Supporting Information for Consecutive hydrazino-ugi-azide reactions: synthesis of acylhydrazines bearing 1,5- disubstituted tetrazoles Angélica de Fátima S. Barreto*, Veronica Alves dos Santos, and Carlos Kleber Z. Andrade* Address: Laboratório de Química Metodológica e rgânica Sintética, Instituto de Química, Universidade de Brasília, 70910-970, Brasília-DF, Brazil Email: Angélica de Fátima S. Barreto - angelfsb@yahoo.com.br; Carlos Kleber Z. Andrade - ckleber@unb.br *Corresponding author Detailed experimental procedures, MR and mass spectra Table of contents General Information... S2 General procedure for the Ugi-tetrazole reaction... S2 Spectra of compounds... S14 S66 S1
General information MR spectra were recorded on a Bruker Ascend instrument using a 5 mm internal diameter probe operating at 600 Mz for 1 and at 150 Mz for 13 C in the presence of TMS as internal standard. igh resolution ESIMS analyses were carried out on a triple TF 5600+ (AB Sciex) with internal calibration and direct solution (1 ppm) infusion in positive ion mode. TLC plates were revealed by treatment with a 10% solution of phosphomolybdic acid in ethanol, followed by heating. Melting points were recorded on a Marconi melting point and are uncorrected. Commercially available reagents and solvents were of analytical grade or were purified by standard procedures prior to use. Compounds were analyzed by 1 MR, 13 C MR and high resolution ESI mass spectra giving data consistent with the proposed structures. Compounds names were given based on ChemDraw software 7.0. General procedure for the hydrazino-ugi-azide reactions: To a stirred solution of hydrazide 2a c (0.40 mmol) in TFE (1.0 ml) were added successively oxo compound 7a h (0.40 mmol, 0.80 mmol when a ketone was used), trimethylsilylazide (8, TMS azide, 0.40 mmol), methyl isocyanoacetate (9, 0.40 mmol) and ZnCl 2 (10 mol %). The resulting mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain the Ugi tetrazole product. S2
Me 10a C 3 {5-[1-('-Acetylhydrazino)-2-methylpropyl] tetrazol-1-yl}acetic acid methyl ester (10a): Prepared following the general procedure using acetylhydrazide (2a, 0.73 mmol, 0.054 g), isobutyraldehyde (7a, 0.73 mmol, 0.053 g), trimethylsilyl azide (8, 0.73 mmol, 0.084 g), methyl isocyanoacetate (9, 0.73 mmol, 0.066 ml) and ZnCl 2 (0.073 mmol, 0.010 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10a in 44% yield (0.086 g, 0.32 (C 2 Cl 2 /Me 5%) 0.28. mmol) as a yellow oil. R f 1 MR (600 Mz, CDCl 3 ) δ 7.47 (br s, 1), 5.39 (s, 2), 5.06 (br s, 1), 4.31 (d, J = 8.8 z, 1), 3.85 (s, 3), 2.08-2.01 (m, 1), 1.88 (s, 3), 1.21 (d, J = 6.6 z, 3), 0.81 (d, J = 6.6 z, 3). 13 C MR (150 Mz, CDCl 3 ): δ 169.8, 167.6, 154.9, 63.0, 53.4, 48.8, 30.7, 20.9, 19.6, 19.2. RMS (ESI) m/z: calcd. for [M+a] + C 10 18 6 3 a: 293.1338; found: 293.1342. Me C 3 10b {5-[1-('-Acetylhydrazino)-1-methylethyl]-tetrazol- 1-yl}acetic acid methyl ester (10b): Prepared following the general procedure using acetylhydrazide (2a, 0.73 mmol, 0.054 g), acetone (7b, 0.146 mmol, 0.107 ml), trimethylsilyl azide (8, 0.73 mmol, 0.084 g), methyl isocyanoacetate (9, 0.73 mmol, 0.066 ml) and ZnCl 2 (0.073 mmol, 0.010 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10b in 36% yield (0.067 g, 0.26 mmol) as a white solid. Mp 112 114 C; R f (C 2 Cl 2 /Me 5%) 0.34. 1 MR (600 Mz, CDCl 3 ) δ 7.18 (br s, 1), 5.47 (s, 2), 4.98 (br s, 1), 3.86 (s, 3), 1.92 (s, 3), 1.63 (s, 6). 13 C MR (150 Mz, CDCl 3 ): δ 169.8, 168.2, 158.3, 57.4, 53.4, 49.7, 24.8, 20.8. RMS (ESI) m/z: calcd. for [M+a] + C 9 16 6 3 a: 279.1182; found: 279.1184. S3
