Synthesis and determination of alkali metal binding selectivities of chiral macrocyclic bisamides derived from D-mannitol and L-threitol possessing 2,6-pyridinedicarboxamide subunits

Article abstract of DOI:10.1016/j.tetasy.2005.04.028

Five chiral macrocyclic bisamides derived from d-mannitol and l-threitol, possessing C₂ symmetry, were obtained by a macrocyclization reaction under two different conditions (MeOH, 12 kbar, rt or MeONa/MeOH, 1 bar, rt). Their applications for alkali metal binding processes are studied using ESI-MS technique.

Full text of DOI:10.1016/j.tetasy.2005.04.028

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1939–1946
Synthesis and determination of alkali metal binding selectivities
of chiral macrocyclic bisamides derived from D-mannitol and
L-threitol possessing 2,6-pyridinedicarboxamide subunits
Mariusz M. Gruza,a Arletta Pokropa and Janusz Jurczaka,b,
*
aDepartment of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Science, 01-224 Warsaw, Poland
Received 1 February 2005; revised 24 April 2005; accepted 27 April 2005
Abstract—Five chiral macrocyclic bisamides derived from D-mannitol and L-threitol, possessing C2 symmetry, were obtained by a
macrocyclization reaction under two different conditions (MeOH, 12 kbar, rt or MeONa/MeOH, 1 bar, rt). Their applications for
alkali metal binding processes are studied using ESI-MS technique.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
a,x-diaminoethers containing three or five ethylene
units were applied for macrocyclization reactions lead-
ing to eight chiral bisamides. Electrospray ionization
mass spectrometry (ESI-MS) was used to evaluate the
alkali metal binding selectivities of these chiral bisamide
compounds possessing 2,6-pyridine subunits.
The chiral recognition and complexation properties of
natural receptors have attracted considerable attention
due to the design and synthesis of new chiral macrocyclic
rings, for example, poliaza1 and polyoxacoronands.2
In the early 1990s, we found that a,x-diaminoethers
reacted under ambient conditions with dimethyl a,x-
dicarboxylates in methanol as a solvent, to afford the
macrocyclic bisamides.3 This method was also exten-
sively investigated by using the high-pressure tech-
nique.4 The amide group exhibits a dual complexing
feature (C@O and N or NH), thus meaning amide-based
molecular receptors can bind metal5 and ammonium
cations,6 neutral organic molecules7 as well as anionic
species.8 Moreover, macrocyclic bisamides can be syn-
thesized in their optically active forms and applied to
chiral recognition processes.9 Recently, we pub-
lished10,11 an effective method for the synthesis of chiral
bisamides using a,x-diamines derived from D-mannitol
and L-threitol. In contrast to achiral macrocyclic com-
pounds, the synthesis of their chiral analogs is more dif-
ficult due to use of chiral a,x-diaminoethers as
substrates. Three diaminoethers 2–4 have been prepared
by us previously.10 Herein, we report a useful synthetic
way of preparing their analog 1. All four C2-symmetric
2. Results and discussion
2.1. Synthesis
1,2;5,6-Di-O-isopropylidene-D-mannitol and 1,4-di-
O-benzyl-L-threitol were selected as inexpensive and
convenient sources of chirality. These readily available
building blocks were used for the synthesis of numerous
chiral coronands.12 The synthesis of D-mannitol-derived
a,x-diaminoethers 2 and 4 containing three and five
ethylene units and L-threitol-derived a,x-diaminoether
3 possessing five ethylene units have been already
reported10 (Fig. 1).
The synthesis of L-threitol-derived a,x-diaminoether 1
possessing three ethylene units is presented at Scheme
1. 1,4-Di-O-benzyl-L-threitol 5 reacts with allyl bromide
to give compound 6, which was converted into diol 7 by
ozonolysis and the following reduction with sodium
borohydride. The conversion of diol 7 into intermediate
diphthalimide derivative 9 was carried out in two ways:
using either the Mitsunobu13 or Gabriel reaction.14 In
*
Corresponding author. Tel./fax: +48 22 823 09 44; e-mail: jjurczak@
chem.uw.edu.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.028

