Enantiospecific synthesis of isomers of AES, a new environmentally friendly chelating agent

Article abstract of DOI:10.1016/j.tet.2004.09.024

Three four-step enantiospecific syntheses of different diastereomers of AES, a new biodegradable chelating agent, are described. The stereocenters in each of the isomers are accessible from L- and D-malic and aspartic acids.

Full text of DOI:10.1016/j.tet.2004.09.024

Tetrahedron 60 (2004) 10949–10954
Enantiospecific synthesis of isomers of AES, a new
environmentally friendly chelating agent
a
b
Petri M. Pihko,a, Terhi K. Rissa and Reijo Aksela
*
aLaboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology, P.O.B. 6100,
FI-02015 HUT Espoo, Finland
bKemira Oyj, Espoo Research Center, Luoteisrinne 2, FI-02271 Espoo, Finland
Received 20 July 2004; revised 24 August 2004; accepted 9 September 2004
Available online 1 October 2004
Abstract—Three four-step enantiospecific syntheses of different diastereomers of AES, a new biodegradable chelating agent, are described.
The stereocenters in each of the isomers are accessible from L- and D-malic and aspartic acids.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(R,R,S) isomers. For this reason, there are only six possible
isomers of AES, consisting of three pairs of enantiomers
(Fig. 2).
Due to the increasing use of chelating agents, their
environmental fate has become an important issue.1
Approximately 50,000 tons of aminopolycarboxylates
such as EDTA and DTPA are used annually; mainly in
the textile, detergent and pulp and paper industries.2 EDTA
and DTPA have proven to be practically non-biodegradable
in standard tests.3 For this reason, alternative chelating
agents such as the aspartic acid derivatives ethylene diamine
disuccinic acid (EDDS) and iminodisuccinic acid (IDS)
have become more popular as biodegradable chelating
agents, particularly for detergent applications.4
Based on previous studies with the EDDS isomers,8 the
different AES isomers are expected to have different
biodegradability characteristics. For full characterization
of these new chelating agents, we therefore needed access to
all AES isomers. Herein, we present a simple and efficient
protocol for the enantiospecific synthesis of AES.
2. Results and discussion
A series of novel diethanolamine derivatives such as
aspartic acid ethoxysuccinate (AES) have recently been
introduced as chelating agents suitable for pulp and paper
applications (Fig. 1).5 Due to its higher biodegradability,
lower nitrogen content and capacity to form inert complexes
with iron and manganese ions, AES is a more environmen-
tally friendly alternative to EDTA and DTPA in the pulp
and paper industry.6 A non-selective but industrially viable
route to AES via a lanthanum catalyzed Michael addition of
diethanolamine to maleate has recently been described.7
The presence of three stereogenic centers in the AES
molecule gives rise to stereoisomerism. When the pseudo-
symmetrical nature of the AES molecule is taken into
account, one can observe that the (S,S,R) and the (R,S,S)
isomers are identical to each other, as are the (S,R,R) and the
The three chiral centers of AES are, in principle, accessible
from (R)- and (S)-isomers of the readily available malic and
aspartic acids. Connecting these building blocks to form the
AES framework, however, is not straightforward. There are
numerous possible side-reactions including the formation of
lactams and lactones as well as retro-Michael reactions.
Retrosynthetic analysis of the target molecule reveals two
suitable synthetic strategies which use malic and aspartic
Keywords: Aldehydes; Amino acids; Chelating agents; Reductive amin-
ation; Stereoisomerism.
* Corresponding author. Tel.: C358 9 451 2536; fax: C358 9 451 2538;
e-mail: petri.pihko@hut.fi
Figure 1. Structure of AES (1).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.024

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P. M. Pihko et al. / Tetrahedron 60 (2004) 10949–10954
Figure 2. Structures of all AES isomers.
Scheme 1. Retrosynthetic analysis.
acid as starting materials: double O-alkylation and double
N-alkylation (Scheme 1). Of the two disconnections, the
double N-alkylation strategy appears more attractive since it
would, at least in principle, allow the stepwise construction
of the molecule by two consecutive N-alkylation steps.
Thus, the (S,S,R) isomers could also be accessed by this
method.
requisite dialkylation reaction could be a difficult task given
the low nucleophilicity of the monoalkylation product.
