A simple synthesis of chiral macrocyclic tetraamides derived from α-amino acids

Article abstract of DOI:10.1016/S0957-4166(02)00506-2

Bisamidation of oxalyl chloride using four L-α-amino acid esters afforded chiral diesters which were reacted with three α,ω-diamines under high-pressure conditions (10 kbar) to give macrocyclic tetramides of C₂-symmetry.

Full text of DOI:10.1016/S0957-4166(02)00506-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2053–2059
A simple synthesis of chiral macrocyclic tetraamides derived
from a-amino acids
Tomasz Zielin´ski,a,b Michał Achmatowiczb and Janusz Jurczaka,b,
*
aDepartment of Chemistry, Warsaw University, Pasteura 1, PL-02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
Received 25 July 2002; accepted 27 August 2002
Abstract—Bisamidation of oxalyl chloride using four -a-amino acid esters afforded chiral diesters which were reacted with three
L
a,v-diamines under high-pressure conditions (10 kbar) to give macrocyclic tetramides of C2-symmetry. © 2002 Published by
Elsevier Science Ltd.
1. Introduction
2. Results and discussion
There is growing interest in the application of macro-
cyclic polyethers1 and their polyaza analogues as lig-
ands for transition metal catalysis,2 and for their
applications in molecular recognition3 and biomedical
techniques.4 Among the latter class of molecules, spe-
cial attention is given to polylactam systems, which are
efficient neutral receptors for anions.5 Although there
are a great number of synthetic methods for the prepa-
ration of macrocyclic molecules, only a few chiral aza-
macrocyclic compounds have been reported.6 Bearing
in mind the great interest there is in asymmetric cataly-
sis and chiral recognition, one important objective in
this area is the improvement of existing procedures for
the synthesis of chiral azaoxamacrocyclic compounds7
in order to allow the efficient preparation of chiral
azacoronands.
We decided to use
-phenylalanine as precursors of chiral diesters, which,
L-alanine, L-leucine, L-valine and
L
after macrocyclisation with achiral diamines, should
afford chiral C2-symmetric azacoronands. To this end,
we prepared the corresponding methyl ester hydrochlo-
rides 1, which were subsequently reacted with 0.5 equiv.
of oxalyl chloride in the presence of triethylamine to
afford diesters of the type 2 (Scheme 1).
Since the macrocyclisation reaction, carried out in neat
methanol, did not proceed at room temperature or
under reflux, the use of bis-amidation accelerators was
necessary. The use of basic catalysts (DBU, NaCN)
resulted in racemisation of the diesters 2,9 whereas the
use of an acidic aminolysis catalyst (BBr3)10 gave no
macrocyclic products. A solution to this problem was
to carry out the reaction under high-pressure condi-
tions, where the formation of macrocyclic products is
preferred.
Our research team has investigated and developed the
synthesis of diazacoronands based on the condensation
of a,v-diamines with dimethyl esters of dicarboxylic
acids, which was introduced by Tabushi and co-work-
ers,8 and developed by us.7b,c Herein, we present the use
of this method for the synthesis of a number of chiral
tetraazacoronands using natural
L-amino acids as the
source of chirality; this is an extension of the synthetic
approach reported by us previously.9
* Corresponding author. Tel.: +00 48 22 632 05 78; e-mail: jurczak@
icho.edu.pl
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00506-2

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T. Zielin´ski et al. / Tetrahedron: Asymmetry 13 (2002) 2053–2059
Since the methyl esters of
L
-alanine 2a and
L
-phenylala-
hypothesis regarding the unfavourable effect of the
hexyl ester may be supported by the fact that the
high-pressure reaction of the butyl diester occurs in
55% yield. The concentration of the reaction mixture is
three times lower, so the results have to be compared
carefully.
nine 2d are sparingly soluble in methanol, the use of
other, more soluble, derivatives was necessary. In order
to increase the solubility of the esters, we decided to
replace the methyl group with the more lipophilic n-
hexyl group. Two other esters, methyl
L
-leucinate 2c
and methyl -valinate 2b were sufficiently soluble in
L
methanol. In this way we found the general conditions
for the preparation of macrocyclic systems of the type
5–8: diesters 2b,c,e and f were dissolved, together with
the appropriate amines 3, in methanol (0.1 M concen-
tration) and the reaction mixture was subjected to
high-pressure treatment (Scheme 2). The results are
shown in Table 1.
