. Thin layer chromatography was performed using precoated silica gel plates and visualized with UV light at 254 nm. Flash column chromatography was performed with silica gel (40-60 μm). 1 H and 13 C nuclear magnetic resonance spectra (MR) were obtained on a Bruker Avance II 400 MHz or Bruker Avance III 500 MHz recorded in ppm (δ) downfield of TMS (δ=0) in CDCl 3 unless noted otherwise. Signal splitting patterns were described as singlet (s), doublet (d), triplet(t), quartet (q), quintet (quint), or multiplet (m), with coupling constants (J) in hertz (Hz). High resolution mass spectra (HRMS) were performed by Agilent apparatus on an Electron Spray Injection (ESI) mass spectrometer. Melting points were determined by XP-4 melting point apparatus. ptical rotations were measured on a Rudolph Autopol IV automatic polarimeter. 2. General procedure for the preparation of substrates: 2.1 Preparation of bromoalkynes S1 To a stirred solution of terminal alkyne (10 mmol) in acetone (10 ml) was added -bromosuccinimide (BS) (1.2eq, 12 mmol) under 2 atmosphere. The reaction mixture was stirred at room temperature and stirred for 3 h, then removal of solvent under reduced pressure. The residue was filtered through a pad of Celite with petroleum ether (PE) solvent. If necessary, further purification was performed by column chromatography on silica gel (PE as eluent) to afford bromoalkyne. 2.2 Preparation of ynamides Following a slight modification of Hsung s procedure S2 To a stirred solution of bromoalkyne (1.2 eq, 9.6 mmol), 2-oxazolidinone (680 mg, 1 eq, 8 mmol), K 3 P 4 (3.39 g, 2 eq, 16 mmol), CuS 4 5H 2 (199 mg, 0.1 eq, 0.8 mmol) and 1,10-phenanthroline (288 mg, 0.2 eq, 1.6 mmol) in toluene (16 ml) was heated at S2

80 C for 48 h. After cooling to room temperature, the mixture was filtered through a short pad of silica gel using CH 2 Cl 2 (20 ml) as the eluent, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography (25% EtAc/hexane) gave the ynamide 1a. Substrates 1a-1i were prepared by similar procedure. 2.3 Preparation of tert-butyl phenylcarbamate S3 The preparation of tert-butyl phenylcarbamate for acyclic substrates 3h and 3i: To a stirred solution of aniline (0.911 ml, 1 eq, 10 mmol) in MeH (30 ml) was added di-tert-butyl pyrocarbonate (2.61g, 1.2 eq, 12 mmol). The reaction mixture was allowed to stir at 70 o C overnight. When the reaction was complete as determined by TLC, the mixture was poured into H 2 (50 ml). The mixture was extracted with dichloromethane (DCM) (3 50 ml). The combined organic layers were washed with brine (1 100 ml), dried over anhydrous a 2 S 4, filtered and concentrated in vacuo to give product (1.8 g, 94%) as a white solid. It was used directly without further purification. 2.4 Preparation of azides S4 For the preparation of azides 3j, 3k, 3m and 3n To a stirred solution of a 3 (71.5 mg, 1.1 mmol) in DMS (2 ml) was added bromoalkane (1 mmol). The reaction mixture was stirred at 80 o C overnight. Then the reaction mixture was cooled to room temperature and diluted with water (5 ml). The mixture was extracted with ether (3 5 ml) and washed by brine, dried over a 2 S 4 and concentrated under vacuum to give the products in quantitative yields. It was used directly without further purification. 2.5 Preparation of substrate 1q S5 To a stirred solution of pyrrolidin-2-one (0.183 ml, 1.2 eq, 2.4 mmol) in anhydrous DMF (2 ml) was added ah (60% in mineral oil, 116 mg, 1,45 eq, 2.9 mmol) and the resulting solution was stirred at room temperature for 30 min. Propargyl bromide (0.23 ml, 1.55 eq, 3.1 mmol) was added to the mixture dropwisely. The reaction mixture was stirred at room temperature for 2h and then added by cannula to a S3

