SUPPLEMENTARY INFORMATION...which had been obtained by treatment of Boc L Val Aib OMe ( ) with 4 M HCl in dioxane, and then DIEA (68 L, 0.41 mmol) at room temperature. The reaction

NATURE CHEMISTRY | www.nature.com/naturechemistry 1

SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.1146

S1

Supplementary Information

Naoki Ousaka, Yuki Takeyama, Hiroki Iida, and Eiji Yashima*

Department of Molecular Design and Engineering, Graduate School of Engineering,

Nagoya University, Chikusaku, Nagoya 4648603, Japan.

*To whom correspondence should be addressed. Email:

[email protected]

Table of Contents

Experimental Section

1. Instruments S2

2. Materials S2

3. Synthetic Procedures for the Ligand Peptides S2

4. Xray Crystallographic Analysis S19

5. Simulations of Chiral Amplification in the Ligand Exchange Reaction S21

between HomoCoII Complexes of ΛD and Racemic

6. Supporting References S25

Supporting Data S26

Chart S1 S26

Figures S1S20 S27

© 2011 Macmillan Publishers Limited. All rights reserved.



S2

The NMR spectra were taken using a Varian UNITY INOVA 500AS spectrometer. Chemical

shifts are reported in parts per million (δ) downfield from tetramethylsilane (TMS) as the internal

standard in CDCl3, and from residual undeuterated solvent as the internal standard in (CD3)2SO and

CD3CN. The electron and cold spray ionization mass spectra (ESIMS and CSIMS) were recorded

on a Bruker Daltonics microTOFQ II spectrometer (Billerica, MA). The matrixassisted laser

desorptionionization timeofflight mass spectra (MALDITOFMS) were measured using a

Bruker Daltonics ultraflex III MALDITOF/TOF mass spectrometer or a Shimadzu AXIMACFR

Plus spectrometer (Kyoto, Japan) with a positive mode using 1,8,9anthracene triol (dithranol) as

the matrix. The absorption and CD spectra were measured in 0.1 and 1.0cm quartz cells on a

JASCO V570 spectrophotometer and a JASCO J820 spectropolarimeter, respectively. The

temperature was controlled by a JASCO PTC423L apparatus. The single crystal Xray diffraction

measurements were performed on a Bruker SMART APEX II Ultra diffractometer with MoKα

radiation (λ = 0.71073 Å) at 93 K.

All starting materials and dehydrated solvents were purchased from Aldrich Co. (WI), Wako Pure

Chemical Industries (Osaka, Japan), Kokusan Chemical Co. Ltd. (Tokyo, Japan), and Tokyo Kasei

Kogyo (TCI) (Tokyo, Japan) unless otherwise noted. All solvents for the preparations and the

spectroscopic measurements of iron and cobalt complexes were deoxygenated by bubbling argon

gas prior to use.

Abbreviations of chemicals:

Boc: butoxycarbonyl,

TosOH: toluenesulfonic acid,

Aib: αaminoisobutyric acid,

Ac6c: 1aminocyclohexanecarboxylic acid,

Bzl: benzyl,

HATU: (7azabenzotrizol1yl)1,1,3,3tetramethyluronium hexafluorophosphate,

EDC: 1ethyl3(3dimethylaminopropyl)carbodiimide hydrochloride,

HOAt: 7aza1hydroxy1,2,3benzotriazole,




S3

HOBt: 1hydroxybenzotriazole monohydrate,

DIEA: ,diisopropylethylamine,

NMM: methylmorpholine,

Tg: 2(2(2methoxyethoxy)ethoxy)ethyl,

BrBz: bromobenzyl

ABocprotecting group was removed by treatment

with HCO2H or 4M HCl in dioxane. The Ndeprotected peptide formic acid salt was neutralized

with aqueous 5% NaHCO3. The resulting Ndeprotected peptide and Ndeprotected peptide

hydrochloride salts were used without further purification unless otherwise noted. The

Bzlprotecting group was removed by treatment with 10% PdC/H2. Peptide coupling reactions

were carried out by HOAt/HATU or EDC/HOBt methods. 2,2'Bipyridine5,5'dicarbonyl

dichloride was prepared by heating the corresponding dicarboxylic acid with thionyl chloride at

reflux for overnight.

To a suspension of 2,2'bipyridine5,5'dicarbonyl dichloride (23 mg, 0.08 mmol) in dry

CH2Cl2 (2 mL) was added HClHLValAibOMe (46 mg, 0.18 mmol) in dry CH2Cl2 (4 mL),

which had been obtained by treatment of BocLValAibOMe () with 4 M HCl in dioxane, and

then DIEA (68 L, 0.41 mmol) at room temperature. The reaction mixture was stirred at room

temperature for 2 h. After the solvent was evaporated to dryness under reduced pressure, the residue

was purified by column chromatography on silica gel [CHCl3/methanol (9/1) as eluent].

Precipitation from CHCl3 to Et2O afforded the ligand (49 mg, 96%) as a white solid.

MALDITOFMS: [M+Na]+ (calcd. 663.31): found. 663.33. HRMS (ESIMS) (positive): [M +

Na]+ (calcd. 663.3113): found. 663.3118. 1H NMR (500 MHz, CDCl3): δ = 9.04 (d, = 2.1 Hz, 2H),

8.46 (d, = 8.2 Hz, 2H), 8.15 (dd, = 2.3, 8.3 Hz, 2H), 7.18 (d, = 8.3 Hz, 2H), 6.65 (s, 2H), 4.52

(dd, = 6.9, 8.3 Hz, 2H), 3.73 (s, 6H), 2.292.23 (m, 2H), 1.58 (s, 12H), 1.08 (d, = 6.8 Hz, 6H),

1.07 (d, = 6.7 Hz, 6H).




S4

To a solution of BocAibOH (4.0 g, 4.92 mmol) in dry CH2Cl2 (20 mL) were

added HATU (1.87 g, 4.92 mmol) and DIEA (1.0 mL, 6.15 mmol) at 0°C. After 30 min,

TosOHHAc6cOBzl (1.99 g, 4.92 mmol) and DIEA (0.82 mL, 4.92 mmol) were added. The

reaction mixture was stirred at 0°C for 1 h and further at room temperature for 3 days. Then, the

solvent was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc,

and the solution was washed with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over

MgSO4. Purification by column chromatography on silica gel (EtOAc as eluent) afforded

BocAibAc6cOBzl (1.73 g, 84.2%) as a white solid. MALDITOFMS: [M+Na]+ (calcd. 441.23):

found. 441.21. 1H NMR (500 MHz, CDCl3): δ = 7.36–7.28 (m + s, 6H), 5.11 (s, 2H), 4.79 (s, 1H),

2.12 (bs, 1H), 2.10 (bs, 1H), 1.821.76 (m, 2H), 1.66–1.22 (m, 6H), 1.44 (s, 9H), 1.42 (s, 6H).

To a solution of BocAibAc6cOH (151 mg, 0.46 mmol), which

had been obtained by treatment of BocAibAc6cOBzl with 10% PdC/H2 in THF/AcOH (15/1;

v/v), HOBt (91 mg, 0.60 mmol) and HClHLValAibOMe (173 mg, 0.69 mmol) in DMF (4 mL)

was added EDC (88 mg, 0.46 mmol) at 0°C. After 30 min, to this was added NMM (80 L, 0.73

mmol) was added, and the reaction mixture was stirred at 0°C for 3 h and further at room

temperature overnight. The solvent was then evaporated to dryness under reduced pressure. The

residue was dissolved in EtOAc, and the solution was washed with 1N aqueous HCl, 5% aqueous

NaHCO3, brine, and dried over MgSO4. Purification by column chromatography on silica gel

(EtOAc as eluent) afforded BocAibAc6cLValAibOMe (182 mg, 76.0%) as a white solid.

MALDITOFMS: [M+Na]+ (calcd. 549.33): found. 549.36. 1H NMR (500 MHz, CDCl3): δ = 7.29

(s, 1H), 7.09 (d, = 8.5 Hz, 1H), 6.76 (s, 1H), 4.91 (s, 1H), 4.37 (dd, = 4.6, 8.6 Hz, 1H), 3.67 (s,

3H), 2.55–2.46 (m, 1H), 2.27 (bd, = 14 Hz, 1H), 2.10–2.04 (m, 1H), 1.91–1.85 (m, 1H), 1.77–1.65

(m, 4H), 1.53 (s, 3H), 1.52 (s, 3H), 1.48 (s, 3H), 1.46 (s + s, 12H), 1.43–1.20 (m, 3H), 0.97 (d, =

7.0 Hz, 3H), 0.92 (d, = 7.0 Hz, 3H).




S5

To a suspension of 2,2'bipyridine5,5'dicarbonyl dichloride (37 mg, 0.13 mmol) and

HClHAibAc6cLValAibOMe (131 mg, 0.28 mmol) in dry CH2Cl2 (4 mL) was added DIEA

(137 L, 0.83 mmol) at room temperature. The reaction mixture was stirred at room temperature for

5 h. After the solvent was evaporated to dryness under reduced pressure, the residue was dissolved

in CHCl3 containing a small amount of MeOH, and the solution was washed with 1N aqueous HCl,

5% aqueous NaHCO3, brine, and dried over MgSO4. Purification by column chromatography on

silica gel [CHCl3/MeOH (9/1; v/v) as eluent] afforded the ligand (29 mg, 20.3%) as a white solid.