The side-chain methyl groups of L-valine are in the
neighbourhood of the diester carbonyl groups, there-
fore they cause a high degree of steric overcrowding
which may be responsible for the low yield in the
macrocyclization reaction using the diester 2c.
3. Conclusion
Some of the results obtained cannot be interpreted
unequivocally. The yields of the tetraazacoronands
decrease with increasing ring size. This relationship is
typical for macrocyclization reactions. However, it is
hard to explain the differences in yields for the reac-
tions of various amino acid derivatives.
The results presented here demonstrate that chiral
diesters of the type 2 can be obtained in good yields
from the amino acid methyl or n-butyl ester hydrochlo-
rides, or alternatively from the corresponding n-hexyl
esters and oxalyl chloride. The chiral esters 2 can be
successfully used for synthesis of tetraazacorronands
5–8 of C2-symmetry through their high-pressure reac-
tion with a,v-diamines of the type 3. The obtained
chiral tetraamides, after reduction can then be used for
the synthesis of more elaborate polyazamacrocyclic
compounds.
The lower yields from the macrocyclization reactions of
diamines 3 with the
L
-alanine derivative 2e can be
explained by the presence of the hexyl diester. The
hexyl esters are not very reactive in the aminolysis
reaction, which must be preceded by transesterification
with methanol (which is the reaction medium). The
4. Experimental
4.1. General methods
The optical rotation was measured using a JASCO DIP
360 apparatus, at sodium D line. The concentration
1
and solvent used are given in parentheses. The H and
13C NMR spectra were recorded using a Varian Gemini
200BB (1H at 200 MHz and 13C at 50 MHz); or a
Bruker AM 500 (1H at 500 MHz and 13C at 125 MHz).
The actual apparatus used is indicated below by the
measurement frequency. The mass spectral analysis was
performed by the ESI-TOF technique on a Mariner
mass spectrometer from Perseptive Biosystem or using
LSIMS, EI technique on an AMD-604 Intectra instru-
ment. The column chromatography was carried out
using Merck Kieselgel 60 (230–400 mesh), the thin-layer
chromatography was carried out using Merck Kieselgel
F254 plates. The high-pressure reactions were conducted
under 10 kbar pressure using a custom-made cylinder–
piston type apparatus.
4.2. General procedure for the preparation of the amino
acid methyl ester hydrochlorides
A suspension of the amino acid (50 mmol) in methanol
(100 ml) was cooled to 0°C. Thionyl chloride (55 mmol;
4 ml) was added dropwise, then the cooling bath was
removed. The clear mixture was left at room tempera-
ture for 1 day. The solvent was then removed by rotary
evaporation and the crude product was crystallised
from methanol–diethyl ether (isopropanol–hexane, in
the case of alanine methyl ester hydrochloride).
Scheme 2.

T. Zielin´ski et al. / Tetrahedron: Asymmetry 13 (2002) 2053–2059
2055
Table 1. Results of macrocyclization reaction of diamines 3a–c with chiral diesters 2b, 2c, 2e and 2f
4.4. General procedure for the preparation of the
amino acid hexyl esters
4.3. General procedure for the preparation of the
amino acid butyl ester hydrochlorides
A suspension of the amino acid (50 mmol) in butanol
(70 ml) was cooled to 0°C. Thionyl chloride (4 ml, 1.1
equiv.) was added dropwise, then the cooling bath was
removed. The reaction mixture was left at room tem-
perature for 24 h. The resulting product was purified by
crystallisation from methanol–diethyl ether.
