The synthesis of amino acid bridged dicatechol derivatives

Article abstract of DOI:10.1055/s-2001-11438

Amino acid bridged dicatechol ligands 1a-e are synthesized by a stepwise coupling procedure. First 2,3-dimethoxybenzoic acid (2) is coupled with the amino acid (3a-e) followed by a second coupling step of the obtained derivatives 4a-e with 2,3-dimethoxybenzyl amine (5). As coupling reagents for the amide bonds either DDC/NHS or EDC/HOBt are used. In the final step of the reaction sequence the methyl ethers of the ligand precursors 6a-e are cleaved with BBr₃ to obtain the dicatechol ligands 1a-e, which are potential building blocks for metallo-supramolecular chemistry.

Full text of DOI:10.1055/s-2001-11438

468
PAPER
The Synthesis of Amino Acid Bridged Dicatechol Derivatives
Markus Albrecht,* Matthias Napp, Matthias Schneider
Institut für Organische Chemie, Universität Karlsruhe, Richard-Willstätter-Allee, 76131 Karlsruhe, Germany
Fax +49(721)698529; E-mail: albrecht@ochhades.chemie.uni-karlsruhe.de
Received 6 October 2000; revised 29 November 2000
Abstract: Amino acid bridged dicatechol ligands 1a e are synthe-
sized by a stepwise coupling procedure. First 2,3-dimethoxybenzoic
acid (2) is coupled with the amino acid (3a e) followed by a second
coupling step of the obtained derivatives 4a e with 2,3-dimethoxy-
benzyl amine (5). As coupling reagents for the amide bonds either
DDC/NHS or EDC/HOBt are used. In the final step of the reaction
sequence the methyl ethers of the ligand precursors 6a e are
cleaved with BBr3 to obtain the dicatechol ligands 1a e, which are
potential building blocks for metallo-supramolecular chemistry.
Key words: amino acids, catechol, ligands, amides, supramolecular
chemistry
Amino acids are the monomeric building blocks of a spe-
cial class of biopolymers: the peptides. Hereby the struc-
tures of peptides are dictated by specific sequences of
Figure Amino acid bridged dicatechol derivatives 1
amino acids. -Helical, -sheet, or different turn struc-
tures are observed due to intra- and/or interstrand hydro-
gen bonding in combination with the steric and
hydrophilic/hydrophobic influence of different amino
acid side chains.1
The ligand precursors 6a, b with hydrophilic amino acids
in the spacer were synthesized as depicted in Scheme 1,
starting with 2,3-dimethoxybenzoic acid (2). For the cou-
pling reaction, the benzoic acid 2 was activated with dicy-
clohexyl carbodiimide (DCC) and N-hydroxysuccinimide
(NHS).8 The precipitated dicyclohexyl urea was removed
by filtration and the amino acids 3a, b, dissolved in aque-
ous NaHCO3, were added to obtain the derivatives 4a, b.
This procedure by Bergeron et al. has been previously ap-
plied to the preparation of the glycine derivative 4a.9 We
additionally prepared the alanine derivative 4b using this
methodology. After recrystallization, the compounds
were obtained as white crystalline solids (4a from ethanol:
81%; 4b from water: 87%).
In our work on the formation of helicate-type dinuclear
complexes, we found a way to control the diastereoselec-
tivity of the self-assembly process and thus the structure
of the complexes by use of simple alkyl-spacers with dif-
ferent chain length (even versus odd).2 It also should be
possible to use amino acids (or short peptides) in the spac-
er as structure controlling moieties. Upon complex forma-
tion two different non-covalent interactions (coordination
to the metal, inter- or intramolecular hydrogen bonding)
would influence the structure of the obtained complexes.3
In addition, the use of chiral amino acids will enable the
formation of enantiopure metal complexes4 and the direc-
tionality of the amino-acids (N-terminus versus C-termi-
nus) will introduce some further information into the
system.5
The derivatives 4a, b bear an acid function, which again
can be activated by use of DCC and NHS. Addition of
2,3-dimethoxybenzyl amine (5) to the in situ formed NHS
derivative resulted in the formation of the methyl protect-
ed ligand precursors 6a (77%) and 6b (73%).
An example of an amino acid bridged dicatecholate ligand
1 is shown in the Figure. The two (deprotonated) catechol
moieties are able to bind to two metal ions and are con-
nected by a spacer that contains one amino acid building
block. Therefore, two H-bond donors (NH) and two H-
bond acceptors (C=O) are present in the strand. The cate-
cholate oxygen atoms can act as additional hydrogen bond
acceptors.6
For the preparation of the ligand precursors with the hy-
drophobic amino acids phenyl alanine (3c), valine (3d),
and leucine (3e), the coupling with DCC/NHS led to some
problems in the purification steps. Therefore, we used hy-
droxybenztriazole (HOBt) in the presence of ethyl(dime-
thylaminopropyl)carbodiimide (EDC) for the activation
of the carboxylic acid functions of 2 as well as of 4c e.10
After coupling of the benzoic acid 2 with the amino acids
3c e, the compounds 4c e were formed but could not be
obtained in analytically pure form. However, the purity
was high enough to perform a subsequent activation of the
acid functions with HOBt/EDC followed by reaction with
In this paper, we present the synthesis of derivatives 1, us-
ing straightforward peptide coupling chemistry.7 As ami-
no acids, we have chosen glycine, alanine, phenyl alanine,
valine and leucine, which do not bear any functionalities
in the side chain.
