Chiral α-aminoxy Acid / Achiral Cyclopropane α-aminoxy Acid Unit as a Building Block for Constructing α N O Helix

Transcript

1 Chiral α-aminoxy Acid / Achiral Cyclopropane α-aminoxy Acid Unit as a Building Block for Constructing α elix Dan Yang,*,, Xiao-Wei Chang, Dan-Wei Zhang,*, Ze-Feng Jiang, Ke-Sheng Song, Yu-ui Zhang, ian-yong Zhu, Lin-ong Weng, Min-Qin Chen Department of Chemistry, Fudan University, Shanghai , China, and Department of Chemistry, The University of ong Kong, Pokfulam Road, ong Kong, China Supporting Information I. General experimental methods... S2 II. Synthetic schemes and characterization data of compounds S3 III. 1 MR experimental result of compound S12 IV. Theoretical study results: energies and Cartesian coordinates for models I IV.... S13 VI. X-Ray data of compounds 1, 2, and S30 VII. MR spectra of compounds S61 S1

2 I. General experimental methods 1 MR spectra were recorded at 300 or 400 Mz, 13 C MR spectra were recorded at 75 or 100 Mz. IR spectra were recorded as a thin film unless otherwise noted. Reactions were monitored by thin layer chromatography (TLC) using silica gel 60 precoated glass plates, 0.25 mm thickness. Components were visualized by illumination with short-wavelength ultra-violet light and/or staining with phosphomolybdic acid solution followed by heating. Flash column chromatography was performed on silica gel 60 ( mesh ATM). C 2 Cl 2 and tetrahydrofuran (TF) were dried by fresh distillation from Ca 2, and a/benzophenone respectively. Tirethylamine was dried by distillation over K. Abbreviations: Acc: 1-Aminoxycyclopropane carboxylic acid; ΔAla: 2-(aminooxy)acrylic acid; AA (Xxx): α-aminoxy acid segment; Xxx represent 3 letter codes for amino acids; Piv: pivaloyl group. S2

3 II. Synthetic schemes and characterization data of compounds Scheme S1. Synthesis of compound 1 starting from L-serine. 2 a Phth b c Me Phth Me Phth Me 33% 86% 59% d e Me 33% 33% 13 1 Reagents and conditions: a) a 2, KBr, 2 S 4, 0 ºC; Me, Ts, reflux; -hydroxy phthalimide, Et 3, DMF, rt; b) MsCl, Et 3, C 2 Cl 2, rt; c) C 2 2 ; toluene, reflux; d) 2 4 2, Me; Piv, EDCI, At; e) Li, 2 /Me/TF; EDCI, At, iso-butyl amine. Scheme S2. Synthesis of dipeptide 2. D C t Bu a,b 59% D C t Bu c d CMe a 44% D Me e,f 71% 12 D 14 2 Reagents and conditions: a) 2 4 2, Me; b) EDCI, At, iso-butyric acid; c) trifluoroacetic acid, C 2 Cl 2 ; d) EDCI, At, C 2 Cl 2 ; e) Li, Me/ 2 /TF; f) EDCI, At, iso-butyl amine, C 2 Cl 2. S3

4 Scheme S3. Synthesis of dipeptide 3. CMe c D C t Bu a, b 93% 13 D d 15 e 63% D 3 Reagents and conditions: a) trifluoroacetic acid, C 2 Cl 2 ; b) EDCI, At, iso-butyl amine, C 2 Cl 2 ; c) Li, Me/ 2 /TF; d) 2 4 2, Me; e) EDCI, At, C 2 Cl 2. Scheme S4. Synthesis of dipeptide 4. D C t Bu C t Bu a b c 85% D t Bu a, d 80% D Reagents and conditions: a) trifluoroacetic acid, C 2 Cl 2 ; b) 2 4 2, Me; c) EDCI, At, C 2 Cl 2 ; d) EDCI, At, iso-butyl amine, C 2 Cl 2. 4 S4

5 Scheme S5. Synthesis of dipeptide 5. C t Bu a,b 83% C t Bu c D C t Bu c,d 83% D a e 76% D 5 Reagents and conditions: a) 2 4 2, Me; b) Pyridine, pivaloyl chloride, C 2 Cl 2, 0ºC; c) trifluoroacetic acid, C 2 Cl 2 ; d) EDCI, At, iso-butyl amine, C 2 Cl 2 ; e) EDCI, At, C 2 Cl 2. Scheme S6. Synthesis of tripeptide 6. D C t Bu a,b 63% D C t Bu CMe a c d 45% D 16 Me 16 e d 52% D 12 Me 12 a e, f 81% 17 D Reagents and conditions: a) 2 4 2, Me; b) EDCI, At, iso-butyric acid, C 2 Cl 2 ; c) trifluoroacetic acid, C 2 Cl 2 ; d) EDCI, At, C 2 Cl 2 ; e) Li, Me/ 2 /TF; f) EDCI, At, iso-butyl amine, C 2 Cl 2. 6 S5

6 Scheme S7. Synthesis of tetrapeptide 7. C t Bu a, b C t Bu c CMe a d Me e D Me D e, f d e a D 7 D D 82% 73% 55% 71% Me D d 93% a Reagents and conditions: a) 2 4 2, Me; b) EDCI, At, pivalic acid, C 2 Cl 2 ; c) trifluoroacetic acid, C 2 Cl 2 ; d) EDCI, At, C 2 Cl 2 ; e) Li, Me/ 2 /TF; f) EDCI, At, iso-butyl amine, C 2 Cl 2. Scheme S8. Synthesis of tripeptide 8. Me D C t Bu d a, b c e D D 8 D D 95% 71% 14 Reagents and conditions: a) trifluoroacetic acid, C 2 Cl 2 ; b) EDCI, At, iso-butyl amine, C 2 Cl 2 ; c) 2 4 2, Me; d) Li, Me/ 2 /TF; e) EDCI, At, C 2 Cl 2. S6

7 Scheme S9. Synthesis of pentapeptide 9. Me D C t Bu a c 9 CMe b c CMe b d D D D D D Me d b D D D 93% c 49% 47% Reagents and conditions: a) trifluoroacetic acid, C 2 Cl 2 ; b) 2 4 2, Me; c) EDCI, At, C 2 Cl 2 ; d) Li, Me/ 2 /TF. S7

8 Characterization data of compounds Phth-Gly- t Bu and Piv-Gly- t Bu, 1 Phth-D-Val- t Bu and Phth-D-leu- t Bu, 2 Piv-D-Leu- t Bu, 3 Phth-D-Leu- i Bu, 4 Phth-L-Val- t Bu, 5 i PrC-D-Leu- t Bu 6 are known compounds. Their preparations were reported in literature. Phth-D-Ser-Me (10). Colorless oil; [α] 20 D (c 1.0, CCl 3 ); R f = 0.4 (EtAc:hexane = 1:1); 1 MR (400 Mz, CDCl 3 ) δ (m, 4), 4.76 (dd, J = 4.8, 2.5 z, 1), (m, 2), 3.87 (s, 3); 13 C MR (100 Mz, CDCl 3 ) δ 167.3, 164.3, 135.2, 128.7, 124.2, 85.9, 60.8, 52.9; IR (C 2 Cl 2 ) 3402 (br), 3382, 1672 cm 1 ; EI-MS (20 ev) m/z 148 (100), 266 (M + +1, 1); RMS-EI m/z for C (M + ) calcd , found Phth-ΔAla-Me (11). A white solid. M.p C; R f = 0.3 (EtAc:hexane = 1:4); 1 MR (400 Mz, CDCl 3 ): δ (m, 4), 5.71 (d, J = 3.7 z, 1), 5.07 (d, J = 3.7 z, 1), 3.91 (s, 3); 13 C MR (100 Mz, CDCl 3 ) δ 162.0, 160.6, 150.8, 135.2, 128.8, 124.2, 99.4, 53.0; IR (KBr) 3437, 3124, 1749, 1643 cm 1 ; EI-MS (20 ev) m/z 130 (100), 216 (M + C 3, 4); RMS-EI m/z for C (M + +1) calcd , found Phth-Acc-Me (12). A white solid. M.p C; R f = 0.3 (EtAc:hexane = 1:4); 1 MR (400 Mz, CDCl 3 ) δ (m, 4), 3.80 (s, 3), (m, 2), (m, 2); 13 C MR (100 Mz, CDCl 3 ) δ 171.1, 163.7, 134.8, 129.1, 123.8, 67.7, 52.7, 17.7; IR (KBr) 3441, 3021, 1731 cm 1 ; EI-MS (20 ev) m/z 160 (100), 261 (M +, 1); RMS-EI m/z for C (M + ) calcd , found Piv-Acc-Me (13). Colorless oil. R f = 0.5 (EtAc:hexane = 1:1); 1 MR (400 Mz, CDCl 3 ) δ 9.10 (s, 1), 3.77 (s, 3), (m, 2), (m, 2), 1.20 (s, 9); 13 C MR (100 Mz, CDCl 3 ) δ 176.3, 173.4, 66.2, 52.5, 38.3, 27.3, 16.8; IR (C 2 Cl 2 ) 3385, S8