MALDITOFMS: [M+Na]+ (calcd. 1083.59): found. 1083.70. HRMS (ESIMS) (positive): [M +

Na]+ (calcd. 1083.5849): found. 1083.5848. 1H NMR (500 MHz, CD3CN): δ = 9.16 (dd, = 0.8, 2.3

Hz, 2H), 8.59 (dd, = 0.7, 8.3 Hz, 2H), 8.37 (dd, = 2.3, 8.3 Hz, 2H), 7.72 (s, 2H), 7.32 (d, = 8.8

Hz, 2H), 7.28 (s, 2H), 6.73 (s, 2H), 4.08 (dd, = 5.9, 8.7 Hz, 2H), 3.58 (s, 6H), 2.42–2.35 (m, 2H),

2.25–1.27 (m, 20H), 1.64 (s, 6H), 1.56 (s, 6H), 1.41 (s, 6H), 1.38 (s, 6H), 0.99 (d, = 6.8 Hz, 6H),

0.92 (d, = 6.9 Hz, 2H).

To a suspension of BocAibAc6cOH (2.00 g, 6.09 mmol) and HOAt

(418 mg, 3.07 mmol) in dry CH2Cl2 (20 mL) were added HATU (2.32 g, 6.09 mmol) and DIEA

(1.30 mL, 7.83 mmol) at 0°C. After 30 min, TosOHHAibOBzl (2.89 g, 7.91 mmol) and DIEA

(1.0 mL, 6.02 mmol) were added, and the reaction mixture was stirred at 0°C for 1 h and further at

room temperature for 3 days. The solvent was then evaporated to dryness under reduced pressure.

The residue was dissolved in EtOAc, and the solution was washed with 1N aqueous HCl, 5%

aqueous NaHCO3, brine, and dried over MgSO4. Purification by column chromatography on silica

gel (EtOAc as eluent) afforded BocAibAc6cAibOBzl (2.06 g, 67.5%) as a white solid.


(s, 1H), 7.377.27 (m, 5H), 6.30 (s, 1H), 5.13 (s, 2H), 4.84 (s, 1H), 2.01 (s, 1H), 1.98 (s, 1H),

1.84–1.79 (m, 2H), 1.64–1.55 (m, 3H), 1.52 (s, 6H), 1.45 (s, 6H), 1.44 (s, 6H), 1.29–1.22 (m, 3H).




S6

To a suspension of BocAibAc6cAibOH (2.19 g, 5.29 mmol), which had

been obtained by treatment of BocAibAc6cAibOBzl with 10% PdC/H2 in THF/AcOH (7.5/1;

v/v), and HOAt (360 mg, 2.64 mmol) in dry CH2Cl2 (30 mL), HATU (2.01 g, 5.29 mmol) and

DIEA (1.1 mL, 6.60 mmol) were added at 0°C. After 30 min, TosOHHAc6cOBzl (2.78 g, 6.87

mmol) and DIEA (0.88 mL, 5.30 mmol) were added, and the reaction mixture was stirred at 0°C for

3 h and further at room temperature for 3 days. The solvent was then evaporated to dryness under

reduced pressure. The residue was dissolved in EtOAc, and the solution was washed with 1N

aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Purification by column

chromatography on silica gel (EtOAc as eluent) afforded Boc(AibAc6c)2OBzl (3.04 g, 91.6%) as

a white solid. MALDITOFMS: [M+Na]+ (calcd. 651.37): found. 651.42. 1H NMR (500 MHz,

CDCl3): δ = 7.39 (s, 1H), 7.35–7.23 (m, 6H), 6.52 (s, 1H), 5.12 (s, 2H), 4.89 (s, 1H), 2.20 (s, 1H),

2.17 (s, 1H), 1.96–1.83 (m, 6H), 1.73–1.63 (m, 5H), 1.58–1.52 (m, 2H), 1.45 (s, 9H), 1.44 (s + s,

12H), 1.33–1.23 (m, 5H).

To a solution of Boc(AibAc6c)2OH (160 mg, 0.30 mmol),

which had been obtained by treatment of Boc(AibAc6c)2OBzl with 10% PdC/H2 in THF/H2O

(15/1; v/v), HOBt (59 mg, 0.39 mmol) and HClHLValAibOMe (113 mg, 0.45 mmol) in DMF

(2.5 mL) and then EDC (57 mg, 0.30 mmol) were added at 0°C. After 30 min, to this was added

NMM (52 L, 0.47 mmol), and the reaction mixture was stirred at 0°C for 2 h and further at room

temperature for 2 days. The solvent was then evaporated to dryness under reduced pressure. The

residue was dissolved in CHCl3, and the solution was washed with 1N aqueous HCl, 5% aqueous

NaHCO3, brine, and dried over MgSO4. Recrystallization from CHCl3/MeOH/Et2O (ca. 1/0.01/5;

v/v/v) afforded Boc(AibAc6c)2LValAibOMe (211 mg, 96.4%) as a white solid.


(s, 1H), 7.38 (d, = 8.9 Hz, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 5.04 (s, 1H), 4.40 (dd, =

5.6, 8.9 Hz, 1H), 3.68 (s, 3H), 2.53–2.46 (m, 2H), 2.12–1.95 (m, 4H), 1.84–1.18 (m, partially




S7

overlapping with H2O signal), 1.53 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H), 1.49 (s + s, 12H), 1.01 (d, =

6.9 Hz, 3H), 0.93 (d, = 6.9 Hz, 3H).

To a solution of H(AibAc6c)2LValAibOMe (66.5 mg,

0.09 mmol), bromobenzoic acid (36.7 mg, 0.18 mmol), and HOBt (36.0 mg, 0.23 mmol) in DMF

(3 mL), was added EDC (34.7 mg, 0.18 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for

2.5 h and further at room temperature for 2 days. The solvent was then evaporated to dryness under

reduced pressure. The residue was dissolved in CHCl3, and the solution was washed with 1N

aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Recrystallization from

CHCl3/Et2O (ca. 1/10, v/v) afforded BrBz(AibAc6c)2LValAibOMe (73.5 mg, 99.6 %) as a

white solid. 1H NMR (500 MHz, CDCl3): δ = 7.71–7.64 (m. 5H), 7.34 (d, = 8.7 Hz, 1H), 7.33 (s,

1H), 7.16 (s, 1H), 6.84 (s, 1H), 6.43 (s, 1H), 4.31 (dd, J = 5.8, 8.7 Hz, 1H), 3.66 (s, 3H), 2.47–2.42

(m, 2H), 2.12 (s, 1H), 2.10 (s, 1H), 2.03–1.96 (m, 3H), 1.79–1.08 (m, partially overlapping with

H2O signal), 1.68 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H), 1.00 (d,

= 6.9 Hz, 3H), 0.91 (d, = 6.9 Hz, 3H). MALDITOFMS: [M + Na+] (calcd: 842.35): found.

842.36.

To 2,2'bipyridine5,5'dicarbonyl dichloride (26 mg, 0.093 mmol), a solution of

H(AibAc6c)2LValAibOMe (130 mg, 0.204 mmol) in dry CH2Cl2 (7 mL) containing DIEA (77

L, 0.46 mmol) was added at room temperature. After the reaction mixture was stirred at room

temperature for 3 h, the solvent was evaporated to dryness under reduced pressure. Recrystallization

from CHCl3/MeOH/EtOAc/hexane (ca. 2/1/8/4; v/v/v/v) afforded the ligand (126 mg, 91.8%)

as a white solid. MALDITOFMS: [M+Na]+ (calcd. 1503.86): found. 1504.00. HRMS (ESIMS)

(positive): [M + Na]+ (calcd. 1503.8586): found. 1503.8590. 1H NMR [500 MHz, (CD3)2SO]: δ =

9.26 (dd, = 0.7, 2.2 Hz, 2H), 9.00 (s, 2H), 8.58 (d, = 8.4 Hz, 2H), 8.53 (dd, = 2.3, 8.3 Hz, 2H),

7.83 (s, 2H), 7.62 (s, 2H), 7.38 (s, 2H), 7.32 (d, = 8.7 Hz, 2H), 7.20 (s, 2H), 3.95 (dd, = 6.7, 8.6

Hz, 2H), 3.54 (s, 6H), 2.28–2.26 (m, 2H), 2.24–2.17 (m, 2H), 2.00–1.10 (m, 40H), 1.56 (s, 6H),




S8

1.53 (s, 6H), 1.49 (s, 6H), 1.39 (s, 6H), 1.34 (s, 12H), 0.92 (d, = 6.9 Hz, 6H), 0.85 (d, = 6.9 Hz,

6H).

