Synthesis of macrocyclic tetraamides derived from α-amino acids and their investigations using ESI-MS technique

Article abstract of DOI:10.1016/S0040-4020(03)00691-4

Chiral α,ω-diesters react under high-pressure conditions (10 kbar) with α,ω-diamines to give chiral cyclic tetraamides of C₂-symmetry. The complexation properties of tetraamides towards alkali metal cations (Li⁺, Na⁺, K

Full text of DOI:10.1016/S0040-4020(03)00691-4

Tetrahedron 59 (2003) 4775–4783
Synthesis of macrocyclic tetraamides derived from a-amino acids
and their investigations using ESI-MS technique
a
Agnieszka Szczepanska, Piotr Sal⁄anski and Janusz Jurczak
a
a,b
,
*
´
´
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44-52, PL-01-224 Warsaw, Poland
bDepartment of Chemistry, Warsaw University, Pasteura 1, PL-02-093, Warsaw, Poland
Received 29 January 2003; revised 7 April 2003; accepted 1 May 2003
Abstract—Chiral a,v-diesters react under high-pressure conditions (10 kbar) with a,v-diamines to give chiral cyclic tetraamides of C2-
symmetry. The complexation properties of tetraamides towards alkali metal cations (Liþ, Naþ, Kþ, Rbþ and Csþ) were estimated on the
basis of ESI-MS spectra. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
synthetic approach and discuss the complexation of alkali
metal cations employing electrospray ionization (ESI-MS)
technique. Up to now there are only several reports using
ESI-MS for determination the binding selectivities of crown
ethers and related compounds for alkali metal cations.7 Our
studies are to evaluate the alkali metal binding selectivities
and estimate relations between the structure and the
observed binding strengths.
Natural ionophores and synthetic receptors are capable of
selective binding of charged hydrophilic species and
shielding it from the lipophilic region of membrane.1 The
natural ion carriers valinomycin and nonactin are well
known for their selectivity for potassium ions. Ionophores
can discriminate between metal cations of different charge
and different size. Thus they can work as ion carriers2 as
well as phase-transfer catalysts.3 Crown ethers and
analogous macrocyclic compounds are widely investigated
for their complexation properties and used as host molecules
for the simplest guests like alkali and alkaline earth cations.4
We have developed a method for the synthesis of
diazacoronands. This method, introduced by Tabushi and
co-workers,5 is based on the condensation of a,v-diamines
with dimethyl esters of dicarboxylic acids.6 Herein, we
demonstrate the synthesis of chiral tetraamides using this
Scheme 1.
Keywords: tetraamide; amino acid; alkali metal ion receptor; electrospray;
high pressure.
*
Corresponding author. Tel.: þ48-22-632-05-78; fax: þ48-22-632-66-81;
e-mail: jurczak@icho.edu.pl
Scheme 2.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00691-4

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4776
2. Results and discussion
any improvement in forming the macrocyclic products. For
instance, the reaction of diester 3b with a,v-diamine 4a
performed in 0.05 M solution at room temperature and
under high-pressure conditions gave tetraamide 6a in 30%
yield. On the other hand, the reactions of diester 3b with
diamines 4a and 4b carried out under high-pressure
conditions in 0.7 and 0.6 M solutions gave tetraamides 6a
and 6b in very low yields of 5 and 6%, respectively. The
increase of temperature to about 508C and elongation of the
reaction time also did not influence on yields what
demonstrate results obtained in reaction of diester 3a and
diamine 4a. Tetraamide 5a was synthesized in 44% yield at
room temperature and 42% yield at 508C.
2.1. Synthesis
In our syntheses we used L-alanine and L-serine as
precursors of chiral diesters. To this end, we prepared the
corresponding methyl ester hydrochlorides 1a,b, which
were reacted with 0.5 equiv. of dicarboxylic acids chlorides
2a–c to afford diesters of the type 3 (Scheme 1).
They were subsequently subjected to cyclization reactions
with achiral amines 4a–c to afford chiral C2-symmetric
azacoronands of type 5–10 as shown in Scheme 2. The
macrocyclization reactions were carried out in methanol
under high-pressure conditions. The results are shown in
Tables 1–4.
Except for typical (1:1) cyclization products, we also
observed formation of macrocyclic triamides 11 and 12.
However, the yields of triamides were usually lower than
the yields of tetraamides (Table 2). These results prompted
us to undertake further investigation on synthesis of
macrocyclic tetraamides. By the same route, we obtained
several tetraamides 8–10 using methyl L-serinates 3d–f
that were reacted with achiral diamines 4a–c. The yields
Since the macrocyclization reaction did not proceed at
ambient conditions, we decided to check the influence of
temperature and concentration on yields. We noticed that, in
comparison to reactions carried out in 0.1 M solutions,
decreasing the concentration of the substrates did not cause
Table 1. Results of macrocyclization reaction of chiral diesters 3a–c with diamines 4a–c
a
MeOH, rt, 10 kbar, 20 h.
MeOH, 608C, 10 kbar, 20 h.
b

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4777
Table 2. Results of macrocyclization reaction of chiral diester 3a with diamines 4a,b giving unexpected macrocycles
MeOH, rt, 10 kbar, 20 h.
Table 3. Results of macrocyclization reaction of chiral diesters 3d–f with diamines 4a–c
a MeOH, rt, 10 kbar, 20 h.
b
MeOH, 608C, 10 kbar, 20 h.

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Table 4. Results of macrocyclization reaction of chiral diesters 3d–f with diamines 4a,b giving unexpected macrocycles
a
MeOH, rt, 10 kbar, 20 h.
MeOH, 608C, 10 kbar, 20 h.
b
ranging from 10–27% were lower than the yield obtained
for methyl L-alaninates. This can be explained by the higher
steric hindrance of the hydroxymethyl substituent (Table 3).
We also found that high temperature did not cause any
increase of macrocyclization yields. Diester 3e reacted with
diamine 4a under high-pressure conditions at 608C to give
tetraamide 9a in 25% yield, very similar to the yield
obtained at room temperature. As a rule, the yields decrease
with the increasing ring size. This relationship is typical for
macrocyclization reactions. In some cases we also isolated
macrocyclic triamides (Table 4).
