Mild Reductive Cleavage of Tryptophan and Histidine Side-Chain Protecting Groups
FULL PAPER
MgSO4, the extract was concentrated to dryness at reduced pres-
added; then, 1 equiv. of tosyl chloride, benzoyl chloride or p-nitro-
benzyl chloroformate, respectively, was slowly added with vigorous
sure to afford the respective Nα-acyltryptophan methyl ester: 1a
(1.428 g, 77%), m.p. 128.0Ϫ129.0 °C (from ethyl acetate/n-hexane) stirring and cooling in an ice bath. After further stirring at 0 °C
(ref.[17] 128.5Ϫ130.0 °C); 1c (1.445 g, 90%), m.p. 107.5Ϫ109.0 °C
for 30 min and at room temperature for 2 h, 30 cm3 of chloroform
(from diethyl ether/n-hexane) (ref.[17] 110.8Ϫ112.5 °C); and 1e was added to the reaction mixture and the solution washed with
(1.564 g, 79%), m.p. 134Ϫ135 °C (from ethyl acetate/n-hexane)
water, KHSO4 (1 mol dmϪ3) and brine (3 times, 50 cm3 each). After
(ref.[18] 121.0Ϫ124.0 °C). Ϫ C20H19N3O6 (397.39): calcd. C 60.45, drying with MgSO4, the extract was concentrated to dryness at
H 4.82, N 10.57; found C 60.59, H 5.11, N 10.59.
reduced pressure and the residue submitted to eventual recrystallis-
ation to afford the required product; 2b (2.052 g, 97%) was ob-
tained as an oil; 2d (1.865 g, 100%), m.p. 104.5Ϫ105.5 °C (from n-
hexane) and 2f (2.195 g, 98%), m.p. 72.0Ϫ73.5 °C (from diethtyl
ether/petroleum ether). Ϫ 2d: C19H23N3O5 (373.41): calcd. C 61.12,
H 6.21, N 11.25; found C 60.92, H 6.29, N 11.05. Ϫ2f: C20H24N4O8
(448.43): calcd. C 53.57, H 5.39, N 12.49; found C 53.81, H 5.41,
N 12.39.
Synthesis of Boc-Trp(Tos)-OMe (1b), Boc-Trp(Bz)-OMe (1d) and
Boc-Trp[Z(NO2)]-OMe (1f): These compounds were prepared by
treating Boc-Trp-OMe (5 mmol) with tosyl chloride, benzoyl chlor-
ide or p-nitrobenzyl chloroformate, respectively, according to the
procedure described by Illi,[19] to give 1b (2.313 g, 98%), m.p.
53Ϫ54 °C (from diethyl ether) [C24H28N2O6S (472.56): calcd. C
61.01, H 5.97, N 5.92, S 6.78; found C 61.04, H 6.27, N 6.03, S
6.69]; 1d (1.815 g, 86%), m.p. 101.0Ϫ103.0 °C (from ethyl acetate/
diethyl ether) [C24H26N2O5 (422.48): calcd. C 68.23, H 6.19, N 6.63;
found C 68.28, H 6.19, N 6.71]; and 1f (2.038 g, 82%), m.p.
139Ϫ140 °C (from ethyl acetate/n-hexane) [C25H27N3O8 (497.50):
calcd. C 60.36, H 5.47, N 8.44; found C 60.29, H 5.48, N 8.41].
Synthesis of Tos-His(Tos)-OMe (2g) and Bz-His(Bz)-OMe (2h): The
procedure described above was followed by substituting H-His-
OMe·2HCl (5 mmol) for Boc-His-OMe and treating it with 2 equiv.
of tosyl chloride or benzoyl chloride, respectively, in the presence
of 4 equiv. of triethylamine to give 2g (1.980 g, 83%), m.p. 168Ϫ169
°C (from dichloromethane/n-hexane) (ref.[20] 183Ϫ185 °C)
[C21H23N3O6S2 (477.56): calcd. C 52.82, H 4.85, N 8.80, S 13.42;
found C 52.71, H 5.07, N 9.17, S 13.24] and 2h (1.376 g, 73%), m.p.
126.5Ϫ127.5 °C (from ethyl acetate/n-hexane).
Synthesis of Tos-Trp(Tos)-OMe (1g): This compound was prepared
by tosylation of H-Trp(Tos)-OMe which in turn was obtained by
acidolysis of 1b.
Acidolysis of Boc-Trp(Tos)-OMe (1b): To 1b (3 mmol) 9 cm3 of
TFA was added and the solution left to stand for 1 h. Excess TFA
was removed by evaporation at reduced pressure and the residue
triturated with diethyl ether and filtered to give H-Trp(Tos)-
OMe·TFA (1.341 g, 92%), m.p. 152Ϫ153 °C (from diethyl ether).
Ϫ C21H21N2O6SF3 (486.47): calcd. C 51.85, H 4.35, N 5.75, S 6.59;
found C 51.99, H 4.58, N 5.92, S 6.69.