To a solution of BocAibOH (1.04 g, 5.17 mmol) in dry THF (8 mL) was added

,’carbonyldiimidazole (0.83 g, 5.17 mmol) at 0°C. After 1 h, to this was added a solution of

triethylene glycol monomethyl ether (1.68 g, 10.23 mmol) and ,dimethylaminopyridine (64 mg,

0.52 mmol) in dry THF (4 mL) at 0°C. The reaction mixture was gradually warmed to room

temperature, and then heated to 60°C for 22 h under stirring. After the solvent was evaporated to

dryness under reduced pressure, the residue was dissolved in EtOAc, and the solution was washed

with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Evaporation of the

solvent afforded BocAibOTg (1.42 g, 78.5%) as a colorless oil. MALDITOFMS: [M+Na]+

(calcd. 386.22): found. 386.12. 1H NMR (500 MHz, CDCl3): δ = 5.08 (bs, 1H), 4.29–4.27 (m, 2H),

3.71–3.69 (m, 2H), 3.66–3.64 (m, 6H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 1.51 (s, 6H), 1.43 (s, 9H).

To a solution of BocLValOH (362 mg, 1.67 mmol), HOBt (332 mg, 2.17

mmol), and HClHAibOTg (477 mg, 1.67 mmol) in DMF (4 mL) was added EDC (320 mg, 1.67

mmol) at 0°C. After 1 h, NMM (184 L, 1.67 mmol) was added and the reaction mixture was

stirred at 0°C for 3 h and further at room temperature for 2 days. The solvent was then evaporated

to dryness under reduced pressure. The residue was dissolved in CHCl3, and the solution was

washed with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Purification by

column chromatography on silica gel (EtOAc as eluent) afforded BocLValAibOTg (543 mg,

72.6%) as a colorless oil. MALDITOFMS: [M+Na]+ (calcd. 471.27): found. 471.18. 1H NMR

(500 MHz, CDCl3): δ = 6.52 (s, 1H), 5.12 (d, = 7.6 Hz, 1H), 4.34–4.24 (m, 2H), 3.84 (t, = 7.3

Hz, 1H), 3.69 (t, = 4.9 Hz, 2H), 3.66–3.64 (m, 6H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 2.15–2.09 (m,

1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.45 (s, 9H), 0.96 (d, = 6.8 Hz, 3H), 0.92 (d, = 6.9 Hz, 3H).




S9

To a suspension of BocAc6cOH (1.50 g, 6.17 mmol) and HOAt (0.42 g, 3.08

mmol) in dry CH2Cl2 (25 mL), HATU (2.34 g, 6.17 mmol) and DIEA (1.28 mL, 7.71 mmol) were

added at 0°C. After 45 min, TosOHHAc6cOBzl (2.50 g, 6.17 mmol) and DIEA (1.08 mL, 6.47

mmol) were added, and the reaction mixture was stirred at 0°C for 30 min and further at room

temperature for 5 days. The solvent was then evaporated to dryness under reduced pressure. The


NaHCO3, brine, and dried over MgSO4. Purification of the residue by precipitation from EtOAc to

hexane and further by column chromatography on silica gel [EtOAc/CHCl3 (8/2; v/v) as eluent]

afforded Boc(Ac6c)2OBzl (1.79 g, 63.4%) as a white solid. MALDITOFMS: [M+Na]+ (calcd.

481.27): found. 481.28. 1H NMR (500 MHz, CDCl3): δ = 7.52 (s, 1H), 7.357.28 (m, 5H), 5.11 (s,

2H), 4.55 (s, 1H), 2.11 (bs, 1H), 2.09 (bs, 1H), 1.95 (bs, 1H), 1.93 (bs, 1H), 1.82–1.75 (m, 4H),

1.65–1.54 (m, 6H), 1.50–1.20 (m + s, 15H).

NH

O

O

OO

3

To a suspension of Boc(Ac6c)2OH (1.00 g, 2.71 mmol), which had been

obtained by treatment of Boc(Ac6c)2OBzl with 10% PdC/H2 in THF/H2O (10/1; v/v), and HOAt

(0.19 g, 1.36 mmol) in dry CH2Cl2 (8 mL), HATU (1.03 g, 2.71 mmol) and DIEA (0.56 mL, 3.39

mmol) were added at 0°C. After 40 min, TosOHHAc6cOBzl (1.54 g, 6.17 mmol) and DIEA

(0.66 mL, 3.99 mmol) were added and the reaction mixture was stirred at 0°C for 2 h and further at

room temperature for 4 days. The solution was then diluted with CHCl3 and the mixture was

washed with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Purification by

column chromatography on silica gel (EtOAc as eluent) afforded Boc(Ac6c)3OBzl (1.53 g, 96.6%)

as a white solid. MALDITOFMS: [M+Na]+ (calcd. 606.35): found. 606.47. 1H NMR (500

MHz,CDCl3): δ = 7.64 (s, 1H), 7.34–7.27 (m, 5H), 6.42 (s, 1H), 5.08 (s, 2H), 5.80 (s, 1H), 2.16 (bs,

1H), 2.13 (bs, 1H), 2.05 (bs, 1H), 2.02 (bs, 1H), 1.92–1.76 (m, 8H), 1.70–1.54 (m, 10H), 1.43 (s,

9H), 1.33–1.20 (m, 8H).




S10

NH

O

O

OO

4

To a suspension of Boc(Ac6c)3OH (700 mg, 1.42 mmol), which had been

obtained by treatment of Boc(Ac6c)3OBzl with 10% PdC/H2 in THF/H2O (10/1; v/v), and HOAt

(97 mg, 0.71 mmol) in dry CH2Cl2 (6 mL), HATU (539 mg, 1.42 mmol) and DIEA (294 L, 1.77

mmol) were added at 0°C. After 45 min, to this was added TosOHHAc6cOBzl (805 mg, 1.99

mmol) and DIEA (346 mL, 2.09 mmol) and the reaction mixture was stirred at 0°C for 2 h and

further at room temperature for 6 days. The solution was then diluted with CHCl3 and the mixture

was washed with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4.

Recrystallization from CHCl3/EtOAc/hexane (ca. 1/20/15; v/v/v) afforded Boc(Ac6c)4OBzl (968

mg, 96.3%) as a white solid. MALDITOFMS: [M+Na]+ (calcd. 731.44): found. 731.44. 1H NMR

(500 MHz, CDCl3): δ = 7.49 (s, 1H), 7.34–7.22 (m, 5H), 6.82 (s, 1H), 6.79 (s, 1H), 5.10 (s, 2H),

4.91 (s, 1H), 2.19–2.16 (m, 4H), 1.98–1.75 (m, 12H), 1.70–1.60 (m, 8H), 1.58–1.50 (m, 4H), 1.46

(s, 9H), 1.37–1.21 (m, 12H).

To a solution of Boc(Ac6c)4OH (160 mg, 0.26 mmol), which had

been obtained by treatment of Boc(Ac6c)4OBzl with 10% PdC/H2 in THF/H2O (10/1; v/v), HOBt

(52 mg, 0.34 mmol) and HClHLValAibOTg (139 mg, 0.36 mmol) in DMF (2.5 mL), and then

EDC (50 mg, 0.26 mmol) were added at 0°C. After 45 min, NMM (42 L, 0.38 mmol) was added

and the reaction mixture was stirred at 0°C for 2 h and further at room temperature for 2 days. The

solvent was then evaporated to dryness under reduced pressure. The residue was dissolved in

EtOAc, and the solution was washed with 1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried

over MgSO4. The residue was precipitated from EtOAc to hexane and further purified by washing

with Et2O, affording Boc(Ac6c)4LValAibOTg (188 mg, 76.7%) as a white solid.


(d, = 8.3 Hz, 1H), 7.29 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.80 (s, 1H), 5.08 (s, 1H), 4.34–4.31 (m,

1H), 4.29–4.20 (m, 2H), 3.71–3.63 (m, 8H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 2.50–2.39 (m + m,




S11

2H), 2.13–1.93 (m, 8H), 1.86–1.16 (m, partially overlapping with H2O signal), 1.52 (s, 3H), 1.49 (s,

9H), 1.48 (s, 3H), 0.99 (d, = 6.9 Hz, 3H), 0.93 (d, = 6.9 Hz, 3H).

Boc(Ac6c)4DValAibOTg was synthesized in the similar

procedure to that for the corresponding Lenantiomer (129 mg, 84.3%). MALDITOFMS:

[M+Na]+ (calcd. 971.60): found. 971.82.

To a suspension of 2,2'bipyridine5,5'dicarbonyl dichloride (23 mg, 0.084 mmol) in

dry CH2Cl2 (1 mL) was added H(Ac6c)4LValAibOTg (156 mg, 0.18 mmol) in dry CH2Cl2 (5

mL) containing DIEA (70 L, 0.42 mmol) at room temperature. After the reaction mixture was

stirred at room temperature for 3 h, the solvent was evaporated to dryness under reduced pressure.

Purification by reprecipitation from CHCl3/MeOH (ca. 3/1; v/v) to EtOAc afforded the ligand L

(153 mg, 96%) as a white solid. MALDITOFMS: [M+Na]+ (calcd. 1928.14): found. 1928.69.

