Synthesis of dianionic and trianionic chiral, chelating ligands based on amino acids

Article abstract of DOI:10.1071/CH07430

The synthesis of two new families of amino acid-containing chiral ligands, based on methyliminodiacetic acid and nitrilotriacetic acid cores, has been accomplished using a simple protection, solution-phase amide coupling, and deprotection strategy. The amino acids glycine, leucine, aspartic acid, and phenylalanine were used to demonstrate the versatility of the synthetic route, and that no epimerization occurs. The tridentate ligands bear C₃ symmetry, whereas the bidentate ligands have C₁ symmetry. CSIRO 2008.

Full text of DOI:10.1071/CH07430

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 297–302
Synthesis of Dianionic and Trianionic Chiral, Chelating
Ligands Based on Amino Acids
Madeleine Schultz,A,C Jakov Kulis,B Julie Murison,B
and Genevieve W. AndrewsA
ASchool of Physical and Chemical Sciences, Queensland University of Technology,
Brisbane, Qld 4001, Australia.
BSchool of Molecular and Microbial Sciences, University of Queensland,
St Lucia, Qld 4072, Australia.
CCorresponding author. Email: madeleine.schultz@qut.edu.au
The synthesis of two new families of amino acid-containing chiral ligands, based on methyliminodiacetic acid and nitrilo-
triacetic acid cores, has been accomplished using a simple protection, solution-phase amide coupling, and deprotection
strategy. The amino acids glycine, leucine, aspartic acid, and phenylalanine were used to demonstrate the versatility of the
synthetic route, and that no epimerization occurs. The tridentate ligands bear C3 symmetry, whereas the bidentate ligands
have C1 symmetry.
Manuscript received: 13 December 2007.
Final version: 17 March 2008.
HO
Introduction
O
O
Amino acids form a cheap and ubiquitous source of chirality,
and use has been made of amino acids as metal-binding compo-
nents of ligands for classical coordination chemistry.[1–4] Free
amino acids and derivatives thereof have also been used exten-
sively as ligands and chiral auxiliaries in a variety of asymmetric
syntheses; this field has been reviewed.[5–7] For example, chiral
amino acids have been incorporated into phosphine and phos-
phite ligands for asymmetric catalysis.[8,9] However, in many
cases the amino acids are not incorporated into the ligand by
amide bonds, and most of these ligands contain other functional
groups. In addition, many bear the chiral amino acids remote
from the metal. In this project, we sought to prepare ligands
that resemble peptides in only having amide bonds as functional
groups, with the goal that these ligands should be biologically
compatible.The ligands are designed to bind to the metal through
the deprotonated acid groups of their amino acids.
Incorporation of more than one amino acid into the ligand
leads to multiple chiral centres and also to multiple charges.
Our final goal is to prepare neutral complexes of divalent and
trivalent metals. Thus, we require dianionic and trianionic lig-
ands. For dianionic ligands, iminodiacetic acid (IDA), which
resembles glycine, was selected as a basis for the core of the
ligands (Fig. 1a); however, the NH bond can participate in pep-
tide coupling and so the methyl substituted methyliminodiacetic
acid (MIDA) (Fig. 1b) was prepared. MIDA structurally resem-
bles half an ethylenediaminetetraacetate (EDTA) molecule and
was reported 60 years ago.[10] The chelate nitrilotriacetic acid
(NTA) (Fig. 1c) was selected as the core for trianionic ligands,
because it is extremely cheap, readily available, and also struc-
turally resembles glycine. Thus, amino acids protected at their
C-terminus can be coupled to MIDA and NTA. We have adopted
the nomenclature A-[X(OY)]n where A is NTA or MIDA, X is
O
N
O
HN
O
N
OH
OH
OH
HO
O
HO
O
HO
IDA
A
MIDA
B
NTA
C
Fig. 1. Cores of ligands synthesized.
the amino acid, Y is the protecting group or H for the free acid,
and n = 2 or 3 for MIDA and NTA, respectively.