2.2. ESI-MS results
We used ESI-MS technique to determine the binding
selectivities. Our experiments included both checking the
competition of several alkali metal cations towards one
ligand and two different macrocyclic compounds towards
one metal cation. We assumed that the resulting ion signal
intensities in ESI spectra are proportional to the distribution
of the complexes in solution. We prepared equimolar
methanolic solutions containing the ligand and five alkali
metal chlorides (1.0£1024 M each). The obtained results are
shown in Table 5. We find that tetraamides 8a and 9a are
selective towards cesium ions. This surprising result can be
explained by a special influence of the hydroxymethyl
substituents probably involved in complexation of cesium
cation. Ligands 8a and 9a have similar complexation
We found an explanation for the formation of this kind of
compound. In the reaction of carboxylic acid dichloride 2a
with methyl L-serinate conducted under ambient conditions
at room temperature in the presence of triethylamine, we
obtained 0.2% of diester 16 in addition to the main product
3d. We assume that amines catalyze the reaction where the
nucleophilic attack of the methanol molecule on the
carbonyl group results in elimination of the amino acid
molecule. The formed diester can react with a,v-diamines
to give the triamide (Scheme 3).
Table 5. Signal intensities for ESI-MS spectra of one ligand and five alkali
metal cations
Entry Ligand Type of complex Signal intensities of complexes with
alkali metal cations Mþ
Liþ Naþ
Kþ
(%)
Rbþ
(%)
Csþ
(%)
Under the high-pressure conditions it is perhaps possible
that the amine can also act as a nucleophile on the amide
CvO group hence providing a direct mechanism for
transamidation.
(%)
(%)
1
2
3
4
5
8a
[LþM]þ
61.7
78.5 56.1
0.4 0.3
22.1 15.8
60.9 100.0 59.2
0.1 0.1
58.5 100.0
–
[2LþM]þ
0.8
0.2
28.1
34.4
–
11.3
Total percentage 17.5
16.4
49.5
0.1
16.3
79.2 100.0
0.1
18.6
56.7
8b
9a
[LþM]þ
[2LþM]þ
–
Total percentage 20.0
32.9 19.5
86.5 69.6
[LþM]þ
89.1
1.7
[2LþM]þ
0.4
20.4 16.3
54.0 100.0 64.8
0.1 0.1
32.2 20.9
95.7 94.7 100.0
0.1 0.1
22.5 22.2
0.2
–
23.4
34.3
–
11.1
68.0
Total percentage 21.3
9b
10a
[LþM]þ
[2LþM]þ
–
–
18.3
Total percentage 17.4
[LþM]þ
68.1
0.1
[2LþM]þ
–
23.4
–
15.9
Total percentage 16.0
Scheme 3.

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4779
Table 6. Signal intensities for ESI-MS spectra for two ligands and one alkali metal cation
Entry
Ligands
Signal intensities ratio in ESI-MS spectra
L1
L2
[L1þLi]þ/[L2þLi]þ
[L1þNa]þ/[L2þNa]þ
[L1þK]þ/[L2þK]þ
[L1þRb]þ/[L2þRb]þ
[L1þCs]þ/[L2þCs]þn
1
2
3
4
5
6
7
8
9
5a
5b
6a
6b
7a
8b
9a
9b
10a
8a
8b
9a
9b
10a
8a
8a
9a
9a
5.1
4.1
3.2
3.0
3.2
2.1
2.3
3.5
1.5
7.1
5.0
4.7
3.0
3.3
3.6
2.5
4.0
2.0
7.0
5.4
4.2
3.6
4.1
4.7
3.6
3.7
2.5
5.5
4.3
3.9
4.0
4.3
6.8
4.4
3.2
2.2
5.9
4.6
3.7
4.4
4.1
5.9
4.9
2.6
2.6
properties when forming stable complexes in the following
sequences: Csþ.Naþ.Liþ.Rbþ.Kþ and Csþ.Liþ.
Naþ.Rbþ.Kþ, respectively. Also 21-membered tetra-
amide 8b and 24-membered tetraamide 9b show very
similar selectivities. We also observe small amounts of the
sandwich complexes having the 2:1 stoichiometry where a
cation is bound by two ligand molecules. The highest
percentage of sandwich complexes is noticed for tetra-
amides 8a and 9a. Sandwich complexes are formed mainly
with lithium cations and their percentage decreases with an
increase of the radius of the complexed ion. Similar
complexing features are shown by tetraamides having the
same heteroatom system between nitrogen atoms situated at
a b position with respect to alkyl substituents.
a,v-carboxylic acid dichlorides. High-pressure reactions
with a,v-diamines lead to tetraazacoronands of C2 sym-
metry. Electrospray ionization mass spectrometry was used
to estimate the alkali metal binding selectivities of a group
of macrocyclic amides of type 5–10.
4. Experimental
4.1. General methods
Melting points were taken on a Boetius hot stage apparatus
and were not corrected. The optical rotation was measured
on a JASCO DIP-360 polarimeter using the sodium D line at
589 nm. The 1H NMR and 13C NMR spectra were recorded
on Varian Gemini AC-200 (1H at 200 MHz and 13C at
50 MHz), Mercury-400 BB (1H at 400 MHz and 13C at
100 MHz) and/or Bruker Avance 500 (1H at 500 MHz and
13C at 125 MHz) in CDCl3, DMSO-d6, D2O or CD3OD.
Chemical shifts are given in ppm, using tetramethylsilane
(TMS) as an internal standard. Infrared spectra were run on
a Perkin–Elmer FT-IR Spectrum 2000 spectrophotometer.
High-resolution mass spectra (LSIMS) were recorded on an
AMD-604 Intectra instrument. Elemental analyses (C, H,
and N) were taken by the ‘in-house’ analytical service. The
high-pressure reactions were conducted under 10 kbar
pressure using a custom-made cylinder-piston type appar-
atus. Analytical TLC was carried out on commercially
prepared Plate coated with 0.25 mm of self-indicating gel
(Merck Kieselgel 60 F254) that were developed using
ninhydrin solution in a butanol/acetic acid mixture, or
visualized with iodine. The column chromatography was
carried out on silica gel (Merck Kieselgel 60, 230–400
mesh). All reagents and solvents were purified and dried as
necessary according to the standard procedures. L-Alanine
and L-serine methyl ester hydrochlorides 1a,b,8 a,v-
dicarboxylic acids chlorides 2a–c,9 as well as diamines 4a
and 4c10 were prepared according to the literature
procedures. a,v-Diamine 4b was purchased from Fluka.