HRMS (ESIMS) (positive): [M + Na]+ (calcd. 1928.1411): found. 1928.1360. 1H NMR (500 MHz,

CD3CN): δ = 9.20 (dd, = 0.71, 2.3 Hz, 2H), 8.60 (d, = 0.66 Hz, 2H), 8.59 (d, = 0.71 Hz, 2H),

7.50 (s, 2H), 7.40 (s, 2H), 7.26 (d, = 7.25 Hz, 2H), 7.23 (s, 2H), 7.18 (s, 2H), 6.90 (s, 2H),

4.20–4.15 (m, 2H), 4.09–4.04 (m, 2H), 3.95 (dd, = 1.6, 6.9 Hz, 2H), 3.61–3.60 (m, 4H), 3.57–3.52

(m, 12H), 3.46–3.44 (m, 4H), 3.28 (s, 6H), 2.36–1.04 (m, partially overlapping with H2O and the

residual undeuterated solvent signals), 1.40 (s, 6H), 1.39 (s, 6H), 0.97 (d, = 6.8 Hz, 6H), 0.91 (d,

= 6.9 Hz, 6H).

To a suspension of Boc(Ac6c)4OH (145 mg, 0.23 mmol) and HOAt (16

mg, 0.12 mmol) in dry CH2Cl2 (3 mL), HATU (89 mg, 0.23 mmol) and DIEA (49 L, 0.29 mmol)




S12

were added at 0°C. After 30 min, TosOHHAibOBzl (120 mg, 0.33 mmol) and DIEA (57 L,

0.34 mmol) were added and the reaction mixture was stirred at 0°C for 1 h and further at room

temperature for 3 days. The solution was then diluted with CHCl3 and the mixture was washed with

1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Purification by

reprecipitation from EtOAc to hexane afforded Boc(Ac6c)4AibOBzl (155 mg, 83.4%) as a

white solid. MALDITOFMS: [M+Na]+ (calcd. 816.49): found. 816.54. 1H NMR (500

MHz,CDCl3): δ = 7.43 (s, 1H), 7.38–7.23 (m, 5H), 7.16 (s, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 5.14 (s,

2H), 5.05 (s, 1H), 2.36 (bs, 2H), 2.04–1.18 (m, partially overlapping with H2O signal), 1.53 (s, 6H),

1.48 (s. 9H).

A mixture of HLValOH (600 mg, 5.12 mmol), TosOH monohydrate (1.17 g,

6.15 mmol) and triethylene glycol monomethyl ether (2.52 g, 15.37 mmol) in benzene (10 mL) was

stirred under reflux with a Dean Stark apparatus for 20 h. Then, the solvent was evaporated to

dryness under reduced pressure. The residue was dissolved in CHCl3, and the solution was washed

with 5% aqueous NaHCO3, and dried over MgSO4. Removal of the solvent in vacuo afforded

HLValOTg as colorless oil with approximately 50% purity (1.98 g), which was used without

further purification in the next step. To a solution of HLValOTg (860 mg, 3.27 mmol) in CH2Cl2

(3 mL), Boc2O (0.57 g, 2.61 mmol) was added at 0°C. After the reaction mixture was stirred at

room temperature for 3 h, the solvent was evaporated to dryness under reduced pressure. The


NaHCO3, brine, and dried over MgSO4. Evaporating the solvent in vacuo afforded analytically pure

BocLValOTg (940 mg, 99%) as a colorless oil. MALDITOFMS: [M+Na]+ (calcd. 386.22):

found. 386.12. 1H NMR (500 MHz,CDCl3): δ = 5.05 (d, = 8.9 Hz, 1H), 4.36–4.24 (m, 3H),

3.723.64 (m, 8H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 2.19–2.12 (m, 1H), 1.45 (s, 9H), 0.96 (d, =

6.8 Hz, 3H), 0.89 (d, = 6.9 Hz, 3H).




S13

To a solution of Boc(Ac6c)4AibOH (115 mg, 0.16 mmol), which

had been obtained by treatment of Boc(Ac6c)4AibOBzl with 10% PdC/H2 in THF/H2O (10/1;

v/v), HOBt (33 mg, 0.21 mmol) and HClHLValOTg (68 mg, 0.23 mmol) in DMF (2 mL) and

then EDC (31 mg, 0.16 mmol) were added at 0°C. After 45 min, NMM (27 L, 0.24 mmol) was

added and the reaction mixture was stirred at 0°C for 1.5 h and further at room temperature for 2

days. The solvent was then evaporated to dryness under reduced pressure. The residue was

dissolved in EtOAc, and the solution was washed with 1N aqueous HCl, 5% aqueous NaHCO3,

brine, and dried over MgSO4. Precipitation from EtOAc to hexane (ca. 1/5; v/v) afforded

Boc(Ac6c)4AibLValOTg (123 mg, 79.4%) as a white solid. MALDITOFMS: [M+Na]+ (calcd.

971.60): found. 971.60. 1H NMR (500 MHz, CDCl3): δ = 7.47 (s, 1H), 7.34 (d, = 7.9 Hz, 1H),

7.20 (s, 1H), 7.10 (s, 1H), 6.80 (s, 1H), 5.07 (s, 1H), 4.39 (dd, = 6.2, 8.0 Hz, 1H), 4.32–4.19 (m,

2H), 3.70–3.68 (m, 2H), 3.67–3.62 (m, 6H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 2.33–1.21 (m,

partially overlapping with H2O and the residual undeuterated solvent signals), 1.54 (s, 3H), 1.53 (s,

3H), 1.49 (s, 9H), 1.02 (d, = 6.8 Hz, 3H), 1.00 (d, = 6.8 Hz, 3H).

To a suspension of 2,2'bipyridine5,5'dicarbonyl dichloride (14 mg, 0.051 mmol) in dry

CH2Cl2 (1 mL) was added H(Ac6c)4AibLValOTg (96 mg, 0.11 mmol) in dry CH2Cl2 (4 mL)

containing DIEA (42 L, 0.26 mmol) at room temperature. After the reaction mixture was stirred at

room temperature for 3 h, the solvent was evaporated to dryness under reduced pressure.

Purification by reprecipitation from CHCl3/MeOH (ca. 5/1; v/v) to EtOAc afforded the ligand (73

mg, 75%) as a white solid. MALDITOFMS: [M+Na]+ (calcd. 1928.14): found. 1928.64. HRMS

(ESIMS) (positive): [M + Na]+ (calcd. 1928.1411): found. 1928.1409. 1H NMR [500 MHz,

(CD3)2SO]: δ = 9.26 (d, = 1.6 Hz, 2H), 8.70 (s, 2H), 8.59 (d, = 8.3 Hz, 2H), 8.51 (dd, = 2.1,

8.3 Hz, 6H), 7.69 (s, 2H), 7.45 (s, 2H), 7.38 (s, 2H), 7.17 (s, 2H), 7.14 (d, = 7.6 Hz, 2H),

4.18–4.14 (m, 2H), 4.10–4.02 (m, 4H), 3.59–3.57 (m, 4H), 3.52–3.47 (m, 12H), 3.42–3.40 (m, 4H),




S14

3.23 (s, 6H), 2.25–1.09 (m, partially overlapping with H2O signal), 1.37 (s, 12H), 0.93 (d, = 6.7

Hz, 6H), 0.89 (d, = 6.8 Hz, 6H).

Ligand D was synthesized in the similar manner to that for the corresponding

Lenantiomer (80 mg, 87.6%). MALDITOFMS: [M+Na]+ (calcd. 1928.14): found. 1928.58.

HRMS (ESIMS) (positive): [M + Na]+ (calcd. 1928.1411): found. 1928.1425.

To a suspension of BocAibOH (290 mg, 1.43 mmol) and HOAt (97 mg, 0.72

mmol) in dry CH2Cl2 (3 mL), HATU (544 mg, 1.43 mmol) and DIEA (300 L, 1.79 mmol) were

added at 0°C. After 30 min, HClHAibOTg (409 mg, 1.43 mmol) in dry CH2Cl2 (4 mL) and DIEA

(240 L, 1.43 mmol) were added. The reaction mixture was stirred at 0°C for 1 h and further at

room temperature for 2 days. The solvent was then evaporated to dryness under reduced pressure.

The residue was dissolved in EtOAc, and the solution was washed with 1N aqueous HCl, 5%

aqueous NaHCO3, brine, and dried over MgSO4. Purification by column chromatography on silica

gel (EtOAc as eluent) afforded BocAib2OTg (366 mg, 59%) as a colorless oil. MALDITOFMS:

[M+Na]+ (calcd. 457.25): found. 457.22. 1H NMR (500 MHz,CDCl3): δ = 7.19 (bs, 1H), 5.07 (s,

1H), 4.29–4.27 (m, 2H), 3.70–3.68 (m, 2H), 3.66–3.63 (m, 6H), 3.56–3.54 (m, 2H), 3.38 (s, 3H),

1.54 (s, 6H), 1.47 (s, 6H), 1.45 (s, 9H).