9 1744, 1666 cm 1 ; EI-MS (20 ev) m/z 156 (100), 215 (M +, 3); RMS (EI) for C (M + ): calcd , found i PrC-D-Val-Acc-Me (14). Colorless oil; R f = 0.5 (EtAc:hexane = 1:1); [α] 20 D (c 1.0, CCl 3 ); 1 MR (300 Mz, CDCl 3 ) δ (s, 1), 9.68 (s, 1), 4.09 (d, J = 3.9 z, 1), 3.84 (s, 3), (m, 2), (m, 4), (m, 6), 1.06 (d, J = 6.9 z, 3), 0.95 (d, J = 6.9 z, 3); 13 C MR (75 Mz, CDCl 3 ) δ 177.9, 172.8, 169.0, 91.5, 66.4, 52.9, 32.5, 31.1, 19.7, 19.4, 19.3, 17.2, 17.0, 16.9; IR (C 2 Cl 2 ) 3178 (br), 1740, 1672 cm 1 ; EI-MS (20 ev) m/z 198 (100), 316 (M +, 13); RMS-EI m/z for C (M + ) calcd , found Phth-D-Val- i Bu (15). A white solid. M.p C; R f = 0.4 (EtAc:hexane = 1:4); [α] 20 D +128 (c 0.83, C 2 Cl 2 ); 1 MR (400 Mz, CDCl 3 ) δ (m, 4), 7.71 (s, br, 1), 4.63 (d, J = 4.2 z, 1), (m, 1), (m, 1), (m, 1), (m, 1), 1.27 (d, J = 7.4 z, 3), 1.10 (d, J = 6.9 z, 3), 0.99 (d, J = 7.3 z, 3), 0.96 (d, J = 6.9 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 169.4, 164.2, 135.0, 128.8, 123.9, 92.1, 46.7, 31.5, 28.5, 20.3(2), 19.2, 16.9; IR (C 2 Cl 2 ) 3389, 1742, 1657 cm 1 ; EI-MS (20 ev) m/z 160 (100), 318 (M +, 2); RMS (EI) m/z for C (M + ) calcd , found i PrC-D-Leu-Acc-Me (16). Colorless oil. R f = 0.5 (5% acetone in C 2 Cl 2 ); [α] 20 D (c 1.0, CCl 3 ); 1 MR (400 Mz, CDCl 3 ) δ (s, 1), 9.05 (s, 1), (m, 1), 3.86 (s, 3), (m, 1), (m, 7), (m, 6), (m, 6); 13 C MR (100 Mz, CDCl 3 ) δ 177.6, 172.6, 169.6, 85.4, 66.2, 52.7, 41.0, 32.4, 24.7, 23.3, 21.7, 19.4, 19.1, 16.9(2); IR (C 2 Cl 2 ) 3177 (br), 1738, 1673 cm 1 ; EI-MS (20 ev) m/z 172 (100), 330 (M +, 4); RMS (EI) for C (M + ): calcd , found S9

10 i PrC-D-Leu-Acc-Acc-Me (17). Colorless oil. R f = 0.6 (10% acetone in C 2 Cl 2 ); [α] 20 D (c 1.0, CCl 3 ); 1 MR (400 Mz, CDCl 3 ) δ (s, 1), (s, 1), 9.69 (s, 1), 4.34 (dd, J = 8.2, 5.0 z, 1), 3.84 (s, 3), (m, 1), (m, 11), 1.14 (d, J = 6.8 z, 3), 1.11 (d, J = 6.8 z, 3), 0.95 (d, J = 6.4 z, 3), 0.94 (d, J = 6.9 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 178.5, 172.7, 171.4, 169.4, 85.3, 67.6, 66.3, 52.6, 40.8, 32.2, 24.6, 23.3, 21.6, 19.3, 19.1, 17.3, 17.0, 16.8, 15.8; IR (C 2 Cl 2 ) 3221, 1735, 1642 cm 1 ; EI-MS (20 ev) m/z 172 (M +, 100), 429 (M +, 16); RMS (EI) for C (M + ): calcd , found Piv-D-Leu-Acc-Me (18). Colorless oil. R f = 0.5 (5% acetone in C 2 Cl 2 ); [α] 20 D (c 1.0, CCl 3 ); 1 MR (400 Mz, CDCl 3 ) δ (s, 1), 8.60 (s, 1), 4.30 (dd, J = 8.7, 3.6 z, 1), 3.86 (s, 3), (m, 7), 1.20 (s, 9), 0.97 (d, J = 6.9 z, 3), 0.95 (d, J = 6.9 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 179.1, 172.7, 169.2, 85.3, 66.3, 52.7, 41.0, 38.2, 27.2, 27.1, 24.8, 23.3, 21.8, 17.0; IR (C 2 Cl 2 ) 3277, 1751, 1678 cm 1 ; EI-MS (20 ev) m/z 188 (100), 344 (M +, 13); RMS (EI) for C (M + ): calcd , found Piv-D-Leu-(Acc) 2 -Me (19). Colorless oil. R f = 0.4 (5% acetone in C 2 Cl 2 ); [α] 20 D (c 1.0, CCl 3 ); 1 MR (400 Mz, CDCl 3 ) δ (s, 1), (s, 1), 9.41 (s, 1), 4.37 (t, J = 6.4 z, 1), 3.85 (s, 3), (m, 11), 1.18 (s, 9), 0.95 (d, J = 6.4 z, 3), 0.94 (d, J = 6.4 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 179.9, 172.7, 171.3, 169.3, 85.2, 67.6, 66.3, 52.6, 41.0, 38.2, 27.1, 24.6, 23.3, 21.7, 17.3, 17.0, 16.9, 15.6; IR (C 2 Cl 2 ) 3344, 1735, 1632 cm 1 ; EI-MS (20 ev) m/z 186 (100), 443 (M +, 16); RMS (EI) for C (M + ): calcd , found Piv-D-Leu-(Acc) 3 -Me (20). Colorless oil. R f = 0.5 (10% acetone in C 2 Cl 2 ); [α] 20 D S10