An amino acid (50 mmol), p-toluenesulphonic acid
monohydrate (10.5 g, 1.1 equiv.) and hexanol (6.3 ml,
50 mmol) were placed into the reaction flask which was
then equipped with the Dean–Stark trap containing 250
ml of toluene. The reaction mixture was heated until
water ceased to collect in the trap. The reaction mixture

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T. Zielin´ski et al. / Tetrahedron: Asymmetry 13 (2002) 2053–2059
was washed with saturated aqueous Na2CO3 (2×25 ml),
and water (25 ml). The toluene was then removed by
rotary evaporation.
white crystals (yield 75%). Mp 115.2–116.4°C; [h]2D0=
−61 (c 3.7, DMSO); H NMR (200 MHz, CDCl3) l=
1
7.92 (d, 1H, J=9.0 Hz; NH), 4.57 (m, 1H, CHCO2),
3.7 (s, 3H, OCH3), 1.55–1.70 (m, 3H, CH2CHCO2,
CH(CH3)2), 0.9 (d, 6H, J=6.0 Hz; (CH3)2CH); 13C
NMR (50 MHz, CDCl3) l (ppm): 171.7, 158.9, 52.2,
50.9, 40.9, 24.5, 22.6, 21.5; HR EI calcd for
C16H28N2O6: 344,1947 found: 344,1975.
4.5. General procedure for preparation of diesters derived
from amino acids and oxalyl chloride
Procedure 1 (preparation of the diesters from the corre-
sponding amino acid ester hydrochlorides):
4.5.4. Dimethyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dibenzyl-
octano-1,8-dicarboxylate, 2d. Prepared using Procedure
1. Recrystallisation from methanol yielded 2d as white
crystals (yield 61%). Mp 191.5–192.3°C; [h]2D0=−43 (c 3,
Triethylamine (7 ml, 50 mmol) was added dropwise to
a suspension of the amino acid ester hydrochloride (25
mmol) in dry methylene chloride (200 ml). The mixture
was cooled to −78°C. Oxalyl chloride (1.1 ml, 12.5
mmol) was added slowly drop by drop. Stirring was
continued for 24 h at room temperature. The precipi-
tate of triethylamine hydrochloride was filtered off, and
the volume of the filtrate reduced to 100 ml by evapora-
tion. This mixture was washed subsequently with water
(2×20 ml), saturated aqueous ammonium chloride (3×
20 ml), and water again (2×20 ml). The organic layer
was dried over magnesium sulphate, then the volatiles
were removed by rotary evaporation. Finally, the
product was purified by crystallisation from boiling
methanol.
1
DMSO); H NMR (200 MHz, CDCl3) l=7.7 (d, 1H,
J=8.5 Hz; NH), 7.28 (m, 3H, Ph), 7.1 (m, 2H, Ph), 4.8
(dt, 1H, J1=8.5 Hz, J2=6.3 Hz; CHCO2), 3.7 (s, 3H,
OCH3), 3.15 (m, 2H, CHPh); 13C NMR (50 MHz,
CDCl3) l (ppm): 170.5, 158.5, 135.2, 129.1, 128.7,
127.3, 53.5, 52.5, 37.9; HR LSIMS calcd for
C22H25N2O6 [M+H]+: 413,1712 found: 413,1726.
4.5.5. Dibutyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dimethyl-
octano-1,8-dicarboxylate, 2g. Prepared using Procedure
1. Recrystallisation from methanol yielded 2g as white
crystals (yield 58%). Mp 105.3–106.2°C; [h]2D0=−58 (c 2,
1
Procedure 2 (preparation of the diesters from the corre-
sponding amino acid hexyl esters):
DMSO); H NMR (200 MHz, CDCl3) l=7.89 (d, 1H,
J=7.9 Hz; NH), 4.56 (dq, 1H, J1=7.9 Hz, J2=7.2 Hz;
CHCO2), 4.16 (t, 2H, J=6.5 Hz; OCH2), 1.647 (m, 2H,
CH2CH2O), 1.47 (d, 3H, J=7.2 Hz; CH3CH), 1.36 (m,
2H, CH3CH2), 0.97 (t, 3H, J=7.2 Hz; CH3CH2); 13C
NMR (50 MHz, CDCl3) l (ppm): 171.5, 158.7, 65.53,
48.4, 30.4, 18.9, 18.0, 13.6; HR ESI (CH3OH) calcd for
C16H28N2NaO6 [M+Na]+: 367.1840 found: 367.1861.