To a suspension of Boc(Ac6c)4OH (77 mg, 0.124 mmol) and HOAt (8.5

mg, 0.062 mmol) in dry CH2Cl2 (1 mL), HATU (47.3 mg, 0.124 mmol) and DIEA (26 L, 0.156

mmol) were added at 0°C. After 45 min, HClHAib2OTg (65 mg, 0.174 mmol) and DIEA (30 L,

0.183 mmol) were added and the reaction mixture was stirred at 0°C for 1 h and further at room

temperature for 6 days. The solution was then diluted with CHCl3 and the mixture was washed with




S15

1N aqueous HCl, 5% aqueous NaHCO3, brine, and dried over MgSO4. Recrystallization from

EtOAc/hexane (ca. 1/5; v/v) afforded Boc(Ac6c)4Aib2OTg (76 mg, 65.5%) as a white solid.

MALDITOFMS: [M+Na]+ (calcd. 957.59): found. 957.73. 1H NMR (500 MHz,CDCl3): δ = 7.34

(s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 6.79 (s, 1H), 5.09 (s, 1H), 4.26–4.24 (m, 2H),

3.72–3.62 (m, 8H), 3.56–3.54 (m, 2H), 3.38 (s, 3H), 2.18 (bs, 2H), 1.99–1.23 (m, partially

overlapping with H2O signal), 1.51 (s, 6H), 1.50 (s, 6H), 1.49 (s, 9H).

To 2,2’bipyridine5,5’dicarbonyl dichloride (10 mg, 0.036 mmol) was added

H(Ac6c)4Aib2OTg (62 mg, 0.074 mmol) in dry CH2Cl2 (3.5 mL) containing DIEA (30 L, 0.178

mmol) at room temperature. After the reaction mixture was stirred at room temperature for 2.5 h,

the solvent was evaporated to dryness under reduced pressure. Recrystallization from

CHCl3/MeOH/EtOAc (ca. 4/1/4; v/v/v) afforded the ligand (49 mg, 73.7%) as a white solid.

MALDITOFMS: [M+Na]+ (calcd. 1900.11): found. 1900.45. HRMS (ESIMS) (positive):

[M+Na]+ (calcd. 1900.1098): found. 1900.1050. 1H NMR [500 MHz, CD3CN/CDCl3 (7/3; v/v)]: δ

= 9.20 (d, = 1.9 Hz, 2H), 8.60 (d, = 8.3 Hz, 2H), 8.39 (dd, = 2.1, 8.3 Hz, 2H), 7.47 (s, 2H),

7.39 (s, 2H), 7.34 (s, 2H), 7.30 (s, 2H), 7.25 (s, 2H), 6.82 (s, 2H), 4.14–4.12 (m, 4H), 3.64–3.54 (m,

16H), 3.49–3.47 (m, 4H), 3.31 (s, 6H), 2.21–1.13 (m, partially overlapping with H2O and the

residual nondeuterated solvent signals), 1.42 (s + s, 24H).

1H NMR (500 MHz, CD3CN): (equilibrium state) ()isomer: δ =

8.63 (d, = 8.5 Hz, 6H), 8.44 (dd, = 1.8, 8.4 Hz, 6H), 7.67 (d, = 1.5 Hz, 6H), 7.48 (d, = 8.8 Hz,

6H), 6.98 (s, 6H), 4.22 (m, overlapping with Λisomer), 3.58 (s, 18H), 2.05–1.97 (m, overlapping

with Λisomer and H2O signals), 1.38 (s, 18H), 1.37 (s, 18H), 0.87 (d, = 6.8 Hz, 18H), 0.76 (d, =

6.8 Hz, 18H); (Λ)isomer: δ = 8.61 (d, = 8.3 Hz, 6H), 8.40 (dd, = 1.9, 8.3 Hz, 6H), 7.53 (d, =

1.7 Hz, 6H), 7.51 (d, = 8.8 Hz, 6H), 7.01 (s, 6H), 4.22 (m, overlapping with isomer), 3.61 (s,

18H), 2.051.97 (m, overlapping with isomer and H2O signals), 1.41 (s, 18H), 1.39 (s, 18H), 0.89




S16

(d, = 6.9 Hz, 18H), 0.83 (d, = 6.8 Hz, 18H). HRMS (CSIMS) (positive): [M–BF4]+ (calcd.

2063.9040): found. 2063.9109.

1H NMR (500 MHz, CD3CN): (equilibrium state) ()isomer: δ =

8.85 (d, = 8.5 Hz, 6H), 8.58 (dd, = 1.7, 8.5 Hz, overlapping with Λisomer), 7.91 (s, 6H), 7.74 (s,

6H), 7.12 (s, 6H), 6.88 (d, = 8.9 Hz, 6H), 6.59 (s, 6H), 4.10–4.06 (m, overlapping with Λisomer),

3.56 (s, 18H), 2.09–1.25 (m, partially overlapping with H2O and the residual undeuterated solvent

signals), 1.23 (s, 18H), 0.82 (d, = 6.8 Hz, 18H), 0.59 (d, = 6.8 Hz, 18H). (Λ)isomer: δ = 8.77 (d,

= 8.5 Hz, 6H), 8.58 (dd, = 1.7, 8.5 Hz, overlapping with isomer), 7.83 (s, 6H), 7.69 (s, 6H),

7.14 (s, 6H), 6.81 (d, = 8.8 Hz, 6H), 6.58 (s, 6H), 4.10–4.06 (m, overlapping with isomer), 3.58

(s, 18H), 2.09–1.25 (m, partially overlapping with H2O and the residual undeuterated solvent

signals), 1.20 (s, 18H), 0.84 (d, = 6.8 Hz, 18H), 0.68 ( = 6.9 Hz, 18H). HRMS (CSIMS)

(positive): [M–BF4]+ (calcd. 3324.7250): found. 3324.7263.

1H NMR (500 MHz, CD3CN): (equilibrium state) major () isomer

(some peaks were overlapping with Λisomer); δ = 8.75 (d, = 8.2 Hz, 6H), 8.66 (dd, = 1.8, 8.5

Hz, 6H), 7.75 (d, = 1.3 Hz, 6H), 7.64 (s, 6H), 7.36 (s, 6H), 7.29 (d, = 7.9 Hz, 6H), 7.08 (s, 6H),

6.66 (s, 6H), 3.95 (bs, 6H), 3.59 (s, 18H), 2.311.83 and 1.63–1.02 (m, overlapping with H2O and

the residual undeuterated solvent signals), 1.53 (s, 18H), 1.41 (s, 36H), 1.40 (s, 18H), 1.38 (s, 18H),

1.27 (s, 18H), 0.95 (d, = 6.6 Hz, 18H), 0.89 (d, = 6.5 Hz, 18H). HRMS (CSIMS) (positive):

[M–2BF4]2+ (calcd. 2249.2711): found. 2249.2637.




S17

1H NMR (500 MHz, CD3CN): major () isomer (some peaks were

overlapped with Λisomer); δ = 8.96 (d, = 8.5 Hz, 6H), 8.70 (d, = 8.4 Hz, 6H), 7.87 (s, 6H), 7.20

(s, 6H), 7.17 (d, = 7,4 Hz, 6H), 7.09 (s, 6H), 7.07 (s, 6H), 6.65 (s, 6H), 4.19–4.04 (m, 12H), 3.95

(bs, 6H), 3.613.45 (m, 60H), 3.27 (s, 18H), 2.431.12 (m, overlapping with H2O and the residual

undeuterated solvent signals), 1.40 (s, 36H), 0.93 (d, = 6.7 Hz, 18H), 0.88 (d, = 6.4 Hz, 18H),

0.84–0.74 (m, 12H). HRMS (CSIMS) (positive): [M+2Na]2+ (calcd. 2995.6909): found.

2995.6847.

1H NMR (500 MHz, CD3CN): Major (Λ) isomer (some peaks were

overlapping with isomer); δ = 8.95 (d, = 8.5 Hz, 6H), 8.68 (d, = 8.4 Hz, 6H), 7.87 (s, 6H),

7.40 (s, 6H), 7.22 (s, 6H), 7.20 (bs, 6H), 7.09 (s, 6H), 7.08 (s, 6H), 6.65 (s, 6H), 4.22–4.09 (m, 18H),

3.61 (t, = 8.5 Hz, 12H), 3.54 (bs, 36H), 3.46 (bs, 12H), 3.28 (s, 18H), 2.37–1.14 (m, partially

overlapping with H2O and the residual undeuterated solvent signals), 1.40 (s, 18H), 1.38 (s, 18H),

0.98 (d, = 6.8 Hz, 18H), 0.94 (d, = 6.8 Hz, 18H), 0.84–0.74 (m, 12H). HRMS (CSIMS)

(positive): [M+2Na]2+ (calcd. 2995.6909): found. 2995.6911.