11 +35.2 (c 1.0, CCl 3 ); 1 MR (400 Mz, CDCl 3 ) δ (s, 1), (s, 1), (s, 1), 8.74 (s, 1), 4.31 (t, J = 6.4 z, 1), 3.82 (s, 3), (m, 15), 1.21 (s, 9), 0.97 (d, J = 5.9 z, 3), 0.96 (d, J = 6.4 z, 3); 13 C MR (100 Mz, CDCl 3 ) δ 180.5, 172.7, 171.6, 170.7, 169.2, 85.6, 67.8, 67.6, 66.3, 52.6, 40.7, 38.3, 27.1, 24.7, 23.3, 21.7, 17.5, 17.0, 16.9, 16.5, 16.4, 16.3; IR (C 2 Cl 2 ) 3396, 1722, 1628 cm 1 ; EI-MS (20 ev) m/z 145 (100), 542 (M +, 13); RMS (EI) for C (M + ): calcd , found Phth-D-Val-Acc-Me (21). A white solid. M.p C; R f = 0.4 (EtAc:hexane = 1:1); [α] 20 D (c 1.0, CCl 3 ); 1 MR (300 Mz, CDCl 3 ) δ (s, 1), (m, 4), 4.57 (d, J = 4.7 z, 1), 3.90 (s, 3), (m, 2), (m, 1), (m, 2), 1.24 (d, J = 7.0 z, 3), 1.13 (d, J = 7.0 z, 3); 13 C MR (75 Mz, CDCl 3 ) δ 172.5, 167.2, 164.0, 135.0, 128.5, 123.9, 92.1, 66.4, 52.5, 31.5, 18.7, 17.0(2), 16.5; IR (C 2 Cl 2 ) 3252, 1735, 1680 cm 1 ; EI-MS (20 e V) m/z 163 (100), 214 (M + C 8 4 3, 52); RMS (EI) m/z for C (M + C ) calcd , found i PrC-(D-Val-Acc) 2 -Me (22). Colorless oil. R f = 0.5 (5% acetone in C 2 Cl 2 ); [α] 20 D (c 1.0, CCl 3 ); 1 MR (300 Mz, CDCl 3 ) δ (s, 1), (s, 1), (s, 1), 8.45 (s, 1), 4.14 (d, J = 3.8 z, 1), 4.12 (d, J = 3.6 z, 1), 3.81 (s, 3), (m, 3), (m, 8), (m, 12), (d, J = 6.9 z, 3), (d, J = 7.0 z, 3); 13 C MR (75 Mz, CDCl 3 ) δ 178.5, 172.4, 171.2, 170.8, 168.6, 91.6, 91.1, 67.4, 66.0, 52.4, 32.1, 30.7, 30.6, 19.1, 18.9, 18.8, 18.7, 17.9, 16.8, 16.6, 16.1, 15.9, 15.1; IR (C 2 Cl 2 ) 3186, 1740, 1671 cm 1 ; EI-MS (20 ev) m/z 110 (100), 530 (M +, 32); RMS (EI) m/z for C (M + ) calcd , found S11

12 III. 1 MR experimental result of compound 1. a) δ (ppm) b a a b 1 b) δ (ppm) a 1 b a b Log Conc volume of DMS-d 6 added (μl) Figure S1. (a) Chemical shifts of amide protons as a function of the logarithm of the concentration of compound 1 in CDCl 3 at room temperature; (b) Chemical shifts of amide protons as a function of the amount of DMS-d 6 added in a solution of compound 1 in 5 mm CDCl 3. S12

13 IV. Theoretical study results: energies and Cartesian coordinates for models I IV All the calculations were performed with Gaussian03 7 software package. All of the molecules were full optimized using B3LYP 8 /6-311+G** followed by harmonic vibration frequency calculations to ensure that each structure was a minimum. Energies were evaluated by MP2 9 /6-311+G** calculations on B3LYP/6-311+G** geometries. Solvent effect was evaluated by the PCM 10 model using B3LYP/6-311+G** method. The relative free energies of conformers were calculated with the MP2/6-311+G** energies plus the enthalpy and entropy corrections along with the solvent energy corrections as shown in Eq. 1. ΔG = ΔE (MP2) + [ΔE (B3LYP, solvent) ΔE (B3LYP, gas)]+ enthalpy corrections TΔS (Eq. 1) S13

14 Table S1. Calculated energies and corrections of models I IV. (S) I Me (S) II Me Me Me III IV Gas phase Solvent ΔG (C 2 Cl 2 ) Enthalpy Entropy MP2/6-311+G(d, p) B3LYP/ MP2/ B3LYP/ correction correction (Gas phase) (C 2 Cl 2 ) G** G** G** (hartree) (hartree) (Kcal/mol) (Kcal/mol) (hartree) (hartree) (hartree) Ia Ib IIa IIb IIIa IIIb IIIc IIId IVa IVb IVc IVd S14

15 Table S2. Geometries (Cartesian coordinates) of models I IV optimized using B3LYP/6-311+G** 1. Ac-L-Ala-Acc-Me, Ia and Ib (1) Ia S15

16 (2) Ib C C C C C C C C C C S16

17 2. Ac-Acc-L-Ala-Me, IIa and IIb (1) IIa S17

18 (2) IIb C C C C C C C C C C S18

19 3. Ac-Acc-Me, IIIa d (1) IIIa (2) IIIb S19

20 (3) IIIc S20

21 (4) IIId S21

22 4. Ac-Acc-Me IVa d a) IIIa 0.0 (0.0) IIIb 0.0 (0.0) IIIc 3.7 (3.1) IIId 2.7 (1.7) b) IVa 0.0 (0.0) IVb 0.0 (0.0) IVc 3.9 (4.5) IVd 2.6 (1.8) Figure S2. Calculated structures of model a) Ac-Acc-Me III and b) Ac-Acc-Me IV and their relative energies at MP2/6-311+G** level in vacuum and in C 2 Cl 2 (in bracket). (1) IVa C C C C C C S22

23 C (2) IVb C C C C C C C S23

24 (3) IVc C C C C C C C (4) IVd C C C C C C S24

25 C S25

26 V. CD spectra of oligopeptides 2 9. D a b D a c D a 2 3 b c b D a 4 5 b c c a D b c d a b 6 7 D c d e a D D D D D b c d a b c d e 8 9 f a) Mol.Ellip. (deg cm 2 dmol 1 ) dipeptide 2 4mM dipeptide 2 1mM dipeptide 2 0.4mM b) Mol.Ellip. (deg cm 2 dmol 1 ) dipeptide 3 4mM dipeptide 3 1mM dipeptide 3 0.4mM wavelength (nm) wavelength (nm) c) Mol.Ellip. (deg cm 2 dmol 1 ) dipeptide 5 4 mm dipeptide 5 1 mm dipeptide mm d) Mol.Ellip. (deg cm 2 dmol 1 ) dipeptide 6 4 mm dipeptide 6 1 mm dipeptide mm wavelength (nm) wavelength (nm) S26

27 e) Mol.Ellip. (deg cm 2 dmol 1 ) tripeptide 6 4mM tripeptide 6 1mM tripeptide 6 0.4mM f) Mol.Ellip. (deg cm 2 dmol 1 ) tetrapeptide 7 tetrapeptide 7 tetrapeptide 7 4mM 1mM 0.4mM wavelength (nm) wavelength (nm) g) Mol.Ellip. (deg cm 2 dmol 1 ) tripeptide 8 4mM tripeptide 8 1mM tripeptide 8 0.4mM h) Mol.Ellip. (deg cm 2 dmol 1 ) pentapeptide 9 pentapeptide 9 pentapeptide 9 4 mm 1 mm 0.4 mm wavelength (nm) wavelength (nm) Figure S3. Circular dichroism spectra of oligopeptides at different concentration in trifluoroethanol. The spectra of 2 7 (figures a f) have been normalized for the concentration only, whereas those of 8 and 9 (figures g and h) have been normalized for both the concentration and the number of potential maximum turns. S27

28 Mol.Ellip. (deg cm 2 dmol 1 ) dipeptide 2 dipeptide 3 tripeptide 6 tetrapeptide 7 tripeptide 8 pentapeptide wavelength (nm) Figure S4. Circular dichroism spectra of oligopeptides 2, 3, and 6 9 at 4 mm concentration in methanol (after normalization for both the concentration and the number of potential maximum turns). References: (1) Yang, D.; g, F.-F.; Li, Z.-J. J. Am. Chem. Soc. 1996, 118, (2) Yang, D.; Li, B.; g, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. rg. Chem. 2001, 66, (3) Yang, D.; Qu, J.; Li, B.; g, F.-F.; Wang, X.-C.; Cheung, K.-K.; Wang, D.-P.; Wu, Y.-D. J. Am. Chem. Soc. 1999, 121, 589. (4) Li, X.; Shen, B.; Yao, X.; Yang, D. J. Am. Chem. Soc. 2007, 129, (5) Yang, D.; Li, W.; Qu, J.; Luo, S.-W.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, (6) Yang, D.; Liu, G.-J.; Jiao, Z.-G.; Zhang, D.-W.; Luo, Z.; Song, K.-S.; Chen, M.-Q. Chem. Eur. J. 2008, 14, (7) Frisch, M. J.; Trucks, G. W.; Schlegel,. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, Jr., T.; Kudin, K..; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega,.; Petersson, G. A.; akatsuji,.; ada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; asegawa, J.; Ishida, M.; akajima, T.; onda, Y.; Kitao,.; akai,.; Klene, M.; Li, X.; Knox, J. E.; ratchian,. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,.; Austin, A. J.; Cammi, R.; Pomelli, C.; chterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; rtiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; S28