solution containing PdCl 2 (PPh 3 ) 2 (70.2 mg, 0.05 eq, 0.1 mmol), CuI (38.9 mg, 0.1 eq, 0.2 mmol) and 1-iodo-4-methoxybenzene (468 mg, 1 eq, 2 mmol) in Et 3 (20 ml). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified with flash column chromatography (10% EtAc in PE) to give the pure product (202 mg, 44%). All substrates, 1a-1q, 2a-2o are known compounds. 3. ptimization of Reaction Conditions Table S1 ptimization of Reaction Conditions a entry cat. solv yield (3a+3a ) [%] b 3a/3a b 1 CuI DCM 0-2 CuS 4 DCM 0-3 [Cp*RhCl 2 ] 2 DCM 0-4 [Rh(cod)Cl] 2 DCM complex - 5 [Cp*Ru(cod)Cl] DCM 85 4:1 6 [Cp*Ru(PPh 3 ) 2 Cl] DCM 79 4:1 7 [Ir(cod)Cl] 2 DCM 96 1:0 8 [Ir(cod)Cl] 2 water 87 1:0 9 c [Ir(cod)Cl] 2 DCM 92 1:0 10 d [Ir(cod)Cl] 2 DCM 65 1:0 11 [Ir(cod)Cl] 2 THF 92 1:0 12 [Ir(cod)Cl] 2 toluene 93 1:0 13 [Ir(cod)Cl] 2 EtH 91 1:0 14 [Ir(cod)Cl] 2 MeC 92 1:0 15 e [Ir(cod)Cl] 2 water 85 1:0 a. Conditions: 1a (1.0 equiv), 2a (1.5 equiv), solvent (0.1 M), catalyst (2.5 mol %), at rt under air for 12 h. b. Determined by 1 H MR of the crude mixture with an internal standard. c. The reaction was set in 8 h. d. The reaction was set in 4 h. The starting materials still left. e. The reaction was set in open vial way in water. S4

4. Representative procedures for Ir-catalyzed cycloaddition Condition A: To a vial containing [Ir(cod)Cl] 2 (3.3 mg, 0.025 eq, 0.005 mmol) in DCM (2 ml) under air was added 3-(phenylethynyl)oxazolidin-2-one (37.4 mg, 1 eq, 0.2 mmol) and (azidomethyl)benzene (40.2 mg, 1.5 eq, 0.3 mmol). It was necessary to add azides finally. The vial was closed and the mixture was stirred at room temperature overnight. The mixture was purified with flash column chromatography (10% EtAc in PE) to give the pure product (59.5 mg, 93%) as yellow solid. Condition B: To a vial containing [Ir(cod)Cl] 2 (3.3 mg, 0.025 eq, 0.005 mmol) in water (2 ml) under air was added 3-(phenylethynyl)oxazolidin-2-one (37.4 mg, 1 eq, 0.2 mmol) and (azidomethyl)benzene (40.2 mg, 1.5 eq, 0.3 mmol). It was necessary to add azides finally. The vial was closed and the mixture was stirred at room temperature overnight. When the reaction was completed as determined by TLC, the reaction mixture was extracted with ethyl acetate (4 5 ml). The combined organic layers were washed with brine (1 15 ml), dried over anhydrous a 2 S 4, filtered and concentrated in vacuo. The residue was purified with flash column chromatography (10% EtAc in PE) to give the pure product (54.4 mg, 85%) as yellow solid. 5. Gram-scale preparation for Ir-catalyzed cycloaddition To a flask containing [Ir(cod)Cl] 2 (101 mg, 0.025 eq, 0.15 mmol) in DCM (60 ml) under air was added 3-(phenylethynyl)oxazolidin-2-one (1.12 g, 1 eq, 6 mmol) and (azidomethyl)benzene (1.20 g, 1.5 eq, 9 mmol). It was necessary to add azides finally. S5