1H NMR (500 MHz, CD3CN): δ = 84.93 (bs, 6H), 15.87 (s, 6H),

6.98 (s, 6H), 6.62 (s, 6H), 6.59 (d, = 8.7 Hz, 6H), 5.60 (s, 6H), 4.30 (bs, 6H), 4.03–3.99 (m, 6H),

3.91–3.86 (m, 6H), 3.70–3.67 (m, 6H), 3.56–3.26 (m, 72H), 3.13 (s, 18H), 2.94–2.63 (m, 30H),

2.49–1.57 (m, partially overlapping with H2O and the residual undeuterated solvent signals), 1.41 (s,

18H), 1.22 (s, 18H), 0.72 (bs, 12H), 0.43 (bs, 6H), 0.29 (d, = 6.9 Hz, 18H), 0.08 (d, = 6.2 Hz,




S18

18H), –0.08 (bs, 6H), –0.51 (bs, 12H), –0.87 (bs, 12H), –1.20 (bs, 6H), –2.10 (bs, 18H), –2.66 (bs,

6H), –3.00 (bs, 12H), –4.80 (bs, 6H), –6.83 (bs, 6H), –8.01 (bs, 6H), –11.91 (bs, 6H). [M+2Na]2+

(calcd. 2972.1714): found. 2995.1754.

1H NMR (500 MHz, CD3CN): δ = 85.4 (bs, 6H), 15.90 (bs, 6H),

7.14 (s, 6H), 6.68 (s+s, 12H), 5.88 (bs, 6H), 4.00 (bs, 24H), 3.50–3.20 (m, 72H), 3.14 (bs, 18H),

2.86 (bs, 6H), 2.8–1.6 (br m, partially overlapping with H2O and the residual undeuterated solvent

signals), 1.50 (s, 18H), 1.44 (s, 18H), 1.07 (s, 18H), 0.77 (s, 18H), 0.58– –8.0 (br m). HRMS

(CSIMS) (positive): [M+2Na]2+ (calcd. 2930.1245): found. 2930.1181.




S19

Xray diffraction data for with Cl2 were collected on a Bruker SMART APEX II Ultra

diffractometer with MoKα radiation (λ = 0.71073 Å) at 93 K.

Single crystals of [Fe()3](Cl)2(CH3CN)9(O)4(NaCl) [C246H375Cl3FeN51NaO52, = 5064.16]

suitable for Xray diffraction study were grown by slow evaporation of a CH3CN solution of

[Fe()3](BF4)2 in the presence of three equivalents of TBAC at room temperature, and a single

violet crystal with dimensions 0.18 × 0.09 × 0.08 mm3 was selected for intensity measurements.

The unit cell was orthorhombic with the space group . Lattice constants with = 4, ρcalcd =

1.169 g cm–3, (MoKα) = 0.158 mm–1, (000) = 10848, 2θmax = 43.98° were = 19.1682(12), =

36.703(2), = 40.905(3) Å, and = 28779(3) Å3. A total of 88,376 reflections was collected, of

which 30014 reflections were independent (int = 0.0642). The structure was refined to final 1 =

0.1096 for 19014 data [>2σ()] with 3026 parameters and 2 = 0.3283 for all data, = 1.173,

and residual electron density max/min = 1.026/–0.510 e Å–3, CCDC deposit number 805308. The

ORTEP drawing is shown in Fig. S20, and crystal data and structure refinement are listed in Table

S1.

Data collection, indexing, and initial cell refinements were carried out using the program

APEX2 (). Frame integration and final cell refinements were performed using SAINT software

(). A multiple absorption correction for each data set was applied using the program SADABS

(). The structure was solved by direct methods and Fourier techniques using the program

SHELXS97 () and refined by fullmatrix least squares methods on 2 using SHELXL97 ().

A full set of data was collected for the crystal. However, the data at high angles larger than d >

1 Å were dominated by noise [I/sigma(I) < 1.0], and accordingly, may affect adversely the analysis

of the crystal structure. Therefore, those data were omitted. All nonhydrogen atoms were refined

anisotropically. All hydrogen atoms were calculated geometrically and refined using the riding

models. The water hydrogen atoms were not located because they have disordered configurations.

Some cyclohexyl, isopropyl, and methyl ester groups showed high or low Ueqs for C or O atoms.

We tried to resolve these problems by assigning alternative positions with partial occupancies, but

some of the atoms continue to have the high or low Ueqs as compared to neighbors, which are

indicative of the dynamic nature of the disorder in these groups.

Five LevelA and twenty LevelB alerts are suggested for the Xray data by PLATON/CIF

check program. These can be attributed as described above.




S20

Crystal data and structure refinement for with Cl2.

Empirical formula C246H375Cl3FeN51NaO52

Formula weight 5064.16

Temperature 93 K

Wavelength 0.71073 Å

Crystal system

Space group

Unit cell dimensions = 19.1682(12) Å α = 90°.

= 36.703(2) Å β = 90°.

= 40.905(3) Å γ = 90°.

Volume 28779(3) Å3

4

Density (calculated) 1.169 g/cm3

Absorption coefficient 0.158 mm1

F(000) 10848

Crystal size 0.18 × 0.09 × 0.08 mm3

Theta range for data collection 1.11 to 20.82°.

Index ranges 19≤ h≤ 19, 36≤ k≤ 22, 40≤ l≤ 38

Reflections collected 88376

Independent reflections 30014 [int = 0.0642]

Completeness to theta 99.8%

Absorption correction Empirical

Max. and min. transmission 0.9874 and 0.9721

Refinement method Fullmatrix leastsquares on F2

Data / restraints / parameters 30014 / 3207 / 3026

Goodnessoffit on F2 1.173

Final R indices [>2σ()] 1 = 0.1096, 2 = 0.2812

R indices (all data) 1 = 0.1644, 2 = 0.3283

Largest diff. peak and hole 1.026 and 0.510 e.Å3




S21

ΛΛΛΛ

Upon mixing of two homoCoII complexes (ΛD (Co(D)3) and racemic (Co())) in

different molar ratios in CH3CN/CD3CN, the two heteroCoII complexes, namely [Co(D)2()] and

[Co(D)()2] were newly formed along with the homoCoII complexes through the ligand exchange

reaction (eq 1).

Co(D)3 + Co() = Co(D)3 + Co(D)2() + Co(D)()2 + Co() (1)

The relative molar ratios of each CoII complex after reaching an equilibrium within several

hours were estimated by 1H NMR and the results are summarized in Table S2. We then estimated

the diastereomeric excess () values at the metal centers and the helixsense excess () values of

the peptide chains for the newly formed [Co(D)2()] and [Co(D)()2] complexes based on those

for the homoCoII complexes (ΛCo(D)3 ( = 100% (Λ) and = 100% ()) and racemic

Co()3 (= 0% and = 0%)) and the molar ratios for each species determined by the 1H NMR

spectra (Table S2), followed by the curve fitting of the observed CD changes at 332 and 213 nm,

respectively.

The relative molar ratios of Co(D)3, Co(D)2(), Co(D)()2, and Co()3 at

equilibrium estimated by 1H NMR

feed (mol/mol) at equilibrium

[Co(D)3]/[]* Co(D)3 Co(D)2() Co(D)()2 Co()

10/0 1.0 0 0 0

8/2 0.63 0.17 0.18 0.02

6/4 0.38 0.17 0.31 0.14

4/6 0.17 0.16 0.38 0.29

2/8 0.04 0.06 0.36 0.54

0/10 0 0 0 1.0 *[Co(D)3] + [Co()3] = constant (5.9 × 104 M).




S22

The observed CD intensity at 332 nm reflecting the metalcentered chirality induction after

reaching an equilibrium (θtotal) is the sum of the CD intensities of the four metal complexes (θCo(D)3,

θCo(D)2(), θCo(D)()2, and θCo()3) and then,

θtotal = αθCo(D)3 + βθCo(D)2() + γθCo(D)()2 + δθCo()3

The Co() is racemic and θCo()3 = 0 and then,

θtotal = αθCo(D)3 + β(θCo(D)3) + γ(θCo(D)3). (2)

where α, β, and γ are the relative molar ratios of the optically active Co(D)3, Co(D)2(), and

Co(D)()2, respectively, and and represent the values ( = θCo(D)2()/ θCo(D)3, =

θCo(D)()2/θCo(D)3, 0 ≤ ≤ ≤ 1) at the metal centers of Co(D)2() and Co(D)()2, respectively.

The CD intensity at 332 nm for ΛCo(D)3 (θCo(D)3 = 92.5) obtained from the CD spectrum of

ΛCo(D)3 (Fig. 4A) was used as the base value. Therefore, θtotal in eq (2) is expressed as

θtotal = 92.5(α + β+ γ). (3)

The CD intensities (θtotal) at the various molar ratios of Co(D)3 and Co() in the feed can

then be calculated based on the relative molar ratios of each metal complex at equilibrium (Table

S2).

Therefore,

[Co(D)3]/[ Co()] = 8/2: 15.4 + 16.7 = 29.7. (4)

[Co(D)3]/[ Co()] = 6/4: 15.9 + 28.4 = 40.5. (5)

[Co(D)3]/[ Co()] = 4/6: 14.3 + 35.6 = 43.1. (6)

[Co(D)3]/[ Co()] = 2/8: 5.8 + 33.8 = 30.9. (7)

By using eqs (4) — (7), the values ( and ) as a function of the Co(D)3 content in the

feed can be calculated by the curve fitting of the observed CD changes at 332 nm (Fig. 5b and Fig.