The amino acid hexyl ester (25 mmol) was dissolved in
methylene chloride (200 ml). Subsequently, triethyl-
amine (3.5 ml, 1 equiv.) was added and the mixture was
cooled to −78°C. Then oxalyl chloride (1.1 ml, 12.5
mmol) was added slowly drop by drop, followed by
stirring for 24 h. The work-up was identical as in
Procedure 1 above.
4.5.6. Dibutyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dibenzyl-
octano-1,8-dicarboxylate, 2h. Prepared using Procedure
1. Recrystallisation from methanol yielded 2h as white
crystals (yield 55%). Mp 132.7–133.6°C; [h]2D0=59 (c 1,
4.5.1. Dimethyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dimethyl-
octano-1,8-dicarboxylate, 2a. Prepared using Procedure
1. Recrystallisation from methanol yielded 2a as white
crystals (yield 72%). Mp 157.8–158.2°C; [h]2D0=−82 (c
1
CHCl3); H NMR (200 MHz, CDCl3) l=7.65 (d, 1H,
J=8.6 Hz; NH), 7.2 (m, 3H, Ph), 7.05 (m, 2H, Ph),
4.71 (dt 1H, J1=8.6 Hz, J2=6.4 Hz; CHCO2), 4.02 (t,
2H, J=6.6 Hz; OCH2), 3.05 (m, 2H, CH2Ph), 1.5 (m,
2H, CH2CH2O), 1.25 (m, 2H, CH2CH3), 0.85 (t, 3H,
J=7.2 Hz; CH3CH2); 13C NMR (50 MHz, CDCl3) l
(ppm): 170.1, 158.5, 135.5, 129.5, 128.6, 127.2, 65.5,
53.6, 38.0, 19.0, 13.6; HR ESI (CH3OH) calcd for
C28H36N2NaO6 [M+Na]+: 519.2466 found: 519.2492.
1
2.9, DMSO); H NMR (200 MHz, CDCl3): l=7.87 (d,
1H, NH), 4.59 (dq, 1H, CHCO2), 3.77 (s, 3H, OCH3),
1.48 (d, 3H, CH3); 13C NMR (50 MHz, CDCl3) l=
171.9, 158.7, 52.6, 48.3, 17.9; HR LSIMS calcd for
C10H17N2O6 [M+H]+: 261,1086, found: 261,1079.
4.5.2. Dimethyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-diiso-
propyloctano-1,8-dicarboxylate, 2b. Prepared using Pro-
cedure 1. Recrystallisation from methanol yielded 2b as
white crystals (yield 70%). Mp 98.2–99.1°C; [h]2D0=−53
4.5.7. Dihexyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dimethyl-
octano-1,8-dicarboxylate, 2e. Prepared using Procedure
2. Recrystallisation from methanol yielded 2e as white
crystals (yield 56%). Mp 97–99°C; [h]2D0=−51 (c 2,
1
(c 2, DMSO); H NMR (200 MHz, CDCl3) l=7.78 (d,
1H, J=9.4 Hz; NH), 4.49 (dd, 1H, J1=9.4 Hz, J2=5.2
Hz; CHCO2), 3.77 (s, 3H, OCH3), 2.25 (m, 1H,
CH(CH3)2), 0.98 (d, 3H, J=6.9 Hz; CH3(CH3)CH),
0.95 (d, 3H, J=6.9 Hz; CH3(CH3)CH); 13C NMR (50
MHz, CDCl3) l (ppm): 171.0, 159.2, 57.8, 52.36, 31.3,
18.9, 17.7; HR ESI (CH3OH) calcd for C14H24N2NaO6
[M+Na]+: 339,1527 found: 339,1543.
1
DMSO); H NMR (200 MHz, CDCl3) l=7.94 (d, 1H,
J=7.8 Hz; NH), 4.55 (dq, 1H, J1=7.8 Hz, J2=7.2 Hz;
CHCO2), 4.14 (t, 2H, J=6.7 Hz; OCH2), 1.65 (m, 2H,
CH2CH2O), 1.47 (d, 3H, J=7.2 Hz; CH3CH), 1.30 (m,
6H, CH2), 0.9 (t, 3H, J=6.3 Hz; CH3CH2); 13C NMR
(50 MHz, CDCl3) l (ppm): 171.5, 158.6, 65.7, 48.4,
31.2, 28.3, 25.3, 22.3, 17.9, 13.8; HR ESI (CH3OH)
calcd for C20H36N2NaO6 [M+Na]+: 423.2466 found:
423.2482.