We also compared two different tetraamides interacting
with one alkali metal cation. Isomeric ligands having the
same m/z ratio are not distinguishable on the basis of mass
spectra. Information concerning the complexing properties
of this kind of ligands were concluded indirectly from a
comparison of selectivities towards another macrocyclic
tetraamide as a reference compound. In these experiments,
the equimolar methanolic solutions containing two ligands
and one alkali metal chloride (1.0£1024M each) were
prepared. The results are shown in Table 6. The strength of
interactions in host-guest complexes increases with an
increase of the macrocyclic opening. Tetraamide 8b
demonstrates stronger interactions with alkali metal cations
in comparison to tetraamide 9a as determined from a
comparison to ligand 8a. The 24-membered ligand 9b binds
cations better than its isomer 10a as concluded from
comparison to tetraamide 9a. Only the cesium cation is
complexed by both tetraamides at a similar level. The
analysis of the obtained results allows the conclusion that
better complexing properties towards alkali metal cations
are shown by these ligands, whose nitrogen atoms situated
at b position with respect to methyl substituents are linked
to the 3,6-dioxaoctane bridge. Moreover, the tetraamides
having the methyl substituents bind alkali metal cations
better than these having the hydroxymethyl substituents.
4.2. ESI-MS measurements
3. Conclusion
All electrospray ionization mass spectra were recorded on a
Quattro LC (3Q) Micromass instrument equipped with an
ESI source. Electrospray ionization was achieved by
application of a potential of 3.5 kV to a stainless needle.
A Harvard Apparatus syringe pump system was set at
The results presented here demonstrate the considerable
influence of high pressure on both the rate and equilibrium
of macrocyclization reactions. The chiral diesters of the type
3a–f can be prepared in good yields from L-amino acids and

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4780
15.0 mL/min. Nitrogen as a nebulizer gas was delivered to
the spectrometer by a nitrogen line.
calcd for 3b (C14H24N2O8): C, 48.27; H, 6.94; N, 8.04.
Found: C, 48.25; H, 6.81; N, 8.02.
All solutions were made with methanol of HPLC purity and
consisted of either one host and multiple guests or two hosts
and one guest. The concentration ratios were either
1:1:1:1:1:1 for the one host-five guests mixture or 1:1:1
for two hosts-one guest mixture, and the concentration of
each component was 1.0£1024M. The alkali metal guests
(Li, Na, K, Rb, and Cs) were added to the solution as their
chloride salts. Solutions were filled up to 1 mL and after
30 min a spectrum scanned the quadrupole Q1 in the range
of 100–1500 Da was recorded. The time of a single scan
was 2 s. Average intensities from 2 min acquisition were
taken to calculations. Corrections for natural abundance of
isotopes were considered. The resulting intensities were
multiplied by 1.08 for lithium, 1.0722 for potassium, and by
1.3856 for rubidium. The signal intensities in a modified
spectrum were normalized against the strongest signal
having 100% intensity.
4.3.3. Dimethyl (2S,16S)-3,15-diaza-4,14-dioxo-2,16-
dimethyl-6,9,12-trioxaheptadecane-1,17-dicarboxylate,
3c. According the above procedure, the product 3c was
obtained as a yellow oil in 75% yield. [a]2D0¼223.5 (c 1.0,
EtOH); 1H NMR (200 MHz, CDCl3) d 1.40 (d, 6H,
J¼7.3 Hz; 2£CH3), 3.65–3.75 (m, 14H; 2£CO2CH3,
2£OCH2CH2O), 3.99 (s, 4H; 2£COCH2), 4.50–4.70 (m,
2H; 2£CH3CH), 7.28 (bd, 2H, J¼7.4 Hz; 2£NHCO); 13C
NMR (50 MHz, CDCl3) d 18.7, 47.9, 52.9, 70.8, 70.9, 71.4,
169.9, 173.5; IR (CHCl3): n¼3411, 2956, 1743, 1673, 1527,
1454, 1438, 1378 cm21; HRMS (LSIMS) calcd for
C16H29N2O9 [MþH]þ: 393.1873. Found 393.1870.
4.3.4. Dimethyl (2S,10S)-3,9-diaza-4,8-dioxo-2,10-dihy-
droxymethyl-6-oxaundecane-1,11-dicarboxylate,
3d.
According the above procedure, the product 3d was
obtained as a yellow oil in 39% yield. [a]2D0¼23.2 (c 1.0,
EtOH); 1H NMR (200 MHz, CDCl3) d 3.75 (s, 6H;
2£CO2CH3), 3.78–4.04 (m, 4H; 2£CHCH2), 4.14 (s, 4H;
2£COCH2), 4.40–4.53 (bs, 2H; 2£OH), 4.60–4.72 (m, 2H;
2£CHCH2), 7.77 (d, 2H, J¼8.2 Hz; 2£CONH); 13C NMR
(50 MHz, CDCl3) d 53.3, 54.8, 62.7, 71.0, 170.3, 171.4; IR
(CHCl3): n¼3415, 2957, 2855, 1746, 1681, 1533, 1458,
1440, 1378 cm21; HRMS (LSIMS) calcd for C12H21N2O9
[MþH]þ: 337.1247. Found 337.1247.
4.3. General procedure for the preparation of diesters
derived from amino acids and a,v-dicarboxylic acids
chlorides
Triethylamine (3 mL, 20 mmol) was added dropwise to a
suspensionoftheaminoacidesterhydrochloride (10 mmol) in
dry methylenechloride(150 mL), cooledto08C. Dicarboxylic
acid chloride (5 mmol) was added dropwise. Stirring was
continued for 20 h at room temperature and the mixture was
concentrated in vacuo. The residue was dissolved in water and
extracted with chloroform (3£100 mL). The organic layer
was dried over magnesium sulphate, and the volatiles were
removed by rotary evaporation. Finally, the resulting oil
was purified by silica gel column chromatography using
CH2Cl2/MeOH 95:5 as an eluent.
4.3.5. Dimethyl (2S,13S)-3,12-diaza-4,11-dioxo-2,13-
dihydroxymethyl-6,9-dioxatetradecane-1,14-dicarboxy-
late, 3e. According the above procedure, the product 3e was
obtained as a yellow oil in 70% yield. [a]2D0¼þ8.1 (c 1.0,
EtOH); 1H NMR (200 MHz, CDCl3) d 3.76–3.84 (m, 10H;
2£CO2CH3, 2£OCH2), 3.86–4.18 (m, 10H; 2£COCH2,
2£CHCH2, 2£OH), 4.69–4.79 (m, 2H; 2£CHCH2), 7.73 (d,
2H, J¼8.1 Hz; 2£CONH); 13C NMR (50 MHz, CDCl3) d
53.3, 54.6, 63.2, 71.0, 71.4, 170.8, 171.7; IR (CHCl3):
n¼3405, 2957, 1744, 1673, 1529, 1440 cm21; HRMS
(LSIMS) calcd for C14H25N2O10 [MþH]þ: 381.1509.