Synthesis 2001, No. 3, 468–472 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Synthesis of Amino Acid Bridged Dicatechol Derivatives
469
the benzyl amine 5. After chromatographic work up, the
ligand precursors were obtained in 46% (6c), 61% (6d),
and 59% yield (6e) over two steps.
In the final step, the ligand precursors 6a e were depro-
tected to obtain the dicatechol derivatives 1a e (Scheme
3).
Scheme 3
Ether cleavage was achieved by reaction of the tet-
ramethoxy derivatives 6a e with BBr3 in dichlo-
romethane at 0 °C followed by stirring over night at room
temperature.11 After quenching of the crude mixture, the
solvent was removed and the residue was either dissolved
several times in methanol and volatile components re-
moved in vacuum to obtain the glycine 1a or alanine de-
rivatives 1b in 95% yield each, or the residue was
dissolved in ethyl acetate and washed with water. In this
case the organic phase contained the phenylalanine 1c, va-
line 1d, or leucine derivative 1e, which after evaporation
of the solvent were obtained in quantitative yield. The
amino acid bridged dicatechol compounds 1a e were iso-
lated as hygroscopic solid materials.
Scheme 1
One of the catechol units of 1 was attached to the N-termi-
nus of the amino acid as a catechol amide like it is ob-
served for some naturally occurring siderophores.12 To the
C-terminus a non-natural dihydroxy benzyl group was
linked via an amide group.
Herein, we have presented the straightforward synthesis
of five amino acid bridged dicatechol derivatives 1a e,
which should be potential ligands for the self-assembly of
oligonuclear metal complexes. Also, we added NHS or
HOBt as a racemization reducing agent during the amide
coupling reactions,7,8,10 we cannot rule out that some race-
mization occurred. As amino acids, we used glycine, ala-
nine, phenyl alanine, valine and leucine. We were able to
introduce these amino acids without the use of protecting
groups. At present, we are performing coordination stud-
ies with the ligands to obtain, in self-assembly processes,
oligonuclear metallo-supramolecular coordination com-
pounds. Also, the synthesis of further derivatives with
other amino acids and with short peptides in the spacer is
underway.
Scheme 2
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470
M. Albrecht et al.
PAPER
1H and 13C NMR spectra were recorded on a Bruker DRX 500 spec-
trometer using DEPT techniques for the assignment of the multi-
plicity of carbon atoms (internal standard: CHCl3 or CHD2OD). FT-
IR spectra were recorded by diffuse reflection (KBr) on a Bruker
IFS spectrometer. EI/HRMS (70 eV) mass spectra were taken on a
Finnigan MAT 90 mass spectrometer. The optical rotation was de-
tected on a Perkin Elmer 241 polarimeter. Elemental analyses were
obtained with a Heraeus CHN-O-Rapid analyzer. Solvents were pu-
rified by standard methods. Mps: Büchi 535 (uncorrected).
Anal. Calcd for C20H24N2O6 (388.42): C, 61.85; H, 6.23; N, 7.21.
Found: C, 62.01; H, 6.38; N, 7.40.
L-Alanine Derivative (2S)-2-(2,3-Dimethoxyphenyl)carbonyl
Amino-N-(2,3-dimethoxybenzyl) Ethyl Amide (6b)
Compound 6b was prepared similar to the synthesis of 6a. Purifica-
tion of the crude product was done by column chromatography (sil-
ica gel, EtOAc); yield: 302 mg (73%); white solid; mp: 138 °C.
[ ]D20 = +22.6° (c 1, MeOH).
1H NMR (CDCl3, 296 K): = 8.66 (d, 1H, J = 7.2 Hz), 7.52 (dd, 1H,
J = 7.9, 1.5 Hz), 7.16 (br, 1H), 7.06 (pseudo t, 1H, J = 7.9 Hz), 7.01
(dd, 1H, J = 7.9, 1.5 Hz), 6.94 (pseudo t, 1H, J = 7.9 Hz), 6.85 (dd,
1H, J = 7.9, 1.2 Hz), 6.79 (dd, 1H, J = 7.9, 1.2 Hz), 4.79 (m, 1H),
4.49 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.80 (s, 6H), 1.46 (d, 3H,
J = 7.0 Hz).