IDA has previously been used as the core of small peptide
mimics with several different groups as the third substituent on
the central nitrogen atom, such as oxycarbonyls.[11,12] However,
until now MIDA has not been used as a ligand core. NTA has
previously been used as the core of some C3 symmetric lig-
ands based on a similar synthetic procedure to that reported
here, with further synthetic steps to form oxazolines[13–15] or
to reduce the amide groups to amines.[16] An NTA-based methyl
protected ester of valine, very similar to some of the com-
pounds prepared in this work, NTA-[Val(OMe)]3, has been
reported as an intermediate on route to the corresponding
oxazoline;[13] the phenylalanine and alanine analogues have also
been synthesized.[15] Other C3 symmetric tripodal peptide bun-
dles have been prepared, using ammonia as the core,[17] and used
asmetalloenzymemimics.[18] ThecurrentinterestinC3 symmet-
ric compounds as biomimetic ligands and catalysts ‘inspired by
nature’ has been reviewed.[19] Achiral cryptands have recently
been reported using NTA in Ugi-type multiple multicomponent
macrocyclizations.[20,21] However, simple amino acid deriva-
tives such as those reported here have not been used as ligands.
The protected ligands and the acid ligands described here are
© CSIRO 2008
10.1071/CH07430
0004-9425/08/040297

298
M. Schultz et al.
DCC
DMAP
NEt3
reaction to verify that an epimerized amino acid leads to a mix-
ture of diastereomers after coupling. In that case the H NMR
spectrum of the resulting NTA-[Phe(OMe)]3 was very compli-
cated and the coupling constants were not resolved.
Deprotection of the six methyl esters of the protected NTA-
[Asp(OMe)(OMe)]3 was achieved using 1.0 m NaOH or LiOH
solution (Scheme 2) to form the alkali metal salt of the C3 lig-
and. These salts were not suitable for use in metal complexation
studies with higher valent metals because the alkali metals were
difficult to remove. Thus, the methyl esters were not pursued
further.
1
R
O
R
CH2Cl2
O
OMe
*
N
*
O
ϩ
N
H2N
N
H
OH
3
3
O
OMe
1
2
HBTU
DMAP
NEt3
CH2Cl2
DMF
R
O
R
*
O
OBz
OBz
N
O
*
ϩ
N
H2N
N
H
OH
OH
2
2
O
OBz
The benzyl esters were removed by hydrogenolysis over Pd/C
(Scheme 3) in ethanol. The protected phenylalanine derivatives
MIDA-[Phe(OBz)]2 and NTA-[Phe(OBz)]3 are only sparingly
soluble in ethanol but this did not affect the reaction. The solu-
bility of the products of hydrogenolysis is substantially different
from the protected compounds; none are soluble in CH2Cl2,
and all are somewhat soluble in water. The glycine derivatives
MIDA-[Gly(OH)]2 and NTA-[Gly(OH)]3 are extremely hygro-
scopic and could only be isolated as powders when not exposed
to air. Upon air exposure, they became sticky oils.
HBTU
DMAP
NEt3
CH2Cl2
DMF
R
*
O
R
O
N
O
*
ϩ
N
H2N
N
H
3
O
OBz
3
3
Scheme 1. Solution-phase coupling to form protected ligands NTA-
[X(OMe)]3 1, MIDA-[X(OBz)]2 2, and NTA-[X(OBz)]3 3. R = H (Gly),
CH2CHMe2 (Leu), CH2Ph (Phe), CH2COOMe (AspOMe).
The NMR spectra of the free acids were recorded in D2O,
(D6)acetone, or deuterated dimethyl sulfoxide ((D6)DMSO).
Theresolvedcouplingconstantsobservedinthe1HNMRspectra
indicate that no epimerization occurred during hydrogenolysis,
so the newly prepared ligands have C3 and C1 symmetry for the
NTA and MIDA cores, respectively.
previously unreported, although the achiral NTA-[Gly(OH)]3
hasbeenmentionedina1992patentwithoutanycharacterization
data.[22]
To allow access to a wide range of amino acid-containing
ligands, solution-phase coupling of the free carboxylic acids of
the cores MIDA and NTA with C-protected amino acids was
adopted. Both methyl and benzyl protected esters were used in
coupling reactions with NTA, and benzyl esters were coupled to
MIDA. Standard coupling conditions from solid-phase peptide
synthesis were adapted for the coupling reactions. The protected
esters were fully characterized and deprotected by standard tech-
niques to form the free di- and tri-acids, which have also been
fully characterized. Our synthesis has the advantages of using
only cheap and safe starting materials, giving access to a small
library of di- and tri-anionic chiral ligands, and was conducted
by undergraduate students.
Conclusions
We have demonstrated a cheap, simple, and reliable route to
the synthesis of a small library of chiral C1 dianionic and C3
trianionic chelating ligands, based on MIDA and NTA cores
respectively, with amino acid substituents. Benzyl esters were
the most suitable protecting groups for the amino acids because
upon deprotection, the free acids are formed. The metal com-
plexation behaviour and acidity of these ligands are currently
under investigation.