29 Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; anayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision B05, Gaussian, Inc.: Pittsburgh, PA, (8) (a) Becke, A.D. J. Chem. Phys. 1993, 98, (b) Miehlich, B.; Savin, A.; Stoll,.; Preuss,. Chem. Phys. Lett. 1989, 157, 200. (c) Lee, C.; Yang, W.; Parr, G. Phys. Rev. B 1988, 37, 785. (9) (a) Moller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618. (b) andy,. C.; Schaefer, III,. F. J. Chem. Phys. 1984, 81, (c) ead-gordon, M.; ead-gordon, T. Chem. Phys. Lett. 1994, 220, 122. (10) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett. 1998, 286, 253. (c) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, (d) Cossi, M.; Scalmani, G.; Rega,.; Barone, V. J. Chem. Phys. 2002, 117, 43. S29

30 VI. X-Ray data of compounds 1, 2 and 8. 1 Figure S5. Twinned structure and -bond in the crystal of compound 1. Table S3. Intramolecular -bond length (Å) and dihedral angle values ( ) of the backbone of dipeptide 2 D a b 2 c φ θ ψ Compound D (Å) ( ) φ ( ) θ ( ) ψ ( ) 2 D-Val Acc S30

31 Table S4 Crystal data and structure refinement for compound 1. Empirical formula C Formula weight Temperature 253(2) K Wavelength Å Crystal system Monoclinic Space group C 2/c Unit cell dimensions a = (8) Å α= 90. b = 8.973(2) Å β= (3). c = (5) Å γ = 90. Volume Z (2) Å3 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 2240 Crystal size 0.4 x 0.3 x 0.2 mm 3 Theta range for data collection 1.71 to Index ranges -39<=h<=35, -8<=k<=8, -27<=l<=27 Reflections collected 7354 Independent reflections 2839 [R(int) = ] Completeness to theta = % Absorption correction one Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2839 / 7 / 370 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e.å-3 S31

32 Table S5 Atomic coordinates (x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for compound 1. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) (1) 7103(1) -1978(4) 540(2) 85(1) (2) 6211(1) -1928(3) -371(2) 62(1) (3) 6032(1) 208(4) -1804(2) 87(1) (1) 6449(2) -1080(4) 258(2) 58(1) (2) 6636(2) -1102(5) -916(2) 65(1) C(1) 5976(2) -987(6) -974(3) 58(1) C(2) 5485(2) -1375(7) -1493(3) 91(2) C(3) 5626(2) 6(6) -1073(3) 88(2) C(4) 6217(2) -563(6) -1268(3) 58(2) C(5) 6899(2) -1316(6) 716(3) 61(2) C(6) 7125(2) -681(6) 1442(3) 75(2) C(7) 7056(3) -1808(7) 1856(3) 147(3) C(8) 7620(2) -464(9) 1791(3) 174(4) C(9) 6915(2) 783(7) 1433(3) 120(2) C(10) 6907(2) -882(6) -1157(3) 83(2) C(11) 7213(3) 442(7) -833(4) 103(2) C(12) 7578(2) 279(7) -54(4) 133(3) C(13) 7433(3) 689(8) -1209(4) 168(3) (4) 5335(1) -4431(4) 1469(2) 83(1) (5) 5347(1) -1481(3) 1437(2) 60(1) (6) 5825(1) -828(4) 521(2) 71(1) (3) 5669(2) -2305(5) 2055(2) 61(1) (4) 5507(2) -2915(5) 591(2) 61(1) C(14) 5556(2) -687(5) 1193(2) 51(1) C(15) 5392(2) 885(5) 990(3) 69(2) C(16) 5856(2) 572(5) 1637(3) 66(2) C(17) 5642(2) -1505(7) 742(2) 56(2) C(18) 5601(2) -3784(7) 2027(3) 60(2) C(19) 5888(2) -4581(6) 2731(3) 73(2) C(20) 5637(12) -4290(40) 3060(15) 179(14) C(21) 6371(10) -3940(30) 3271(14) 172(16) C(22) 5957(11) -6160(30) 2610(12) 133(12) C(20') 5910(20) -4090(60) 3310(20) 240(40) C(21') 6358(11) -4490(70) 2970(20) 230(30) S32

33 C(22') 5691(16) -6120(40) 2600(20) 170(20) C(23) 5560(2) -3849(5) 147(2) 74(2) C(24) 5799(2) -5287(7) 502(4) 107(2) C(25) 6238(2) -5181(8) 1171(4) 157(3) C(26) 5800(2) -6271(7) -28(3) 151(3) S33

34 Table S6 Bond lengths [Å] and angles [ ] for compound 1. (1)-C(5) 1.226(6) (2)-(1) 1.414(4) (2)-C(1) 1.418(5) (3)-C(4) 1.232(6) (1)-C(5) 1.351(6) (2)-C(4) 1.337(6) (2)-C(10) 1.449(6) C(1)-C(3) 1.478(7) C(1)-C(4) 1.489(7) C(1)-C(2) 1.501(7) C(2)-C(3) 1.475(6) C(5)-C(6) 1.502(7) C(6)-C(8) 1.507(7) C(6)-C(9) 1.524(7) C(6)-C(7) 1.542(7) C(10)-C(11) 1.497(7) C(11)-C(12) 1.500(7) C(11)-C(13) 1.558(7) (4)-C(18) 1.219(5) (5)-C(14) 1.416(5) (5)-(3) 1.418(4) (6)-C(17) 1.247(6) (3)-C(18) 1.345(6) (4)-C(17) 1.329(6) (4)-C(23) 1.455(5) C(14)-C(16) 1.486(6) C(14)-C(17) 1.490(6) C(14)-C(15) 1.496(6) C(15)-C(16) 1.485(6) C(18)-C(19) 1.513(7) C(19)-C(20') 1.39(4) C(19)-C(21') 1.49(4) C(19)-C(22) 1.50(2) C(19)-C(22') 1.51(4) C(19)-C(21) 1.56(3) C(19)-C(20) 1.57(3) C(23)-C(24) 1.504(7) C(24)-C(25) 1.435(7) C(24)-C(26) 1.544(7) S34

35 (1)-(2)-C(1) 111.0(3) C(5)-(1)-(2) 116.3(4) C(4)-(2)-C(10) 122.3(5) (2)-C(1)-C(3) 117.5(4) (2)-C(1)-C(4) 116.8(5) C(3)-C(1)-C(4) 120.0(5) (2)-C(1)-C(2) 112.9(5) C(3)-C(1)-C(2) 59.3(3) C(4)-C(1)-C(2) 117.2(5) C(3)-C(2)-C(1) 59.6(3) C(2)-C(3)-C(1) 61.1(3) (3)-C(4)-(2) 123.9(6) (3)-C(4)-C(1) 121.0(6) (2)-C(4)-C(1) 115.1(5) (1)-C(5)-(1) 121.7(5) (1)-C(5)-C(6) 123.2(6) (1)-C(5)-C(6) 115.1(5) C(5)-C(6)-C(8) 109.1(5) C(5)-C(6)-C(9) 112.7(5) C(8)-C(6)-C(9) 110.2(5) C(5)-C(6)-C(7) 107.0(5) C(8)-C(6)-C(7) 111.0(5) C(9)-C(6)-C(7) 106.7(5) (2)-C(10)-C(11) 113.7(5) C(10)-C(11)-C(12) 113.4(5) C(10)-C(11)-C(13) 108.7(6) C(12)-C(11)-C(13) 109.0(6) C(14)-(5)-(3) 111.1(3) C(18)-(3)-(5) 116.6(4) C(17)-(4)-C(23) 123.3(5) (5)-C(14)-C(16) 117.0(4) (5)-C(14)-C(17) 117.6(4) C(16)-C(14)-C(17) 119.3(5) (5)-C(14)-C(15) 112.9(4) C(16)-C(14)-C(15) 59.7(3) C(17)-C(14)-C(15) 117.1(4) C(16)-C(15)-C(14) 59.8(3) C(15)-C(16)-C(14) 60.5(3) (6)-C(17)-(4) 124.4(5) (6)-C(17)-C(14) 118.7(5) (4)-C(17)-C(14) 116.9(5) S35