N-2,3-Dimethoxybenzoyl-glycine (4a)
The glycine derivative 4a was synthesized as described in the liter-
ature; yield: 81% (Lit.: 91%).9
N-2,3-Dimethoxybenzoyl-L-alanine (4b)
13C NMR (CDCl3, 296 K): = 172.2 (C), 164.9 (C), 152.6 (C),
152.5 (C), 147.9 (C), 147.0 (C), 131.7 (C), 126.0 (C), 124.2 (CH),
124.1 (CH), 122.5 (CH), 121.0 (CH), 115.7 (CH), 111.8 (CH), 61.3
(CH3), 60.6 (CH3), 56.1 (CH3), 55.7 (CH3), 49.2 (CH), 38.5 (CH2),
18.5 (CH3).
A mixture of the benzoic acid 2 (1.00 g, 5.49 mmol) and NHS
(760 mg, 6.62 mmol) was dissolved in dioxane (35 mL) and DCC
(1.37 g, 6.62 mmol) in dioxane (30 mL) was added slowly. After 17
h at r.t., the precipitated urea was removed by filtration and a solu-
tion of NaHCO3 (610 mg, 7.29 mmol) and L-alanine (650 mg, 7.29
mmol) in H2O (20 mL) was added. After stirring for additional 19
h, solvents were removed in vacuum and the residue was recrystal-
lized from H2O; yield: 1.21 g (87%); white solid; mp: 80 °C.
IR (KBr): = 3323, 3081, 2836, 1578, 1482, 1308, 1225, 1064, 753
1
cm .
MS (EI, 70 eV): m/z (%) = 402 (23) [M+], 165 (100).
HRMS (EI, 70 eV): m/z calcd for C21H26N2O6 (M+, 402.45):
[ ]D20 = +10.6° (c 1, MeOH).
1H NMR (CDCl3, 296 K): = 9.61 (br, 1H), 8.77 (d, 1H, J = 6.9
Hz), 7.66 (dd, 1H, J = 8.0, 1.5 Hz), 7.15 (pseudo t, 1H, J = 8.0 Hz),
7.06 (dd, 1H, J = 8.0, 1.5 Hz), 4.81 (m, 1H), 3.93 (s, 3H), 3.89 (s,
3H), 1.56 (d, 3H, J = 7.2 Hz).
402.1791. Found: 402.1777.
Anal. Calcd for C21H26N2O6 (402.45): C, 62.67; H, 6.51; N, 6.96.
Found: C, 62.27; H, 6.69; N, 6.90.
13C NMR (CDCl3, 296 K): = 176.6 (C), 165.5 (C), 152.7 (C),
147.9 (C), 125.5 (C), 124.5 (CH), 122.7 (CH), 116.0 (CH), 61.5
(CH3), 56.1 (CH3), 48.6 (CH3), 18.1 (CH).
Compounds 4c e; General Procedure
Benzoic acid 2 (1.00 g, 5.49 mmol), HOBt (816 mg, 6.04 mmol) and
EDC (1.05 g, 5.49 mmol) were dissolved in DMF (60 mL) under Ar
at 0 °C, and were stirred at r.t. for 17 h. A mixture of the amino acid
3c e (5.49 mmol) and NaOH (220 mg, 5.49 mmol) in H2O (10 mL)
was added. After stirring for additional 14 h, the solvent was re-
moved in vacuum, the residue was dissolved in EtOAc, washed
with sat. NH4Cl, dried (MgSO4), and solvent was removed again.
The compounds 4c e could not be obtained in analytically pure
form by this procedure but were sufficiently pure for further reac-
tions.
IR (KBr): = 3338, 3017, 2944, 1941, 1750, 1574, 1459, 1308,
1
1223, 1189, 1146, 1063, 981, 938, 818 cm .
MS (EI, 70 eV): m/z (%) = 253 (13) [M]+, 165 (100).
HRMS (EI, 70 eV): m/z calcd for C12H15NO5 (M+, 253.26):
253.0950. Found: 253.0937.
Anal. Calcd for C12H15NO5·H2O (271.26): C, 53.13; H, 6.32; N,
5.16. Found: C, 53.19; H, 5.85; N, 6.56.
N-2,3-Dimethoxybenzoyl-L-phenyl Alanine (4c)
Glycine Derivative 2-(2,3-Dimethoxyphenyl)carbonyl Amino-
N-(2,3-dimethoxybenzyl) Acetamide (6a); Typical Procedure
DCC (260 mg, 1.26 mmol) in dioxane (30 mL) was added to a mix-
ture of the glycine derivative 4a (250 mg, 1.05 mmol) and NHS
(145 mg, 1.26 mmol) in dioxane (35 mL). After 16 h at r.t., the pre-
cipitated urea was removed by filtration and a solution of NaHCO3
(117 mg, 1.39 mmol) and benzyl amine 5 (234 mg, 1.39 mmol) in
H2O (20 mL) was added. The mixture was stirred for 20 h, solvents
were removed in vacuum and the residue was recrystallized from
H2O; yield: 312 mg (77%); white solid; mp: 133 °C.