Experimental
General
Results and Discussion
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexa-
fluorophosphate (HBTU), Leu(OBz)·TsOH and Phe(OBz)·HCl
were purchased from NovaBioChem; N,N-dicyclohexylcarbo-
diimide (DCC) was purchased from Fluka. All other chemicals
and solvents including dimethylaminopyridine (DMAP), tri-
ethylamine (NEt3), and palladium over carbon (Pd/C) were
purchased from Aldrich. Gly(OBz)·TsOH was prepared accord-
ing to the reported method using BzOH and TsOH in C6H6.[23]
The hydrochloric acid salts of the methyl protected amino
acids Gly(OMe)·HCl, Leu(OMe)·HCl, Phe(OMe)·HCl, and
Asp(OMe)(OMe)·HCl were prepared from the free amino acids
by stirring overnight at room temperature in methanol with
2 equiv. of thionyl chloride, followed by removal of all volatile
material under vacuum. Silica gel 60, 0.04–0.06 mm (230–400
mesh)fromScharlauwasusedforflashcolumnchromatography.
Eluents were optimized byTLC on silica gel 60 F254 sheets from
Merck. A phosphomolybdic acid (PMA) in EtOH dip followed
by charring with a hot air gun was used to visualize TLC plates.
NMR spectra were collected on Bruker AMX-300, DRX-400,
and DRX-500 instruments at room temperature in the solvent
specified, and are referenced to residual protons of the proteosol-
vent for 1H spectra, or to the carbon of the solvent for 13C{1H}
Typical solution-phase peptide coupling conditions (DCC or
HBTU, DMAP, NEt3, CH2Cl2 solution, overnight, room tem-
perature, see Experimental) were successfully used to couple
the methyl and benzyl C-protected amino acids to the carboxylic
acids of NTA and MIDA (Scheme 1). Use of DCC as a coupling
agent was successful for the methyl esters; however, for the ben-
zyl esters HBTU was adopted because DCC coupling led to low
yields. This is presumably because of the steric bulk of the ben-
zyl ester, which limits access of the N-terminus of the amino
acid to the activated ester for coupling.
The protected products, other than NTA-[Gly(OMe)]3, are
soluble in organic solvents, such as CH2Cl2, and were purified
by silica gel chromatography and characterized by NMR and
IR spectroscopy and high-resolution mass spectrometry. The
1H NMR spectra of these compounds show well resolved
coupling constants and all resonances can be unambiguously
assigned using a combination of one- and two-dimensional
spectra; Fig. 2 shows a typical example. This indicates that no
epimerization occurs under the coupling conditions. This is to
be expected using conditions adapted from solid-phase peptide
synthesis. Methyl-protected d,l-phenylalanine was used in one

Synthesis of Chiral, Chelating Ligands
299
5.4
5.2
5.0
4.8
ppm
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
ppm
Fig. 2. 1H NMR spectrum of NTA-[Leu(OBz)]3 in CDCl3. The inset shows the resolved coupling of the benzylic protons
and the α-proton of the amino acid. The resonance at δ 5.29 is residual CH2Cl2.
O O
MAT 900 XL-Trap electrospray (ESI) mass spectrometer with a
Finnigan API III electrospray source. Low-resolution ESI mass
spectrometry was conducted on a Quattro II triple-quadruple
liquid chromatography–mass spectrometer (Micromass, Manch-
ester, UK) or a Finnigan MAT 900 XL-Trap electrospray mass
spectrometer with a Finnigan API III electrospray source.
MO
O
OM
*
HN
O
MOH
H2O
O
OMe
O
O
O
N
N
H
*
MO
O
N
OMe
3
NH OM
*
NH
*
O
O
O
OM
Synthesis of MIDA (Modification of a Reported
MO
Technique[10]
)
Iminodiacetic acid (6.65 g, 0.05 mol) was weighed into a
round-bottomed flask equipped with a magnetic stirrer bar.