Found 381.1483. Anal. calcd for 3e (C14H24N2O10): C,
44.21; H, 6.36; N, 7.37. Found: C, 43.99; H, 6.55; N, 7.24.
4.3.1. Dimethyl (2S,10S)-3,9-diaza-4,8-dioxo-2,10-
dimethyl-6-oxaundecane-1,11-dicarboxylate, 3a. Accord-
ing to the above procedure, the product 3a was obtained as a
1
yellow oil in 58% yield. [a]2D0¼225.6 (c 1.0, EtOH); H
NMR (200 MHz, CDCl3) d 1.37 (d, 6H, J¼7.2 Hz; 2£CH3),
3.67 (s, 6H; 2£CO2CH3), 4.02 (s, 4H; 2£CH2O), 4.45–4.65
(m, 2H; 2£CH3CH), 7.10 (bd, 2H, J¼7.2 Hz; 2£NHCO);
13C NMR (50 MHz, CDCl3) d 18.8, 48.1, 53.1, 71.4, 168.7,
173.6; IR (CHCl3): n¼3417, 2957, 2854, 1742, 1680, 1530,
1454, 1438, 1379, 1350 cm21; HRMS (LSIMS) calcd for
C12H21N2O7 [MþH]þ: 305.1349. Found 305.1354. Anal.
calcd for 3a (C12H20N2O7): C, 47.37; H, 6.62; N, 9.21.
Found: C, 47.27; H, 6.85; N, 9.18.
4.3.6. Dimethyl (2S,16S)-3,15-diaza-4,14-dioxo-2,16-
dihydroxymethyl-6,9,12-trioxaheptadecane-1,17-dicar-
boxylate, 3f. According the above procedure, the product 3f
was obtained as a yellow oil in 63% yield. [a]2D0¼þ12.0 (c
1
1.0, EtOH); H NMR (200 MHz, CDCl3) d 3.68–3.85 (m,
14H; 2£CO2CH3, 2£CH2CH2O), 3.86–4.05 (m, 6H;
2£CH2OH), 4.06–4.15 (m, 4H; 2£COCH2), 4.75–4.80
(m, 2H; 2£CHCH2), 7.73 (d, 2H, J¼8.1 Hz; 2£CONH); 13
C
4.3.2. Dimethyl (2S,13S)-3,12-diaza-4,11-dioxo-2,13-
dimethyl-6,9-dioxatetradecane-1,14-dicarboxylate, 3b.
According to the above procedure, the product 3b was
obtained as a yellow oil in 54% yield. [a]2D0¼228.3 (c 1.0,
EtOH); 1H NMR (200 MHz, CDCl3) d 1.37 (dd, 6H,
J1¼7.2 Hz, J2¼7.2 Hz; 2£CH3), 3.64–3.72 (m, 10H;
2£CO2CH3, 2£OCH2), 3.98 (s, 4H; 2£COCH2), 4.50–
4.70 (m, 2H; 2£CH3CH), 7.20 (bs, 2H; 2£NHCO); 13C
NMR (50 MHz, CDCl3) d 18.7, 47.9, 52.9, 71.0, 71.2,
169.7, 173.6; IR (CHCl3): n¼3409, 2956, 2919, 1742, 1674,
1528, 1455, 1438, 1378 cm21; HRMS (LSIMS) calcd for
C14H25N2O8 [MþH]þ: 349.1611. Found 349.1601. Anal.
NMR (50 MHz, CDCl3) d 53.2, 54.7, 63.3, 71.0, 71.3,
171.0, 171.2; IR (CHCl3): n¼3409, 2956, 2917, 1746, 1672,
1531, 1461, 1439, 1378 cm21; HRMS (LSIMS) calcd for
C16H29N2O11 [MþH]þ: 425.1771. Found 425.1776.
4.4. General procedure for the synthesis of macrocyclic
tetraamides 5–10
A Teflon ampoule was filled with an equimolar solution of
the dimethyl a,v-diester (0.5 mmol) and the appropriate
diamine (0.5 mmol) in 10 mL of methanol and was placed in
a high-pressure vessel filled with ligroin as a transmission

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4781
medium and compressed (10 kbar) at room temperature for
20 h. After decompression, the reaction mixture was
transferred quantitatively to a round-bottomed flask and
the solvent was evaporated. The residue was purified by
column chromatography using silica gel and CH2Cl2/MeOH
95:5 as an eluent.
as a white solid in 20% yield. Mp 173–1758C; [a]2D0¼231.6
(c 1.0, MeOH); 1H NMR (200 MHz, CD3OD) d 3.34–3.47
(m, 4H; 2£NHCH2), 3.54 (dd, 4H, J1¼8.9 Hz, J2¼4.5 Hz;
2£CHCH2), 3.87 (ddt, 4H, J1¼11.1 Hz, J2¼5.3 Hz,
J3¼4.3 Hz; 2£CH2O), 4.28 (s, 4H; 2£COCH2), 4.43 (dd,
2H, J1¼4.5 Hz, J2¼5.1 Hz; 2£CHCH2); 13C NMR
(100 MHz, CD3OD) d 40.7, 57.2, 62.7, 70.5, 72.7, 172.5,
173.4; IR (KBr): n¼3467, 3406, 3309, 3094, 2938, 2875,
1665, 1541, 1457, 1374, 1347 cm21; HRMS (LSIMS) calcd
for C14H25N4O8 [MþH]þ: 377.1672. Found 377.1695.