36 (4)-C(18)-(3) 121.9(5) (4)-C(18)-C(19) 122.9(5) (3)-C(18)-C(19) 115.2(6) C(20')-C(19)-C(21') 105(3) C(20')-C(19)-C(22) 125(2) C(21')-C(19)-C(22) 80(2) C(20')-C(19)-C(22') 103(3) C(21')-C(19)-C(22') 116(2) C(22)-C(19)-C(22') 37.8(17) C(20')-C(19)-C(18) 121.6(17) C(21')-C(19)-C(18) 105.6(15) C(22)-C(19)-C(18) 108.8(10) C(22')-C(19)-C(18) 106.0(14) C(20')-C(19)-C(21) 74(3) C(21')-C(19)-C(21) 33(3) C(22)-C(19)-C(21) 105.0(15) C(22')-C(19)-C(21) 133.2(18) C(18)-C(19)-C(21) 115.2(10) C(20')-C(19)-C(20) 32(3) C(21')-C(19)-C(20) 137(2) C(22)-C(19)-C(20) 118.6(17) C(22')-C(19)-C(20) 84(2) C(18)-C(19)-C(20) 103.9(11) C(21)-C(19)-C(20) 106(2) (4)-C(23)-C(24) 112.5(4) C(25)-C(24)-C(23) 117.1(5) C(25)-C(24)-C(26) 112.2(6) C(23)-C(24)-C(26) 109.1(5) Symmetry transformations used to generate equivalent atoms: S36

37 Table S7 Anisotropic displacement parameters (Å 2 x 10 3 )for compoud 1. The anisotropic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 (1) 78(3) 116(3) 57(3) 10(2) 40(2) 32(2) (2) 72(3) 64(2) 43(2) -6(2) 33(2) -4(2) (3) 112(3) 97(3) 51(2) 30(2) 50(3) 30(2) (1) 55(4) 79(3) 38(3) -4(2) 27(3) -3(3) (2) 76(4) 88(3) 48(3) -1(3) 46(4) 0(3) C(1) 52(4) 77(4) 36(4) 3(3) 23(4) 14(4) C(2) 58(5) 141(6) 53(4) -12(4) 22(4) -4(4) C(3) 89(5) 107(5) 74(4) 17(4) 53(4) 30(4) C(4) 60(5) 67(4) 47(4) -6(3) 33(4) 6(4) C(5) 65(5) 71(4) 38(4) 13(3) 28(4) 12(4) C(6) 70(5) 99(5) 42(4) -9(3) 27(4) 3(4) C(7) 203(8) 166(6) 49(4) 14(4) 65(5) -10(5) C(8) 51(5) 315(10) 97(6) -88(6) 15(5) -15(6) C(9) 109(6) 134(6) 92(5) -48(4) 47(4) -15(5) C(10) 92(5) 101(5) 64(4) -6(3) 52(4) -3(4) C(11) 107(6) 110(6) 106(6) 15(5) 72(6) -1(5) C(12) 123(7) 128(6) 128(7) -25(5) 66(6) -36(5) C(13) 177(8) 206(8) 193(8) 34(6) 150(8) -29(6) (4) 105(3) 72(2) 57(3) -16(2) 41(3) -27(2) (5) 69(3) 64(2) 52(2) 3(2) 40(2) 5(2) (6) 91(3) 71(3) 77(3) -4(2) 65(2) -5(2) (3) 85(4) 57(3) 45(3) 2(3) 41(3) 5(3) (4) 84(4) 57(3) 52(3) -10(2) 47(3) -5(3) C(14) 63(4) 50(3) 48(3) -1(3) 38(3) 0(3) C(15) 88(5) 60(4) 66(4) 12(3) 50(4) 15(3) C(16) 90(5) 59(4) 58(4) -15(3) 49(4) -13(3) C(17) 61(4) 60(4) 42(3) -3(3) 29(3) 6(3) C(18) 71(5) 52(4) 61(5) 6(4) 42(4) -1(4) C(19) 100(6) 58(4) 48(4) 10(3) 39(4) 3(4) C(20) 210(30) 290(30) 99(18) 127(16) 130(20) 120(20) C(21) 150(20) 118(14) 82(19) 31(11) -12(16) -17(13) C(22) 190(30) 80(12) 80(11) 14(8) 60(17) 30(18) C(20') 330(90) 280(40) 90(30) 90(30) 130(50) 250(50) C(21') 29(19) 460(80) 110(30) 170(40) -4(18) 70(30) C(22') 190(40) 80(20) 160(20) 81(17) 60(20) 10(20) S37

38 C(23) 103(5) 64(4) 63(4) -14(3) 55(4) -2(3) C(24) 98(6) 114(6) 75(5) -28(4) 35(5) 24(4) C(25) 118(7) 189(8) 98(6) -27(5) 31(6) 57(6) C(26) 154(7) 139(6) 106(5) -41(4) 51(5) 60(5) S38

39 Table S8 ydrogen coordinates (x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for compoud 1. x y z U(eq) (2A) (2B) (3A) (3B) (7A) (7B) (7C) (8A) (8B) (8C) (9A) (9B) (9C) (10A) (10B) (11) (12A) (12B) (12C) (13A) (13B) (13C) (2) 6745(16) -1660(40) -492(19) 90(19) (1) 6246(15) -970(50) 380(30) 110(20) (15A) (15B) (16A) (16B) (20A) (20B) (20C) (21A) (21B) (21C) (22A) (22B) S39

40 (22C) (20D) (20E) (20F) (21D) (21E) (21F) (22D) (22E) (22F) (23A) (23B) (24) (25A) (25B) (25C) (26A) (26B) (26C) (3) 5773(14) -1640(40) 2450(19) 84(17) (4) 5384(15) -3240(50) 840(20) 92(19) S40

41 Table S9 Crystal data and structure refinement for dipeptide 2. Empirical formula C Formula weight Empirical formula C Formula weight Temperature 298(2) K Wavelength Å Crystal system, space group rthorhombic, P2(1)2(1)2(1) Unit cell dimensions a = 8.869(2) Å alpha = 90 deg. b = (3) Å beta = 90 deg. c = (5) Å gamma = 90 deg. Volume (10) Å 3 Z, Calculated density 4, Mg/m 3 Absorption coefficient mm -1 F(000) 776 Crystal size 0.45 x 0.45 x 0.35 mm Theta range for data collection 1.95 to deg. Limiting indices -10<=h<=10,-8<=k<=15,-22<=l<=18 Reflections collected / unique 7334 / 3652 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3652 / 0 / 245 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.9(12) Extinction coefficient (16) Largest diff. peak and hole and e.å -3 S41

42 Table S10 Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for dipeptide 2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) (1) 6679(2) 5243(2) 3384(1) 80(1) (2) 7405(2) 4755(1) 1708(1) 63(1) (3) 10301(2) 3573(2) 1276(1) 61(1) (1) 7943(2) 6763(1) 3541(1) 92(1) (2) 6430(1) 5563(1) 1937(1) 73(1) (3) 6139(2) 3556(1) 2374(1) 100(1) (4) 8910(1) 3282(1) 974(1) 60(1) (5) 9974(2) 5232(1) 884(1) 71(1) C(1) 7740(6) 3447(3) 4939(2) 139(1) C(2) 7716(4) 3849(2) 4186(2) 106(1) C(3) 6812(3) 4863(2) 4121(1) 93(1) C(4) 7303(2) 6123(2) 3147(1) 70(1) C(5) 7164(2) 6336(2) 2359(1) 68(1) C(6) 8324(3) 7004(2) 1996(1) 78(1) C(7) 6796(3) 7428(2) 2125(2) 92(1) C(8) 7062(2) 3772(2) 1905(1) 66(1) C(9) 7886(2) 2902(2) 1516(1) 60(1) C(10) 6757(2) 2185(2) 1142(1) 68(1) C(11) 5878(3) 2760(2) 559(2) 95(1) C(12) 7518(3) 1203(2) 852(2) 102(1) C(13) 10780(2) 4559(2) 1147(1) 56(1) C(14) 12367(2) 4783(2) 1402(1) 63(1) C(15) 13180(3) 5467(2) 867(1) 89(1) C(16) 12294(3) 5279(3) 2132(1) 107(1) C(17) 9238(5) 3953(5) 3904(3) 200(2) S42