The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified with flash column chromatography (10% EtAc in PE) to give the pure product (1.69 g, 88%) as yellow solid. 6. Characterization data of products 3-(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3a) Condition A: 59.5 mg, 81%. Condition B: 54.5 mg, 85%. Yellow solid, mp = 114-115 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.69 (d, J = 5.0 Hz, 2H), 7.36-7.34 (m, 6H), 7.29 (d, J = 10.0 Hz, 2H), 5.60 (s, 2H), 4.14 (t, J = 10.0 Hz, 2H), 2.96 (br s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 156.6, 141.9, 134.4, 129.4, 129.3, 129.1, 128.9, 128.8, 127.9, 126.3, 63.3, 53.1, 44.5. HRMS (ESI) m/z calcd for C 18 H 16 4 2 (M+a) + 343.1171, found 343.1172. 3-(1-benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3b) Condition A: 67.2 mg, 96%. Condition B: 60.9 mg, 87%. Yellow oil. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.53 (d, J = 10.0 Hz, 2H), 7.31-7.27 (m, 3H), 7.21 (d, J = 10.0 Hz, 2H), 6.87 (d, J = 10.0 Hz, 2H), 5.50 (s, 2H), 4.06 (t, J = 10.0 Hz, 2H), 3.73 (s, 3H), 2.86 (br s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 160.0, 155.7, 141.9, 134.5, 129.2, 128.9, 127.9, 127.7, 127.2, 121.9, 114.5, 63.3, 56.3, 53.1, 44.5. HRMS (ESI) m/z calcd for C 19 H 18 4 3 (M+a) + 373.1277, found 373.1277. 3-(1-benzyl-4-(4-chlorophenyl)-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3c) Condition A: 60.2 mg, 85%. Condition B: 56.6 mg, 80%. White solid, mp = 140-141 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.64 (d, J = 10.0 Hz, 2H), 7.42-7.37 (m, 5H), S6

7.31 (d, J = 10.0 Hz, 2H), 5.62 (s, 2H), 4.15 (t, J = 10.0 Hz, 2H), 2.91 (br s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 155.6, 141.1, 134.9, 134.4, 129.4, 129.4, 129.1, 128.1, 128.0, 128.0, 127.8, 63.3, 53.4, 44.7. HRMS (ESI) m/z calcd for C 18 H 15 Cl 4 2 (M+a) + 377.0781, found 377.0783. 1-(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)pyrrolidin-2-one (3d) Condition A: 54.7 mg, 86%. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.58 (d, J = 10.0 Hz, 2H), 7.32-7.25 (m, 6H), 7.14 (d, J = 10.0 Hz, 2H), 5.49 (s, 2H), 2.74 (br s, 2H), 2.32 (t, J = 10.0 Hz, 2H), 1.73 (s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 175.4, 141.3, 134.6, 129.9, 129.3, 129.1, 128.9, 128.8, 128.5, 127.6, 126.3, 53.3, 47.7, 30.3, 19.2. Compound 3d is known compound, and the proton and carbon spectrum is fully consistent with literature reported. S6 The regioselectivity is absolutely determined in this case. (S)-3-(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)-4-phenyloxazolidin-2-one (3e) Condition A: 61.0 mg, 77%. [α] D 25 = +36.9 (c = 1.70, CH 2 Cl 2 ). Yellow oil. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.50-7.40 (m, 10H), 7.10-7.05 (m, 1H), 6.95-6.85 (m, 2H), 6.42 (d, J = 5.0 Hz, 2H), 5.39 (m, 2H), 4.57 (s, 2H), 4.32 (t, J = 10.0 Hz, 1H). 13 C MR (125 MHz, (CD 3 ) 2 S): δ 156.3, 134.9, 134.7, 129.3, 129.2, 128.6, 128.6, 128.4, 128.1, 128.0, 126.8, 99.5, 70.0, 60.8, 50.5. HRMS (ESI) m/z calcd for C 24 H 20 4 2 (M+a) + 419.1484, found 419.1488. (S)-3-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-4-phenyloxazolidin-2-one (3e ), as the regiomer of 3e, is known compound. S7 According to the literature reported, the proton spectrum (in the same solvent, CDCl 3 ) of 3e is different from 3e. The regioselectivity is indirectly determined in this case. S7