Water (6.7 mL, 0.38 mol), formic acid (3.8 mL, 0.10 mol), and
formaldehyde (7.5 mL, 0.27 mol) were added and the mixture
was stirred overnight at reflux. Ethanol (50 mL) was added to
the resulting pale yellow solution, which led to the formation
of a white precipitate, which was collected by filtration and
washed with ethanol.Yield: 4.18 g (57%). δH (500 MHz, 298 K,
Scheme 2. Deprotection of NTA-[Asp(OMe)(OMe)]3 with NaOH or
LiOH (M = Na or Li).
spectra. Assignments are based on a combination of one- and
two-dimensional spectra. Infrared spectra were collected on a
Perkin–Elmer 1600 or 1000 FTIR using CsF plates or in solution
as specified, and only carbonyl stretches are reported. High-
resolution mass measurements were obtained from a Finnigan

300
M. Schultz et al.
2
2
H2
(d, 2H, J 12, OCH2Ph), 5.11 (d, 2H, J 12, OCH2Ph), 4.90
(m, 2H, NHCH), 3.19–2.92 (m, 8H, MeNCH2 and CHCH2Ph),
2.13 (s, 3H, NCH3). δC (101 MHz, 298 K, CDCl3) 171.6
(COOCH2Ph), 169.4 (CONH), 135.9 and 135.1 (ipso-C of
C6H5), 129.1, 128.6, 128.6, 128.5, 128.5, 127.0 (ortho, meta,
para-C of C6H5), 67.3 (OCH2C6H5), 61.2 (MeNCH2), 52.8
(NHCH), 43.6 (NMe), 37.6 (CHCH2Ph). m/z (ESI+) 622.4
[M + H]. Calc. for C37H39N3O6Na: 644.2731 [M + Na]. Found:
644.2729.
Pd/C
EtOH
O
N
O
R
R
NH OH
*
N
O
N
H
NH
O
*
O
R
O
OBz
2
1
OH
O
N
HO
R
O
*
H2
Pd/C
EtOH
HN
O
R
N
O
Typical Coupling Conditions of Benzyl Esters to NTA
N
H
O
The solids, NTA (0.15 g, 0.76 mmol) and HBTU (0.96 g,
2.54 mmol, 3.3 equiv.), were placed in a flask equipped with
a magnetic stirrer bar. Dichloromethane (50 mL) was added,
followed by DMAP (0.062 g, 0.51 mmol, 0.67 equiv.), NEt3
(1.42 mL, 10.2 mmol, 13 equiv.), and the benzyl-protected amino
acid (2.54 mmol, 3.3 equiv.). The mixture was stirred overnight
at room temperature, and then washed with dilute HCl (1.0 M)
and NaHCO3 (1.0 M), followed by distilled water. The prod-
uct was purified by silica gel chromatography (CH2Cl2/MeOH,
96/4). Yield: 40–60% after chromatography. The later column
fractions were sometimes contaminated with tetramethylurea,
a by-product of coupling by HBTU.
OBz
R
NH OH
*
3
NH
O
*
O
R
O
2
OH
Scheme 3. Deprotection of benzyl protected ligands by hydrogenolysis to
form free acids MIDA-[X(OH)]2 1, and NTA-[X(OH)]3 2.
D2O) 3.83 (s, 4H, MeNCH2), 2.87 (s, 3H, NMe), carboxylic
acid protons not observed. δC (125 MHz, 298 K, D2O) 169.1
(COOH), 57.3 (MeNCH2), 42.4 (NMe).
NTA-[Gly(OBz)]3: δH (300 MHz, 298 K, CDCl3) 7.67 (t, 3H,
3J 6.0, NH), 7.31 (m, 15H, CH2C6H5), 5.12 (s, 6H, CH2C6H5),
4.06 (d, 6H, 3J 6.0, NHCH2), 3.37 (s, 6H, NCH2). δC (125 MHz,
298 K, CDCl3) 170.5 (NHCO and COOBz), 135.1 (ipso-C of
C6H5), 128.7, 128.6, 128.3 (ortho, meta, para-C of C6H5),
67.3 (CH2C6H5), 58.6 (NCH2), 41.1 (NHCH2). m/z (ESI+)
655 [M + Na]. Calc. for C33H36N4O9Na: 655.2380 [M + Na].
Found: 655.2371.
Typical Conditions for Coupling Benzyl-Protected
Amino Acids to MIDA
MIDA (1.10 g, 6.8 mmol) and HBTU (5.69 g, 15 mmol,
2.2 equiv.) were weighed into a flask equipped with a magnetic
stirrer bar and dichloromethane (50 mL) was added, followed
by DMAP (0.138 g, 1.5 mmol, 0.22 equiv.), NEt3 (4.17 mL,
30 mmol, 4.4 equiv.), and the benzyl ester of the amino acid to be
coupled (15 mmol, 2.2 equiv.).The mixture was stirred overnight
at room temperature, after which it was a yellow solution. If a
solid precipitated, this was removed by filtration. The product
was purified using silica gel chromatography (CH2Cl2/MeOH,
96:4). Yield: 45–60% after chromatography. The later column
fractions were sometimes contaminated with tetramethylurea,
a by-product of coupling by HBTU.