Anal. calcd for 8a (C14H24N4O8): C, 44.68; H, 6.43; N,
14.89. Found: C, 44.42; H, 6.67; N, 14.58.
4.4.1. (2S,18S)-1,4,16,19-Tetraaza-2,18-dimethyl-
7,10,13,22-tetraoxa-3,17,20,24-cyclotetraeicosatetraone,
5c. Compound 5c was prepared using the diamine 4c and
dimethyl ester 3a. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 5c
as a white solid in 27% yield. Mp 648C; [a]2D0¼230.6 (c 0.5,
EtOH); 1H NMR (400 MHz, CD3OD) d 1.38 (d, 6H,
J¼7.3 Hz; 2£CH3), 3.29–3.46 (m, 4H; 2£NHCH2), 3.50–
3.58 (m, 4H; 2£NHCH2CH2O), 3.58–3.66 (m, 8H; 2£
OCH2CH2O), 4.14 (s, 4H; 2£COCH2), 4.43 (q, 2H,
J¼7.3 Hz; 2£CH3CH); 13C NMR (100 MHz, CD3OD) d
17.9, 40.6, 50.3, 70.4, 71.3, 71.4, 71.6, 172.1, 174.9; IR
(CHCl3): n¼3363, 2937, 2875, 1672, 1522, 1454, 1374,
1349 cm21; HRMS (LSIMS) calcd for C18H32N4O8Na
[MþNa]þ: 455.2118. Found 455.2122.
4.4.5. (2S,15S)-1,4,13,16-Tetraaza-2,15-dihydroxy-
methyl-7,10,19-trioxa-3,14,17,21-cyclouneicosatetraone,
8b. Compound 8b was prepared using the diamine 4b and
dimethyl ester 3d. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 8b
as a white solid in 16% yield. Mp 184–1868C; [a]2D0¼239.5
1
(c 0.25, MeOH); H NMR (200 MHz, DMSO-d6) d 3.10–
3.85 (m, 16H; 2£NHCH2CH2OCH2, 2£CHCH2), 4.16 (dAB
,
4H, JAB¼10.6 Hz; 2£COCH2), 4.24–4.32 (m, 2H;
2£CHCH2), 5.02 (bs, 2H; 2£OH), 7.87 (dt, 2H,
J1¼5.5 Hz, J2¼5.4 Hz; 2£CONHCH2), 8.29 (dd, 2H,
J1¼8.5 Hz, J2¼8.6 Hz; 2£CHNHCO); 13C NMR
(50 MHz, DMSO-d6) d 55.4, 61.6, 69.1, 70.1, 71.0, 169.8,
170.0, 170.1; IR (KBr): n¼3418, 3365, 3103, 2928, 2874,
1653, 1520, 1452, 1429, 1350 cm21; HRMS (LSIMS)
calcd for C16H28N4O9Na [MþNa]þ: 443.1754. Found
443.1757.
4.4.2. (2S,18S)-1,4,16,19-Tetraaza-2,18-dimethyl-
7,10,13,22,25-pentaoxa-3,17,20,27-cycloheptaeicosa-tet-
raone, 6c. Compound 6c was prepared using the diamine 4c
and dimethyl ester 3b. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 6c as
a white solid in 21% yield. Mp 142–1438C; [a]2D0¼224.5 (c
1
1.0, EtOH); H NMR (400 MHz, CDCl3) d 1.42 (d, 6H,
J¼7.1 Hz; 2£CH3), 3.33–3.57 (m, 4H; 2£NHCH2), 3.57–
3.69 (m, 12H; 2£CH2OCH2CH2O), 3.70–3.81 (m, 4H;
2£OCH2), 3.99 (dAB, 4H, JAB¼15.4 Hz; 2£COCH2), 4.52–
4.61 (m, 2H; 2£CH3CH), 7.19 (bt, 2H, J¼5.1 Hz; 2£
CONHCH2), 7.35 (d, 2H, J¼8.2 Hz; 2£CHNHCO); 13C
NMR (100 MHz, CDCl3) d 19.1, 39.4, 48.7, 69.4, 69.9,
70.4, 71.4, 71.8, 169.7, 172.6; IR (CHCl3): n¼3357, 2920,
2875, 1739, 1659, 1525, 1454, 1376, 1349 cm21; HRMS
(LSIMS) calcd for C20H36N4O9Na [MþNa]þ: 499.2380.
Found 499.2392.
4.4.6. (2S,18S)-1,4,16,19-Tetraaza-2,18-dihydroxy-
methyl-7,10,13,22-tetraoxa-3,17,20,24-cyclotetraeicosa-
tetraone, 8c. Compound 8c was prepared using the diamine
4c and dimethyl ester 3d. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 8c as
a white solid in 10% yield. Mp 1798C; [a]2D0¼29.4 (c 1.0,
MeOH); 1H NMR (200 MHz, CD3OD) d 3.33–3.47 (m, 4H;
2£NHCH2), 3.51–3.70 (m, 14H; 6£CH2O, 2£OH), 3.80
(dd, 4H, J1¼10.5 Hz, J2¼16.2 Hz; 2£CH2OH), 4.19 (dAB
,
4H, JAB¼15.4 Hz; 2£COCH2), 4.44–4.55 (m, 2H;
2£CHCH2); 13C NMR (50 MHz, CD3OD) d 40.7, 56.7,
62.9, 70.4, 71.3, 71.4, 71.6, 172.3, 172.4; IR (CHCl3):
4.4.3. (2S,18S)-1,4,16,19-Tetraaza-2,18-dimethyl-
7,10,13,22,25,28-hexaoxa-3,17,20,30-cyclotriaconta-tet-
raone, 7c. Compound 7c was prepared using the diamine 4c
and dimethyl ester 3c. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 7c as
a white solid in 12% yield. Mp 82–838C; [a]2D0¼212.6 (c
n¼3404, 3358, 2930, 2877, 1669, 1524, 1457, 1350 cm21
;
HRMS (LSIMS) calcd for C18H32N4O10Na [MþNa]þ:
487.2016. Found 487.2009.
1
1.0, MeOH); H NMR (400 MHz, CDCl3) d 1.42 (d, 6H,
4.4.7. (2S,12S)-1,4,10,13-Tetraaza-2,12-dihydroxy-
methyl-7,16,19-trioxa-3,11,14,21-cyclouneicosatetraone,
9a. Compound 9a was prepared using the diamine 4a and
dimethyl ester 3e. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 9a
as a white solid in 26% yield. Mp 181–1838C; [a]2D0¼þ23.6
(c 1.0, MeOH); 1H NMR (400 MHz, D2O) d 3.20–3.29 (m,
2H; 2£NHCHH), 3.33–3.49 (m, 2H; 2£NHCHH), 3.54–
3.69 (m, 6H; 2£CH2O, 2£OH), 3.79–4.01 (m, 8H;
2£CH2O, 2£CHCH2), 4.23 (ddAB, 4H, JAB1¼16.3 Hz,
JAB2¼15.8 Hz; 2£COCH2), 4.47–4.53 (m, 2H;
2£CHCH2); 13C NMR (100 MHz, D2O) d 38.6, 54.3,
54.4, 60.1, 60.3, 68.0, 68.1, 68.2, 68.3, 69.3, 69.4, 170.6,
170.7, 171.9, 172.7; IR (KBr): n¼3436, 3298, 3102, 2944,
2877, 1649, 1556, 1441, 1359 cm21; HRMS (LSIMS) calcd
for C16H28N4O9Na [MþNa]þ: 443.1754. Found 443.1741.