Me C 3 1-yl}acetic acid methyl ester (10c): Prepared following the general procedure using acetylhydrazide (2a, 0.40 mmol, 0.030 g), 3-pentanone (7c, 0.40 mmol, 0.034 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.0054 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10c in 47% yield (0.053 g, 0.19 mmol) as a white solid. Mp 130 132 C; R f (C 2 Cl 2 /Me 5%) 0.31. 1 MR (600 Mz, CDCl 3 ) δ 7.08 (br s, 1), 5.54 (s, 2), 5.26 (br s, 1), 3.84 (s, 3), 2.04-1.98 (m, 2), 1.96-1.90 (m, 2), 1,89 (s, 3), 0.88 (t, J = 7.0 z, 6). 13 C MR (150 Mz, CDCl 3 ): δ 169.1, 168.4, 157.2, 63.6, 53.4, 49.9, 24.9, 21.0, 7.2. RMS (ESI) m/z: calcd. for [M+a] + C 11 20 6 3 a: 307.1495; found: 307.1500. Me 10d C 3 10c {5-[1-('-Acetylhydrazino)-1-ethylpropyl]-tetrazol- {5-[1-('-Acetylhydrazino)-2-phenylethyl]-tetrazol- 1-yl}acetic acid methyl ester (10d): Prepared following the general procedure using acetylhydrazide (2a, 0.73 mmol, 0.054 g), phenylacetaldehyde (7d, 0.73 mmol, 0.098 g), trimethylsilyl azide (8, 0.73 mmol, 0.084 g), methyl isocyanoacetate (9, 0.73 mmol, 0.066 ml) and ZnCl 2 (0.073 mmol, 0.010 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10d in 30% yield (0.069 g, 0.22 mmol) as a yellow oil. R f (C 2 Cl 2 /Me 5%) 0.39. 1 MR (600 Mz, CDCl 3 ) δ 7.50 (s, 1), 7.30-7.27 (m, 3), 7.08-7.06 (m, 2), 4.94 and 4.91 (2s, 1, rotamers), 4.87 (t, J = 7.0 z, 1), 4.79 and 4.76 (2s, 1, rotamers), 3.79 (s, 3), 3.23-3.15 (m, 2), 1.85 (s, 3). 13 C MR (150 S4
Mz, CDCl 3 ): δ 170.1, 167.2, 155.1, 135.0, 129.2, 128.9, 127.6, 57.1, 53.3, 48.0, 38.9, 20.9. RMS (ESI) m/z: calcd. for [M+a] + C 14 18 6 3 a: 341.1338; found: 341.1344. Me 10e C 3 yl}acetic acid methyl ester (10e): Prepared following the general procedure using acetylhydrazide (2a, 0.73 mmol, 0.054 g), cyclohexanone (7e, 0.73 mmol, 0.072 g), trimethylsilyl azide (8, 0.73 mmol, 0.084 g), methyl isocyanoacetate (9, 0.73 mmol, 0.066 ml) and ZnCl 2 (0.073 mmol, 0.010 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10e in 40% yield (0.093 g, 0.29 mmol) as a white solid. Mp 116 118 C, R f (C 2 Cl 2 /Me 5%) 0.32. 1 MR (600 Mz, CDCl 3 ) δ 7.17 (d, J = 5.9 z, 1), 5.51 (s, 2), 5.30 (d, J = 7.3 z, 1), 3.84 (s, 3), 2.19-2.15 (m, 2), 1.89 (s, 3), 1.86-1.82 (m, 2), 1.77-1.71 (m, 2), 1.65-1.59 (m, 2), 1.51-1.48 (m, 2). 13 C MR (150 Mz, CDCl 3 ): δ 169.5, 168.1, 157.6, 59.5, 53.4, 49.8, 33.1, 24.9, 21.8, 20.9. RMS (ESI) m/z: calcd. for [M+a] + C 12 20 6 3 a: 319.1495; found: 319.1501. Me 10f C 3 {5-[1-('-Acetylhydrazino)cyclohexyl]-tetrazol-1- {5-[1-('-Acetylhydrazino)cyclopentyl]-tetrazol-1- yl}acetic acid methyl ester (10f): Prepared following the general procedure using acetylhydrazide (2a, 0.73 mmol, 0.054 g), cyclopentanone (7f, 0.73 mmol, 0,061 g), trimethylsilyl azide (8, 0.73 mmol, 0.084 g), methyl isocyanoacetate (9, 0.73 mmol, 0.066 ml) and ZnCl 2 (0.073 mmol, 0.010 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10f in 36% yield (0.074 g, 0.26 mmol) as a yellow solid. Mp 105 107 C; R f (C 2 Cl 2 /Me 5%) 0.36. S5
1 MR (600 Mz, CDCl 3 ) δ 7.21 (d, J = 7.5 z, 1), 5.41 (s, 2), 5.15 (d, J = 7.7 z, 1), 3.84 (s, 3), 2.29-2.24 (m, 2), 2.08-2.04 (m, 1), 1.97-1.92 (m, 2), 1.90 (s, 3), 1.84-1.77 (m, 2). 13 C MR (150 Mz, CDCl 3 ): δ 170.0, 168.1, 158.4, 67.6, 53.4, 49.3, 35.0, 27.0, 24.8, 23.9, 20.9. RMS (ESI) m/z: calcd. for [M+a] + C 11 18 6 3 a: 305.1338; found: 305.1350. Me 10g C 3 yl}acetic acid methyl ester (10g): Prepared following the general procedure using acetylhydrazide (2a; 0.40 mmol, 0.030 g), cycloheptanone (7g, 0.40 mmol, 0.045 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10g in 53% yield (0,066 g, 0.21 mmol) as a white solid. Mp 102 104 C; R f (C 2 Cl 2 /Me 5%) 0.44. 