Controlled-Potential Electrolysis of Tryptophan and Histidine Side-
Chain Protecting Groups
Electrolysis of Boc-Trp(Tos)-OMe (1b), Boc-Trp(Bz)-OMe (1d) and
Boc-Trp[Z(NO2)]-OMe (1f): The two compartments of a con-
trolled-potential electrolysis cell were filled with acetonitrile con-
taining Et4NCl (0.1 mol dmϪ3) as supporting electrolyte and
Et3NHCl (0.03 mol dmϪ3) as proton donor. 1b (1 mmol), 1d (1
mmol), or 1f (1 mmol) was added to the cathodic compartment
and a cyclic voltammogram recorded at a sweep rate of 100 mV sϪl
in order to measure the corresponding first peak potential. The
potential was adjusted to a value corresponding to 50 mV lower
than the peak potential measured and the apparatus switched on.
When the flow of the current was almost zero, the reaction mixture
(catholyte) was transferred to a round-bottomed flask and the solv-
ent evaporated at reduced pressure. The residue was partitioned
between 100 cm3 of diethyl ether and 50 cm3 of aqueous KHSO4
(1 mol dmϪ3). The organic layer was then washed with aqueous
KHSO4 (1 mol dmϪ3), aqueous NaHCO3 (1 mol dmϪ3) and brine
(3 times, 30 cm3 each), and dried with MgSO4. Concentration at
reduced pressure gave the Boc-Trp-OMe derivatives in yields of
84% (0.267 g), 77% (0.245 g) and 74% (0.235 g), respectively.
Tosylation of H-Trp(Tos)-OMe,TFA: The procedure described for
the preparation of 1a was followed by substituting H-Trp(Tos)-
OMe·TFA (2.5 mmol) for H-Trp-OMe·HCl to give 1g (1.131 g,
86%), m.p. 102Ϫ104 °C (from diethyl ether/n-hexane).
Ϫ
C26H26N2O6S2 (526.63): calcd. C 59.30, H 4.97, N 5.32, S 12.17;
found C 58.95, H 5.14, N 5.60, S 11.98.
Synthesis of Bz-Trp(Bz)-OMe (1h): The procedure described above
for the synthesis of 1b, 1d and 1f was followed by substituting H-
Trp-OMe·HCl (5 mmol) for Boc-Trp-OMe and treating it with 2
equiv. of benzoyl chloride to give 1h (1.534 g, 72%), m.p.
195.0Ϫ196.0 °C (dichloromethane/n-hexane).
Ϫ C26H22N2O4
(426.47): calcd. C 73.23, H 5.20, N 6.57; found C 73.43, H 5.24,
N 6.60.
Synthesis of Tos-His-OMe (2a): This compound was obtained by
controlled-potential electrolysis and also by Mg/MeOH-mediated
cleavage of 2g as described below.
Electrolysis of Tos-Trp(Tos)-OMe (1g) and Bz-Trp(Bz)-OMe (1h):
The procedure described above was followed with 1g (1 mmol) and
1h (1 mmol) as the substrate to give 1a (0.275 g, 74%) and 1c
(0.254 g, 72%), respectively.
Synthesis of Z(NO2)-His-OMe (2e): H-His(HCl)-OMe·HCl (1
mmol) was dissolved in dichloromethane (0.2 mol dmϪ3) and
4 equiv. of triethylamine was added followed by slow addition of
1 equiv. of p-nitrobenzyl chloroformate under vigorous stirring and
cooling in an ice bath. The reaction mixture was then concentrated
at reduced pressure and the residue chromatographed through a
silica column and using chloroform/methanol as the eluent to give
2e (0.261 g, 75%), m.p. 150.5Ϫ152.0 °C (from dichloromethane/
diethyl ether). Ϫ C15H16N4O6 (348.31): calcd. C 51.72, H 4.63, N
16.09; found C 51.37, H 4.87, N 16.05.
Electrolysis of Boc-His(Tos)-OMe (2b), Boc-His(Bz)-OMe (2d) and
Boc-His[Z(NO2)]-OMe (2f): The procedure described above was
followed using 2b (1 mmol), 2d (1 mmol) and 2f (1 mmol) as sub-
strates, but the residue obtained from concentration of the catho-
lyte at reduced pressure was partitioned between 100 cm3 of chloro-
form and 50 cm3 of aqueous NaHCO3 (1 mol dmϪ3). The organic
layer was then washed with aqueous NaHCO3 (1 mol dmϪ3) and
brine (3 times, 30 cm3 each), and dried with MgSO4. The solvent
was evaporated at reduced pressure and the residue chromato-
Synthesis of Boc-His(Tos)-OMe (2b), Boc-His(Bz)-OMe (2d) and graphed on a silica-gel column; chloroform/methanol was used as
Boc-His[Z(NO2)]-OMe (2f): Boc-His-OMe (5 mmol) was dissolved
the eluent to give the Boc-His-OMe derivatives in yields of 63%
(0.169 g), 87% (0.234 g) and 70% (0.188 g), respectively.
in chloroform (0.2 mol dmϪ3) and 1 equiv. of triethylamine was
Eur. J. Org. Chem. 2001, 1967Ϫ1970
1969