1H NMR (CD3OD, 296 K): = 7.46 (dd, 1H, J = 7.6, 1.9 Hz), 7.27
(m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 4.90 (m, 1H, hidden under the
signal of HOD), 3.85 (s, 3H), 3.59 (s, 3H), 3.31 (dd, 1H, J = 13.9,
6.6 Hz), 3.20 (dd, 1H, J = 13.9, 6.6 Hz).
13C NMR (CD3OD, 296 K): = 174.4 (C), 167.2 (C), 154.3 (C),
149.3 (C), 137.9 (C), 130.5 (CH), 130.5 (CH), 129.6 (CH), 129.6
(CH), 128.0 (CH), 127.1 (C), 125.3 (CH), 122.9 (CH), 117.2 (CH),
61.7 (CH), 56.6 (CH3), 55.1 (CH3), 38.1 (CH2).
MS (EI, 70 eV): m/z (%) = 329 (2) [M]+, 165 (100).
1H NMR (CDCl3, 296 K): = 8.65 (br, 1H), 7.68 (dd, 1H, J = 8.1,
1.6 Hz), 7.14 (t, 1H, J = 8.1 Hz), 7.06 (dd, 1H, J = 8.1, 1.6 Hz), 7.00
(pseudo t, 1H, J = 7.9 Hz), 6.88 (dd, 1H, J = 7.9, 1.3 Hz), 6.51 (br,
1H), 4.50 (d, 2H, J = 5.9 Hz), 4.16 (d, 2H, J = 5.5 Hz), 3.94 (s, 3H),
3.90 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H).
13C NMR (CDCl3, 296 K): = 168.8 (C), 165.8 (C), 152.7 (C),
148.0 (C), 147.3 (C), 131.5 (C), 125.9 (C), 125.8 (C), 124.4 (CH),
124.3 (CH), 122.8 (CH), 121.3 (CH), 115.9 (CH), 112.1 (CH), 61.5
(CH3), 60.7 (CH3), 56.2 (CH3), 55.8 (CH3), 43.9 (CH2), 39.1 (CH2).
HRMS (EI, 70 eV): m/z calcd for C18H19NO5 (M+, 329.35):
329.1263. Found: 329.1256.
N-2,3-Dimethoxybenzoyl-L-valine (4d)
1H NMR (CD3OD, 296 K): = 7.49 (dd, 1H, J = 7.9, 1.8 Hz), 7.20
(dd, 1H, J = 7.9, 1.8 Hz), 7.16 (pseudo t, 1H, J = 7.9 Hz), 4.62 (d,
1H, J = 4.7 Hz), 3.95 (s, 3H), 3.90 (s, 3H), 2.31 (m, 1H), 1.04 (d,
3H, J = 7.3 Hz), 1.02 (d, 3H, J = 7.3 Hz).
13C NMR (CD3OD, 296 K): = 174.5 (C), 167.5 (C), 154.3 (C),
149.2 (C), 127.3 (C), 125.5 (CH), 122.9 (CH), 117.2 (CH), 62.2
(CH3), 59.0 (CH), 56.6 (CH3), 32.2 (CH), 19.6 (CH3), 18.2 (CH3).
MS (EI, 70 eV): m/z (%) = 281 (0.4) [M]+, 182 (100).
HRMS (EI, 70 eV): m/z calcd for C14H19NO5 (M+, 281.31):
IR (KBr): = 3322, 3006, 2936, 1642, 1528, 1439, 1273, 1123,
1
979, 745 cm .
MS (EI, 70 eV): m/z (%) = 388 (47) [M+].
HRMS (EI, 70 eV): m/z calcd for C20H24N2O6 (M+, 388.42):
281.1263. Found: 281.1258.
388.1634. Found: 388.1620.
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The Synthesis of Amino Acid Bridged Dicatechol Derivatives
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1
N-2,3-Dimethoxybenzoyl-L-leucine (4e)
IR (KBr): = 3316, 2964, 1643, 1578, 1429, 1224, 1265 cm .
MS (EI, 70 eV): m/z (%) = 430 (14) [M]+, 165 (100).
1H NMR (CD3OD, 296 K): = 7.41 (dd, 1H, J = 7.7, 1.9 Hz), 7.18
(dd, 1H, J = 8.2, 1.9 Hz), 7.15 (pseudo t, 1H, J = 7.7 Hz), 4.71 (dd,
1H, J = 8.7, 5.3 Hz), 3.91 (s, 3H), 3.89 (s, 3H), 1.75 (m, 3H), 0.99
(d, 6H, J = 6.1 Hz).
HRMS (EI, 70 eV) m/z calcd for C23H30N2O6 (M+, 430.50):
430.2104. Found: 430.2098.
13C NMR (CD3OD, 296 K): = 175.8 (C), 167.8 (C), 154.3 (C),
149.0 (C), 128.1 (C), 125.4 (CH), 122.6 (CH), 117.0 (CH), 62.0
(CH3), 56.6 (CH3), 52.5 (CH), 42.3 (CH2), 26.2 (CH), 23.3 (CH3),
22.2 (CH3).
MS (EI, 70 eV): m/z (%) = 295 (2) [M]+, 165 (100).