1 MR (600 Mz, CDCl 3 ) δ 7.17 (br s, 1), 5.49 (s, 2), 5.24 (d, J = 8.1 z, 1), 3.85 (s, 3), 2.32-2.26 (m, 2), 1.97-1.93 (m, 2), 1.90 (s, 3), 1.70-1.66 (m, 4), 1.61-1.56 (m, 4). 13 C MR (150 Mz, CDCl 3 ): δ 169.6, 168.6, 158.8, 63.8, 53.5, 49.9, 35.2, 30.4, 22.3, 20.9. RMS (ESI) m/z: calcd. for [M+a] + C 13 22 6 3 a: 333.1651; found: 333.1650. Me 10h C 3 {5-[1-('-Acetylhydrazino)cycloheptyl]-tetrazol-1- {5-[1-('-Acetyl-hydrazino)-1,3-dimethyl-butyl]- tetrazol-1-yl}-acetic acid methyl ester (10h): Prepared following the general procedure using acetylhydrazide (2a, 0.40 mmol, 0.030 g), methyl isobutyl ketone (7h, 0.40 mmol, 0.040 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), S6
methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10h in 47% yield (0.056 g, 019 mmol) as a white solid. Mp 94 96 C; R f (C 2 Cl 2 /Me 5%) 0.42. 1 MR (600 Mz, CDCl 3 ) δ 7.15 (br s, 1), 5.54 (d, J = 17.0 z, 1), 5.38 (s, J = 17.0 z, 1), 5.03 (br s, 1), 3.86 (s, 3), 1.91 (s, 3), 1.72 (s, 3), 1.70-1.66 (m, 3), 0.97 (d, J = 6.2 z, 3), 0.52 (d, J = 6.2 z, 3). 13 C MR (150 Mz, CDCl 3 ): δ 169.9, 168.4, 157.7, 60.7, 53.5, 49.7, 47.2, 24.7, 24.2, 23.2, 21.2, 20.9. RMS (ESI) m/z: calcd. for [M+a] + C 12 22 6 3 a: 321.1651; found: 321.1650. Me Cbz 10i (5-{1-['-(2-(Benzyloxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1-yl)acetic acid methyl ester (10i): Prepared following the general procedure using Cbz-glycine hydrazide (2b, 0.40 mmol, 0.089 g), acetone (7b, 0.80 mmol, 0.046 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10i in quantitative yield (0.162 g, 0.40 mmol) as a white solid. Mp 120 122 C; R f (C 2 Cl 2 /Me 5%) 0.36. 1 MR (600 Mz, CDCl 3 ) δ 7.77 (d, J = 7.4 z, 1), 7.35-7.29 (m, 5), 5.47 (s, 2), 5.45 (br s, 1), 5.09 (s, 2), 4.92 (d, J = 7.4 z, 1), 3.83 (d, J = 5.9 z, 2), 3.80 (s, 3), 1.60 (s, 6). 13 C MR (150 Mz, CDCl 3 ): δ 169.1, 168.3, 158.1, 156.5, 136.0, 128.5, 128.2, 128.1, 67.2, 57.5, 53.6, 49.8, 43.3, 24.9. RMS (ESI) m/z: calcd. for [M+a] + C 17 23 7 5 a: 428.1658; found: 428.1666. S7
Me Boc 10j (5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1-yl)acetic acid methyl ester (10j): Prepared following the general procedure using Bocglycine hydrazide (2c, 0.40 mmol, 0.076 g), acetone (7b, 0.80 mmol, 0.046 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10j in 97% yield (0.144 g, 0.39 mmol) as a colorless oil. R f (C 2 Cl 2 /Me 5%) 0.34. 1 MR (600 Mz, CDCl 3 ) δ 7.72 (br s, 1), 5.47 (s, 2), 5.04 (br s, 1), 4.93 (br s, 1), 3.84 (s, 3), 3.77 (d, J = 5.9 z, 2), 1.62 (s, 6), 1.41 (s, 9). 13 C MR (150 Mz, CDCl 3 ): δ 169.6, 167.9, 158.1, 155.9, 80.2, 57.3, 53.4, 49.8, 42.9, 28.1, 24.8. RMS (ESI) m/z: calcd. for [M+a] + C 14 25 7 5 a: 394.1815; found: 394.1814. Me 10k Cbz (5-{1-['-(2- (Benzyloxycarbonylamino)acetyl)hydrazino]-cyclohexyl}-tetrazol-1- yl)acetic acid methyl ester (10k): Prepared following the general procedure using Cbz-glycine hydrazide (2b, 0.40 mmol, 0.089 g), cyclohexanone (7e, 0.40 mmol, 0.039 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 2% Me/C 2 Cl 2 ) furnished product 10k in 85% yield (0.151 g, 0.34 mmol) as a white solid. Mp 62 64 C; R f (C 2 Cl 2 /Me 5%) 0.42. 1 MR (600 Mz, CDCl 3 ) δ 7.62 (br s, 1), 7.36-7.29 (m, 5), 5.49 (s, 2), 5.32 (br s, 1), 5.23 (br s, 1), 5.08 (s, 2), 3.80 (s, 5), 2.18-2.14 (m, 2), 1.86-1.79 (m, 2), 1.75-1.69 (m, 2), 1.64-1.57 (m, 2), 1.51-1.47 (m, 2). S8