4.5.3. Dimethyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-diiso-
butyloctano-1,8-dicarboxylate, 2c. Prepared using Pro-
cedure 1. Recrystallisation from methanol yielded 2c as

T. Zielin´ski et al. / Tetrahedron: Asymmetry 13 (2002) 2053–2059
2057
4.5.8. Dihexyl (2S,7S)-3,6-diaza-4,5-dioxo-2,7-dibenzyl-
octano-1,8-dicarboxylate, 2f. Prepared using Procedure
2. Recrystallisation from methanol yielded 2f as white
crystals (yield 54%). Mp 90.5–92°C; [h]2D0=45 (c 1,
J=8.1 Hz; NHCH), 7.73 (t, 1H, J=5.3 Hz; NHCH2),
4.25 (dq 1H, J1=8.1 Hz, J2=7.0 Hz; CHCO), 3.10–
3.50 (m, 8H, NCH2CH2CH2O, OCH2CH2O), 1.62 (m,
2H, CH2CH2CH2), 1.27 (d, 3H, J=7.0 Hz; CH3CH);
13C NMR (200 MHz, DMSO) l (ppm): 171.1, 159.2,
69.6, 69.4, 67.8, 49.1, 35.9, 28.8, 17.6; HR ESI
(CH3OH) calcd for C18H32N4NaO7 [M+Na]+: 439.2163,
found: 439.2145.
1
CHCl3); H NMR (200 MHz, CDCl3) l=7.73 (d, 1H,
J=8.6 Hz; NH), 7.26 (m, 3H, Ph), 7.13 (m, 2H, Ph),
4.8 (dt, 1H, J1=8.6 Hz, J2=6.2 Hz; CHCO2), 4.08 (t,
2H, J=6.8 Hz; OCH2), 3.13 (m, 2H, CH2Ph), 1.56 (m,
2H, CH2CH2O), 1.25 (m, 6H, CH2), 0.88 (t, 3H, J=6.2
Hz; CH3CH2); 13C NMR (50 MHz, CDCl3) l (ppm):
170.2, 158.6, 135.3, 129.2, 128.6, 127.2, 65.9, 53.7, 38.1,
31.3, 28.3, 25.4, 22.4, 13.9; HR ESI (CH3OH) calcd for
C32H44N2NaO6 [M+Na]+: 575.3092 found: 575.3105.
4.6.4. (3S,8S)-1,4,7,10-Tetraaza-3,8-diisopropyl-13,16-
dioxa-2,5,6,9-cyclooctadekatetraone, 6a. Compound 6a
was prepared using the methyl diester 2b and the
diamine 3a. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 6a as
a white solid in 25% yield. Mp decomposition at 309°C;
4.6. The synthesis of tetraazacoronands
1
[h]2D0=−93 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3)
The appropriate diester (0.5 mmol) was placed in a
thin-walled Teflon vessel, followed by the diamine (0.5
mmol) and methanol (up to 5 ml). The vessel was
placed in a high-pressure chamber under a pressure of
10 kbar. The reaction was allowed to run for 24 h.
Then the solvent was evaporated from the reaction
mixture and the residue was purified by column chro-
matography using silica gel in a gel:mixture ratio of
60:1, and using CH2Cl2:MeOH 100:4 as an eluent.
l=7.64 (d, 1H, J=9.0 Hz; NHCH), 6.76 (bs, 1H,
NHCH2), 4.33 (dd, 1H, J1=9.1 Hz, J2=4.4 Hz;
CHCO), 3.4–3.57 (m, 6H, NCH2CH2O, OCH2CH2O),
2.6 (m, 1H, CH(CH3)2), 1.01 (d, 3H, J=6.9 Hz;
CH3(CH3)CH), 0.95 (d, 3H, J=6.9 Hz; CH3(CH3)CH);
13C NMR (125 MHz, CDCl3) l (ppm): 169.4, 159.9,
70.6, 69.9, 59.2, 39.3, 28.8, 19.6, 16.7; HR ESI
(CH3OH) calcd for C18H32N4NaO6 [M+Na]+: 423.2214,
found: 423.2200.