For the synthesis of the key aldehyde building block 9
(Scheme 3) and its enantiomer 16 (see Scheme 4), we
initially used a procedure adapted from the previous
synthesis of 9 by Samuelsson and co-workers.10 Thus,
dimethyl (S)- or (R)-malate was alkylated with allyl
bromide using freshly prepared Ag2O as the bromide
scavenger. We found that the amount of Ag2O was critical
for this transformation since use of more than 20 mol%
excess of the reagent led to allylation of the solvent as well.
After OsO4-catalyzed dihydroxylation and subsequent
cleavage of the resulting diol with sodium periodate, the
aldehyde 9 was obtained in 60–65% overall yield from
dimethyl malate. This procedure worked very efficiently on
the small scale described by the authors (0.5 mmol). On
scaleup, however, several modifications to the procedure
were required. The aldehyde 9 is very prone to polymeriz-
ation and decomposition, particularly when dry. Even traces
of acids in deuterated chloroform were enough to com-
pletely destroy a batch of aldehyde 9 in a matter of hours!
However, when pure, 9 could easily be stored in a freezer in
a frozen cyclohexane matrix for several months without
decomposition.
We were also further discouraged from pursuing the
O-alkylation strategy by our initial attempts at O-alkylation
of (S)-malic acid dialkyl esters with tosylated diethanola-
mine derivatives (Scheme 2). Instead of the desired
O-alkylation, the reaction invariably produced the corre-
sponding morpholines derived from the tosylate 6.
There are several reductive amination methods available
which reliably give the monoalkylation product so we
decided to use this approach next to perform double
N-alkylation of the aspartate methyl ester using a suitable
malic acid derived aldehyde.9 This approach would provide
easy access to all AES isomers since the final reductive
amination could then be performed with either of the
enantiomeric aldehydes. However, we recognized that the
Scheme 3. Synthesis of aldehyde 9. Reagents and conditions: (a) allyl
bromide (9 equiv), Ag2O (1 equiv), toluene, rt, 2 h; (b) OsO4 (2 mol%), N-
methylmorpholine-N-oxide (NMO, 2 equiv), 3:1 THF/H2O, 0 8C/rt, 21 h;
then NaIO4 (2 equiv), 3:1 THF/H2O, 80% from 5.
Scheme 2. Initial attempts at O-alkylation of dimethyl malate with
diethanolamine-derived electrophiles.

P. M. Pihko et al. / Tetrahedron 60 (2004) 10949–10954
10951
Scheme 4. Synthesis of AES isomers. Reagents and conditions: (a) aldehyde 9 (2.6 equiv), aspartate 10 or 13 (1 equiv), NaBH3CN (2.1 equiv), MeOH, 0 8C/
rt, 24 h; 40% 11, 48% 12 or 40% 14, 42% 15; (b) aldehyde 9 (3.65 equiv), aspartate 10 (1 equiv), NaBH3CN (3 equiv), MeOH, 0 8C/rt, 48 h, 80% 11; (c)
aldehyde 9 or 16 (1.1 equiv), amine 12 (1 equiv), NaBH3CN (1.1–1.5 equiv), formic acid (2 equiv), MeOH, 0 8C/rt, 24 h, 40% 11 or 17 (55% 11, 59% 17
based on recovered 12); (d) 1 M aq. NaOH (6.8 equiv), 1:1 MeOH/THF, rt, 18 h, quant.
After considerable experimentation, we found that aldehyde
9 was obtained in 80% overall yield by filtering the crude
reaction mixture through silica, concentration in vacuo,
addition of brine followed by careful gradient extraction
with Et2O and CH2Cl2. The first Et2O extract had to be
purified by filtration through a pad of silica, however, all
subsequent extracts gave pure 9 upon concentration! If
further purification was needed, 9 could readily be distilled
in high vacuum using a Kugelrohr apparatus. With these
modifications, multigram amounts of 9 and 16 could readily
be prepared.
purification of the product became progressively more
difficult with increased amounts of the aldehyde. Thus, it
was easier and more reliable to recycle the monoalkylated
product 12 and to resubject it to the reaction conditions
(in this case, 2 equiv of formic acid was added to the
reaction mixture to facilitate the iminium ion formation).
The overall yield of the dialkylated product after one cycle
was 55%. The corresponding (S,R,S) isomer was
synthesized in a similar manner using the (R)-aspartic acid
dimethyl ester 13 as the starting material (Scheme 4). The
hexamethylester 14 was obtained in 40% yield after one
cycle, along with 42% of the monoalkylated product 15.