(S)-4-benzyl-3-(1-benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3f) Condition A: 67.2 mg, 82%. [α] D 25 = +59.7 (c = 2.15, CH 2 Cl 2 ). Brown oil. 1 H MR (500 MHz, CD 3 D, TMS): δ 7.65-7.55 (m, 2H), 7.50-7.36 (m, 10H), 7.09-7.03 (m, 3H), 6.51 (s, 2H), 5.55 (s, 2H), 4.33 (t, J = 10.0 Hz, 1H), 4.09-4.06 (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 155.3, 134.5, 134.1, 129.6, 129.3, 129.0, 128.8, 128.5, 128.2, 127.5, 127.2, 127.1, 69.1, 60.4, 53.5, 53.1. HRMS (ESI) m/z calcd for C 25 H 22 4 2 (M+a) + 433.1640, found 433.1642. (S)-4-benzyl-3-(1-benzyl-4-butyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3g) Condition A: 60.8 mg, 78%. [α] D 25 = +68.0 (c = 0.44, CH 2 Cl 2 ). Brown oil. 1 H MR (500 MHz, CD 3 D, TMS): δ 7.33-7.27 (m, 5H), 7.20-7.15 (m, 3H), 6.85-6.75 (m, 2H), 5.54 (s, 2H), 4.41-4.14 (m, 3H), 2.65-2.45 (m, 4H), 1.75-1.55 (m, 2H), 1.45-1.30 (m, 2H), 0.93 (t, J = 10.0 Hz, 3H). 13 C MR (125 MHz, CD 3 D): δ 157.4, 136.1, 130.2, 129.7, 129.2, 128.2, 69.9, 59.7, 53.0, 39.2, 31.7, 25.3, 23.3, 14.2. HRMS (ESI) m/z calcd for C 23 H 26 4 2 (M+a) + 413.1953, found 413.1948. tert-butyl (1-benzyl-4-butyl-1H-1,2,3-triazol-5-yl)(phenyl)carbamate (3h) Condition A: 59.3 mg, 73%. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.42-7.33 (m, 5H), 7.20-7.14 (m, 3H), 7.00 (d, J = 10.0 Hz, 2H), 5.40 (d, J = 20.0 Hz, 1H), 4.99 (d, J = 20.0 Hz, 1H), 2.57-2.53 (m, 2H), 1.72-1.66 (m, 2H), 1.42-1.36 (m, 2H), 1.29 (s, 9H), 0.92 (t, J = 10.0 Hz, 3H). 13 C MR (125 MHz, CDCl 3 ): δ 151.9, 143.7, 139.8, 134.6, 132.8, 129.1, 128.9, 128.5, 128.0, 126.0, 124.1, 82.9, 51.9, 30.4, 28.0, 24.7, 22.8, 13.9. Compound 3h is known compound, and the proton and carbon spectrum is fully consistent with literature reported. S8 The regioselectivity is absolutely determined in this case. S8