1940
M. M. Gruza et al. / Tetrahedron: Asymmetry 16 (2005) 1939–1946
The macrocyclization reactions (Scheme 2) were carried
O
NH2
NH2
out in methanol as a solvent; however, two different
reaction conditions were used. The first one (a) was car-
ried out under high pressure (12 kbar) without any addi-
tives while the second (b) was performed at atmospheric
pressure in the presence of 1 mol equiv of MeONa.
Table 1 shows the results of the macrocyclization
reactions.
NH2
NH2
R
R
O
O
R
R
O
O
*
*
*
*
O
1
2
3
4
BnO
R =
According to the first method (a), the reaction time was
always 48 h. In the latter method (b), the reaction time
was variable, based on monitoring by TLC. In all macro-
cyclization reactions, bisamides were almost exclusive
products; the traces of higher macrocyclic oligomers
were observed only using the spectrometric technique
and were not isolated.
O
O
R =
H
Figure 1.
In most cases, the slightly better yields of macrocyclic
diamides were obtained using method (b), performed
under atmospheric pressure in the presence of MeONa.
Moreover, method (b) is much more simple in compar-
ison with (a), however, in the case on the macrocycliza-
tion of base-sensitive systems, method (a) is
recommended.
BnO
BnO
BnO
BnO
H
H
OH
O
O
a
OH
H
H
5
6
2.2. ESI-MS experiments
b
Electrospray ionization mass spectrometry (ESI-MS) al-
lows the analysis of a the broad range of non-covalent
interactions of the host-molecules having various struc-
ture (crown ethers,15–18 diazacoronands,19 proteines,20,21
cages,22–24 and cyclodextrins25,26) with various types of
guest-molecules (metal cations,15–24 small neutral mole-
cules,25 and amino acids26). The ESI-MS analysis is
quick, enables direct investigation of the solution of
interest, and requires only a minute amount of sample.
Therefore, this method is suitable for screening of the
specifically selective receptors. Recently, we proposed
an application of this method as an analytical tool for
the determination of a general relationship between
the simple diazacoronand structure and the complexa-
tion properties of these ligands with respect to the alkali
metal cations.19
BnO
BnO
BnO
BnO
H
H
OTs
OH
O
O
O
O
d
OTs
OH
H
H
8
7
e
c
BnO
BnO
BnO
BnO
H
H
NH2
NH2
NPht
NPht
O
O
O
O
f
We decided to expand our studies with a series of eight
ligands 12a–h, keeping in mind that our approach is use-
ful merely for estimating which of the comparison of
two ligands is more selective toward one particular cat-
ion, as any quantitative determination of this selectivity
is not possible.
H
H
1
9
Scheme 1. Reagents: (a) CH2@CHCH2Br, KOH, toluene; (b) O3,
NaBH4, MeOH; (c) DIAD, PPh3, PhtNH, THF; (d) TsOH, NaOH,
THF; (e) PhtNꢀK+, DMF; (f) N2H4ÆH2O, EtOH.
It is well known that in the ESI-MS technique, the
response factors depend on the solvation energy of the
given ions. In order to perform a quantitative analysis
of the results one should introduce the corresponding
coefficients for correlation of the different ligand
response factors. Such a procedure is possible but quite
tedious and unnecessary from the viewpoint of this
work. For our purposes it is rational to assume that
the peak intensity ratios higher than 4:1 are indicative
of the stronger complexing properties of one of the
two complexing ligands.
the first method, compound 7 reacted with phthalimide
in the presence of triphenylphosphine and diisopropyl
azodicarboxylate to give compound 9 in 82% yield. In
the second reaction, which is based on the reaction of
tosylate 8 with a phthalimide potassium salt, the yield
was worse (55%). Finally, hydrazinolysis of 9 resulted
in the formation of free chiral a,x-diamine 1, in high
yield (91%).