With the aldehydes 9 and 16 in hand, the reductive
amination was explored. Initial experiments using Pd/C
catalysis (2.2 equiv of aldehyde, 1 equiv 10, EtOAc or
EtOH solvents) gave complex reaction mixtures with only
traces of the desired alkylation products. Very poor
conversions were also obtained with sodium triacetoxybor-
ohydride. However, sodium cyanoborohydride gave more
satisfactory results. If all the reagents were added at the
same time to a cooled mixture of 2.5 equiv of the aldehyde,
1 equiv of amine and 2 equiv of NaBH3CN, substantial
decomposition of the aldehyde was observed, even at 0 8C.
However, with gradual addition of the amine and the
cyanoborohydride over 1.5 h, and with 2 equiv of aldehyde,
the monoalkylation product 12 was obtained in 63% yield
and the dialkylation product 11 in 23% yield.
To access the (S,S,R)-isomer, the (S,S)-tetraester 12 was
treated with the (R)-malic acid derived aldehyde 16
(1.1 equiv). The (S,S,R) ester 17 was obtained in 40%
yield (59% based on recovered 12). All the hexamethyl
esters were diastereomerically O95% pure according to
NMR spectroscopic analysis (the 1H and 13C NMR signals,
although very close, are clearly distinct in all isomers).
Finally, the corresponding sodium salts of the AES isomers
were readily obtained in quantitative yields by careful
saponification of the products. Here, slow addition of a
slight excess of NaOH was necessary to prevent unwanted
retro-Michael reactions. Using an excess of NaOH led to the
partial loss of one of the malic acid groups as the fumarate.
However, no isomerization could be detected in the NMR
spectra. The final products were judged to be O95%
diastereomerically pure by 1H and 13C NMR spectroscopy.
Better yields of the dialkylation product were obtained with
2.5 equiv of the aldehyde (40% 11, 48% 12). A more
dramatic improvement in yield was realized when a further
portion of the aldehyde (1.3 equiv) was added to the
reaction mixture after 24 h. Using this procedure, the yield
of the dialkylation product climbed to 80%. However,
The three isomers of AES synthesized herein, the (S,S,S), the
(S,R,S) and the (S,S,R) isomers, are each members of the three
possible enantiomeric pairs of AES isomers. The remaining

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P. M. Pihko et al. / Tetrahedron 60 (2004) 10949–10954
isomers are thus enantiomeric to the ones described herein and
accessible through identical procedures.
The corresponding (R)-isomer was synthesized according to
the method for preparation of 8 described above, with the
exception that 1.05 equiv of Ag2O was used and the reaction
time was 5 h. Compound 19 was obtained in quantitative
yield. The NMR data of 6 and its enantiomer match those
reported in the literature.
3. Conclusion
In summary, a concise and versatile synthesis of isomers of
AES, a novel biodegradable chelating agent is described.
The synthesis is applicable to the asymmetric synthesis of
all isomers of AES in pure form and it is amenable to
scaleup.
To an ice-cold solution of 8 (2.01 g, 9.94 mmol, 1 equiv)
and N-methylmorpholine N-oxide monohydrate (2.26 g,
16.72 mmol, 2 equiv) in THF/H2O 3:1 (62 mL) was added
OsO4 (2.5 wt% solution in t-BuOH, 2.1 mL, 0.167 mmol,
2.0 mol%). The reaction mixture was stirred for 3 h at 0 8C
and then allowed to warm to rt, overnight. Solid sodium
hydrogen sulfite (2.10 g) was then added and the mixture
was stirred for an additional 30 min at rt. The mixture was
filtered through a pad of silica (2!20 mL THF rinse) and
the solvents were evaporated to give the crude diol
intermediate.
With the pure isomers 2–4 in hand, the differences in
biodegradability and capacity as chelating agents can now
be fully explored. These studies will be described in detail
elsewhere.
4. Experimental
The crude diol (9.94 mmol, 1 equiv) was dissolved in
THF/H2O 3:1 (107 mL) and sodium periodate (4.25 g,
19.9 mmol, 2 equiv) was added. The mixture was stirred at
rt for 30 min and then filtered through silica (2!20 mL
THF rinse). After concentration, brine (100 mL) and Et2O
(100 mL) were added. The layers were separated and the
aqueous phase was extracted with Et2O (2!75 mL).The
combined organic layers were dried (Na2SO4), filtered and
concentrated, and the crude product was purified by dry
flash chromatography (4!8 cm silica, EtOAc/hexanes
stepwise gradient from 0 to 100% EtOAc, final flush with
pure MeOH) to give a first batch, 0.44 g (22%), of the
aldehyde. The aqueous layer was further extracted with
CH2Cl2 (6!100 mL). These extracts were combined,
dried (Na2SO4) and concentrated to give pure aldehyde 9
(1.27 g, 63%). Total yield of 9 1.71 g, 84% (80% from 5). 9:
viscous, colorless oil, [a]2D2ZK62.8 (c 0.9, CH2Cl2), lit.10
[a]2D2ZK44.1 (c 0.5, CHCl3). A reliable comparison of the
rotation in CHCl3 could not be made because the aldehyde
decomposed relatively easily in dry CHCl3! The NMR
spectral data corresponded to those reported in the
literature10 but were best recorded with a trace of added
Et3N.