J¼7.1 Hz; 2£CH3), 3.39–3.47 (q, 4H, J¼5.3 Hz;
2£NHCH2), 3.52–3.85 (m, 20H; 10£CH2O), 4.06 (dAB
,
4H, JAB¼15.4 Hz; 2£COCH2), 4.54–4.63 (m, 2H;
2£CH3CH), 7.22 (bt, 2H, J¼5.3 Hz; 2£CONHCH2), 7.54
(d, 2H, J¼8.0 Hz; 2£CHNHCO); 13C NMR (100 MHz,
CDCl3) d 18.3, 39.3, 48.5, 69.6, 70.0, 70.4, 70.5, 70.7, 70.8,
169.9, 172.4; IR (CHCl3): n¼3404, 2879, 1744, 1663, 1603,
1526, 1453, 1348 cm21; HRMS (LSIMS) calcd for
C22H41N4O10 [MþH]þ: 521.2823. Found 521.2829.
4.4.4. (2S,12S)-1,4,10,13-Tetraaza-2,12-dihydroxy-
methyl-7,16-dioxa-3,11,14,18-cyclooctadecatetraone, 8a.
Compound 8a was prepared using the diamine 4a and
dimethyl ester 3d. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 8a

´
A. Szczepanska et al. / Tetrahedron 59 (2003) 4775–4783
4782
Anal. calcd for 9a (C16H28N4O9): C, 45.71; H, 6.71; N,
13.33. Found: C, 45.61; H, 6.81; N, 13.24.
gave 10b as a white solid in 22% yield. Mp 138–1408C;
[a]2D0¼28.0 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) d
3.25–3.52 (m, 4H; 2£NHCH2), 3.52–3.65 (m, 8H;
4£CH2O), 3.65–3.74 (dt, 4H, J1¼4.6 Hz, J2¼3.8 Hz;
2£NHCH2CH2O), 3.74–3.87 (m, 4H; 2£CH2O), 3.87–
4.04 (m, 4H; 2£CHCH2), 4.08 (ddAB, 4H, JAB1¼15.6 Hz,
JAB2¼15.7 Hz; 2£COCH2), 4.20–4.36 (m, 2H; 2£OH),
4.55–4.67 (m, 2H; 2£CHCH2), 7.43 (t, 2H, J¼5.5 Hz;
2£CONHCH2), 7.81 (dd, 2H, J1¼8.1 Hz, J2¼7.9 Hz;
2£CHNHCO); 13C NMR (100 MHz, CDCl3) d 39.2, 39.3,
54.4, 62.6, 62.7, 69.3, 69.4, 70.1, 70.2, 70.4, 70.5, 70.6,
70.6, 70.7, 70.8, 170.5, 170.6, 170.7, 170.8; IR (KBr):
n¼3423, 3095, 2928, 1657, 1541, 1466, 1350 cm21; HRMS
(LSIMS) calcd for C20H36N4O11Na [MþNa]þ: 531.2278.
Found 531.2280.
4.4.8. (2S,15S)-1,4,13,16-Tetraaza-2,15-dihydroxy-
methyl-7,10,19,22-tetraoxa-3,14,17,24-cyclotetraeicosa-
tetraone, 9b. Compound 9b was prepared using the diamine
4b and dimethyl ester 3e. Purification by silica gel column
chromatography using CH2Cl2 and MeOH (95:5) gave 9b as
a white solid in 27% yield. Mp 123–1248C; [a]2D0¼211.7 (c
1.0, MeOH); 1H NMR (200 MHz, CDCl3) d 3.10–3.85 (bm,
22H; 2£OCH2, 2£NHCH2CH2OCH2, 2£CH2OH), 4.08
(dAB, 4H, JAB¼16.0 Hz; 2£COCH2), 4.40–4.65 (m, 2H;
2£CHCH2), 7.21 (bs, 2H; 2£CONHCH2), 7.90 (d, 2H,
J¼7.9 Hz; 2£CHNHCO); 13C NMR (50 MHz, CDCl3) d
39.4, 55.3, 63.2, 69.7, 70.4, 71.2, 71.4, 171.1, 171.4; IR
(KBr): n¼3378, 3299, 3101, 2932, 2891, 1652, 1531, 1470,
1437, 1338 cm21
;
HRMS (LSIMS) calcd for
4.4.12. (2S,18S)-1,4,16,19-Tetraaza-2,18-dihydroxy-
methyl-7,10,13,22,25,28-hexaoxa-3,17,20,30-cyclotri-
acontatetraone, 10c. Compound 10c was prepared using
the diamine 4c and dimethyl ester 3f. Purification by silica
gel column chromatography using CH2Cl2 and MeOH
(95:5) gave 10c as a colorless oil in 12% yield. [a]2D0¼21.1
(c 1.0, EtOH); 1H NMR (500 MHz, CDCl3) d 3.25–3.85 (m,
26H; 10£CH2O, 2£NHCH2, 2£OH), 4.07 (dAB, 4H,
C18H32N4O10Na [MþNa]þ: 487.2016. Found 487.2008.
Anal. calcd for 9b (C18H32N4O10): C, 46.55; H, 6.94; N,
12.06. Found: C, 46.36; H, 7.00; N, 11.80.
4.4.9. (2S,18S)-1,4,16,19-Tetraaza-2,18-dihydroxy-
methyl-7,10,13,22,25-pentaoxa-3,17,20,27-cycloheptaei-
cosatetraone, 9c. Compound 9c was prepared using the
diamine 4c and dimethyl ester 3e. Purification by silica gel
column chromatography using CH2Cl2 and MeOH (95:5)
gave 9c as a white solid in 20% yield. Mp 127–1298C;
JAB¼15.6 Hz;
2£COCH2),
3.93–4.10
(m,
4H;
2£CHCH2), 4.50–4.61 (m, 2H; 2£CHCH2), 7.26 (bs, 2H;
2£CH2NHCO), 7.80 (d, 2H, J¼7.8 Hz; 2£CHNHCO); 13C
NMR (125 MHz, CDCl3) d 39.2, 54.6, 62.9, 69.5, 70.0,
70.6, 70.9, 71.0, 71.1, 170.5, 170.7; IR (CHCl3): n¼3676,
3397, 2918, 2880, 1745, 1667, 1526, 1456, 1439,
1348 cm21; HRMS (LSIMS) calcd for C22H40N4O12Na
[MþNa]þ: 575.2540. Found 575.2548.