S13). The fitting curves (red line in Fig. 5b and green line in Fig. S13) satisfy the observed CD

changes (red circles in Fig. 4b and Fig. S13) when and are 1.0 and 0.81, respectively (see also

Fig. S14). For comparison, the simulated curves with the variable and values are also shown in

Fig. S13.

The CD intensity at 213 nm of the metal complexes at equilibrium reflects the excess

handedness of the helical peptide chains of the ligand D and racemic ligand coordinating to the




S23

metal, because there is an isodichroic point at 213 nm, at which the CD intensity remains constant

independent of the molar ratios of D and CoII as observed in the CD titration experiments (Fig.

S15). Thus, the CD intensity at 213 nm can be used to estimate the helixsense excess () of the

dynamically racemic helical ligand when coordinating to CoII.

A positive nonlinear effect (Fig. 5b, blue line) suggests that the ()helix was predominantly

induced in the dynamically racemic ligand during the complexation to CoII in the presence of D.

Thus, we first estimated the values of all the peptide ligands.

In a similar manner to Section , the observed CD intensity θtotal(213) at 213 nm after reaching

equilibrium is the sum of the CD intensities (θCo(D)3(213), θCo(D)2()

(213), and θCo(D)()2(213)) of the

three optically active metal complexes and then,

θtotal(213) = αθCo(D)3

(213) + βθCo(D)2()(213) + γθCo(D)()2

(213)

= αθCo(D)3(213) + β(θCo(D)3

(213)) + γ(θCo(D)3(213)) (8)

where α, β, and γ are the relative molar ratios of the optically active Co(D)3, Co(D)2(), and

Co(D)()2, respectively, and and represent the values ( = θCo(D)2()(213)/θCo(D)3

(213),

= θCo(D)()2(213)/θCo(D)3

(213), 0 ≤ ≤ ≤ 1) of all the ligand peptides of Co(D)2() and

Co(D)()2, respectively. The CD intensity at 213 nm for ΛCo(D)3 (θCo(D)3(213) = 11.6) obtained

from the CD spectrum of ΛCo(D)3 (Fig. 5a) was used as the base value. Therefore, θtotal(213) in eq

(8) is expressed as

θtotal(213) = 11.6(α + β+ γ). (9)

The CD intensities θtotal(213) at the various molar ratios of Co(D)3 and Co() in feed can be

then calculated based on the relative molar ratios of each metal complex at equilibrium (Table S2)..

Therefore,

[D]/[] = 8/2: 1.93 + 2.09 = 2.77. (10)

[D]/[] = 6/4: 1.99 + 3.55 = 3.65. (11)

[D]/[] = 4/6: 1.79 + 4.45 = 3.71. (12)

[D]/[] = 2/8: 0.73 + 4.22 = 2.26. (13)

In the Co(D)2() and Co(D)()2 complexes, four and two of the six peptide chains are

assumed to have the 100% ()helix (= 100%) based on the variabletemperature 1H NMR

results using the model peptide in CD2Cl2, although the present CD measurements were carried out

in the CH3CN/CD3CN mixture (3/1; v/v). We also presumed that the CD intensity of the ligand

may become equal to that of the ligand D when it takes the 100% ()helix. Accordingly, the CD

intensity of θCo(D)2()(213) is most likely higher than that of θCo(D)3

(213) by a factor of 0.67 and the




S24

CD intensity of θCo(D)()2(213) is higher than that of θCo(D)3

(213) by a factor of 0.33 by taking into

account the number of ligand Ds, leading to the relationships, 0.67 ≤ ≤ 1, 0.33 ≤ ≤1, and

≥ .

By using eqs (10) — (13), the values ( and ) as a function of the Co(D)3 content in

the feed can be calculated by the curve fitting of the observed CD changes at 213 nm (Fig. 5b and

Fig. S16). The fitting curve (blue line in Fig. 5b and green line in Fig. S16) satisfies the observed

CD changes (blue circles in Fig. 5b and Fig. S16) when and are 1.0–0.8 and 0.5–0.43,

respectively (see also Fig. S14). For comparison, the simulated curves with variable and

values are also shown in Fig. S16.

Next, we calculated the values and for the peptide ligand in the Co(D)2() and

Co(D)()2 complexes, respectively, based on the obtained and values and the equations (14

– 17).

In the Co(D)2() complex,four of the six peptide chains are optically active D with the

of 100%. Thus, the ligand contribution (θCo(D)3(213)) to the total CD intensity (θCo(D)2()

(213)) is

expressed as

θCo(D)3(213) = θCo(D)2()

(213) – 4/6 ×θCo(D)3(213)

= θCo(D)3(213) – 4/6 ×θCo(D)3

(213) (14)

θCo(D)3(213) is also expressed as

θCo(D)3(213) = 2/6 ×θCo(D)3

(213) × /100 (15)

where is the of the ligand in Co(D)2(). Therefore, by using eqs (14) and (15), is

expressed as

= 300 – 200 (0.67 ≤ ≤ 1) (16)

In the same way, the of the ligandin Co(D)()2, can be expressed as

= 150 – 50 [0.33 ≤ ≤1 ( ≥ )] (17)

By using the obtained and values and eqs (16) and (17), the values of the ligand in

Co(D)2() and Co(D)()2 are estimated to be = 70 ± 30 and = 20 ± 5%, respectively (see also

Fig. S14).




S25

(S1) Nagaraj, R., Shamala, N. & Balaram, P. Stereochemically constrained linear peptides.

conformations of peptides containing αaminoisobutyric acid. . , 16–20

(1979).

(S2) Bruker. APEX2, Bruker AXS Inc., Madison, Wisconsin, USA, 2010.

(S3) Bruker. SAINT, Bruker AXS Inc., Madison, Wisconsin, USA, 2004.

(S4) Sheldrick, G. M. SADABS, ., University of Göttingen:

Göttingen, Germany, 1996.

(S5) Sheldrick, G. M. , University of

Göttingen: Göttingen, Germany, 1997.

(S6) Sheldrick, G. M. , University of

Göttingen: Göttingen, Germany, 1997.




S26

The fulllength structures of peptide ligands and their metal (FeII, CoII) complexes.

Ligand :R =(0) = LValAibOCH3

Ligand : R =(1) = AibAc6cLValAibOCH3

Ligand : R = (2) = AibAc6cAibAc6cLValAibOCH3

Ligand L: R =(LVal) = Ac6cAc6cAc6cAc6cLValAibOTg

Ligand :R = = Ac6cAc6cAc6cAc6cAibLValOTg

Ligand D: R =(DVal) = Ac6cAc6cAc6cAc6cDValAibOTg

Ligand : R =(Aib) = Ac6cAc6cAc6cAc6cAibAibOTg

: Fe()3(BF4)2

: Fe()3(BF4)2

: Fe()3(BF4)2

: Fe(L)3(BF4)2

: Fe()3(BF4)2

D: Co(D)3(NO3)2

: Co()3(NO3)2

Ligand

(0)

(1)

(2)

(LVal)

(DVal)

(Aib)




S27

2060 2062 2064 2066 2068 2070mass (m/z)

3322 3324 3326 3328 3330 3332mass (m/z)

2248 2250 2252 2254mass (m/z)

2994 2996 2998 3000mass (m/z)

2994 2996 2998 3000mass (m/z)

2972 2974 2976 2978mass (m/z)

2930 2932 2934mass (m/z)

Experimental (upper) and simulated (bottom)

coldspray ionization (CSI) mass spectra of the metal

complexes –.

[M–BF4]+ [M–BF4]+ [M–2BF4]2+

[M+2Na]2+ [M+2Na]2+ [M+2Na]2+

[M+2Na]2+

D

Observed

Simulated




S28

Timedependent CD (upper) and absorption (bottom) spectra of FeII complex in

CH3CN/CD3CN mixture (3/1; v/v) at 25 ºC: [] = 1.5 × 104 M. The complex was prepared by

mixing CD3CN solutions of the ligand and FeII salt (t = 0), and the complex solution was

immediately diluted with CH3CN to follow the changes in its absorption and CD spectra.

Timedependent 1H NMR (500 MHz) spectra of FeII complex in CD3CN at 25 ºC:

[] = 6.2 × 104 M. The complex was prepared by mixing CD3CN solutions of the ligand and

FeII salt (t = 0).

200 250 300 350 40000.40.81.2

Wavelength (nm)

ε x

105

240

200

160

120

80

40

0

40

80

120

ε

24 h 650 min 300 min 270 min 240 min 210 min 180 min 150 min 120 min 100 min 80 min 60 min 40 min 20 min 4 min




S29

Plots of the– CD intensities at ca. 330 nm (|ε|) against the diastereomeric excesses

(%) for – estimated from their 1H NMR spectra at thermodynamically equilibrium state at 25

ºC.