Me2NCONMe2: δH (500 MHz, 298 K, CDCl3) 2.71 (s,
NMe2). δC (126 MHz, 298 K, CDCl3) 165.4 (CO), 38.3 (NMe2).
MIDA-[Gly(OBz)]2: νmax/cm−1 (CsF) 1747, 1660. δH
(400 MHz, 298 K, CDCl3) 7.40 (t, 2H, 3J 5.8, NH), 7.33–
7.30 (m, 10H, CH2C6H5), 5.12 (4H, CH2C6H5), 4.09 (d, 4H,
3J 5.8, NHCH2), 3.17 (s, 4H, MeNCH2), 2.44 (s, 3H, NMe). δC
(101 MHz, 298 K, CDCl3) 170.3 (CO), 170.0 (CO), 135.0 (ipso-
C of C6H5), 128.6, 128.5, 128.3 (ortho, meta, para-C of C6H5),
67.2 (CH2C6H5), 61.2 (MeNCH2), 43.9 (NMe), 40.8 (NHCH).
m/z (ESI+) 480 [M + K], 464 [M + Na], 442 [M + H]. Calc. for
C23H28N3O6: 442.1973 [M + H]. Found: 442.1980.
NTA-[Leu(OBz)]3: νmax/cm−1 (CsF) 1746, 1666. δH
3
(300 MHz, 298 K, CDCl3) 7.77 (d, 3H, J 8.4, NH), 7.35 (m,
15H, CH2C6H5), 5.20 (d, 3H, 2J 12, CH2Ph), 5.11 (d, 3H,
2
2J 12, CH2Ph), 4.65 (m, 3H, NHCH), 3.41 (d, 3H, JHH 15,
NCH2), 3.25 (d, 3H, 2J 15, NCH2), 1.73–1.57 (m, 9H, CHMe2
and CHCH2CH), 0.92 (d, 9H, 3J 3.4, CHCH3), 0.90 (d, 9H, 3J
3.4, CHCH3). δC (125 MHz, 298 K, CDCl3) 174.7 (NHCO and
COOBz), 140.1 (ipso-C of C6H5), 128.7, 127.8, 127.4 (ortho,
meta, para-C of C6H5), 63.8 (CH2C6H5), 58.5 (NCH2), 52.9
(NHCH), 39.6 (CHCH2CH), 24.0 (CH(CH3)2), 21.8 (CHCH3),
20.8 (CHCH3). m/z (ESI+) 823 [M + Na], 801 [M + H]. Calc.
for C45H61N4O9: 801.4433 [M + H]. Found: 801.4422.
NTA-[Phe(OBz)]3: νmax/cm−1 (CsF) 1732, 1660. δH
(400 MHz, 298 K, CDCl3) 7.60 (d, 3H, 3J 8.4, NH), 7.35–
7.12 (m, 30H, C6H5), 5.19 (d, 3H, 2J 12.2, OCH2Ph), 5.13
(d, 3H, 2J 12.2, OCH2Ph), 4.90 (m, 3H, NHCH), 3.19–2.91
(m, 12H, NCH2 and CHCH2Ph). δC (100 MHz, 298 K, CDCl3)
172.6 (CH3OOBz), 170.1 (NHCH3O), 136.1 and 135.0 (ipso-
C of C6H5), 129.0, 128.5, 128.4, 128.4, 128.2, 126.9 (ortho,
meta, para-C of C6H5), 67.3 (OCH3H2C6H5), 57.6 (NCH2),
53.4 (NHCH3H), 37.3 (CHCH3H2Ph). m/z (ESI+) 903 [M + H].
Calc. for C54H55N4O9: 903.3964 [M + H]. Found: 903.3962.