4.1. General methods
All reactions were carried out under an argon atmosphere
in flame-dried glassware, unless otherwise noted. Non-
aqueous reagents were transferred under argon via syringe
or cannula and dried prior to use. THF was distilled from
Na/benzophenone. CH2Cl2 was distilled over CaH2. All
synthetic intermediates were azeotropically dried with
toluene prior to use. Other solvents and reagents were
used as obtained from supplier, unless otherwise noted.
Analytical TLC was performed using Merck silica gel F254
(230–400 mesh) plates and analyzed by UV light or by
staining upon heating with vanillin solution (6 g vanillin,
5 mL conc. H2SO4, 3 mL glacial acetic acid, 250 mL EtOH)
or with ninhydrin solution (1 g ninhydrin, 100 mL iso-
propanol, five drops glacial acetic acid). For silica gel
chromatography, the flash chromatography technique was
used, with Merck silica gel 60 (230–400 mesh) and p.a.
grade solvents unless otherwise noted.
The 1H NMR and 13C NMR spectra were recorded in CDCl3
on a Bruker Avance 400 (1H 399.98 MHz; 13C 100.59 MHz)
spectrometer. The chemical shifts are reported in ppm
1
relative to CHCl3 (d 7.26) for H NMR and the residual
CDCl3 (d 77.0) for 13C NMR spectra. IR spectra were
recorded on a Perkin–Elmer Spectrum One spectrometer.
Optical rotations were obtained with a Perkin–Elmer 343
polarimeter. High resolution mass spectrometric data were
obtained by the University of Oulu Analytical Services on
Micromass LCT spectrometer. The elemental analyses
were performed at the Analytical Services of the Depart-
ment of Chemical Technology, Laboratory of Organic
Chemistry.
The aldehyde 9 could be stored in a frozen cyclohexane
matrix at K20 8C for several months without appreciable
decomposition. If necessary, it could be purified by
Kugelrohr distillation (0.1 mmHg, bp 80–90 8C).
The corresponding enantiomeric aldehyde 16 was prepared
using the same procedure from dimethyl (R)-malate in 61%
overall yield. Its NMR spectra were identical to that of 9.
[a]2D2ZC56.8 (c0.8, CH2Cl2).
4.1.1. (S)-(2-Oxoethoxy)succinic acid, dimethyl ester 9
and (R)-(2-oxoethoxy)succinic acid, dimethyl ester 16. To
a solution of dimethyl (S)-malate 5 (5.60 g, 34.6 mmol,
1 equiv) in toluene (60 mL) was added allyl bromide
(27.0 mL, 312 mmol, 9 equiv) and silver (I) oxide (8.01 g,
34.6 mmol, 1 equiv). After stirring for 2 h 20 min at rt the
mixture was filtered through Celite and the solvent was
evaporated to give the crude product 8 (6.72 g, 96%) as a
pale yellow oil. The crude product was used directly in the
next reaction.
4.1.2. (2S,20S0,200S)-{2-[[20-(100,200-Bis-methoxycarbonyl-
ethoxy)-ethyl]-(10,20-bis-methoxycarbonyl-ethyl)-
amino]-ethoxy}-succinic acid hexamethyl ester (11) and
(2S,20S)-2-[20-(10,20-bis-methoxycarbonyl-ethylamino)-
ethoxy]-succinic acid tetramethyl ester (12). To a solution
of aldehyde 9 (480 mg, 2.35 mmol, 2.35 equiv) in MeOH
(1.8 mL) at 0 8C was added L-aspartic acid dimethyl ester
hydrochloride 10 (197.6 mg, 1.00 mmol, 1 equiv) and
NaBH3CN (94.3 mg, 1.50 mmol, 1.5 equiv) in three equal
portions at 30 min intervals. After the last addition, the

P. M. Pihko et al. / Tetrahedron 60 (2004) 10949–10954
10953
resulting suspension was allowed to warm to rt over 18 h.