43 Table S11 Bond lengths [Å] and angles [deg] for dipeptide 2. (1)-C(4) 1.321(3) (1)-C(3) 1.454(3) (2)-C(8) 1.334(3) (2)-(2) 1.406(2) (3)-C(13) 1.341(3) (3)-(4) 1.405(2) (1)-C(4) 1.231(2) (2)-C(5) 1.413(2) (3)-C(8) 1.225(2) (4)-C(9) 1.439(2) (5)-C(13) 1.215(2) C(1)-C(2) 1.486(4) C(2)-C(17) 1.454(5) C(2)-C(3) 1.519(4) C(4)-C(5) 1.491(3) C(5)-C(7) 1.487(4) C(5)-C(6) 1.494(3) C(6)-C(7) 1.477(4) C(8)-C(9) 1.507(3) C(9)-C(10) 1.520(3) C(10)-C(12) 1.515(3) C(10)-C(11) 1.519(4) C(13)-C(14) 1.512(3) C(14)-C(16) 1.495(3) C(14)-C(15) 1.503(3) C(4)-(1)-C(3) 124.0(2) C(8)-(2)-(2) (17) C(13)-(3)-(4) (17) (2)-(2)-C(5) (13) (3)-(4)-C(9) (13) C(17)-C(2)-C(1) 110.8(4) C(17)-C(2)-C(3) 112.6(3) C(1)-C(2)-C(3) 111.9(2) (1)-C(3)-C(2) 113.4(2) (1)-C(4)-(1) 123.5(2) (1)-C(4)-C(5) 120.1(2) (1)-C(4)-C(5) (19) S43

44 (2)-C(5)-C(7) (19) (2)-C(5)-C(4) (19) C(7)-C(5)-C(4) (19) (2)-C(5)-C(6) (19) C(7)-C(5)-C(6) 59.43(17) C(4)-C(5)-C(6) (19) C(7)-C(6)-C(5) 60.06(18) C(6)-C(7)-C(5) 60.51(16) (3)-C(8)-(2) 123.7(2) (3)-C(8)-C(9) (19) (2)-C(8)-C(9) (17) (4)-C(9)-C(8) (16) (4)-C(9)-C(10) (15) C(8)-C(9)-C(10) (17) C(12)-C(10)-C(11) 111.7(2) C(12)-C(10)-C(9) (19) C(11)-C(10)-C(9) (19) (5)-C(13)-(3) (18) (5)-C(13)-C(14) (18) (3)-C(13)-C(14) (18) C(16)-C(14)-C(15) 112.2(2) C(16)-C(14)-C(13) (19) C(15)-C(14)-C(13) (18) Symmetry transformations used to generate equivalent atoms: S44

45 Table S12 Anisotropic displacement parameters (Å 2 x 10 3 ) for dipeptide 2. The anisotropic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U h k a* b* U 12 ] U11 U22 U33 U23 U13 U12 (1) 89(1) 72(1) 80(1) -22(1) 17(1) -20(1) (2) 56(1) 69(1) 65(1) -15(1) 10(1) -2(1) (3) 47(1) 59(1) 77(1) -2(1) -5(1) 4(1) (1) 116(1) 75(1) 85(1) -21(1) -9(1) -24(1) (2) 48(1) 81(1) 90(1) -29(1) -4(1) 5(1) (3) 105(1) 97(1) 97(1) -40(1) 46(1) -50(1) (4) 53(1) 69(1) 58(1) -6(1) 0(1) -7(1) (5) 56(1) 68(1) 89(1) 15(1) 0(1) 4(1) C(1) 189(4) 130(3) 99(2) -6(2) 15(3) 28(3) C(2) 120(2) 110(2) 88(2) -20(2) 9(2) 15(2) C(3) 112(2) 87(2) 81(2) -20(1) 28(1) -5(2) C(4) 66(1) 64(1) 79(1) -19(1) 7(1) -4(1) C(5) 53(1) 68(1) 82(1) -21(1) 1(1) 3(1) C(6) 82(1) 71(1) 82(1) -9(1) 3(1) -5(1) C(7) 96(2) 78(2) 103(2) -14(1) -7(2) 24(1) C(8) 61(1) 75(1) 62(1) -17(1) 8(1) -23(1) C(9) 60(1) 65(1) 56(1) 1(1) 0(1) -5(1) C(10) 72(1) 64(1) 68(1) -12(1) 8(1) -17(1) C(11) 84(2) 107(2) 93(2) -17(2) -25(1) -17(2) C(12) 123(2) 72(2) 111(2) -28(1) 22(2) -14(2) C(13) 51(1) 58(1) 59(1) 0(1) 5(1) 4(1) C(14) 50(1) 66(1) 72(1) -2(1) 1(1) 0(1) C(15) 67(1) 102(2) 97(2) 7(1) -3(1) -20(1) C(16) 82(2) 149(3) 89(2) -35(2) -8(2) -5(2) C(17) 135(3) 303(7) 161(4) 29(4) 58(3) 82(4) S45

46 Table S13 ydrogen coordinates (Å x 10 4 ) and isotropic displacement parameters (2 x 10 3 ) for dipeptide 2. x y z U(eq) (1A) (1B) (1C) (2A) (3C) (3D) (6A) (6B) (7A) (7B) (9) (10) (11A) (11B) (11C) (12A) (12B) (12C) (14) (15A) (15B) (15C) (16A) (16B) (16C) (17A) (17B) (17C) (3) 10910(20) 3055(17) 1357(10) 56(6) (1) 6240(20) 4827(18) 3044(12) 67(6) (2) 7990(19) 4929(13) 1338(9) 39(4) Symmetry transformations used to generate equivalent atoms: #1 -x+2,y-1/2,-z+1/2 S46

47 Table S14 Crystal data and structure refinement for tripeptide 8. Empirical formula C Formula weight Temperature 295(2) K Wavelength Å Crystal system, space group Tetragonal, P 4(1) 2(1) 2 Unit cell dimensions a = (19) Å alpha = 90.00(3) deg. b = 9.200(3) Å beta = 90.00(3) deg. c = 64.15(2) Å gamma = 90.00(2) deg. Volume 5430(3) Å 3 Z, Calculated density 8, Mg/m 3 Absorption coefficient mm^-1 F(000) 2048 Crystal size 0.20 x 0.20 x 0.15 mm Theta range for data collection 1.27 to deg. Index ranges 0<=h<=11, 0<=k<=11, -1<=l<=76 Reflections collected / unique 5646 / 4881 [R(int) = ] Completeness to 2theta = % Absorption correction one Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4881 / 4 / 320 Goodness-of-fit on F^ Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -10(8) Extinction coefficient (3) Largest diff. peak and hole and e. Å -3 S47