HRMS (EI, 70 eV): m/z calcd for C15H21NO5 (M+, 295.34):
L-Leucine Derivative (2S)-2-(2,3-Dimethoxyphenyl)carbonyl
Amino-N-(2,3-dimethoxybenzyl)-4-methylpentylamide (6e)
Yield: 59% over 2 steps; colorless oil.
20
[ ]D
= 3.8° (c 1.32, CHCl3).
1H NMR (CDCl3, 296 K): = 8.38 (d, 1H, J = 8.0 Hz), 7.53 (dd,
1H, J = 8.0, 1.7 Hz), 7.05 (m, 2H), 6.99 (dd, 1H, J = 8.0, 1.4 Hz),
6.91 (pseudo t, 1H, J = 8.0 Hz), 6.83 (d, 1H, J = 8.0 Hz), 6.76 (d,
1H, J = 8.0 Hz), 4.74 (m, 1H), 4.47 (dd, 1H, J = 14.9, 6.0 Hz), 4.41
(dd, 1H, J = 14.9, 6.0 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H),
3.78 (s, 3H), 1.76 (m, 1H), 1.67 (m, 2H), 0.91 (d, 6H, J = 6.2 Hz).
13C NMR (CDCl3, 296 K): = 171.9 (C), 165.1 (C), 152.5 (C),
152.4 (C), 147.7 (C), 147.0 (C), 131.7 (C), 126.1 (C), 124.2 (CH),
124.0 (CH), 122.5 (CH), 120.9 (CH), 115.6 (CH), 111.7 (CH), 61.3
(CH3), 60.5 (CH3), 56.0 (CH3), 55.6 (CH3), 52.0 (CH), 41.3 (CH2),
38.4 (CH2), 24.8 (CH), 22.9(CH3), 22.0 (CH3).
295.1420. Found: 295.1410.
Compounds 6c e; General Procedure
The crude amino acid derivative 4c e (4.55 mmol), HOBt (737 mg,
5.46 mmol) and EDC (960 mg, 5.01 mmol) were dissolved in DMF
(60 mL) under Ar, and the benzylamine 5 (4.55 mmol) was added
with ice cooling. The mixture was stirred for 21 h at r.t. before the
solvent was removed in vacuum. The residue was dissolved in
EtOAc, washed with sat. NH4Cl and NaHCO3, dried (MgSO4), and
solvent was removed again. The crude product was purified by col-
umn chromatography (silica gel, hexane/EtOAc, 1:1 for 6c; 2:1 for
6d, e).
1
IR (KBr): = 3311, 2955, 1645, 1578, 1429, 1225, 1264 cm .
MS (EI, 70 eV): m/z (%) = 444 (13) [M]+, 165 (100).
HRMS (EI, 70 eV) m/z calcd for C24H32N2O6 (M+, 444.53):
L-Phenyl Alanine Derivative (2S)-2-(2,3-Dimethoxyphenyl)car-
bonyl Amino-N-(2,3-dimethoxybenzyl)-3-phenylethylamide
444.2260. Found: 444.2256.
(6c)
Compounds 1a e; General Procedure
Yield: 46% over 2 steps; white solid, mp: 123 °C.
The ligand precursors 6a e (0.30 mmol) were dissolved in CH2Cl2
(30 mL) and a 1 M solution of BBr3 in CH2Cl2 (2 mL) was added at
0 °C under Ar. The mixture was stirred for 18 h at r.t. before MeOH
(5 mL) was added, and the solvent was removed under vacuum. The
purification of 1a, b was done by dissolution of the residue followed
by removal of volatile components under vacuum several times.
The compounds 1c e were purified by dissolution in EtOAc, wash-
ing with H2O, drying (MgSO4), and removal of the solvent under
vacuum.
20
[ ]D
= 5.7° (c 1, CHCl3)
1H NMR (CDCl3, 296 K): = 8.57 (d, 1H, J = 7.4 Hz), 7.62 (dd,
1H, J = 1.6, 8.0 Hz), 7.22 7.15 (m, 5H), 7.10 (t, 1H, J = 8.0 Hz),
7.02 (dd, 1H, J = 1.6, 8.0 Hz), 6.95 (t, 1H, J = 8.0 Hz), 6.82 (dd, 1H,
J = 1.2, 8.2 Hz), 6.74 (d, 1H, J = 7.7 Hz), 6.42 (t, 1H, J = 5.5 Hz)
4.91 (dd, 1H, J = 7.2, 14.2 Hz), 4.42 (m, 2H), 3.86 (s, 3H), 3.83 (s,
3H), 3.74 (s, 3H), 3.66 (s, 3H), 3.20 (m, 2H).
13C NMR (CDCl3, 296 K): = 170.7 (C), 165.2 (C), 152.6 (C),
152.5 (C), 148.0 (C), 147.1 (C), 136.8 (C), 131.5 (C), 129.3 (CH),
129.3 (CH), 128.6 (CH), 128.6 (CH), 126.8 (CH), 125.9 (C), 124.2
(CH), 124.1 (CH), 122.7 (CH), 121.1 (CH), 115.8 (CH), 112.0
(CH), 61.2 (CH3), 60.6 (CH3), 56.1 (CH3), 55.8 (CH3), 55.0 (CH),
38.7 (CH2), 38.2 (CH2).