13 C MR (150 Mz, CDCl 3 ): δ 168.8, 168.3, 157.5, 156.4, 136.0, 128.5, 128.2, 128.1, 67.2, 59.7, 53.6, 49.9, 43.3, 33.2, 25.0, 21.8. RMS (ESI) m/z: calcd. for [M+a] + C 20 27 7 5 a: 468.1971; found: 468.1974. Me 10l Boc (5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-cyclohexyl}-tetrazol-1-yl)acetic acid methyl ester (10l): Prepared following the general procedure using Bocglycine hydrazide (2c, 0.40 mmol, 0.076 g), cyclohexanone (7e, 0.40 mmol, 0.039 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 3% Me/C 2 Cl 2 ) furnished product 10l in 57% yield (0.094 g, 0.23 mmol) as a white solid. Mp 68 70 C; R f (C 2 Cl 2 /Me 5%) 0.41. Me 10m Boc 1 MR (600 Mz, CDCl 3 ) δ 7.67 (s, 1), 5.50 (s, 2), 5.01 (s, 1), 3.82 (s, 3), 3.74 (s, 2), 2.21-2.17 (m, 2), 1.87-1.82 (m, 2), 1.76-1.70 (m, 2), 1.65-1.59 (m, 2), 1.51-1.47 (m, 2), 1.41 (s, 9). 13 C MR (150 Mz, CDCl 3 ): δ 169.3, 168.1, 157.3, 155.8, 80.4, 59.7, 53.5, 49.9, 43.0, 33.2, 28.2, 24.9, 21.8. RMS (ESI) m/z: calcd. for [M+a] + C 17 29 7 5 a: 434.2128; found: 434.2143. (5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-cycloheptyl}-tetrazol-1-yl)acetic acid methyl ester (10m): Prepared following the general procedure using Boc- S9
glycine hydrazide (2c, 0.40 mmol, 0.076 g), cycloheptanone (7g, 0.40 mmol, 0.045 g), trimethylsilyl azide (8, 0.40 mmol, 0.046 g), methyl isocyanoacetate (9, 0.40 mmol, 0.036 ml) and ZnCl 2 (0.040 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 4% Me/C 2 Cl 2 ) furnished product 10n in 62% yield (0.106 g, 0.25 mmol) colorless oil. R f (C 2 Cl 2 /Me 5%) 0.50. 1 MR (600 Mz, CDCl 3 ) δ 7.68 (s, 1), 5.49 (s, 2), 5.04 (s, 1), 3.83 (s, 3), 3.76 (d, J = 5.5 z, 2), 2.32-2.28 (m, 2), 1.96-1.92 (m, 2), 1.68-1.53 (m, 8), 1.40 (s, 9). 13 C MR (150 Mz, CDCl 3 ): δ 169.3, 168.2, 158.6, 155.8, 80.3, 63.8, 53.5, 50.8, 49.9, 43.8, 35.3, 30.4, 28.2, 24.3, 22.3. RMS (ESI) m/z: calcd. for [M+a] + C 18 31 7 5 a: 448.2284; found: 448.2296. 2 11 Boc {'-[1-(1-ydrazinocarbonylmethyl-1tetrazol-5-yl)-1-methylethyl]-hydrazinocarbonylmethyl}carbamic acid tertbutyl ester (11): To a solution of compound 10j (0.371 g, 1.00 mmol) in 2.0 ml of ethanol was added hydrazine hydrate (0.200 g, 4.00 mmol). After refluxing for 5 h, the residue was concentrated in vacuum and purified by column chromatography (C 2 Cl 2 10% Me/C 2 Cl 2 ) furnishing product 6 in 55% yield (0.204 g, 0.55 mmol) as a white solid. Mp 44 46 C; R f (C 2 Cl 2 /Me 15%) 0.39. 1 MR (600 Mz, DMS-d 6 ) δ 9.59 (s, 1), 9.00 (d, J = 5.9 z, 1), 6.95 (t, J = 6.1 z, 1), 5.51 (s, 2), 5.37 (d, J = 5.9 z, 1), 4.39 (br, 1), 3.43 (d, J = 5.9 z, 2), 1.46 (s, 6), 1.35 (s, 9). 13 C MR (150 Mz, DMS-d 6 ): δ 169.1, 165.2, 158.3, 155.8, 78.1, 56.5, 49.5, 34.7, 28.2, 25.1, 18.6, 13.9. RMS (ESI) m/z: calcd. for [M+a] + C 13 25 9 4 a: 394.1927; found: 394.1923. S10
Me 12a Boc [5-(1-{'-[2-(5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1- yl)acetyl]hydrazino}-cycloheptyl)-tetrazol-1-yl]acetic acid methyl ester (12a): Prepared following the general procedure using hydrazide 11 (0.13 mmol, 0.048 g), cycloheptanone (7g, 0.13 mmol, 0.014 g), trimethylsilyl azide (8, 0.13 mmol, 0.015 g), methyl isocyanoacetate (9, 0.13 mmol, 0.013 ml) and ZnCl 2 (0.013 mmol, 0.002 g). Purification by column chromatography (C 2 Cl 2 4% Me/C 2 Cl 2 ) furnished product 12a in 68% yield (0.055 g, 0.090 mmol) as a white solid. Mp 105 107 C; R f (C 2 Cl 2 /Me 10%) 0.52. 1 MR (600 Mz, DMS-d 6 ) δ 9.59 (d, J = 4.4 z, 1), 8.94 (d, J = 5.1 z, 1), 6.88 (s, 1), 5.87 (s, 2), 5.64 (d, J = 4.4 z, 1), 5.45 (s, 2), 5.27 (d, J = 5.5 z, 1), 3.71 (s, 3), 3.39 (d, J = 5.9 z, 2), 2.17-2.13 (m, 2), 1.96-1.92 (m, 2), 1.65-1.59 (m, 2), 1.53-1.48 (m, 4), 1.41-1.30 (m, 17). 13 C MR (150 Mz, DMS-d 6 ): δ 169.0, 167.6, 165.6, 158.0 (2C), 155.7, 78.0, 62.4, 56.1, 54.9, 52.7, 49.6, 49.3, 45.7, 41.7, 35.0, 29.6, 28.1, 24.9, 21.9. RMS (ESI) m/z: calcd. for [M+a] + C 24 41 13 6 a: 630.3200; found: 630.3230. Me Boc 12b [5-(1-{'-[2-(5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1- yl)acetyl]hydrazino}-1-ethylpropyl)-tetrazol-1-yl]acetic acid methyl ester (12b): Prepared following the general procedure using hydrazide 11 (0.35 mmol, 0.130 g), 3-pentanone (7c, 0.35 mmol, 0.030 g), trimethylsilyl azide (8, 0.35 mmol, 0.040 g), methyl isocyanoacetate (9, 0.35 mmol, 0.032 ml) and S11