48 Table S15 Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for tripeptide 8. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) C(1) 9010(8) 12332(7) 132(1) 87(3) C(2) 8154(9) 11329(9) 4(1) 117(4) C(3) 8817(9) 13894(7) 61(1) 121(4) C(4) 8612(7) 12249(7) 367(1) 84(3) (1) 8829(5) 10767(5) 450(1) 68(2) C(5) 7784(8) 10080(7) 535(1) 68(2) (1) 6503(5) 10415(5) 565(1) 86(2) C(6) 8140(6) 8515(7) 603(1) 60(2) C(7) 7117(7) 7346(7) 516(1) 62(2) C(8) 7064(7) 7375(7) 281(1) 72(2) C(9) 7497(7) 5869(6) 594(1) 74(3) (2) 9616(4) 8134(4) 545(1) 61(1) (2) 10469(6) 7747(5) 710(1) 69(2) C(10) 11649(7) 8638(6) 766(1) 60(2) (3) 11689(4) 9875(4) 691(1) 83(2) C(11) 12519(6) 8050(6) 931(1) 58(2) C(12) 13031(9) 9070(7) 1100(1) 101(3) C(13) 14076(6) 8686(8) 940(1) 83(3) (4) 12338(4) 6592(4) 992(1) 58(1) (3) 13044(5) 5615(5) 856(1) 59(2) C(14) 12253(6) 4586(6) 759(1) 55(2) (5) 10922(4) 4741(4) 745(1) 64(2) C(15) 13080(5) 3419(6) 649(1) 57(2) C(16) 12720(8) 3426(8) 410(1) 84(3) C(17) 13152(10) 4820(8) 303(1) 123(4) C(18) 13417(10) 2035(7) 317(1) 97(3) (6) 14618(4) 3672(4) 667(1) 47(1) (4) 15296(5) 2680(5) 801(1) 67(2) C(19) 15869(7) 3181(8) 974(1) 71(2) (7) 15603(4) 4408(5) 1043(1) 71(2) C(20) 16883(6) 2145(7) 1087(1) 70(2) C(21) 16572(10) 2134(11) 1310(1) 150(4) C(22) 18448(7) 2546(9) 1037(1) 113(4) S48

49 Table S16 Bond lengths [Å] and angles [deg] for tripeptide 8. C(1)-C(2) 1.463(10) C(1)-C(3) 1.517(9) C(1)-C(4) 1.556(10) C(1)-(1) C(2)-(2A) C(2)-(2B) C(2)-(2C) C(3)-(3A) C(3)-(3B) C(3)-(3C) C(4)-(1) 1.476(8) C(4)-(4A) C(4)-(4B) (1)-C(5) 1.272(8) (1)-(1X) 0.864(14) C(5)-(1) 1.234(8) C(5)-C(6) 1.540(9) C(6)-(2) 1.450(7) C(6)-C(7) 1.534(9) C(6)-(6) C(7)-C(9) 1.491(8) C(7)-C(8) 1.507(9) C(7)-(7) C(8)-(8A) C(8)-(8B) C(8)-(8C) C(9)-(9A) C(9)-(9B) C(9)-(9C) (2)-(2) 1.366(6) (2)-C(10) 1.407(8) (2)-(2X) 0.862(12) C(10)-(3) 1.238(7) C(10)-C(11) 1.433(9) C(11)-(4) 1.406(7) C(11)-C(12) 1.506(10) C(11)-C(13) 1.549(8) C(12)-C(13) 1.449(10) S49

50 C(12)-(12A) C(12)-(12B) C(13)-(13A) C(13)-(13B) (4)-(3) 1.411(6) (3)-C(14) 1.345(7) (3)-(3X) 0.864(11) C(14)-(5) 1.236(6) C(14)-C(15) 1.496(8) C(15)-(6) 1.439(6) C(15)-C(16) 1.564(9) C(15)-(15) C(16)-C(17) 1.507(10) C(16)-C(18) 1.551(10) C(16)-(16) C(17)-(17A) C(17)-(17B) C(17)-(17C) C(18)-(18A) C(18)-(18B) C(18)-(18C) (6)-(4) 1.400(6) (4)-C(19) 1.311(8) (4)-(4X) 0.864(13) C(19)-(7) 1.238(8) C(19)-C(20) 1.519(9) C(20)-C(21) 1.458(10) C(20)-C(22) 1.521(9) C(20)-(20) C(21)-(21A) C(21)-(21B) C(21)-(21C) C(22)-(22A) C(22)-(22B) C(22)-(22C) C(2)-C(1)-C(3) 111.6(6) C(2)-C(1)-C(4) 112.7(6) C(3)-C(1)-C(4) 107.9(6) C(2)-C(1)-(1) C(3)-C(1)-(1) S50

51 C(4)-C(1)-(1) C(1)-C(2)-(2A) C(1)-C(2)-(2B) (2A)-C(2)-(2B) C(1)-C(2)-(2C) (2A)-C(2)-(2C) (2B)-C(2)-(2C) C(1)-C(3)-(3A) C(1)-C(3)-(3B) (3A)-C(3)-(3B) C(1)-C(3)-(3C) (3A)-C(3)-(3C) (3B)-C(3)-(3C) (1)-C(4)-C(1) 111.3(5) (1)-C(4)-(4A) C(1)-C(4)-(4A) (1)-C(4)-(4B) C(1)-C(4)-(4B) (4A)-C(4)-(4B) C(5)-(1)-C(4) 120.7(5) C(5)-(1)-(1X) 130.6(19) C(4)-(1)-(1X) 105(2) (1)-C(5)-(1) 131.7(6) (1)-C(5)-C(6) 113.1(5) (1)-C(5)-C(6) 115.2(6) (2)-C(6)-C(7) 108.2(5) (2)-C(6)-C(5) 110.7(5) C(7)-C(6)-C(5) 115.0(5) (2)-C(6)-(6) C(7)-C(6)-(6) C(5)-C(6)-(6) C(9)-C(7)-C(8) 111.2(5) C(9)-C(7)-C(6) 111.9(5) C(8)-C(7)-C(6) 111.7(5) C(9)-C(7)-(7) C(8)-C(7)-(7) C(6)-C(7)-(7) C(7)-C(8)-(8A) C(7)-C(8)-(8B) (8A)-C(8)-(8B) C(7)-C(8)-(8C) S51

52 (8A)-C(8)-(8C) (8B)-C(8)-(8C) C(7)-C(9)-(9A) C(7)-C(9)-(9B) (9A)-C(9)-(9B) C(7)-C(9)-(9C) (9A)-C(9)-(9C) (9B)-C(9)-(9C) (2)-(2)-C(6) 113.8(4) (2)-(2)-C(10) 119.3(5) (2)-(2)-(2X) 114(3) C(10)-(2)-(2X) 120(3) (3)-C(10)-(2) 117.3(5) (3)-C(10)-C(11) 128.3(6) (2)-C(10)-C(11) 113.5(5) (4)-C(11)-C(10) 119.9(5) (4)-C(11)-C(12) 115.7(5) C(10)-C(11)-C(12) 118.0(5) (4)-C(11)-C(13) 117.4(5) C(10)-C(11)-C(13) 113.6(5) C(12)-C(11)-C(13) 56.6(5) C(13)-C(12)-C(11) 63.2(5) C(13)-C(12)-(12A) C(11)-C(12)-(12A) C(13)-C(12)-(12B) C(11)-C(12)-(12B) (12A)-C(12)-(12B) C(12)-C(13)-C(11) 60.2(4) C(12)-C(13)-(13A) C(11)-C(13)-(13A) C(12)-C(13)-(13B) C(11)-C(13)-(13B) (13A)-C(13)-(13B) C(11)-(4)-(3) 112.5(4) C(14)-(3)-(4) 119.0(4) C(14)-(3)-(3X) 123(4) (4)-(3)-(3X) 118(4) (5)-C(14)-(3) 119.3(5) (5)-C(14)-C(15) 123.4(5) (3)-C(14)-C(15) 116.7(5) (6)-C(15)-C(14) 110.2(5) S52

53 (6)-C(15)-C(16) 106.7(5) C(14)-C(15)-C(16) 110.7(5) (6)-C(15)-(15) C(14)-C(15)-(15) C(16)-C(15)-(15) C(17)-C(16)-C(18) 114.7(6) C(17)-C(16)-C(15) 113.1(6) C(18)-C(16)-C(15) 106.6(6) C(17)-C(16)-(16) C(18)-C(16)-(16) C(15)-C(16)-(16) C(16)-C(17)-(17A) C(16)-C(17)-(17B) (17A)-C(17)-(17B) C(16)-C(17)-(17C) (17A)-C(17)-(17C) (17B)-C(17)-(17C) C(16)-C(18)-(18A) C(16)-C(18)-(18B) (18A)-C(18)-(18B) C(16)-C(18)-(18C) (18A)-C(18)-(18C) (18B)-C(18)-(18C) (4)-(6)-C(15) 112.5(4) C(19)-(4)-(6) 118.0(5) C(19)-(4)-(4X) 132(2) (6)-(4)-(4X) 108.5(19) (7)-C(19)-(4) 123.0(6) (7)-C(19)-C(20) 121.4(6) (4)-C(19)-C(20) 115.6(6) C(21)-C(20)-C(19) 110.7(6) C(21)-C(20)-C(22) 113.3(6) C(19)-C(20)-C(22) 109.1(6) C(21)-C(20)-(20) C(19)-C(20)-(20) C(22)-C(20)-(20) C(20)-C(21)-(21A) C(20)-C(21)-(21B) (21A)-C(21)-(21B) C(20)-C(21)-(21C) (21A)-C(21)-(21C) S53