The mixture was cooled to 0 8C and more 9 (265 mg,
1.30 mmol, 1.3 equiv) dissolved in MeOH (1.2 mL) was
added, followed by NaBH3CN (94.3 mg, 1.50 mmol,
1.5 equiv). The reaction mixture was allowed to gradually
warm to rt over 5 h. After a total reaction time of 48 h, the
mixture was filtered and concentrated. The residue was
dissolved in CH2Cl2 (50 mL) and washed with sat. NaHCO3
(20 mL). The aqueous layer was extracted with CH2Cl2
(3!15 mL). The combined organic layers were dried
(Na2SO4) and concentrated, and the crude product was
purified by flash chromatography (silica gel, 85% EtOAc in
hexanesC1.5% triethylamine). Yield of 11 428 mg, 80%.
11: colorless viscous oil, [a]2D2ZK82.7 (c1.0, CH2Cl2); IR
(film) 3634, 3462, 2998, 2955, 1737, 1438, 1371, 1279,
(s, 6H), 3.71 (s, 3H), 3.70 (s, 6H), 3.68 (s, 3H), 3.66 (td, JZ
6.0, 9.8 Hz, 2H), 3.44 (td, JZ6.4, 9.6 Hz, 2H), 2.89–2.74
(m, 8H), 2.73 (dd, JZ7.4, 16.0 Hz, 1H), 2.59 (dd, JZ7.4,
16.0 Hz, 1H); 13C NMR (CDCl3, 400 MHz) d 172.6, 171.8,
171.7, 170.5, 75.5, 70.6, 61.4, 52.14, 52.12 (2), 51.9, 51.7,
51.6, 37.6, 35.7; ESI MS calcd for (MCCH) C22H36NO14
538.2169, found 538.2136, DZ6.1 ppm. 15: colorless oil,
[a]2D2ZK25.6 (c0.9, CH2Cl2); IR (film) 3419, 2956, 1739,
1646, 1439, 1368, 1279, 1198, 1172, 1133, 1044, 999, 857,
784 cmK1; 1H NMR (CDCl3, 400 MHz) d 4.29 (dd, JZ4.8,
8.1 Hz, 1H), 3.77 (ddd, JZ4.2, 5.5, 9.5 Hz, 1H), 3.74 (s,
3H), 3.71 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.66 (t, JZ
6.5 Hz, 1H), 3.52 (ddd, JZ3.8, 7.5, 9.7 Hz, 1H), 2.90–2.63
(m, 5H), 2.64 (dd, JZ6.5, 16.0 Hz, 1H), 2.05 (s, 1H); 13C
NMR (CDCl3, 400 MHz) d 173.7, 171.7, 171.3, 170.5, 75.4,
71.0, 57.6, 52.1, 52.0, 51.9, 51.7, 47.3, 37.7, 37.6; ESI MS
calcd for (MCCH) C14H24NO9 350.1451, found 350.1443,
DZ2.4 ppm.
1
1169, 1128, 1002, 849, 782, 674 cmK1; H NMR (CDCl3,
400 MHz) d 4.29 (dd, JZ5.1, 7.5 Hz, 2H), 3.96 (t, JZ
7.5 Hz, 1H), 3.77 (s, 6H), 3.70 (s, 9H), 3.67 (td, JZ6.3,
9.7 Hz, 2H), 3.68 (s, 3H), 3.44 (td, JZ6.2, 9.5 Hz, 2H),
2.90–2.74 (m, 8H), 2.73 (dd, JZ7.5, 16.1 Hz, 1H), 2.58 (dd,
JZ7.5, 15.9 Hz, 1H); 13C NMR (CDCl3, 400 MHz) d 172.6,
171.8, 171.7, 170.5, 75.5, 70.8, 61.6, 52.2, 52.1 (2), 51.9,
51.7, 51.6, 37.6, 35.6; ESI MS calcd for (MCCH)
C22H36NO14 538.2136, found 538.2147, DZ2.1 ppm.