MIDA-[Leu(OBz)]2: δH (500 MHz, 298 K, CDCl3) 7.28 (m,
10H, Bz), 7.20 (br d, 2H, 3J 8.6, NH), 5.12 (d, 2H, 2J 27, CH2Ph),
5.07 (d, 2H, 2J 27, CH2Ph), 4.64 (m, 2H, NHCH), 3.15 (d, 2H, 2J
15, MeNCH2), 3.02 (d, 2H, 2J 15, MeNCH2), 2.36 (s, 3H, NMe),
1.61 (m, 2H, CHMe2), 1.55 (m, 4H, CHCH2CH), 0.87 (d, 6H, 3J
1.7, CHCH3), 0.86 (d, 6H, 3J 1.7, CHCH3). δC (125 MHz, 298 K,
CDCl3) 172.6 (COOCH2Ph), 169.7 (CONH), 135.1 (ipso-C of
C6H5), 128.1, 127.9, 127.7 (ortho, meta, para-C of C6H5), 66.5
(CH2C6H5), 60.7 (MeNCH2), 50.1 (NHCH), 43.2 (NMe), 40.4
(CHCH2CH), 24.5 (CHMe2), 22.5 (CHCH3), 21.2 (CHCH3).
m/z (ESI+) 1129 [2M + Na], 576 [M + Na], 554 [M + H]. Calc.
for C31H43N3O6Na: 576.3050 [M + Na]. Found: 576.3047.
MIDA-[Phe(OBz)]2: νmax/cm−1 (CsF) 1741, 1663. δH
(400 MHz, 298 K, CDCl3) 7.33–7.01 (m, 22H, Ph and NH), 5.17
Typical Coupling Conditions of Methyl Esters to NTA
The solids, NTA (0.27 g, 1.41 mmol) and DCC (1.05 g,
5.10 mmol, 3.6 equiv.), were placed in a flask equipped with a
magnetic stirrer bar under nitrogen. Distilled dichloromethane
(50 mL) was added, followed by DMAP (0.12 g, 0.98 mmol,
0.7 equiv.), triethylamine (1.29 mL, 9.27 mmol, 6.6 equiv.), and
the methyl protected amino acid (4.63 mmol, 3.3 equiv.).
The mixture was stirred under nitrogen overnight at room

Synthesis of Chiral, Chelating Ligands
301
temperature, and then filtered and washed with dilute acid fol-
lowed by distilled water. The product was purified by silica gel
chromatography (CH2Cl2/MeOH, 96/4). Yield: 40–60% after
chromatography.
2.86 (s, 3H, NMe), 1.49 (m, 6H, CHMe2 and CHCH2CH),
3
3
0.77 (d, 6H, J 10, CHCH3), 0.74 (d, 6H, J 10, CHCH3). δC
(75 MHz, 298 K, D2O) 177.7 (COOH), 164.8 (CONH), 56.8
(MeNCH2), 52.9 (NHCH), 42.8 (NMe), 39.7 (CHCH2CH),
24.5 (CHMe2), 22.2 (CHCH3), 20.6 (CHCH3). m/z (ESI+) 769
[2M + Na], 747 [2M + H], 396 [M + Na], 374 [M + H]. Calc.
for C17H31N3O6Na: 396.2111 [M + Na]. Found: 396.2116.
MIDA-[Phe(OH)]2: νmax/cm−1 (CsF) 1667. δH (400 MHz,
298 K, (D6)DMSO) 8.25 (br, 2H, NH), 7.20 (m, 10H, C6H5),
4.50 (ddd, 3J 9.0, 3J 9.0, 3J 4.8, 2H, NHCH), 3.11 (dd, 2H, 2J
NTA-[Gly(OMe)]3: δH (500 MHz, 298 K, CDCl3) 7.77 (br
3
3
t, 3H, J 3.4, NH), 4.04 (d, 6H, J 3.6, NHCH2), 3.71 (s, 9H,
OMe), 3.39 (s, 6H, NCH2). δH (500 MHz, 298 K, D2O) 3.98
(s, 6H, NHCH2), 3.67 (s, 9H, OMe), 3.44 (s, 6H, NCH2). δC
(125 MHz, 298 K, CDCl3) 171.2 (COOMe), 170.9 (NHCO),
58.7 (NCH2), 52.4 (COOCH3), 40.8 (NHCH2). δC (125 MHz,
298 K, D2O) 173.1 (COOMe), 171.4 (NHCO), 57.1 (NCH2),
52.3 (COOCH3), 40.5 (NHCH2). m/z 427 [M + Na].
3
2
13.8, J 4.8, CH2Ph), 3.01 (br, 4H, NCH2), 2.91 (dd, 2H, J
13.8, 3J 9.7, CH2Ph), 2.03 (br s, NMe) (COOH not observed).
δC (100 MHz, 298 K, (D6)DMSO) 172.9 (CONH), 169.2 (br,
COOH), 137.7 (ipso-C of C6H5), 129.2, 128.3, 126.5 (ortho,
meta, para-C of C6H5), 59.9 (br, NCH2), 53.2 (NHCH), 42.2
(NMe), 36.6 (CH2Ph). m/z (ESI+) 442.2 [M + H]. Calc. for
C23H28N3O6: 442.1973 [M + H]. Found: 442.1965.