ZnCl 2 (0.035 mmol, 0.005 g). Purification by column chromatography (C 2 Cl 2 5% Me/C 2 Cl 2 ) furnished product 12b in 54% yield (0.110 g, 0.19 mmol) as a yellow solid. Mp 101 103 C; R f (C 2 Cl 2 /Me 10%) 0.43. 1 MR (600 Mz, DMS-d 6 ) δ 9.47 (br s, 1), 8.95 (d, J = 5.5 z, 1), 6.88 (t, J = 6.1 z, 1), 5.93 (s, 2), 5.66 (br s, 1), 5.46 (s, 2), 5.25 (d, J = 5.5 z, 1), 3.70 (s, 3), 3.39 (d, J = 5.9 z, 2), 1.96-1.90 (m, 2), 1.80-1.74 (m, 2), 1.35 and 1.33 (2s, 15), 0.69 (t, J = 7.5 z, 6). 13 C MR (150 Mz, DMS-d 6 ): δ 169.0, 167.6, 165.7, 158.0, 156.4, 155.7, 78.0, 62.5, 56.0, 52.7, 49.8, 49.3, 45.7, 41.7, 28.1, 24.8, 24.7, 20.0, 7.03. RMS (ESI) m/z: calcd. for [M+a] + C 22 39 13 6 a: 604.3044; found: 604.3035. Me 12c Boc [5-(1-{'-[2-(5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1- yl)acetyl]hydrazino}-cyclohexyl)-tetrazol-1-yl]acetic acid methyl ester (12c): Prepared following the general procedure using hydrazide 11 (0.26 mmol, 0.095 g), cyclohexanone (7e, 0.26 mmol, 0.025 g), trimethylsilyl azide (8, 0.26 mmol, 0.030 g), methyl isocyanoacetate (9, 0.26 mmol, 0.024 ml) and ZnCl 2 (0.026 mmol, 0.004 g). Purification by column chromatography (C 2 Cl 2 4% Me/C 2 Cl 2 ) furnished product 12c in 70% yield (0.108 g, 0.18 mmol) as a yellow solid. Mp 119 121 C; R f (C 2 Cl 2 /Me 10%) 0.47. 1 MR (600 Mz, DMS-d 6 ) δ 9.59 (br s,1), 8.92 (d, J = 5.3 z, 1), 6.88 (s, 1), 5.84 (s, 2), 5.67 (s, 1), 5.41 (s, 2), 5.25 (d, J = 5.3 z, 1), 3.70 (s, 3), 3.40 (d, J = 5.9 z, 2), 2.05-1.99 (m, 2), 1.80-1.77 (m, 2), 1.69-1.60 (m, 2), 1.47-1.39 (m, 4), 1.35 and 1.33 (2s, 15). 13 C MR (150 Mz, DMS-d 6 ): δ 169.0, 167.6, 165.6, 158.0, 156.8, 155.7, 78.0, 58.2, 56.1, 52.7, 49.5, 49.2, 45.7, 41.7, 32.8, 28.1, 24.9, 21.4. RMS (ESI) m/z: calcd. for [M+a] + C 23 39 13 6 a: 616.3044; found: 616.3033. S12
Me Boc 12d [5-(1-{'-[2-(5-{1-['-(2-(tert- Butoxycarbonylamino)acetyl)hydrazino]-1-methylethyl}-tetrazol-1- yl)acetyl]hydrazino}-cyclopentyl)-tetrazol-1-yl]acetic acid methyl ester (12d): Prepared following the general procedure using hydrazide 11 (0.30 mmol, 0.110 g), cyclopentanone (7f, 0.30 mmol, 0.025 g), trimethylsilyl azide (8, 0.30 mmol, 0.034 g), methyl isocyanoacetate (9, 0.30 mmol, 0.027 ml) and ZnCl 2 (0.030 mmol, 0.004 g). Purification by column chromatography (C 2 Cl 2 4% Me/C 2 Cl 2 ) furnished product 12d in 45% yield (0.079 g, 0.14 mmol) as a yellow solid. Mp 114 116 C; R f (C 2 Cl 2 /Me 10%) 0.47. 1 MR (600 Mz, CDCl 3 ) δ 8.44 (d, J = 7.0 z, 1), 8.39 (br s, 1), 5.47 (s, 2), 5.41 (s, 2), 5.27 (br s, 1), 5.14 (br s, 1), 4.75 (br s, 1), 3.86 (s, 3), 3.77 (d, J = 5.9 z, 1), 2.29-2.24 (m, 1), 2.09-2.02 (m, 1), 1.95-1.88 (m, 2), 1.78-1.76 (m, 2), 1.59 (s, 6), 1.43 (s, 9). 13 C MR (150 Mz, CDCl 3 ): δ 169.9, 168.1, 165.6, 158.2, 157.9, 156.0, 80.3, 67.6, 57.5, 53.7, 49.9, 49.4, 42.9, 35.2, 29.7, 28.3, 25.2, 23.8, 14.1. RMS (ESI) m/z: calcd. for [M+a] + C 22 37 13 6 a: 602.2887; found: 602.2879. S13
ormalized Intensity Spectra of compounds 1.0 Angelica_T-15.001.esp 0.9 0.8 0.7 Me 10a C 3 0.6 0.5 0.4 0.3 0.2 0.1 0 0.95 1.94 0.92 0.96 3.00 1.132.95 3.04 2.98 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S1: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10a. S14
167.55 ormalized Intensity 53.35 169.84 154.91 62.99 19.22 30.71 20.93 48.81 19.58 1.0 0.9 Angelica_T-15.013.esp Me 10a C 3 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S2: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10a. S15
