Supplementary Information - Royal Society of Chemistry

Electronic Supplementary Material (ESI) for Green Chemistry This journal is © The Royal Society of Chemistry 2012

SI1

Electronic Supplementary Information Cysteine as sustainable sulfur-reagent for the protecting-group-free synthesis of sulfur-containing amino acids: Biomimetic synthesis of L-ergothioneine in water Irene Erdelmeier,* Sylvain Daunay, Remi Lebel, Laurence Farescour, and Jean-Claude Yadan TETRAHEDRON, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France Fax: +33 1 41837508; Tel: +33 1 41837501 E-mail: [email protected]

List of Contents

Scheme S1. Synthesis of 2-thiohistidine (3a, path A) and L-ergothioneine (4, path B) using phenylchlorothionoformate, according to Xu and Yadan..................................................... SI2 Scheme S2. Synthesis of 2-thiohistidine (3a) and L-ergothioneine (4) using KSCN, according to Trampota.2 ........................................................................................................................ SI3 Figure S3. 1H-NMR (400MHz, H2O/D2O, 6-9 ppm) of the reaction mixture.......................... SI4 3-{2-[(2-Amino-2-carboxyethyl)thio]-1H-imidazol-4-yl}-2-(trimethylammonio)propanoate (13)SI5 2-Amino-3-{[4-(2-amino-2-carboxyethyl)-1H-imidazol-2-yl]thio}propanoic acid (12a) ........... SI6 2-Amino-3-({4-[2-carboxy-2-(methylamino)ethyl]-1H-imidazol-2-yl}thio)propanoic acid (12b)SI7 2-Amino-3-({4-[2-carboxy-2-(dimethylamino)ethyl]-1H-imidazol-2-yl}thio)propanoic acid ........... (12c) ..................................................................................................................................... SI8 Figure S4. Thermal cleavage of compound 13 in the presence of 15; formation of 4 and 16SI9 2,2-Bis[(2-carboxyethyl)thio]propanoic acid (16)................................................................. SI10 L-Ergothioneine

(4) ............................................................................................................. SI11

D-Ergothioneine (D-4)......................................................................................................... SI12 L-(-)-2-Thiohistidine

(3a)..................................................................................................... SI13

D-(+)-2-Thiohistidine (D-3a) ............................................................................................... SI14 2-(Methylamino)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)propanoic acid (3b)................. SI15 2-(Dimethylamino)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)propanoic acid (3c) .............. SI16


SI2

Scheme S1. Synthesis of 2-thiohistidine (3a, path A) and L-ergothioneine (4, path B) using phenylchlorothionoformate, according to Xu and Yadan.1 (A: 5+1 steps; B: 6+1 steps starting from L-histidine) O OH N

NH2

NH

A

a)

B

95% O OMe

N

NH2

NH

2 HCl

g)

b) 95% O

O

OMe

OMe RN

OMe

+

NHR

N

N

NR

O

c) PCTF 72%

+

S

NR

+

NHR

HN

NHR

NH

HN

NH

NMe2

OMe

h) 99%

EtO2CN

N

NMe2

SCO2Et

S

S

S

60%

OMe

OMe

OMe HN

O

O

O

O

NHR

NMe2

NH

2 HCl

R = Boc

OMe NH

N

NHR

c) PCTF

RN

O

95%

19% i) 85% d)

d)

O O OH RN

NH

NHR

O

O

+

OMe OH

OH HN

NR

HN

NHR

NH

EtO2CN

NHR

N

+-

NMe3 I

SCO2Et S

S

S

j)

55%

f)

e)

86%

86%

4

3a

OH

NaOH

S

+ Cl

Cl

S O

Cl

PCTF a) MeOH, gaseous HCl; b) Boc2O, NaHCO3, H2O/THF, rt; c) (i) PCTF, NaHCO3, H2O/Et2O, rt; (ii) TEA, MeOH, rt; d) LiOH, THF/H2O; e) gaseous HCl, CH2Cl2; f) gaseous HCl, ethyl acetate; g) 37% aqueous CH2O, H2, 10% Pd/C, rt; h) ClCO2Et, TEA, CH2Cl2, 10°C; i) MeI, THF, rt; j) concd HCl, 75 equiv HSC H2CH2CO2H, 110°C. 1) Xu, J. ; Yadan, J.-C. J. Org. Chem. 1995, 60, 6296-6301.