Glycine Bridged Derivative 2-(2,3-Dihydroxyphenyl)carbonyl
Amino-N-(2,3-dihydroxybenzyl) Acetamide (1a)
Yield: 95%; slightly brown solid; mp: 78 °C (dec.).
1H NMR (CD3OD, 296 K): = 7.26 (dd, 1H, J = 7.8, 1.5 Hz), 6.94
(dd, 1H, J = 7.8, 1.5 Hz), 6.74 (pseudo t, 1H, J = 7.8 Hz), 6.71 (dd,
1H, J = 7.8, 1.5 Hz), 6.69 (dd, 1H, J = 7.8, 1.5 Hz), 6.63 (pseudo t,
1H, J = 7.8 Hz), 4.37 (s, 2H), 4.07 (s, 2H).
1
IR (KBr): = 3270, 2941, 1640, 1530, 1232, 750 cm .
MS (EI, 70 eV): m/z (%) = 478 (9) [M]+, 165 (100).
13C NMR (CD3OD, 296 K): = 171.1 (C), 170.8 (C), 149.2 (C),
146.3 (C), 145.6 (C), 143.6 (C), 125.2 (C), 120.3 (CH), 119.6 (CH),
118.8 (CH), 118.7 (CH), 118.1 (CH), 115.7 (C), 114.6 (CH), 42.5
(CH2), 38.9 (CH2).
HRMS (EI, 70 eV) m/z calcd for C27H30N2O6 (M+, 478.55):
478.2104. Found: 478.2098.
Anal. Calcd for C27H30N2O6 (478.55): C, 67.77; H, 6.32; N, 5.85.
Found: C, 67.36; H, 6.30; N, 5.73.
1
IR (KBr): = 3331, 1638, 1589, 1458, 1077, 785 cm .
L-Valine Derivative (2S)-2-(2,3-Dimethoxyphenyl)carbonyl
Amino-N-(2,3-dimethoxybenzyl)-3-methylbutylamide (6d)
Yield: 61% over 2 steps; colorless oil.
20
MS (EI, 70 eV): m/z (%) = 332 (48) [M]+, 137 (100).
HRMS (EI, 70 eV) m/z calcd for C16H16N2O6 (M+, 332.31):
332.1008. Found: 332.1018.
[ ]D
= 2.1° (c 0.95, CHCl3).
1H NMR (CDCl3, 296 K): = 8.64 (d, 1H, J = 8.6 Hz), 7.52 (dd,
1H, J = 7.9, 1.9 Hz), 7.26 7.02 (m, 2H), 6.99 (dd, 1H, J = 10.1, 1.9
Hz), 6.92 (pseudo t, 1H, J = 7.9 Hz), 6.85 (dd, 1H, J = 7.9, 1.4 Hz),
6.76 (dd, 1H, J = 7.9, 1.4 Hz), 4.63 (m, 1H), 4.50 (dd, 1H, J = 14.8,
5.8 Hz), 4.41 (dd, 1H, J = 14.8, 5.8 Hz), 3.90 (s, 3H), 3.84 (s, 3H),
3.78 (s, 3H), 3.76 (s, 3H), 2.23 (m, 1H), 0.97 (d, 3H, J = 5.8 Hz),
0.96 (d, 3H, J = 5.8 Hz).
13C NMR (CDCl3, 296 K): = 171.1 (C), 165.1 (C), 152.6 (C),
152.4 (C), 147.8 (C), 147.0 (C), 131.7 (C), 126.1 (C), 124.1 (CH),
124.0 (CH), 122.6 (CH), 121.0 (CH), 115.6 (CH), 111.7 (CH), 61.5
(CH3), 60.5 (CH3), 58.7 (CH), 56.0 (CH3), 55.6 (CH3), 38.4 (CH2),
31.1 (CH), 19.4 (CH3), 18.0 (CH3).
Anal. Calcd for C16H16N2O6·H2O (350.31): C, 54.86; H, 5.18; N,
8.00. Found: C, 55.13; H, 5.47; N, 7.48.
L-Alanine Bridged Derivative (2S)-2-(2,3-dihydroxyphenyl)car-
bonyl Amino-N-(2,3-dihydroxybenzyl) Ethylamide (1b)
Yield: 95%; slightly brown solid; mp: 112 °C (dec.).
20
[ ]D
= 15° (c 1, MeOH).
1H NMR (CD3OD, 296 K): = 7.32 (dd, 1H, J = 8.0, 1.4 Hz), 6.94
(dd, 1H, J = 8.0, 1.4 Hz), 6.74 (pseudo t, 1H, J = 8.0 Hz), 6.71 (dd,
1H, J = 7.7, 1.7 Hz), 6.68 (dd, 1H, J = 7.7, 1.7 Hz), 6.63 (pseudo t,
1H, J = 7.7 Hz), 4.63 (q, 1H, J = 7.1 Hz), 4.39 (d, 1H, J = 14.8 Hz),
4.35 (d, 1H, J = 14.8 Hz), 1.46 (d, 3H, J = 7.1 Hz).