4.2. General procedure for reductive amination of 12
with formic acid
A solution of aldehyde 16 (584 mg, 2.86 mmol, 1.1 equiv)
and tetramethylester 12 (900 mg, 2.58 mmol, 1 equiv) in
MeOH (5.0 mL) was cooled to 0 8C. NaBH3CN (180 mg,
2.86 mmol, 1.1 equiv) and formic acid (0.19 mL, 5.0 mmol,
2 equiv) were added at 0 8C in one portion. The suspension
was stirred for 3 h, after which time it was allowed to warm
to rt and stirred overnight. The reaction mixture was
concentrated and the residue was partitioned between
CH2Cl2 (50 mL) and sat. NaHCO3 (30 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (3!30 mL). The combined organic layers were
dried (Na2SO4), concentrated, and the crude product was
purified by flash chromatography (85% EtOAc in hexane C
1–1.5% triethylamine) to give 17 (550 mg, 40%) and
recovered 12 (170 mg, 19%).
An alternative procedure to access both amination products
proceeded as follows: to a solution of aldehyde 9 (436 mg,
2.13 mmol, 2.6 equiv) in MeOH (1.8 mL) at 0 8C was added
10 (160 mg, 0.81 mmol, 1 equiv) and NaBH3CN (107 mg,
1.70 mmol, 2.1 equiv), both in three equal portions at
45 min intervals. The resulting suspension was stirred for
3 h at 0 8C, after which time it was allowed to warm to rt and
stirred overnight. The reaction mixture was then treated and
purified as described above to afford 11 (152 mg, 35%) and
12 (143 mg, 51%). Resubjection of 12 to the reductive
amination conditions with 2 equiv formic acid (see the
procedure below) afforded 11 in 40% yield based on 12,
raising the total yield of 11 to 55% (based on 10).
This procedure was also used for the conversion of the
reductive amination product 12 into 11.
Compound 12: colorless oil, [a]2D2ZK47.3 (c 0.7, CH2Cl2);
IR (film) 3338, 2955, 1739, 1661, 1438, 1367, 1279, 1198,
1171, 1132, 998, 850, 785 cmK1 1H NMR (CDCl3,
;
4.2.1. (2S,200S,200R)-{2-[[20-(100,200-Bis-methoxycarbonyl-
ethoxy)-ethyl]-(10,20-bis-methoxycarbonyl-ethyl)-
amino]-ethoxy}-succinic acid hexamethyl ester (17). Pale
yellow oil, [a]2D2ZK27.61 (c 0.7, CH2Cl2); IR (film) 3456,
3155, 3002, 2955, 1736, 1438, 1370, 1280, 1171, 1129,
400 MHz) d 4.34 (dd, JZ4.8, 8.1 Hz, 1H), 3.78 (s, 3H),
3.77 (ddd, JZ3.8, 6.1, 10.4 Hz, 1H), 3.75 (s, 3H), 3.73 (s,
3H), 3.70 (s, 3H), 3.70 (t, JZ5.9 Hz, 1H), 3.57 (ddd, JZ3.8,
9.8 Hz, 3.8 Hz, 1H), 2.92–2.70 (m, 3H), 2.76 (dd, JZ6.9,
15.2 Hz, 2H), 2.67 (dd, JZ6.9, 16.1 Hz, 1H), 1.87 (s, 1H);
13C NMR (CDCl3, 400 MHz) d 173.8, 171.8, 171.3, 170.5,
75.3, 70.9, 57.6, 52.2, 52.1, 52.0, 51.8, 47.2, 37.7, 37.6; ESI
MS calcd for (MCCNa) C14H23NO9Na 372.1271, found
372.1264, DZ1.7 ppm.
1
1002, 909, 732 cmK1; H NMR (CDCl3, 400 MHz) d 4.29
(dd, JZ3.0, 5.0 Hz, 1H), 4.27 (dd, JZ3.0, 5.0 Hz, 1H), 3.94
(t, JZ7.5 Hz, 1H), 3.76 (s, 6H), 3.71 (s, 3H), 3.70 (s, 6H),
3.67 (s, 3H), 3.71–3.63 (m, 2H), 3.46–3.40 (m, 2H), 2.90–
2.73 (m, 8H), 2.72 (dd, JZ7.6, 16.2 Hz, 1H), 2.58 (dd, JZ
7.3, 15.9 Hz, 1H); 13C NMR (CDCl3, 400 MHz) d 172.6,
171.8, 171.7, 171.6, 170.5, 75.5, 70.8, 70.6, 61.5, 52.2, 52.1
(2), 51.9, 51.6, 51.5, 37.6, 35.6; ESI MS calcd for
(MCCNa) C22H35NO14Na 560.1955, found 560.1951,
DZ0.8 ppm.