Me 10a C 3 Calc. [M+a] + : 293.1338 Figure S3: ESI-RMS of compound 10a. S16
ormalized Intensity 1.0 0.9 0.8 Angelica_T-17.001.esp Me 10b C 3 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.98 2.06 0.59 3.00 2.98 6.32 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S4: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10b. S17
168.22 57.39 53.40 20.82 158.29 ormalized Intensity 169.85 49.71 24.81 Angelica_T-17.013.esp 0.7 0.6 Me 10b C 3 0.5 0.4 0.3 0.2 0.1 0 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S5: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10b. S18
Me 10b C 3 Calc. [M+a] + : 279.1182 Figure S6: ESI-RMS of compound 10b. S19
ormalized Intensity 1.0 Angelica_T-24.001.esp 0.9 0.8 0.7 Me 10c C 3 0.6 0.5 0.4 0.3 0.2 0.1 0 0.98 2.01 0.73 3.00 3.98 2.96 6.05 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S7: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10c. S20
168.41 169.07 53.39 20.95 63.63 ormalized Intensity 157.24 7.20 49.94 24.91 Angelica_T-24.013.esp 0.7 0.6 0.5 Me 10c C 3 0.4 0.3 0.2 0.1 0 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0-10 -20 Figure S8: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10c. S21
Me 10c C 3 Calc. [M+a] + : 307.1495 Figure S9: ESI-RMS of compound 10c. S22
ormalized Intensity 1.0 Angelica_T19.001.esp 0.9 0.8 0.7 Me 10d C 3 0.6 0.5 0.4 0.3 0.2 0.1 0 1.00 3.29 2.01 1.16 0.98 0.96 3.00 2.03 3.01 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S10: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10d. S23
170.14 167.17 155.14 135.03 57.07 ormalized Intensity 38.89 20.88 53.31 129.20 48.01 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 Angelica_T-19.013.esp 127.55 128.87 Me 10d C 3 0.15 0.10 0.05 0 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S11: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10d. S24
Me C 3 10d Calc. [M+a] + : 341.1338 Figure S12: ESI-RMS of compound 10d. S25
ormalized Intensity 1.0 0.9 Angelica_T20.001.esp Me C 3 0.8 10e 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.97 2.02 0.91 3.01 2.06 3.06 2.10 2.32 2.14 2.01 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S13: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10e. S26
157.64 59.54 20.88 53.35 ormalized Intensity 49.80 33.14 24.95 21.77 Angelica_T-20.013.esp 0.55 0.50 0.45 Me 10e C 3 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 168.11 169.52 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S14: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10e. S27
Me C 3 10e Calc. [M+a] + : 319.1495 Figure S15: ESI-RMS of compound 10e. S28
ormalized Intensity 1.0 0.9 0.8 Angelica_T-21.001.esp Me 10f C 3 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.83 1.85 0.79 2.94 2.25 1.92 1.98 2.99 2.33 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S16: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10f. S29
158.36 24.78 26.99 169.95 ormalized Intensity 67.60 168.06 20.88 49.34 53.35 35.05 23.92 1.0 Angelica_T-21.013.esp 0.9 0.8 Me C 3 0.7 10f 0.6 0.5 0.4 0.3 0.2 0.1 0 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S17: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10f. S30
Me 10f C 3 Calc. [M+a] + : 305.1338 Figure S18: ESI-RMS of compound 10f. S31
ormalized Intensity 1.0 0.9 0.8 Angelica_T-25.001.esp Me 10g C 3 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.01 1.94 0.94 2.86 2.17 2.02 2.97 4.04 4.10 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S19: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10g. S32