SI3

Scheme S2. Synthesis of 2-thiohistidine (3a) and L-ergothioneine (4) using KSCN, according to Trampota.2 (5 and 9 steps, respectively, starting from L-histidine) O

O OH

N

a)

NH

OMe

95%

NH2

N

NH

NH2

2 HCl

b) O Ph

88%

O

O O

HN

O HN

HN

79%

Ph

O

O

c) HN

HN O

O

Ph

Ph O

Ph

d)

O

O O OH

OH

e)

NH3+ClNH3+Cl-

55% for d) and e)

HN

NH2

NH S

3a

f) 100%

O

N

OH

g)

OH HN

O

95%

NH2

HN

N

NMe2

2HCl StBu

StBu h)

O OH HN

N

NMe3+I-

i) 62% for h) and i)

4

StBu

a) MeOH, gaseous HCl; b) (i) H2O/THF, NaHCO3, BzCl (ii) Et2O/TEA c) MeOH, gaseous HCl d) concd HCl, 90°C, 15h; e) H2O , KSCN, 90°C, 3h; f) (i) H 2O, t-BuOH, concd HCl, 90°C, 3h (ii) NaAc, 2-propano l; g) THF, 37% aqueous CH2O, NaBH(OAc)3, 10°C; h) MeOH, NH 4OH, MeI, rt; i) concd HCl, 20 equiv CH3CHSHCO2H, 110°C; 18h. 2) Trampota, M. Process for the Synthesis of L-(+)-Ergothioneine. U.S. Patent 12240173, September 29, 2008.


SI4

Figure S3. 1H-NMR (400MHz, H2O/D2O, 6-9 ppm) of the reaction mixture. Reaction mixture corresponding to Table 1, entry 1. O O H

unidentified byproducts

O

5

N

H

N

NH

2. Cysteine 1h 0°C

O

5

N

NH

N

S

2 H 8

13 (H-5)

1. H+/Br2, 0°C

O H2N OH

8 (H-2)

8 (H-5)

Reaction mixture corresponding to Table 1, entry 6.

13 (H-5)

unidentified byproducts 8 (H-2)

8 (H-5)

13


SI5

3-{2-[(2-Amino-2-carboxyethyl)thio]-1H-imidazol-4-yl}-2-(trimethylammonio)propanoate (13). 1

H NMR (D2O, 400 MHz) O H

O

5

N

NH

N

S O H 2N

13 x 3HCl x H2O

OH

13

C NMR (D2O, 75 MHz)


SI6

2-Amino-3-{[4-(2-amino-2-carboxyethyl)-1H-imidazol-2-yl]thio}propanoic acid (12a) 1

H NMR (D2O, 400 MHz) O OH N

NH

NH2

S O

12a x3HClxH2O

H2N OH

13

C NMR (D2O, 75 MHz)


SI7

2-Amino-3-({4-[2-carboxy-2-(methylamino)ethyl]-1H-imidazol-2-yl}thio)propanoic acid (12b) 1

H NMR (D2O, 400 MHz) O OH NH HN

N S

O

12b x 3HClxH2O

H2N OH

13

C NMR (D2O, 75 MHz)


SI8

2-Amino-3-({4-[2-carboxy-2-(dimethylamino)ethyl]-1H-imidazol-2-yl}thio)propanoic acid (12c) 1

H NMR (D2O, 400 MHz) O OH N

NH

N

S O H2N

12c x3HClx0.5H2O

OH

13

C NMR (D2O, 75 MHz)


SI9

Figure S4. Thermal cleavage of compound 13 in the presence of 15; formation of 4 and 16. A) UPLC-MS of the reaction mixture after 4h, UV detection.

13

O HS

13

OH OH

O

15 (10 equiv) 18h/90°C

S HO

4

B) UPLC-MS of the reaction mixture after 4h, SIR detection of compound 16.

16

C) Independently synthesized dithioketal 16 (UPLC-MS).

O OH

S

16

O

+

4


SI10

2,2-Bis[(2-carboxyethyl)thio]propanoic acid (16) 1

H NMR (D2O+NaOD, 400 MHz)

OH O S HO

O OH

S

16

13

O

C NMR (D2O+NaOD, 75 MHz)


SI11

L-Ergothioneine 1

(4) H NMR (D2O, 400 MHz) O O HN

NH S

13

N

4

C NMR (D2O, 75 MHz)


SI12

D-Ergothioneine (D-4) 1 H NMR (D2O, 400 MHz) O O HN

NH S

N

D-4


SI13

L-(-)-2-Thiohistidine 1

(3a)

H NMR (D2O+DCl, 400 MHz) O OH HN

NH S

13

NH2

3a

C NMR (D2O+DCl, 75 MHz)


SI14

D-(+)-2-Thiohistidine (D-3a) 1 H NMR (D2O+DCl, 400 MHz) O OH HN

NH S

NH2

D-3a


SI15

2-(Methylamino)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)propanoic acid (3b) 1

H NMR (D2O+DCl, 400 MHz) O OH NH HN

HN S

13

3b



SI16

2-(Dimethylamino)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)propanoic acid (3c) 1

H NMR (D2O+DCl, 400 MHz) O OH HN

NH S

13

N

3c