[a]2D0¼22.6 (c 1.0, EtOH); H NMR (400 MHz, CDCl3) d
1
3.33–3.52 (m, 4H; 2£NHCH2), 3.54–3.80 (m, 18H;
8£CH2O, 2£OH), 3.82–4.02 (m, 4H; 2£CHCH2), 4.10
(dd, 4H, J1¼15.8 Hz, J2¼15.0 Hz; 2£COCH2), 4.49–4.58
(m, 2H; 2£CHCH2), 7.11 (bt, 1H, J¼5.4 Hz; CH2NHCO),
7.30 (bt, 1H, J¼5.2 Hz; CH2NHCO), 7.72 (d, 1H,
J¼7.9 Hz; CHNHCO), 7.80 (d, 1H, J¼8.1 Hz; CHNHCO);
13C NMR (100 MHz, CDCl3) d 39.0, 39.3, 54.5, 54.8, 62.7,
62.8, 69.1, 69.2, 69.7, 69.9, 70.4, 70.6, 70.7, 70.8, 70.9,
71.2, 170.3, 170.4, 170.6, 170.7; IR (CHCl3): n¼3693,
3396, 2931, 2878, 1743, 1674, 1603, 1520, 1456, 1436,
1348 cm21; HRMS (LSIMS) calcd for C20H36N4O11Na
[MþNa]þ: 531.2278. Found 531.2263.
4.4.13. (2S)-1,4,10-Triaza-2-methyl-7,13-dioxa-3,11,15-
cyclopentadecatrione,11. Compound 11 was obtained as
a white solid in 13% yield. Mp 135–1408C; [a]2D0¼226.1 (c
1
1.0, MeOH); H NMR (200 MHz, CDCl3) d 1.41 (d, 3H,
J¼7.1 Hz; CH3), 3.10–3.29 (m, 1H; NHCHH), 3.40–3.62
(m, 6H; CH2CH2OCH2), 3.63–3.82 (m, 1H; NHCHH), 4.10
(ddAB, 4H, JAB1¼15.7 Hz, JAB2¼14.8 Hz; 2£COCH2), 4.64
(m, 1H; CHCH3), 6.81 (bs, 1H; CH2NHCO), 7.01 (d, 1H,
J¼7.9 Hz; CHNHCO), 7.17 (bs, 1H; CH2NHCO); 13C
NMR (50 MHz, CDCl3) d 17.0, 39.0, 39.6, 48.9, 69.6, 70.0,
71.3, 71.4, 169.2, 169.4, 172.0; IR (CHCl3): n¼3689, 3607,
3441, 3413, 3013, 2932, 2873, 2806, 1681, 1603, 1532,
1456, 1436, 1382, 1346 cm21; HRMS (LSIMS) calcd for
C11H20N3O5 [MþH]þ: 274.1403. Found 274.1417.
4.4.10. (2S,12S)-1,4,10,13-Tetraaza-2,12-dihydroxy-
methyl-7,16,19,22-tetraoxa-3,11,14,24-cyclotetraeicosa-
tetraone, 10a. Compound 10a was prepared using the
diamine 4a and dimethyl ester 3f. Purification by silica gel
column chromatography using CH2Cl2 and MeOH (95:5)
gave 10a as a white solid in 22% yield. Mp 1578C;
1
[a]2D0¼28.9 (c 0.5, MeOH); H NMR (200 MHz, DMSO-
d6) d 3.10–3.33 (m, 4H; 2£NHCH2), 3.43 (bs, 4H; 2£CH2O),
3.67 (bs, 12H; 4£CH2O, 2£CHCH2), 4.01 (s, 4H; 2£COCH2),
4.33(dt, 2H, J1¼5.3 Hz, J2¼7.9 Hz; 2£CHCH2), 5.04(bt, 2H,
J¼5.3 Hz; 2£OH), 7.71 (d, 2H, J¼7.9 Hz; CHNHCO), 7.89
(bt, 2H, J¼5.2 Hz; 2£CONHCH2); 13C NMR (50 MHz,
DMSO-d6)d55.1, 61.7, 69.0, 69.9, 70.2, 70.6, 169.8,170.1;IR
(KBr): n¼3436, 3100, 2934, 2874, 1655, 1550, 1445,
1349 cm21; HRMS (LSIMS) calcd for C18H32N4O10Na
[MþNa]þ: 487.2016. Found 487.2040.
4.4.14. (2S)-1,4,13-Triaza-2-methyl-7,10,16-trioxa-3,14,
18-cyclooctadecatrione, 12. Compound 12 was obtained
as a white solid in 15% yield. Mp 68–698C; [a]2D0¼þ63.7 (c
1.0, MeOH); 1H NMR (200 MHz, CDCl3) d 1.41 (d, 3H, J¼
7.2 Hz; CH3), 3.10–3.82 (m, 12H; 6£CH2), 4.07 (ddAB, 4H;
JAB1¼15.2 Hz, JAB2¼14.5 Hz; 2£COCH2), 4.70 (m, 1H;
CHCH3), 6.82 (bm, 1H; CONHCH2), 7.27 (d, 1H, J¼
7.9 Hz; CHNHCO), 7.48 (bm, 1H; CONHCH2); 13C NMR
(50 MHz, CDCl3) d 18.4, 39.0, 39.8, 48.9, 70.3, 70.6, 70.8,
70.9, 71.0, 71.1, 168.6, 168.8, 172.0; IR (CHCl3): n¼3433,
2922, 1676, 1532, 1455, 1348 cm21; HRMS (LSIMS) calcd
for C13H23N3O6Na [MþNa]þ: 340.1485. Found 340.1494.
4.4.11. (2S,15S)-1,4,13,16-Tetraaza-2,15-dihydroxy-
methyl-7,10,19,22,25-pentaoxa-3,14,17,27-cycloheptaei-
cosatetraone, 10b. Compound 10b was prepared using the
diamine 4b and dimethyl ester 3f. Purification by silica gel
column chromatography using CH2Cl2 and MeOH (95:5)
4.4.15. (2S)-1,4,10-Triaza-2-hydroxymethyl-7,13-dioxa-
3,11,15-cyclopentadecatrione, 13. Compound 13 was

´
A. Szczepanska et al. / Tetrahedron 59 (2003) 4775–4783
4783
obtained as a white solid in 9% yield. Mp 185–1878C;
1
Scientific Research (Project T09A 087 21). The authors
wish to thank the Polish Science Foundation for additional
financial support.