168.55 169.62 158.78 63.82 20.94 53.46 ormalized Intensity 49.89 35.21 30.42 22.33 Angelica_T-25.013.esp 0.55 0.50 0.45 0.40 Me 10g C 3 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S20: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10g. S33
Me 10g C 3 Calc. [M+a] + : 333.1651 Figure S21: ESI-RMS of compound 10g. S34
ormalized Intensity 1.0 Angelica_T26.001.esp 0.9 0.8 0.7 Me C 3 0.6 10h 0.5 0.4 0.3 0.2 0.1 0 0.95 0.940.95 0.90 2.89 2.95 2.90 2.78 3.00 2.91 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S22: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10h. S35
ormalized Intensity 168.38 169.92 157.71 53.49 24.66 60.69 24.25 49.74 47.16 20.92 21.16 23.20 1.0 0.9 0.8 Angelica_T26.013.esp Me 10h C 3 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 Figure S23: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10h. S36
Me C 3 10h Calc. [M+a] + : 321.1651 Figure S24: ESI-RMS of compound 10h. S37
ormalized Intensity 1.0 0.9 0.8 Angelica_T-27.001.esp Me 10i Cbz 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.92 4.95 2.11 0.72 2.06 0.95 5.08 6.00 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S25: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10i. S38
168.27 169.12 156.49 158.13 135.95 53.56 43.31 57.52 ormalized Intensity 67.25 49.82 128.06 128.52 24.94 128.23 0.55 Angelica_T-27.013.esp Me 10i Cbz 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S26: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10i. S39
Me 10i Calc. [M+a] + : 428.1658 Cbz Figure S27: ESI-RMS of compound 10i. S40
ormalized Intensity 0.8 Angelica_T-28.001.esp Me 10j Boc 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.06 1.98 0.94 0.99 3.01 1.93 6.06 9.20 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S28: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10j. S41
155.89 80.16 167.88 42.91 57.33 ormalized Intensity 169.65 158.10 53.38 49.75 28.12 24.81 Angelica_T-28.013.esp 0.40 0.35 0.30 0.25 Me 10j Boc 0.20 0.15 0.10 0.05 0 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S29: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10j. S42
Me 10j Calc. [M+a] + : 394.1815 Boc Figure S30: ESI-RMS of compound 10j. S43
ormalized Intensity 1.0 0.9 0.8 Angelica_T-29.001.esp Me 10k Cbz 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1.00 4.78 1.97 1.02 1.00 1.96 5.00 2.00 1.97 2.122.16 2.07 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S31: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10k. S44
43.31 53.56 59.70 ormalized Intensity 156.43 157.49 168.79 135.99 49.90 67.25 33.25 168.31 24.95 21.77 128.52 0.15 Angelica_T-29.013.esp 128.06 128.21 Me 10k Cbz 0.10 0.05 0 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S32: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10k. S45
Me 10k Cbz Calc. [M+a] + : 468.1971 Figure S33: ESI-RMS of compound 10k. S46
ormalized Intensity 0.7 0.6 0.5 Angelica_T-49.001.esp Me 10l Boc 0.4 0.3 0.2 0.1 0 0.84 1.92 0.85 3.06 2.08 1.962.22 2.28 2.18 2.13 8.99 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S34: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10l. S47
155.84 157.32 80.41 168.06 169.29 59.73 43.04 53.52 ormalized Intensity 33.16 49.91 24.94 21.77 28.20 Angelica_T-49.013.esp 0.20 Me 10l Boc 0.15 0.10 0.05 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S35: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10l. S48
Me 10l Boc Calc. [M+a] + : 434.2128 Figure S36: ESI-RMS of compound 10l. S49
ormalized Intensity 0.45 0.40 Angelica_T-52.001.esp Me 10m Boc 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 0.81 1.95 0.97 3.00 1.78 2.21 2.02 7.93 8.98 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S37: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 10m. S50
