si1 e-mail: irene.erdelmeier@tetrahedron · irene erdelmeier,* sylvain daunay, remi lebel, laurence...

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

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

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)

N NH NH2

O

OH

N NH NH2

O

OMe

2 HCl

N NH NMe2

O

OMe

2 HCl

EtO2CN N NMe2

O

OMe

SCO2Et

EtO2CN N NMe3+I-

O

OMe

SCO2Et

4

HN NH NMe2

O

OMe

S

55%

95%

72%

99%

85%

Cl

S

Cl

c) PCTF

a)

g)

h)

i)

j)

O

S

ClOH

PCTF

+NaOH

RN N NHR

O

OMe

N NR NHR

O

OMe+

RN NH NHR

O

OMe

S

HN NR NHR

O

OMe

S

HN NH NHR

O

OMe

S

RN NH NHR

O

OH

S

HN NR NHR

O

OH

S

HN NH NHR

O

OH

S

3a

b)

c) PCTF

d)

e)

+

+

95%95%

R = Boc

+

60% 19%

86% 86%

A B

f)

d)

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)

N NH NH2

O

OH

N NH NH2

O

OMe

2 HCl

HN N NH2

O

OH

StBu

4

100%

95%

79%

55% for d) and e)

c)

a)

b)

d)

e)

f)

Ph

O

HN

HN

O

HN

O

O

O

Ph

Ph

O

HN

O

HN

O

O

O

Ph

Ph

O

NH3+Cl-

O

OH

HN NH NH2

O

OH

S

HN N NMe2

O

OH

StBu

HN N NMe3+I-

O

OH

StBu

g)

h)

i)

88%

2HCl

95%

62%for h) and i)

NH3+Cl-

3a

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.

Reaction mixture corresponding to Table 1, entry 6.

8 (H-2)

8 (H-5)

13 (H-5)

unidentified byproducts

8 (H-2)

8 (H-5)

13 (H-5)

unidentified byproducts

N NH N

O

O

S

OHH2N

O13

1. H+/Br2, 0°C

2. Cysteine1h 0°C

H5

N NH N

O

O

8

H

H

5

2


SI5

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

1H NMR (D2O, 400 MHz)

13C NMR (D2O, 75 MHz)

N NH N

O

O

S

OHH2N

O 13 x 3HCl x H2O

H5


SI6

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



N NH NH2

O

OH

S

OHH2N

O12a x3HClxH2O


SI7

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



N NH HN

O

OH

S

OHH2N

O 12b x 3HClxH2O


SI8

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



N NH N

O

OH

S

OHH2N

O 12c x3HClx0.5H2O


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.

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

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

13

16

4

13 4+

HS OH

O

15 (10 equiv)

18h/90°C16

HOS OH

OS

OH

O

O


SI10

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

1H NMR (D2O+NaOD, 400 MHz)

13C NMR (D2O+NaOD, 75 MHz)

16

HOS OH

OS

OH

O

O


SI11

L-Ergothioneine (4) 1H NMR (D2O, 400 MHz)


4

HN NH N

O

O

S


SI12

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

D-4

HN NH N

O

O

S


SI13

L-(-)-2-Thiohistidine (3a)

1H NMR (D2O+DCl, 400 MHz)

13C NMR (D2O+DCl, 75 MHz)

HN NH NH2

O

OH

S 3a


SI14

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

HN NH NH2

O

OH

S D-3a


SI15

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

1H NMR (D2O+DCl, 400 MHz)


HN NH HN

O

OH

S 3b


SI16

2-(Dimethylamino)-3-(2-thioxo-2,3-dihydro-1H-imidazol-4-yl)propanoic acid (3c) 1H NMR (D2O+DCl, 400 MHz)


HN NH N

O

OH

S 3c


si1 e-mail: irene.erdelmeier@tetrahedron · irene erdelmeier,* sylvain daunay, remi lebel, laurence...

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