54 (21B)-C(21)-(21C) C(20)-C(22)-(22A) C(20)-C(22)-(22B) (22A)-C(22)-(22B) C(20)-C(22)-(22C) (22A)-C(22)-(22C) (22B)-C(22)-(22C) Symmetry transformations used to generate equivalent atoms: S54

55 Table S17 Anisotropic displacement parameters (Å 2 x 10 3 ) for tripeptide 8. The anisotropic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U h k a* b* U 12 ] U11 U22 U33 U23 U13 U12 C(1) 97(5) 66(5) 99(6) 3(5) 5(5) 25(4) C(2) 90(6) 130(7) 131(7) -20(6) -27(6) 5(5) C(3) 145(7) 72(5) 146(8) 42(5) 30(7) 46(5) C(4) 55(4) 101(6) 96(6) -3(5) 10(4) -28(4) (1) 74(3) 38(3) 92(4) 18(3) 29(3) -8(3) C(5) 106(5) 59(4) 37(4) -5(3) -12(4) 30(4) (1) 74(3) 74(3) 110(4) 9(3) 19(3) 34(3) C(6) 19(3) 119(5) 42(4) -35(4) 12(3) -7(3) C(7) 42(3) 76(4) 68(4) -11(4) 17(4) -2(3) C(8) 64(4) 65(4) 87(5) 16(4) -17(4) 0(4) C(9) 74(4) 44(4) 105(6) 18(4) 2(4) -12(4) (2) 68(3) 65(3) 49(2) 2(2) -11(2) -3(2) (2) 76(3) 58(3) 72(4) -1(3) -27(3) -8(3) C(10) 53(4) 55(4) 71(5) -14(4) 13(4) 10(3) (3) 68(3) 30(2) 149(4) 19(3) -29(3) -8(2) C(11) 53(4) 52(4) 67(4) 8(4) -7(4) 16(3) C(12) 133(6) 60(4) 110(6) -30(5) -37(6) 29(4) C(13) 32(3) 95(5) 123(6) -4(5) 23(4) 17(4) (4) 57(2) 56(3) 60(3) 13(2) 6(2) 2(2) (3) 56(3) 32(3) 88(4) 14(3) 18(3) 13(2) C(14) 52(3) 25(3) 87(5) 18(3) -17(4) -15(3) (5) 24(2) 37(2) 132(4) 6(3) -3(3) -1(2) C(15) 11(3) 50(4) 110(5) 11(4) 2(4) 10(3) C(16) 84(5) 108(6) 60(4) -16(5) -26(4) 5(5) C(17) 158(8) 97(6) 115(6) 57(5) -35(6) 12(6) C(18) 157(7) 56(4) 77(5) -12(4) -18(6) -8(5) (6) 60(2) 30(2) 52(2) 11(2) -12(2) 6(2) (4) 50(3) 80(4) 70(4) -22(3) -12(3) 30(3) C(19) 75(5) 82(5) 58(4) -10(4) 7(4) 7(4) (7) 58(2) 83(3) 72(3) -11(3) -21(2) 6(2) C(20) 38(3) 93(5) 80(5) 19(4) -22(4) 43(3) S55

56 C(21) 158(8) 226(10) 65(6) 32(7) 4(6) 96(7) C(22) 52(4) 127(7) 162(8) 9(6) -19(5) 29(5) S56

57 Table S18 ydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for tripeptide 8. x y z U(eq) (1) (2A) (2B) (2C) (3A) (3B) (3C) (4A) (4B) (1X) 9614(13) 10450(3) 391(4) 81 (6) (7) (8A) (8B) (8C) (9A) (9B) (9C) (2X) 10520(6) 6822(10) 731(7) 83 (12A) (12B) (13A) (13B) (3X) 13980(10) 5660(6) 847(8) 90(2) (15) (16) (17A) (17B) (17C) (18A) (18B) (18C) (4X) 15410(5) 1868(12) 735(3) 80 S57

58 (20) (21A) (21B) (21C) (22A) (22B) (22C) S58

59 Table S19 Torsion angles [deg] for tripeptide 8. C(2)-C(1)-C(4)-(1) 58.6(8) C(3)-C(1)-C(4)-(1) (6) C(1)-C(4)-(1)-C(5) (6) C(4)-(1)-C(5)-(1) 0.3(11) C(4)-(1)-C(5)-C(6) 176.7(5) (1)-C(5)-C(6)-(2) 174.5(5) (1)-C(5)-C(6)-(2) -2.6(7) (1)-C(5)-C(6)-C(7) 51.6(7) (1)-C(5)-C(6)-C(7) (6) (2)-C(6)-C(7)-C(9) 57.7(7) C(5)-C(6)-C(7)-C(9) (5) (2)-C(6)-C(7)-C(8) -67.6(6) C(5)-C(6)-C(7)-C(8) 56.6(7) C(7)-C(6)-(2)-(2) (5) C(5)-C(6)-(2)-(2) 121.3(5) C(6)-(2)-(2)-C(10) (6) (2)-(2)-C(10)-(3) 14.2(8) (2)-(2)-C(10)-C(11) (5) (3)-C(10)-C(11)-(4) (6) (2)-C(10)-C(11)-(4) 12.7(8) (3)-C(10)-C(11)-C(12) 31.3(10) (2)-C(10)-C(11)-C(12) (6) (3)-C(10)-C(11)-C(13) -32.1(9) (2)-C(10)-C(11)-C(13) 158.8(5) (4)-C(11)-C(12)-C(13) 107.2(6) C(10)-C(11)-C(12)-C(13) (7) (4)-C(11)-C(13)-C(12) (6) C(10)-C(11)-C(13)-C(12) 109.0(6) C(10)-C(11)-(4)-(3) 79.3(6) C(12)-C(11)-(4)-(3) (5) C(13)-C(11)-(4)-(3) -65.6(7) C(11)-(4)-(3)-C(14) (5) (4)-(3)-C(14)-(5) 19.4(8) (4)-(3)-C(14)-C(15) (5) (5)-C(14)-C(15)-(6) 170.0(5) (3)-C(14)-C(15)-(6) -1.0(8) (5)-C(14)-C(15)-C(16) 52.2(8) (3)-C(14)-C(15)-C(16) (6) S59

60 (6)-C(15)-C(16)-C(17) -57.6(7) C(14)-C(15)-C(16)-C(17) 62.4(7) (6)-C(15)-C(16)-C(18) 69.4(6) C(14)-C(15)-C(16)-C(18) (5) C(14)-C(15)-(6)-(4) 108.2(5) C(16)-C(15)-(6)-(4) (5) C(15)-(6)-(4)-C(19) (6) (6)-(4)-C(19)-(7) 14.4(9) (6)-(4)-C(19)-C(20) (5) (7)-C(19)-C(20)-C(21) 44.5(9) (4)-C(19)-C(20)-C(21) (7) (7)-C(19)-C(20)-C(22) -80.9(8) (4)-C(19)-C(20)-C(22) 99.8(7) Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z #2 -x+5/2,y+1/2,-z+1/4 #3 x+1,y,z #4 x,y-1,z #5 x+1,y-1,z #6 -x+5/2,y-1/2,-z+1/4 S60

61 VII. MR spectra of compounds S61

62 S62

63 S63

64 S64

65 S65

66 S66

67 S67

68 S68

69 S69

70 S70

71 S71

72 S72

73 S73

74 S74

75 S75

76 S76

77 S77

78 S78

79 S79