tert-butyl (1-benzyl-4-(tert-butyl)-1H-1,2,3-triazol-5-yl)(phenyl)carbamate (3i) Condition A: 56.8 mg, 70%. Brown oil. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.29-7.24 (m, 7H), 7.11-7.09 (m, 3H), 5.34 (d, J = 15.0 Hz, 1H), 4.94 (d, J = 15.0 Hz, 1H), 1.31 (s, 9H), 1.23 (s, 9H). 13 C MR (125 MHz, CDCl 3 ): δ 152.0, 149.7, 140.4, 134.3, 130.7, 129.0, 128.9, 128.5, 128.2, 125.0, 122.2, 83.2, 51.3, 31.8, 29.5, 27.9. HRMS (ESI) m/z calcd for C 24 H 30 4 2 (M+a) + 429.2267, found 429.2268. 3-(1-(4-chlorobenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3j) Condition A: 65.1 mg, 92%. Condition B: 60.2 mg, 85%. White solid, mp = 187-188 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.68 (d, J = 10.0 Hz, 2H), 7.44 (t, J = 10.0 Hz, 2H), 7.39-7.36 (m, 3H), 7.27-7.25 (m, 2H), 5.57 (s, 2H), 4.24 (t, J = 10.0 Hz, 2H), 3.10 (br s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 156.6, 141.9, 135.0, 133.0, 129.5, 129.3, 129.2, 129.0, 127.9, 126.5, 63.4, 52.2, 44.8. HRMS (ESI) m/z calcd for C 18 H 15 Cl 4 2 (M+a) + 377.0781, found 377.0781. 3-(1-(4-methylbenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3k) Condition A: 58.9 mg, 88%. Condition B: 54.8 mg, 82%. Yellow oil. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.69 (d, J = 10.0 Hz, 2H), 7.43 (t, J = 10.0 Hz, 2H), 7.36-7.27 (m, 1H), 7.20-7.19 (m, 4H), 5.56 (s, 2H), 4.17 (t, J = 10.0 Hz, 2H), 2.98 (br s, 2H), 2.33 (s, 3H). 13 C MR (125 MHz, CDCl 3 ): δ 156.7, 141.9, 138.9, 131.3, 129.9, 129.5, 129.1, 128.8, 127.8, 126.4, 63.3, 52.9, 44.7, 21.2. HRMS (ESI) m/z calcd for C 19 H 18 4 2 (M+a) + 357.1328, found 357.1331. S9

Methyl 4-(5-(2-oxooxazolidin-3-yl)-4-phenyl-1H-1,2,3-triazol-1-yl)benzoate (3l) Condition A: 53.9 mg, 74%. White solid, mp = 201-202 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 8.26 (d, J = 10.0 Hz, 2H), 7.78 (d, J = 5.0 Hz, 2H), 7.74 (d, J = 10.0 Hz, 2H), 7.52-7.49 (m, 2H), 7.45-7.43 (m, 1H), 4.45 (t, J = 10.0 Hz, 2H), 3.98 (s, 3H), 3.60 (t, J = 10.0 Hz, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 166.8, 156.5, 143.2, 138.5, 131.9, 131.4, 129.3, 129.3, 129.0, 128.2, 126.9, 124.2, 63.4, 52.7, 46.1. HRMS (ESI) m/z calcd for C 19 H 16 4 4 (M+a) + 387.1069, found 387.1074. 3-(1-phenethyl-4-phenyl-1H-1,2,3-triazol-5-yl)oxazolidin-2-one (3m) Condition A: 59.5 mg, 89%. Yellow oil. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.62 (d, J = 10.0 Hz, 2H), 7.42 (t, J = 10.0 Hz, 2H), 7.36 (t, J = 10.0 Hz, 1H), 7.25 (t, J = 10.0 Hz, 2H), 7.18 (t, J = 5.0 Hz, 1H), 7.08 (d, J = 5.0 Hz, 2H), 4.47 (t, J = 10.0 Hz, 2H), 4.30 (t, J = 10.0 Hz, 2H), 3.29 (t, J = 10.0 Hz, 2H), 2.94 (br s, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 155.8, 140.7, 137.9, 129.6, 129.1, 129.0, 128.9, 128.8, 128.4, 127.1, 126.6, 63.5, 49.5, 44.9, 36.4. HRMS (ESI) m/z calcd for C 19 H 18 4 2 (M+a) + 357.1328, found 357.1338. 2-(4-(5-(2-oxooxazolidin-3-yl)-4-phenyl-1H-1,2,3-triazol-1-yl)butyl)isoindoline-1, 3-dione (3n) Condition A: 78.4 mg, 91%. White solid, mp = 161-162 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.84-7.80 (m, 2H), 7.72-7.69 (m, 2H), 7.65 (d, J = 5.0 Hz, 2H), 7.44 (t, J = 10.0 Hz, 2H), 7.37 (t, J = 10.0 Hz, 1H), 4.63 (t, J = 10.0 Hz, 2H), 4.35 (t, J = 10.0 Hz, 2H), 3.80 (t, J = 10.0 Hz, 2H), 3.76 (t, J = 10.0 Hz, 2H), 2.05-2.02 (m, 2H), 1.85-1.82 (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ 168.5, 156.1, 141.3, 134.1, 132.0, 129.6, 129.1, 128.8, 128.1, 126.6, 123.3, 63.5, 47.3, 45.9, 36.7, 26.6, 25.7. HRMS (ESI) m/z calcd for C 23 H 21 5 4 (M+a) + 454.1491, found 454.1492. (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(5-(2-oxooxazolidin-3-yl)-4-phenyl-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3o) S10