4.6.1.
(3S,8S)-1,4,7,10-Tetraaza-3,8-dimethyl-13,16-
4.6.5. (3S,8S)-1,4,7,10-Tetraaza-3,8-diisopropyl-13,16,
19-trioxa-2,5,6,9-cyclohenicosatetraone, 6b. Compound
6b was prepared using the methyl diester 2b and the
diamine 3b. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 6b as
a white solid in 10% yield. [h]2D0=−108 (c 0.25, CHCl3);
1H NMR (500 MHz, DMSO) l=8.42 (d, 1H, J=9.8
Hz; NHCH), 8.10 (t, 1H, J=5.4 Hz; NHCH2), 4.05
(dd, 1H, J1=9.7 Hz, J2=8.2 Hz; CHCO), 3.20–3.50
(m, 8H, NCH2CH2O, OCH2CH2O), 2.05 (m, 1H,
CH(CH3)2), 0.86 (d, 3H, J=6.8 Hz; CH3(CH3)CH),
0.84 (d, 3H, J=6.8 Hz; CH3(CH3)CH); 13C NMR (125
MHz DMSO) l (ppm): 170.0, 159.0, 69.8, 69.8, 68.7,
59.4, 39.5, 30.2, 19.0, 18.5; HR ESI (CH3OH) calcd for
C20H36N4NaO7 [M+Na]+: 467.2476, found: 467.2496.
dioxa-2,5,6,9-cyclooctadekatetraone, 5a. Compound 5a
was prepared using the hexyl diester 2e and the diamine
3a at 50°C. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 5a as
a white solid in 45% yield. Mp decomposition at 293°C;
[h]2D0=−121 (c 0.75, H2O); 1H NMR (200 MHz,
DMSO) l=9.03 (d, 1H, J=8.1 Hz; NHCH), 7.36 (bs,
1H, NHCH2), 4.24 (dq, 1H, J1=8.1 Hz, J2=7.2 Hz;
CHCO), 2.90–3.5 (m, 6H, OCH2CH2O, NCH2CH2O,
NCH2CH2O), 1.30 (d, 3H, J=7.3 Hz CH3CH); 13C
NMR (50 MHz, CDCl3) l (ppm): 171.3, 159.3, 70.1,
69.1, 49.7, 17.1; HR ESI (CH3OH) calcd for
C14H24N4NaO6 [M+Na]+: 367.1588, found: 367.1568.
4.6.2. (3S,8S)-1,4,7,10-Tetraaza-3,8-dimethyl-13,16,19-
trioxa-2,5,6,9-cyclohenicosatetraone, 5b. Compound 5b
was prepared using the hexyl diester 2e and the diamine
3b at 50°C. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH gave 5b as a
white solid in 15% yield. Mp decomposition at 260°C;
4.6.6. (3S,8S)-1,4,7,10-Tetraaza-3,8-diisopropyl-14,17,
20-trioxa-2,5,6,9-cyclotricosatetraone, 6c. Compound 6c
was prepared using the methyl diester 2b and the
diamine 3c. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 6c as
1
1
[h]2D0=−72 (c 0.5, H2O); H NMR (200 MHz, DMSO)
white solid in 7% yield. [h]2D0=−27 (c 0.45, CHCl3); H
l=8.77 (d, 1H, J=8.6 Hz; NHCH), 7.77 (t, 1H, J=5.6
Hz; NHCH2), 4.32 (dq 1H, J1=8.6 Hz, J2=7.2 Hz;
CHCO), 3.15–3.60 (m, 8H, NCH2CH2O, OCH2CH2O),
1.28 (d, 3H, J=7.2 Hz; CH3CH); 13C NMR (50 MHz,
DMSO) l (ppm): 171.3, 158.9, 70, 69.7, 69.0, 49.2, 17.8;
HR ESI (CH3OH) calcd for C16H28N4NaO7 [M+Na]+:
411.1850, found: 411.1915.