Synthesis 2001, No. 3, 468–472 ISSN 0039-7881 © Thieme Stuttgart · New York

472
M. Albrecht et al.
PAPER
13C NMR (CD3OD, 296 K): = 175.5 (C), 170.8 (C), 149.8 (C),
147.2 (C), 146.6 (C), 144.6 (C), 126.1 (C), 121.2 (CH), 120.6 (CH),
119.8 (CH), 119.7 (CH), 119.5 (CH), 117.0 (C), 115.6 (CH), 50.6
(CH), 40.0 (CH2), 18.5 (CH3).
1H, J = 14.7 Hz), 4.33 (d, 1H, J = 14.7 Hz), 1.69 (m, 3H), 0.96 (d,
3H, J = 6.0 Hz), 0.93 (d, 3H, J = 6.0 Hz).
13C NMR (CD3OD, 296 K): = 175.3 (C), 175.3 (C), 170.9 (C),
149.6 (C), 147.1 (C), 146.5 (C), 144.5 (C), 126.1 (C), 121.2 (CH),
120.5 (CH), 119.7 (CH), 119.5 (CH), 117.0 (CH), 115.6 (CH), 53.3
(CH), 42.0 (CH2), 39.9 (CH2), 26.1 (CH), 23.4 (CH3), 22.0 (CH3).
1
IR (KBr): = 3372, 1639, 1589, 1481, 1337, 1079, 788 cm .
MS (EI, 70 eV): m/z (%) = 346 (25) [M]+, 137 (100).
HRMS (EI, 70 eV) m/z calcd for C17H18N2O6 (M+, 346.34):
1
IR (KBr): = 3363, 2960, 1637, 1538, 1263, 1045 cm .
346.1165. Found: 346.1155.
MS (EI, 70 eV): m/z (%) = 388 (22) [M]+, 137 (100).
Anal. Calcd for C17H18N2O6 1.25 H2O (368.84): C, 55.36; H, 5.60;
N, 7.59. Found: C, 55.45; H, 5.33; N, 7.32.
Anal. Calcd for C20H24N2O6 H2O (406.44): C, 59.10; H, 6.45; N,
6.89. Found: C, 59.38; H, 6.45; N, 6.57.
L-Phenyl Alanine Bridged Derivative (2S)-2-(2,3-Dihydrox-
yphenyl)carbonyl Amino-N-(2,3-dihydroxybenzyl)-3-phenyl-
ethylamide (1c)
Acknowledgement
Yield: quantitative; slightly brown solid; mp: 76 °C.
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft.
20
[ ]D
= 46.2 (c 1, CHCl3).
1H NMR (CDCl3, 296 K): = 9.33 (br, 1H), 7.18 (m, 1H), 7.14 (m,
3H), 7.03 (m, 2H), 6.92 (m, 2H), 6.73 (m, 2H), 6.62 (pseudo t, 1H,
J = 6.5 Hz), 6.48 (m, 2H), 5.94 (br, 1H), 4.80 (d pseudo t, 1H,
J = 8.0, 5.4 Hz), 4.28 (dd, 1H, J = 14.6, 6.5 Hz), 4.14 (dd, 1H,
J = 8.6, 6.5 Hz), 3.21 (dd, 1H, J = 13.5, 5.4 Hz), 3.02 (dd, 1H,
J = 13.5, 8.6 Hz).
13C NMR (CDCl3, 296 K): = 173.0 (C), 169.7 (C), 149.0 (C),
146.4 (C), 145.8 (C), 142.5 (C), 135.1 (C), 129.1 (CH), 129.1 (CH),
128.9 (CH), 128.9 (CH), 127.5 (CH), 123.7 (C), 121.6 (CH), 120.7
(CH), 119.0 (CH), 118.8 (CH), 116.5 (CH), 115.1 (CH), 113.4 (C),
54.5 (CH), 40.3 (CH2), 38.9 (CH2).
References
(1) Schulz, G. E.; Schirmer, R. H. Principles of Protein Structure;
Springer Verlag: Weinheim, 1979.
Jakubke, H. -D.; Jeschkeit, H. Aminosäuren, Peptide,
Proteine; VCH: Weinheim, 1982.
(2) Albrecht, M. Chem. Soc. Rev. 1998, 27, 281.
Albrecht, M. Chem.–Eur. J. 2000, 6, 3485.
(3) For amino acid substituted chelating ligands see, e. g.:
Imperiali, B.; Prins, T. J.; Fischer, S. L. J. Org. Chem. 1993,
58, 1613.
1
IR (KBr): = 3376, 1638, 1531, 1263, 738, 702 cm .
Walkup, G. K.; Imperiali, B. J. Org. Chem. 1998, 63, 6727.