Condition A: 89.6 mg, 80%. [α] D 25 = -7.16 (c = 1.24, CH 2 Cl 2 ). White solid, mp = 93-94 o C. 1 H MR (500 MHz, CDCl 3, TMS): δ 7.73 (d, J = 5.0 Hz, 2H), 7.47 (t, J = 10.0 Hz, 2H), 7.41 (t, J = 10.0 Hz, 1H), 5.94 (t, J = 10.0 Hz, 1H), 5.88 (d, J = 10.0 Hz, 1H), 5.43 (t, J = 10.0 Hz, 1H), 5.28 (t, J = 10.0 Hz, 1H), 4.62-4.58 (m, 2H), 4.30 (dd, J = 15.0, 5.0 Hz, 1H), 4.22 (dd, J = 15.0, 5.0 Hz, 1H), 4.02-3.99 (m, 1H), 3.81 (t, J = 10.0 Hz, 2H), 2.08 (s, 6H), 2.05 (s, 3H), 1.95 (s, 3H). 13 C MR (125 MHz, CDCl 3 ): δ 170.6, 170.3, 169.4, 169.0, 156.9, 142.4, 129.3, 129.2, 128.9, 128.9, 126.7, 84.5, 75.0, 73.3, 69.6, 67.6, 63.7, 61.5, 46.4, 20.7, 20.7, 20.6, 20.6. HRMS (ESI) m/z calcd for C 25 H 28 4 11 (M+a) + 583.1652, found 583.1654. S11

7. Reference: (S1) Kim, Y.; Dateer, R. B.; Chang, S. rg. Lett. 2017, 19, 190. (S2) (a) Frederick, M..; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. rg. Lett. 2004, 6, 1151. (c) Tracey, M. R.; Zhang, Y.; Frederick, M..; Mulder, J. A,; Hsung, R. P. rg. Lett. 2004, 6, 2209. (S3) Youn, S. W.; Kim, Y. H. rg. Lett. 2016, 18, 6140. (S4) Xu, J.; Song, Q. rg. Chem. Front. 2017, 4, 938. (S5) Russo,.; Messaoudi, S.; Hamze, A.; livi,.; Peyrat, J. -F.; Brion, J. -D.; Sicsic, S.; Berque-Bestel, I.; Alami, M. Tetrahedron. 2007, 63, 10671. (S6) Worrell, B. T.; Hein, J. E.; Fokin, V. V. Angew. Chem. Int. Ed. 2012, 51, 11791. (S7) Zhang, X.; Hsung, R. P.; You, L. rg. Biomol. Chem. 2006, 4, 2679. (S8) Ferrini, S.; Chandanshive, J. Z.; Lena, S.; Franchini, M. C.; Giannini, G.; Tafi, A.; Taddei, M. J. rg. Chem. 2015, 80, 2562. S12

8. MR Spectra S13

Ph 3a Ph

Ph 3b Me

Ph 3c Cl

Ph Ph 3h

Ph Ph 3i

Cl Ph 3j

Cl 3j Ph

Ac Ac Ac Ac Ph 3o