4.1.3. (2S,20R,200S)-{2-[[20-(100,200-Bis-methoxycarbonyl-
ethoxy)-ethyl]-(10,20-bis-methoxycarbonyl-ethyl)-
amino]-ethoxy}-succinic acid hexamethyl ester (14) and
(2S,20R)-2-[20-(10,20-bis-methoxycarbonyl-ethylamino)-
ethoxy]-succinic acid tetramethyl ester (15). The
hexamethyl ester 14 was synthesized as described above
for 11 and 12. Yield of 14: 40% and 15: 42%. 14: colorless
viscous oil, [a]2D2ZC1.8 (c 0.6, CH2Cl2); IR (film) 3634,
3465, 3000, 2955, 1737, 1438, 1370, 1276, 1170, 1128,
4.3. General procedure for saponification of the
hexamethyl esters
To a solution of hexamethyl ester 11 (133 mg, 0.25 mmol,
1 equiv) in 1:1 MeOH/THF-solution (1.2 mL) was added
1 M NaOH (1.70 mL, 1.70 mmol, 6.8 equiv). The mixture
1
1002, 850, 782 cmK1; H NMR (CDCl3, 400 MHz) d 4.28
(dd, JZ5.3, 7.3 Hz, 2H), 3.94 (t, JZ7.4 Hz, 1H), 3.76

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P. M. Pihko et al. / Tetrahedron 60 (2004) 10949–10954
was stirred at rt for 18 h and then concentrated to give crude
2 as a tan solid. The excess NaOH was removed by
precipitation of the product from H2O (0.5 mL) by adding
ethanol (2 mL), affording 2 (153 mg, quant., calculated as
C16H17NO14Na6$H2O$(C2H5OH)0.5) as a white solid.
79.3, 79.2, 67.5, 67.1, 63.9, 50.7, 50.6, 41.6, 41.5, 36.3; ESI
MS calcd for (MCCH) C16H18NO14Na6 586.0113, found
586.0123, DZ1.7 ppm. Anal. calcd for C16H17NO14Na6$
(H2O)2.5$(C2H5OH)0.5: C, 31.25; H, 3.86; N, 2.14. Found:
C, 31.05; H, 3.74; N, 2.02.
The same procedure was used for the synthesis of 3 and 4,
starting from 14 and 17, respectively.
Acknowledgements
4.3.1. (2S,20S,200S)-2-{20-[[20-(100,200-Dicarboxy-ethoxy)-
ethyl]-(10,20-dicarboxy-ethyl)-amino]-ethoxy}-succinic
acid, hexasodium salt (2). White powder, melting range
340–385 8C (dec.), [a]2D2ZK13.7 (c 0.5, H2O); IR (KBr)
We thank Dr. Jari Koivisto and Dr. Juho Helaja for NMR
services, Ms. Riitta Ilmoniemi and Ms. Outi Vilamo for
early contributions to the synthesis, and Dr. Melanie Clarke
for valuable comments on the manuscript. Dr. Vesa
¨
Myllymaki deserves special thanks for keeping the project
smoothly on track.
3429, 2967, 1591, 1409, 1308, 1196, 1107, 881, 686 cmK1
;
1H NMR (D2O, 400 MHz) d 4.11 (dd, JZ3.2, 9.6 Hz, 2H),
3.67–3.51 (m, 5H), 2.90–2.76 (m, 4H), 2.64–2.34 (m, 8H);
13C NMR (D2O, 400 MHz) d 180.1, 179.4, 79.3, 67.4, 64.4,
50.9, 41.5, 37.3; ESI MS calcd for (MCKNa)
C16H17NO14Na5 562.0138, found 562.0117, DZ3.6 ppm.
Anal. calcd for C16H17NO14Na6$H2O$(C2H5OH)0.5: C,
32.60; H, 3.54; N, 2.24. Found: C, 32.27; H, 3.24; N, 1.95.
References and notes
1. Williams, D. Chem. Ber. 1998, 34, 48.
4.3.2. (2S,20R,200S)-2-{20-[[20-(100,200-Dicarboxy-ethoxy)-
ethyl]-(10,20-dicarboxy-ethyl)-amino]-ethoxy}-succinic
acid, hexasodium salt (3). White powder, melting range
320–370 8C (dec.), [a]2D2ZK2.8 (c 0.8, H2O); IR (KBr)
2. Hart, J. R. Ethylenediacetic Acid and Related Chelating
Agents. In Ullmann’s Encyclopedia of Industrial Chemistry,
7th ed.; Wiley-VCH: Weinheim, 2003; Release 2003.