[a]2D0¼216.6 (c 0.5, EtOH); H NMR (200 MHz, DMSO-
d6) d 3.10–3.80 (m, 10H; 2£NHCH2CH2, CHCH2), 4.08
(ddAB, 4H; JAB1¼15.4 Hz, JAB2¼15.2 Hz; 2£COCH2),
4.30–4.40 (m, 1H; CHCH2), 5.03 (t, 1H, J¼5.8 Hz; OH),
7.54 (bt, 1H, J¼4.4 Hz; CH2NHCO), 8.24 (bt, 1H,
J¼5.0 Hz; CH2NHCO), 8.45 (d, 1H, J¼8.8 Hz; CHNHCO);
13C NMR (50 MHz, DMSO-d6) d 56.1, 61.3, 68.2, 69.5,
71.1, 71.2, 169.5, 169.8, 169.9; IR (CHCl3): n¼3679, 3532,
3441, 3408, 2929, 2857, 1678, 1593, 1533, 1459,
References
1. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry. Wiley:
New York, 2000.
1347 cm21
;
HRMS (LSIMS) calcd for C11H20N3O6
2. (a) Gokel, G. Chem. Commun. 2000, 1–9. (b) Shabany, H.;
Gokel, G. Chem. Commun. 2000, 2373–2374. (c) Shabany,
H.; Murray, C. L.; Gloeckner, Ch. A.; Grayson, M. A.; Gross,
M. L.; Gokel, G. Chem. Commun. 2000, 2375–2376. (d)
Gokel, G. W.; Ferdani, R.; Liu, J.; Pajewski, R.; Shabany, H.;
Uetrecht, P. Chem. Eur. J. 2001, 7, 33–39.
[MþH]þ: 290.1352. Found 290.1328.
4.4.16. (2S)-1,4,13-Triaza-2-hydroxymethyl-7,10,16-
trioxa-3,14,18-cyclooctadecatrione, 14. Compound 14
was obtained as a white solid in 16% yield. Mp 140–
1458C; [a]2D0¼þ30.0 (c 0.5, MeOH); H NMR (200 MHz,
3. Ma˛kosza, M. Mod. Synth. Meth. 1987, 9–86.
1
CDCl3) d 3.15–3.60 (m, 6H; 2£CONHCH2, CH2O), 3.61–
3.89 (m, 8H; 3£CH2O, CHCH2), 4.09 (ddAB, 4H;
JAB1¼15.0 Hz, JAB2¼14.7 Hz; 2£COCH2), 4.24–4.31 (m,
1H; OH), 4.72–4.85 (m, 1H; CHCH2), 7.05 (bm, 1H;
CONHCH2), 7.82 (bm, 1H; CONHCH2), 8.05 (bd, 1H,
J¼8.0 Hz; CHNHCO); 13C NMR (50 MHz, CDCl3) d 29.7,
38.4, 39.3, 53.7, 62.8, 69.7, 70.2, 70.3, 70.5, 168.1, 168.9,
170.0; IR (CHCl3): n¼3410, 2926, 1675, 1602, 1534, 1476,
1457, 1435, 1348 cm21; HRMS (LSIMS) calcd for
C13H23N3O7Na [MþNa]þ: 356.1434. Found 356.1450.
4. (a) Inoue, Y.; Gokel, G. W. Cation Binding by Macrocycles;
Marcel Dekker: New York, 1990. (b) Izatt, R. M.; Pawlak, K.;
Bradshaw, J. S. Chem. Rev. 1995, 95, 2529–2586.
5. (a) Tabushi, I.; Okino, H.; Kuroda, Y. Tetrahedron Lett. 1976,
48, 4339–4342. (b) Tabushi, I.; Taniguchi, Y.; Kato, H.
Tetrahedron Lett. 1977, 12, 1049–1052.
´
6. (a) Jurczak, J.; Stankiewicz, T.; Sal⁄anski, P.; Kasprzyk, S.;
Lipkowski, P. Tetrahedron 1993, 49, 1478–1488. (b) Jurczak,
´
J.; Gryko, D. T.; Lipkowski, P.; Sal⁄anski, P. Rev. High
Pressure Technol. 1998, 7, 1236–1240. (c) Gryko, D. T.;
´
Pia˛tek, P.; Sal⁄anski, P.; Jurczak, J. Tetrahedron: Asymmetry
1998, 9, 1771–1778. (d) Gryko, D. T.; Pia˛tek, P.; Jurczak, J.
4.4.17. (2S)-1,4,10-Triaza-2-hydroxymethyl-7,13,16-
trioxa-3,11,18-cyclooctadecatrione, 15. Compound 15
was obtained as a white solid in 10% yield. Mp 149–
´
Synthesis 1999, 336–340. (e) Szczepanska, A.; Sal⁄anski, P.;
´
Jurczak, J. Heterocycles 2000, 52, 537–540. (f) Achmatowicz,
M.; Szczepanska, A.; Gryko, D. T.; Sal⁄anski, P.; Jurczak, J.
Supramol. Chem. 2000, 12, 93–95.
1
1558C; [a]2D0¼þ2.7 (c 0.5, EtOH); H NMR (200 MHz,
´
´
CD3OD) d 3.18–3.45 (m, 4H; 2£NHCH2), 3.45–3.59 (m,
4H; 2£CH2O), 3.59–3.70 (m, 2H; CH2O), 3.70–3.88 (m,
5H; CH2O, CH2OH), 3.96 (dAB, 2H; JAB¼10.9 Hz;
COCH2), 4.06 (dAB, 2H, JAB¼15.4 Hz; COCH2), 4.53 (m,
1H, CHCH2); 13C NMR (50 MHz, CD3OD) d 40.0, 40.4,
56.0, 63.0, 70.2, 70.6, 70.8, 71.3, 71.4, 71.6, 172.2, 172.3,
172.9; IR (CHCl3): n¼3423, 3401, 2926, 2874, 1674, 1532,
1495, 1434, 1339 cm21; HRMS (LSIMS) calcd for
C13H24N3O7 [MþH]þ: 334.1614. Found 334.1601.
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´
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Acknowledgements
This work was supported by the State Committee for