S30

,1H1H NOESY (500 MHz) spectrum of FeII complex in CD3CN at thermodynamic

equilibrium state at 22 ºC: [] = 6.6 × 104 M; mixing time = 500 ms. , Expanded NOESY

spectrum of . , Graphical summary of the strong NOEs for in CD3CN. Arrows indicate the

observed strong NOEs between the protons. , Schematic representation of a rotation of the

bpy–amide bonds. Each conformer appears to equally exist as evidenced by the strong NOEs (see

Fig. S4b).

NOE NOE

(BF4)22 (BF4)2

2

Fe2+ Fe2+

4,4’ 6,6’

= NOEs between NH–N+1H

NH

O

O

HN

O

NH

O

O

HN

NH

O

O

HN

H

ONH

H H2

Fe2+

Broadening = Strong NOE

6,6’

3,3’ 4,4’

bpyOCH3

N(1)




S31

1H NMR (500 MHz) spectra of FeII complex with TEMPO in CD3CN at room

temperature: initial concentration [] = 6.6 × 104 M; percentage of TEMPO (w/v) = () 0, () 0.3,

() 0.5, () 0.9, and () 1.3. , Intramolecular Hbonding network for a 310helix of the peptide

hexamer residues ((2)). The peptide 310helix is characterized by three residues for one helical

turn accompanied with consecutive 10membered hydrogen bonds of an NH(+3)→CO() pair.

CD spectrum of BrBz(AibAc6c)2LValAibOMe in CH3CN at 25 ºC: [peptide] = 5.0 ×

104 M.

NH

O

O

HN

O

NH

O

O

HN

NH

O

O

HN

H

ONH

H H2

Fe2+ NH(+3)→CO() hydrogen bonding

Two free NHs

TEMPO




S32

1H1H NOESY (500 MHz) spectrum of FeII complex in CD3CN at thermodynamic

equilibrium state at 25 ºC: [] = 6.8 × 104 M; mixing time = 500 ms.

1H NMR (500 MHz) spectra of FeII complex in the absence () and presence () of

TBAC in CD3CN at room temperature: () [] = 6.6 × 104 M; () [] = 6.3 × 104 M, [TBAC] =

1.97 × 103 M.

= 76%

= 76%




S33

Top (left, from Cl–Fe–Cl axis) and side (right) views of the crystal structure of the

isomer of with Cl2 ([Fe()3]Cl2) drawing by space filling model. Cocrystallized solvent

molecules are omitted for clarity.

Variable temperature 1H NMR (500 MHz) spectra of Boc(AibAc6c)2LValAibOMe

in CD2Cl2: [peptide] = 3.0 × 103 M.




S34

1H NMR (500 MHz) spectra of FeII complex in the absence () and presence () of

TBAC in CD3CN at room temperature: () [] = 6.7 × 104 M; () [] = 6.4 × 104 M, [TBAC] =

1.9 × 103 M.

= 85%

> 98%




S35

, 1H1H NOESY (500 MHz) spectrum of FeII complex in CD3CN at thermodynamic

equilibrium state at 22 ºC: [] = 6.6 × 104 M; mixing time = 500 ms. , Expanded NOESY

spectrum of . , Graphical summary of the strong NOEs for in CD3CN. Arrows indicate the

observed strong NOEs between the protons. , Schematic representation of a rotation of the

bpy–amide bonds, which appears to be restricted and its equilibrium shifts to the righthand side

(see Fig S11b).

Broadening = Strong NOE

3,3’ 4,4’

6,6’


(BF4)22 (BF4)2

2

Fe2+ Fe2+

bpyOTg

N(1)

4,4’ 6,6’




S36

, 1H1H NOESY (500 MHz) spectrum of FeII complex with TBAC in CD3CN at

thermodynamic equilibrium state at 22ºC: [] = 6.4 × 104 M, [TBAC] = 1.8 × 103 M; mixing

time = 500 ms. , Expanded NOESY spectrum of complex with TBAC. , Graphical summary

of the strong NOEs for with TBAC in CD3CN. Arrows indicate the observed strong NOEs

between the protons. , Schematic representation of the restricted rotation of the bpy–amide bonds

in the presence of Cl– anions.

(Cl)22

Fe2+ Fe2+

4,4’

6,6’

= Strong NOE

3,3’ 4,4’

6,6’


bpyOTg

N(1)




S37

1H NMR (500 MHz) spectrum of FeII complex in CD3CN at room temperature: []

= 6.6 × 104 M.

0 20 40 60 80 100

0

10

20

30

40

50

60

70

80

90

[D]/([D] + []) x 100 (%)

CD

(mde

g) a

t 332

nm

Observed CD intensity Calculated CD intensity changes

= = 1 = 1, = 0.81 = 1, = 0.70 = 1, = 0.50 = 0.54, = 0.38 = = 0

Plots of the observed (●) and calculated CD intensity changes at 332 nm with variable

( and ) as a function of Dcontents. See Fig. S17 for more detailed simulation procedures.

, = at the metal center = θCo(D)2()/θCo(D)3

( × 100 = of Co(D)2()) = θCo(D)()2/θCo(D)3

( × 100 = of Co(D)()2) 0 ≤ ≤ ≤ 1




S38

Schematic illustrations of the ligand exchange reactions of Co(D)3 and Co()3 and

summary of the simulation results for chiral amplification at the metal centers and in the ligand

during the formation of optically active metal complexes Co(D)2() and Co(D)()2.

Molar ratio α β γ δ

θ332 (mdeg) 92.5 α 92.5 β 92.5 γ 0 (%) 100 100 ( = 1) 81 ( = 0.81) 0

θ213 (mdeg) 11.6 α 11.6 β 11.6 γ 0

of all ligands (%) 100 90 ± 10 ( = 0.9 ± 0.1)

46.5 ± 3.5 ( = 0.465 ± 0.035) 0

of ligand (%) ─ = 70 ± 30 = 20± 5 0

ΛCo(D)3 ΛrichCo(D)2() ΛrichCo(D)()2 /ΛCo()3

ΛΛΛΛ

ΛΛΛΛ

ΛΛΛΛ

ΛΛΛΛ

Mixing Dwith

Ligand exchange

[D]/[] = 8/2 – 2/8 [D] + [] = const.

= ()Helix = ()Helix Λ= Λdiastereomer = diastereomer Helixsense excess (%); = {[]–[]}/{[]+[]} x 100 Diastereomeric excess (%); = {[Λ]–[]}/{[Λ]+[]} x 100

( ~ 100)

( = 0)

atthe metal center

of the all peptide ligands

Helixsense excess of the ligand

D: Λ[Co(D)3](NO3)2 ΛΛΛΛ

(= 100) ( = 100)

Co(D)3

Ligand D

: (/Λ)[Co()3](NO3)2 ΛΛΛΛ

(= 0) ( = 0)

Co()3

Ligand




S39

CD (upper) and absorption (bottom) spectral changes of the ligand D in the presence of

increasing amounts of Co(NO3)2 salt in CH3CN at 25ºC: [D] = 4.3–4.2 × 104 M,

[D]/[Co(NO3)2] = 3/1–3/0.

The CD intensities of the mixture at 213 nm reflect the of the helixsense excess of the peptide

chains. This assignment was done based on the CD titrations of the ligand D with CoII (Fig. S18),

which exhibited a clear isodichroic point at 213 nm in the peptide chromophore region due to the

coordination of the free ligand D composed of the ()peptides to CoII. This means that the CD

intensity at 213 nm for the mixtures of D and racemic should linearly increase with the

increasing content of D in Fig. 5b, if the preferredhanded helix could not be induced in the

dynamically racemic helical peptide chains ((Aib)) in the ligand.

250 300 3500

1

2

Wavelength (nm)

Abso

rban

ce

40

20

0

20

40

60

80

100

CD

(mde

g) 3 / 1 3 / 0.67 3 / 0.33 3 / 0

[D] / [CoII]

Isodichroic point at 213 nm




S40

0 20 40 60 80 100

0

5

10

[D]/([D] + []) x 100 (%)

CD

(mde

g) a

t 213

nm

Observed CD intensity Calculated CD intensity changes

' = ' = 1' = 1, ' = 0.43' = 0.92, ' = 0.47' = 0.80, ' = 0.50' = 0.70, ' = 0.40' = 0.67, ' = 0.33

Plots of the observed (●) and calculated CD intensity changes with variable (’ and

’) at 213 nm as a function of D contents. See Fig. S17 for more detailed simulation procedures.

’, = of all peptide ligands. ’ = θCo(D)2()

(213)/θCo(D)3(213)

(’×100 = of Co(D)2()) ’= θCo(D)()2

(213)/θCo(D)3(213)

(’×100 = of Co(D)()2)0.67 ≤ ≤ 1, 0.33 ≤ ≤1 ( ≥ )




S41

ORTEP drawing of the crystal structure of the isomer of the FeII complex Cl2

([Fe()3]Cl2) with thermal ellipsoids at 50% probability. Hydrogen atoms are omitted for clarity.


Documents

SUPPLEMENTARY INFORMATION...which had been obtained by treatment of Boc L Val Aib OMe ( ) with 4 M HCl in dioxane, and then DIEA (68 L, 0.41 mmol) at room temperature. The reaction