NTA-[Phe(OMe)]3 (Mixture of Diastereomers):[15] νmax
/
cm−1 (CH2Cl2 solution): νCO 1738, 1680. δH (300 MHz, 298 K,
CDCl3) 7.36–7.08 (m, 18H, NH and C6H5), 4.79 (m, 3H,
NHCH), 3.72 (s, 9H, OMe), 3.25–2.90 (m, 12H, CH2Ph and
NCH2). m/z (ESI+) 697 [M + Na], 675 [M + H]. Calc. for
C36H42N4O9Na [M + Na]: 697.2849. Found: 697.2839.
NTA-[Gly(OH)]3: νmax/cm−1 (THF) 1752, 1684. δH
(300 MHz, 298 K, D2O) 3.92 (s, 6H, NHCH2), 3.50 (s, 6H,
NCH2) (COOH not observed). m/z (ESI+) 385 [M + Na].
NTA-[Leu(OH)]3: δH (500 MHz, 298 K, D2O) 7.32 (m, 3H,
NH), 4.31 (m, 3H, NHCH), 3.39 (s, 6H, NCH2), 1.62–1.52 (m,
9H, CHMe2 and CHCH2CH), 0.83 (d, 9H, 3J 3.6, CHCH3), 0.79
NTA-[Leu(OMe)]3: νmax/cm−1 (MeOH solution): νCO 1749,
1664. δH (300 MHz, 298 K, CDCl3) 7.71 (br d, 3H, 3J 8.5, NH),
2
4.60 (m, 3H, NHCH), 3.71 (s, 9H, OMe), 3.41 (d, 3H, J 15,
NCH2), 3.20 (d, 3H, 2J 15, NCH2), 1.74–1.56 (m, 9H, CHMe2
and CHCH2CH), 0.92 (d, 9H, 3J 2.4, CHCH3), 0.90 (d, 9H, 3J
2.3, CHCH3). δC (75 MHz, 298 K, CDCl3) 174.9 (COOMe),
170.5 (CONH), 58.2 (NCH2), 52.4 (OMe), 50.6 (NHCH), 40.3
(CHCH2CH), 24.8 (CHMe2), 23.0 (CHCH3), 21.3 (CHCH3).
m/z (ESI+) 1167 [2M + Na], 1145 [2M + H], 595 [M + Na], 573
[M + H]. Calc. for C27H48N4O9Na [M + Na]: 595.3319. Found:
595.3306.
3
(d, 9H, J 3.5, CHCH3) (COOH not observed). δC (125 MHz,
298 K, D2O) 176.3 (COOH), 172.7 (CONH), 57.7 (NCH2),
51.4 (NHCH), 39.3 (CHCH3H2CH), 24.4 (CH3HMe2), 22.2
(CHCH3), 20.4 (CHCH3). m/z (TOF+) 531 [M + H].
NTA-[Phe(OH)]3: νmax/cm−1 (CsF) 1659. δH (400 MHz,
298 K, (D6)acetone) 8.1 (br, not integrated, NH), 7.23–7.08 (m,
15H, C6H5), 4.67 (dd, 3H, 3J 9.6, 3J 4.5, NHCH), 3.19 (dd, 3H,
2J13.9, 3J4.5, CH2Ph), 2.91(m, 9H, CH2PhandNCH2)(COOH
not observed). δH (400 MHz, 298 K, (D6)DMSO) 8.32 (br, 3H,
NH), 7.22–7.12 (m, 15H, C6H5), 4.54 (br dd, 3H, NHCH), 3.12
(dd, 3H, 2J13.7, 3J4.3, CH2Ph), 2.87(br, 9H, NCH2 andCH2Ph)
(COOH not observed). δH (400 MHz, 298 K, D2O) 7.22 (m,
NTA-[Asp(OMe)(OMe)]3: νmax/cm−1 (CH2Cl2 solution):
3
νCO 1737, 1681. δH (500 MHz, 298 K, CDCl3) 7.72 (d, 3H, J
8.6, NH), 4.92 (m, 3H, NHCH), 3.71 (s, 9H, OMe), 3.66 (s,
2
2
9H, OMe), 3.46 (d, 3H, J 15, NCH2), 3.24 (d, 3H, J 15 Hz,
NCH2), 2.99 (dd, 3H, 2J 17, 3J 6.0, CHCH2CO), 2.88 (dd, 3H,
2J 17, 3J 4.7, CHCH2CO). δC (125 MHz, 298 K, CDCl3) 171.5
(COOMe), 171.2 (COOMe), 169.8 (NHCO), 58.4 (NCH2), 52.8
(OMe), 52.1 (OMe), 48.4 (NHCH), 35.8 (CHCH2CO). m/z
(ESI+) 643 [M + Na], 621 [M + H]. Calc. for C24H36N4O15Na
[M + Na]: 643.2075. Found: 643.2082.