3. Means, J. L.; Kucak, T.; Crerar, D. A. Environ. Pollut. (Ser B)
1
3419, 2180, 1586, 1409, 1308, 1197, 1108, 877 cmK1; H
1980, 1, 45. For further examples, see: Metsarinne, S.;
Rantanen, P.; Aksela, R.; Tuhkanen, T. Chemosphere 2004,
55, 379 and references therein.
¨
NMR (D2O, 400 MHz) d 4.06 (dd, JZ3.4, 9.2 Hz, 2H), 3.70
(dd, JZ5.5, 8.1 Hz, 1H), 3.64 (ddd, JZ5.0, 8.7, 9.7 Hz,
2H), 3.78–3.42 (m, 2H), 2.77–2.52 (m, 9H), 2.61 (dd, JZ
3.4, 15.4 Hz, 2H), 2.46 (dd, JZ9.2 Hz, 15.4 Hz, 2H), 2.38
(ddd, JZ5.4, 9.8, 15.3 Hz, 1H); 13C NMR (D2O, 400 MHz)
d 180.1, 179.4, 79.1, 67.2, 63.8, 50.7, 41.5, 35.2; ESI MS
calcd for (MCCH) C16H18NO14Na6 586.0113, found
586.0095, DZ3.2 ppm. Anal. calcd for C16H17NO14Na6$
H2O$(C2H5OH)0.5: C, 32.60; H, 3.54; N, 2.24. Found: C,
32.52; H, 3.39; N, 2.07.
4. Neal, J. A.; Rose, N. J. Inorg. Chem. 1968, 7, 2405 and
references therein.
5. (a) Aksela, R.; Renvall, I.; Paren, A. PCT Int. Appl. WO
9745396; (b) Aksela, R.; Renvall, I.; Paren, A. PCT Int. Appl.
WO 9946234.
¨
6. Itavaara, M.; Vikman, M. Research Report No BEL 235/97;
Technical Research Centre of Finland: Espoo, Finland.
7. See Ref. 5b. For earlier examples of similar reactions, see: van
Westrenen, J.; Roggen, R. M.; Hoefnagel, M. A.; Peters, A. J.;
Kieboom, A. P. G.; Bekkum, H. Tetrahedron 1990, 46, 5741.
8. The (S,S) isomer of EDDS is completely biodegradable, while
the enantiomeric (R,R) isomer is only marginally degraded in
the standard Sturm test. See: Schowanek, D.; Feijtel, T. C. J.;
Perkins, C. M.; Hartman, F. A.; Federle, T. W.; Larson, R. J.
Chemosphere 1997, 34, 2375.
4.3.3. (2S,20S,200R)-2-{20-[[20-(100,200-Dicarboxy-ethoxy)-
ethyl]-(10,20-dicarboxy-ethyl)-amino]-ethoxy}-succinic
acid, hexasodium salt (4). White powder, melting range
300–310 8C (dec.), [a]2D2ZK9.7 (c 0.7, H2O); IR (KBr)
3434, 2970, 1603, 1385, 1307, 1193, 1105, 880, 683 cmK1
;
1H NMR (D2O, 400 MHz) d 4.08 (dd, JZ3.5, 6.0 Hz, 1H),
4.06 (dd, JZ3.6, 5.9 Hz, 1H), 3.65 (dd, JZ5.6, 8.5 Hz, 1H),
3.63–3.59 (m, 1H), 6.31 (t, JZ6.3 Hz, 2H), 3.46 (td, JZ5.7,
1.0 Hz, 1H), 2.82–2.69 (m, 4H), 2.58 (dd, JZ4.4, 15.2 Hz,
1H), 2.57 (dd, JZ6.5, 15.3 Hz, 1H), 2.57 (dd, JZ6.2,
15.4 Hz, 1H), 2.44 (dd, JZ9.7, 15.2 Hz, 1H), 2.44 (dd, JZ
9.6, 15.3 Hz, 1H), 2.40 (dd, JZ5.9, 15.5 Hz, 1H); 13C NMR
(D2O, 400 MHz) d 180.8, 180.2, 180.1, 179.8, 179.4, 179.3,
9. For a recent review of reductive aminations with borohydrides,
see: Baxter, E. W.; Reitz, A. B. Reductive aminations of
carbonyl compounds with borohydride and borane reducing
agents. Org. React. (N.Y.) 2002, 59, 1.
¨
10. Dahlgren, A.; Johansson, P.-O.; Kvarnstrom, I.; Musil, D.;
Nilsson, I.; Samuelsson, B. Bioorg. Med. Chem. Lett. 2002, 10,
1829.