Bishop, B. M.; McCafferty, D. G.; Erickson, B. W.
Tetrahedron 2000, 56, 4629.
MS (EI, 70 eV): m/z (%) = 422 (19) [M]+, 120 (100).
HRMS (EI, 70 eV) m/z calcd for C23H22N2O6 (M+, 422.44):
(4) For examples of enantiopure helicates see: Carrano, C. J.;
Raymond, K. N. J. Am. Chem. Soc. 1978, 100, 5371.
Corey, E. J.; Cywin, C. L.; Noe, M. C. Tetrahedron Lett. 1994,
35, 69.
422.1478. Found: 422.1483.
Anal. Calcd for C23H22N2O6 1.5 H2O (449.44): C, 61.46; H, 5.61;
N, 6.23. Found: C, 61.65; H 5.24; N, 5.78.
Enemark, E. J.; Stack, T. D. P. Angew. Chem., Int. Ed. Engl.
1995, 34, 996.
Albrecht, M. Synlett 1996, 565.
Baum, G.; Constable, E. C.; Fenske, D.; Housecroft, C. E.;
Kulke, T. Chem.–Eur. J. 1999, 5, 1862.
L-Valine Bridged Derivative (2S)-2-(2,3-Dihydroxyphenyl)car-
bonyl Amino-N-(2,3-dihydroxybenzyl)-3-methyl Butylamide
(1d)
Yield: quantitative; slightly brown solid; mp: 70 °C (dec.).
20
[ ]D
= 31.6° (c 1, CHCl3).
(5) Albrecht, M. J. Incl. Phen. Macrocycl. Chem. 2000, 36, 127;
and references cited therein.
(6) Karpishin, T. B.; Stack, T. D. P.; Raymond, K. N. J. Am.
Chem. Soc. 1993, 115, 6115.
(7) Bodanszky, M.; Bodanszky, A. The Practice of Peptide
Synthesis; Springer Verlag: Berlin, 1984.
Jones, J. Synthese von Aminosäuren und Peptiden; VCH:
Weinheim, 1995.
(8) Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am.
Chem. Soc. 1964, 86, 1839.
(9) Bergeron, R. J.; Kline, S. J.; Stolowich, N. J.; McGovern, K.
A.; Burton, P. S. J. Org. Chem. 1981, 46, 4524.
(10) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. I. J. Org.
Chem. 1961, 26, 2525.
König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(11) Albrecht, M. Synthesis 1996, 230.
1H NMR (CD3OD, 296 K): = 7.35 (dd, 1H, J = 7.9, 1.3 Hz), 6.95
(dd, 1H, J = 7.9, 1.3 Hz), 6.75 6.67 (m, 3H), 6.62 (pseudo t, 1H,
J = 7.9 Hz), 4.44 (m, 2H), 4.32 (d, 1H, J = 15.0 Hz), 2.18 (m, 1H),
0.99 (m, 6H).
13C NMR (CD3OD, 296 K): = 174.1 (C), 170.1 (C), 148.9 (C),
147.0 (C), 146.5 (C), 144.5 (C), 126.0 (C), 121.5 (CH), 120.5 (CH),
120.0 (CH), 119.9 (CH), 119.6 (CH), 117.7 (C), 115.7 (CH), 60.3
(CH), 39.9 (CH2), 32.2 (CH), 19.7 (CH3), 18.8 (CH3).
1
IR (KBr): = 3353, 2968, 1637, 1535, 1262, 1044 cm .
MS (EI, 70 eV): m/z (%) = 374 (12) [M]+, 137 (100).
HRMS (EI, 70 eV) m/z calcd for C19H22N2O6 (M+, 374.39):
374.1478. Found: 374.1472.
Anal. Calcd for C19H22N2O6·1.5 H2O (401.39): C, 56.85; H, 6.28; N,
6.98. Found: C, 56.51; H, 5.81; N, 6.66.
(12) Matzanke, B. F., Müller-Matzanke, G., Raymond, K. N., in
Loehr, T. M., Eds., Iron Carriers and Iron Proteins; VCH:
New York, 1989.
L-Leucine Bridged Derivative (2S)-2-(2,3-Dihydroxyphe-
nyl)carbonyl Amino-N-(2,3-dihydroxybenzyl)-4-methylpenty-
lamide (1e)
Raymond, K. N. Coord. Chem. Rev. 1990, 105, 135.
Yield: quantitative; slightly brown solid; mp: 64 °C (dec.).
20
[ ]D
= 41.2 °(c 1, CHCl3).
Article Identifier:
1437-210X,E;2001,0,03,0468,0472,ftx,en;T03100SS.pdf
1H NMR (CD3OD, 296 K): = 7.32 (dd, 1H, J = 8.0, 1.4 Hz), 6.94
(dd, 1H, J = 8.0, 1.4 Hz), 6.81 6.60 (m, 4H), 4.69 (m, 1H), 4.38 (d,
Synthesis 2001, No. 3, 468–472 ISSN 0039-7881 © Thieme Stuttgart · New York