155.79 158.55 80.32 63.76 50.76 42.98 24.30 43.85 ormalized Intensity 53.54 49.93 35.26 28.18 30.41 22.29 Angelica_T-52.013.esp 0.30 0.25 Me 10m Boc 0.20 0.15 168.25 169.32 0.10 0.05 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S38: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 10m. S51
Figure S39: ESI-RMS of compound 10m. S52
ormalized Intensity 1.0 Angelica_T-38.1-hidrazida.001.esp 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.79 0.80 0.80 1.59 1.02 1.20 1.66 6.00 9.27 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S40: 1 MR (600 Mz, DMS-d 6 ) spectrum of compound 11. S53
169.14 165.19 158.31 155.75 78.06 56.46 49.52 34.68 18.63 13.86 25.11 28.16 ormalized Intensity 1.0 Angelica_T-38.1-hidrazida.013.esp 0.9 0.8 0.7 0.6 2 11 Boc 0.5 0.4 0.3 0.2 0.1 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S41: 13 C MR (150 Mz, DMS-d 6 ) spectrum of compound 11. S54
ormalized Intensity Angelica_T-53-2-Ugi.001.esp 0.45 0.40 0.35 0.30 Me 12a Boc 0.25 0.20 0.15 0.10 0.05 0 0.84 0.84 0.77 1.85 0.88 1.77 1.08 3.03 1.88 1.91 2.07 2.13 3.83 17.02 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S42: 1 MR (600 Mz, DMS-d 6 ) spectrum of compound 12a. S55
155.68 158.03 45.70 169.01 41.73 77.99 49.26 49.62 ormalized Intensity 56.11 62.38 52.74 54.90 35.02 29.60 21.86 24.90 28.13 0.060 Angelica_T-53-2-Ugi.013.esp 0.055 0.050 0.045 0.040 Me 12a Boc 0.035 0.030 0.025 165.60 167.59 0.020 0.015 0.010 0.005 0 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S43: 13 C MR (150 Mz, DMS-d 6 ) spectrum of compound 12a. S56
Figure S44: ESI-RMS of compound 12a. S57
ormalized Intensity 0.55 Angelica-T-41-2-Ugi.001.esp 0.50 0.45 0.40 0.35 0.30 Me 12b Boc 0.25 0.20 0.15 0.10 0.05 0 0.88 0.83 0.79 1.85 0.901.74 0.92 0.92 2.82 1.74 4.16 15.14 6.00 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S45: 1 MR (600 Mz, DMS-d 6 ) spectrum of compound 12b. S58
165.66 167.64 169.01 155.69 156.41 158.01 41.70 19.98 77.99 56.04 45.71 49.26 49.75 24.66 24.85 62.46 52.68 ormalized Intensity 28.14 7.03 Angelica_T-41-2-Ugi.013.esp 0.15 Me 12b Boc 0.10 0.05 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S46: 13 C MR (150 Mz, DMS-d 6 ) spectrum of compound 12b. S59
Me 12b Boc Calc. [M+a] + : 604.3044 Figure S47: ESI-RMS of compound 12b. S60
ormalized Intensity 0.7 0.6 0.5 Angelica-T-44-2=Ugi.001.esp Me 12c Boc 0.4 0.3 0.2 0.1 0 0.93 0.98 0.78 1.91 1.01 1.83 0.97 3.13 1.61 1.98 2.04 2.24 4.25 14.96 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S48: 1 MR (600 Mz, DMS-d 6 ) spectrum of compound 12c. S61
165.57 167.62 169.00 155.68 156.77 158.01 78.00 41.73 56.09 58.23 45.71 49.20 49.54 32.85 24.91 21.43 52.73 28.14 ormalized Intensity Angelica-T-44-2=Ugi.013.esp 0.30 0.25 Me 12c Boc 0.20 0.15 0.10 0.05 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S49: 13 C MR (150 Mz, DMS-d 6 ) spectrum of compound 12c. S62
Me 12c Boc Calc. [M+a] + : 616.3044 Figure S50: ESI-RMS of compound 12c. S63
ormalized Intensity 1.0 Angelica_T-45-2Uhi-2.001.esp 0.9 0.8 0.7 Me 12d Boc 0.6 0.5 0.4 0.3 0.2 0.1 0 0.91 0.67 2.01 1.97 1.00 0.88 0.77 3.03 2.26 2.06 2.30 2.23 2.16 6.11 9.06 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Figure S51: 1 MR (600 Mz, CDCl 3 ) spectrum of compound 12d. S64
165.63 155.97 14.12 158.20 80.26 57.52 42.93 29.70 168.06 ormalized Intensity 157.86 67.60 49.88 25.19 169.88 53.72 49.42 35.25 28.28 23.80 0.07 0.06 Angelica_T-45-2Ugi.013.esp Me 12d Boc 0.05 0.04 0.03 0.02 0.01 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Figure S52: 13 C MR (150 Mz, CDCl 3 ) spectrum of compound 12d. S65
Me 12d Boc Calc. [M+a] + : 602.2887 Figure S53: ESI-RMS of compound 12d. S66