2
15H, C6H5), 4.65 (br dd, 3H, NHCH), 3.30 (dd, 3H, J 14.2,
2
3
3J 4.1, CH2Ph), 2.91 (dd, 3H, J 13.7, J 10.3, CH2Ph), 2.57
(d, 3H, 2J 16.8, NCH2), 2.51 (d, 3H, 2J 16.1, NCH2) (NH
and COOH not observed). δC (100 MHz, 298 K, (D6)acetone)
174.1 (COOH), 171.1 (CONH), 138.3 (ipso-C of C6H5), 130.0,
129.1, 127.4 (ortho, meta, para-C of C6H5), 58.3 (NCH2), 54.3
(NHCH), 37.8 (CH2Ph). m/z (ESI+) 655.4 [M + Na]. Calc. for
C33H36N4O9Na: 655.2376 [M + Na]. Found: 655.2367.
Typical Deprotection Conditions for Benzyl Esters
A small amount of Pd/C (∼2 mg) was added to an ethanol
(50 mL)solutionorsuspensionofthecompound(∼400 mg).The
mixture was subjected to a hydrogen atmosphere from a balloon
with stirring (NTA-[Gly(OBz)]3, NTA-[Leu(OBz)]3, MIDA-
[Leu(OBz)]2), or using a Parr hydrogenator, 30 psi were applied
(NTA-[Phe(OBz)]3, MIDA-[Gly(OBz)]2, MIDA-[Phe(OBz)]2).
After stirring for 1 h, the solution was filtered through Celite and
the solvent was removed under vacuum. The free acids of the
glycine derivatives MIDA-[Gly(OH)]2 and NTA-[Gly(OH)]3 are
extremely hygroscopic so no yield was recorded. For the other
free acids, yields were above 80%.
MIDA-[Gly(OH)]2: δH (300 MHz, 298 K, D2O) 4.01 (s,
4H, CH2COOH), 3.80 (s, 4H, MeNCH2), 2.88 (s, 3H, NMe).
δC (100 MHz, 298 K, D2O) 175.0 (COOH), 166.1 (CONH),
57.6 (MeNCH2), 43.5 (NMe), 42.7 (NHCH2). m/z (ESI+)
561 [2M + K], 545 [2M + Na], 284 [M + Na], 262 [M + H].
Calc. for C9H15N3O6Na: 284.0859 [M + Na]. Found: 284.0868.
Because of the hygroscopic nature of this compound, no IR
spectrum could be obtained.
Deprotection Conditions for NTA-[Asp(OMe)(OMe)]3
The methyl ester (0.50 g, 0.81 mmol) was weighed into a round
bottomed flask and distilled water (10 mL) was added. The ester
was not completely soluble. Six equivalents of the metal hydro-
xide (NaOH or LiOH) per NTA were weighed into a separate
flask and dissolved in water. The base was added to the ester
and the mixture was stirred overnight at room temperature. The
water was removed under vacuum leaving a hygroscopic white
solid that was insoluble in alcohols or THF.
NTA-[Asp(ONa)(ONa)]3: δH (500 MHz, 298 K, D2O) 4.30
(dd, 3H, 3J 9.9, 3J 3.9, NHCH), 3.30 (s, 6H, NCH2), 2.54 (dd,
3H, 2J 16, 3J 4.0, CHCH2), 2.35 (dd, 3H, 2J 16, 3J 10, CHCH2).
δC (125 MHz, 298 K, D2O) 178.8 (COONa), 178.5 (COONa),
172.3 (CONH), 56.6 (NCH2), 53.0 (NHCH), 39.5 (CHCH2).
Acknowledgements
MIDA-[Leu(OH)]2: δH (300 MHz, 298 K, D2O) 8.49 (br d,
J.K. acknowledges UniChe for a summer scholarship. We thank Dr Joanne
Blanchfield for helpful discussions.
2H, 3J 12, NH), 4.17 (m, 2H, NHCH), 3.96 (s, 4H, MeNCH2),

302
M. Schultz et al.
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