NMR (200 MHz DMSO) l=8.37 (d, 1H, J=9.3 Hz;
NHCH), 8.05 (t, 1H, J=4.8 Hz; NHCH2), 4.00 (dd,
1H, J1=9.1 Hz, J2=8.1 Hz; CHCO), 3.20–3.50 (m, 8H,
NCH2CH2CH2O, OCH2CH2O), 2.10 (m, 1H,
CH(CH3)2), 1.61 (m, 2H, NCH2CH2CH2), 0.87 (d, 3H,
J=6.8 Hz; CH3(CH3)CH), 0.83(d, 3H, J=6.8 Hz;
CH3(CH3)CH); 13C NMR (125 MHz DMSO) l (ppm):
169.9, 159.2, 69.6, 69.4, 67.5, 59.4, 35.4, 30.0, 28.8, 19.1,
18.6; HR ESI (CH3OH) calcd for C22H40N4NaO7 [M+
Na]+: 495.2789, found: 495.2828.
4.6.3. (3S,8S)-1,4,7,10-Tetraaza-3,8-dimethyl-14,17,20-
trioxa-2,5,6,9-cyclotricosatetraone, 5c. Compound 5c
was prepared using the hexyl diester 2e and the diamine
3c at 50°C. Purification by silica gel column chromatog-
raphy with CH2Cl2 and MeOH (100:4) gave 5c as a
white solid in 10% yield. Mp 212–214°C; [h]2D0=−30 (c
4.6.7.
(3S,8S)-1,4,7,10-Tetraaza-3,8-diisobutyl-13,16-
dioxa-2,5,6,9-cyclooctadekatetraone, 7a. Compound 7a
was prepared using the methyl diester 2c and the
diamine 3a. Purification by silica gel column chro-
1
0.5, H2O); H NMR (200 MHz, DMSO) l=8.7 (d, 1H,

2058
T. Zielin´ski et al. / Tetrahedron: Asymmetry 13 (2002) 2053–2059
matography with CH2Cl2 and MeOH (100:4) gave 7a
4.6.11. (3S,8S)-1,4,7,10-Tetraaza-3,8-dibenzyl-13,16,19-
trioxa-2,5,6,9-cyclohenicosatetraone, 8b. Compound 8b
was prepared using the hexyl diester 2f and the
diamine 3b at 50°C. Purification by silica gel column
chromatography with CH2Cl2 and MeOH (100:4) gave
8b as a white solid in 16% yield. [h]2D0=−60 (c 0.45,
as a white solid in 65% yield. Mp decomposition at
1
290°C; [h]2D0=−91 (c 1.3, MeOH); H NMR (200 MHz
CDCl3) l=7.75 (d, 1H, J=8.6 Hz; NHCH), 6.84 (bs,
1H, NHCH2), 4.5 (m, 1H, CHCO), 3.56 (s, 2H,
OCH2CH2O), 3.40–3.60 (m, 4H, NCH2CH2O), 1.99
(m, 1H, CH(CH3)2) 1.68 (m, 2H, CH2CHCO), 0.98 (d,
3H, J=6.2 Hz; CH3), 0.95 (d, 3H, J=6.2 Hz; CH3);
13C NMR (50 MHz CDCl3) l (ppm): 170.5, 159.6,
70.4, 69.5, 52.3, 39.7, 39.5, 24.75, 23.0, 22.0; HR
LSIMS calcd for C20H37N4O6 [M+H]+: 429.2713,
found: 429.2727.
1
CHCl3); H NMR (200 MHz DMSO) l=8.77 (d, 1H,
J=9.3 Hz; NHCH), 7.90 (t, 1H, J=5.3 Hz; NHCH2),
7.10–7.30 (m, 5H, Ph), 4.50 (m, 1H, CHCO), 3.20–
3.70 (m, 8H, NCH2CH2O, OCH2CH2O), 3.02 (m, 2H,
CHPh); 13C NMR (50 MHz DMSO) l (ppm): 170.1,
159.2, 137.4, 128.8, 126.3 69.9, 69.8, 69.7, 54.9, 37.0;
HR ESI (CH3OH) calcd for C28H36N4NaO7 [M+Na]+:
563.2476, found: 563.2492.
4.6.8. (3S,8S)-1,4,7,10-Tetraaza-3,8-diisobutyl-13,16,19-
trioxa-2,5,6,9-cyclohenicosatetraone, 7b. Compound 7b
was prepared using the methyl diester 2c and the
diamine 3b. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 7b
as white solid in 20% yield. Mp 225–227°C; [h]2D0=−79
4.6.12. (3S,8S)-1,4,7,10-Tetraaza-3,8-dibenzyl-14,17,20-
trioxa-2,5,6,9-cyclotricosatetraone, 8c. Compound 8c
was prepared using the hexyl diester 2f and the
diamine 3c at 50°C. Purification by silica gel column
chromatography with CH2Cl2 and MeOH (100:4) gave
8c as white solid in 12% yield. [h]2D0=−11 (c 0.4,
1
(c 0.66, DMSO); H NMR (200 MHz CDCl3) l=7.85
1
(d, 1H, J=8.9 Hz; NHCH), 6.95 (bs, 1H, NHCH2),
4.5 (m, 1H, CHCO), 3.30–3.70 (m, 8H, NCH2CH2O,
OCH2CH2O), 1.8–2.0 (m, 1H, CH(CH3)2) 1.5–1.80 (m,
2H, CH(CH3)2) 0.98 (d, 3H, J=6.0 Hz; CH3), 0.94 (d,
3H, J=6.0 Hz; CH3); 13C NMR (50 MHz CDCl3) l
(ppm): 170.7, 159.5, 70.5, 70.1, 69.6, 52.3, 40.2, 39.4,
24.7, 22.9, 21.7; HR EI calcd for C22H40N4O7:
472.2897, found: 472.2886.
CHCl3); H NMR (200 MHz DMSO) l=8.77 (d, 1H,
J=9.3 Hz; NHCH), 7.90 (t, 1H, J=5.4 Hz; NHCH2),
7.10–7.30 (m, 5H, Ph), 4.50 (m, 1H, CHCO), 3.20–
3.50 (m, 8H, CH2CH2CH2, OCH2CH2O), 3.05 (m, 2H,
CH2Ph), 1.62 (m, 2H, CH2CH2CH2); 13C NMR (50
MHz DMSO) l (ppm): 169.8, 159.1, 128.9, 128.1,
126.3, 69.5, 69.4, 67.7, 54.8, 35.7, 35.8, 28.8; HR ESI
(CH3OH) calcd for C30H40N4NaO7 [M+Na]+:
591.2789, found: 591.2793.
4.6.9. (3S,8S)-1,4,7,10-Tetraaza-3,8-diisobutyl-14,17,20-
trioxa-2,5,6,9-cyclotricosatetraone, 7c. Compound 7c
was prepared using the methyl diester 2c and the
diamine 3c. Purification by silica gel column chro-
matography with CH2Cl2 and MeOH (100:4) gave 7c
as white solid in 14% yield. Mp 208–210°C; [h]2D0=−58
Acknowledgements
This work was supported by the State Committee for
Scientific Research (Project T09A 087 21). The authors
wish to thank the Polish Science Foundation for addi-
tional financial support.
1
(c 0.66, DMSO); H NMR (200 MHz CDCl3) l=7.6
(d, 1H, J=9.3 Hz; NHCH), 7.10 (bs, 1H, NHCH2),
4.40 (m, 1H, CHCO), 3.20–3.70 (m, 8H, CH2CH2CH2,
OCH2CH2O), 1.50–1.90 (m, 5H, CH2CH2CH2,
CH2CHCO, CH(CH3)2), 0.95 (d, 3H, J=6.2 Hz;
CH3), 0.92 (d, 3H, J=6.2 Hz; CH3); 13C NMR (50
MHz CDCl3) l (ppm): 170.2, 159.4, 70.4, 69.1, 52.5,
40.9, 38.6, 28.3, 24.8, 22.9, 21.7; HR EI calcd for
C24H44N4O7: 500.3210, found: 500.3165.
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(3S,8S)-1,4,7,10-Tetraaza-3,8-dibenzyl-13,16-
dioxa-2,5,6,9-cyclooctadekatetraone, 8a. Compound 8a
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