M. M. Gruza et al. / Tetrahedron: Asymmetry 16 (2005) 1939–1946
1941
O
O
MeO
n N
NH2
NH2
m
m
m
m
n
O
O
H
O
O
R
R
O
O
R
R
O
O
*
*
*
*
a) or b)
N
N
+
H
N
MeO
n
n
O
O
12 m= 0,1 n=1,2
10 m=0
11 m=1
1-4 n=1,2
Scheme 2. Reagents and conditions: (a) MeOH, 12 kbar, rt; (b) MeOH, NaOMe, 1 bar, rt.
2.2.1. Effect of the ring size. Table 2 shows four pairs of
chiral macrocyclic bisamides 12a–h, characterized by a
different ring size (and very likely a different macrocyclic
cavity). For two first pairs (12a/c and 12b/d) a simple
conclusion is that the bisamide possessing a larger ring
size forms stronger complexes with alkali metal cations.
However, if one compares the other two pairs of ligands
(12e/g and 12f/h) none of the above-mentioned selectiv-
ities are observed.
oxamide analogs 13 and 14. In this case, the presence
of an additional electron donating center in the bisamide
macrocyclic ring does not help macrocycles 12c and d to
bind alkali metal cations better than their analogs 13
and 14, respectively.
3. Conclusions
As a result of our investigation, a new efficient method
of macrocyclization leading to chiral macrocyclic bisa-
mides has been developed. Moreover, we demonstrated
that the ESI-MS technique can be successfully used for
the preliminary determination of the selectivity of bind-
ing of the alkali metal cations by the prepared macrocy-
clic compounds.
2.2.2. Effect of the substituents at the stereogenic
centers. Comparison of complexation results for li-
gands having different substituents at the stereogenic cen-
ters shows no significant difference in selectivity between
the L-threitol and D-mannitol derivatives (Table 3).
In such a situation we decided to investigate two other
compounds 13 and 14 (Fig. 2), which were discussed
by us previously.27 Both of them are benzenedicarbox-
amide analogs of the examined pyridine bisamide mac-
rocycles. An analysis of the complexation results for
this pair of compounds confirms again that the differ-
ence between L-threitol and D-mannitol derivatives pos-
sessing the same ring size is negligible.
4. Experimental
4.1. General methods
Melting points were taken on a Ko¨fler-type (Boetius)
hot-stage apparatus and are uncorrected. Optical rota-
tions were measured using a Perkin–Elmer 241 polarim-
1
eter equipped with a thermally-jacketed 10 cm cell. H
2.2.3. Effect of regioisomerism of the amido group. The
data reported in Table 4 clearly show that both pairs of
regioisomeric bisamides differ in their complexation
ability. It seems to be very crucial that the positions,
where the –NHCO– groups appear, play an important
part in the association process. A comparison of two
isomers (12d/f, and 12c/e) shows the strongest binding
property toward compounds which possess –NHCO–
groups more distant from the 2,6-pyridine subunit. It
is noteworthy that these experiments cannot be carried
out directly because the ESI-MS technique excludes
measurement of a pair of isomers. However, based on
the similarity of the isomeric ligand response factors,
the analysis of their behavior with respect to the same
reference compound was performed.
NMR spectra were recorded with a Varian Gemini
200 (200 MHz) or a Varian Gemini 500 (500 MHz) spec-
trometer in CDCl3 using tetramethylsilane as an inter-
nal standard. 13C NMR spectra were also recorded
using a Varian Gemini 200 (50 MHz) or a Varian Gem-
ini 500 (125 MHz) spectrometer. All chemical shifts are
quoted in parts per million relative to tetramethylsilane
(d 0.00 ppm), and coupling constants (J) are measured
in hertz. The high-resolution mass spectrometry
(HRMS) experiments were performed on a LCT Micro-
mass instrument using the ESI technique. The column
chromatography was carried out on silica gel (Kiesel-
gel-60, 200–400 mesh). Methanol was freshly distilled
from Mg/I2 under Ar. THF was freshly distilled from
Na/benzophenone under Ar. The high-pressure reac-
tions were conducted under 12 kbar pressure using a
custom-made cylinder-piston type apparatus. The ele-
mental analyses (C, H, and N) were performed by the
ꢀin-houseꢁ analytical service.
2.3. Effect of presence of electron donating center in the
macrocyclic ring
Table 5 shows the findings of the study of the system
comprising of bisamide macrocycles 12c and d possess-
ing 2,6-pyridine subunits with their 1,3-benzenedicarb-
Diester 10 was purchased commercially. Diester 11 was
synthesized according to the literature procedures, by

Table 1. Results of macrocyclization reaction
O
O
O
O
O
NH2
NH2
NH2
O
O
O
O
O
O
NH2
NH2
H
H
H
H
H
H
H
H
NH2
NH2
O
O
O
O
O
O
O
O
H
H
H
H
O
O
O
O
O
NH2
1
2
3
4
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OMe
N
H
N
H
H
H
H
H
N
H
H
N
H
O
O
O
O
O
H
H
H
H
N
N
N
N
N
O
H
N
H
N
O
O
O
O
O
O
H
N
H
N
H
H
H
OMe
O
O
O
O
O
O
10
12a
38.7a 42.0b
12b
39.0a 50.3b
12c
41.9a 40.2b
12d
59.7a 50.7b
O
O
O
O
O
N
N
O
O
O
O
H
O
O
H
N
O
O
N
H
O
O
O
O
OMe
O
H
O
O
H
O
O
O
O
H
H
H
O
O
O
O
O
O
O
O
H
H
H
H
N
N
N
N
N
O
O
O
O
H
H
H
H
H
H
O
OMe
O
N
N
H
O
H
O
N
N
O
O
O
O
11
12e
14.1a 30.0b
12f
17.6a 26.3b
12g
22.6b
12h
19.3b
aMeOH, rt, 12 kbar, 48h.
bMeOH, rt, NaOMe.

M. M. Gruza et al. / Tetrahedron: Asymmetry 16 (2005) 1939–1946
1943
Table 2. Effect of the ring size on a competition between two ligands toward one cation
Ligands
Ratios of signal intensities in the ESI-MS spectra ([L1 + M]+/[L2 + M]+)a
L1
L2
[L1 + Li+/L2 + Li+]
[L1 + Na+/L2 + Na+]
[L1 + K+/L2 + K+]
[L1 + Rb+/L2 + Rb+]
[L1 + Cs+/L2 + Cs+]
12c
12d
12g
12h
12a
12b
12e
12f
7.2
7.8
1.3
0.7
6.3
12.5
1.6
9.3
5.6
1.3
1.0
4.3
5.8
1.7
1.1
4.2
3.3
1.3
1.3
1.2
a The standard deviation is 10% of the listed number.
Table 3. Effect of substituents on a complexation ability between the L-threitol and D-mannitol derivatives
Ligands
Ratios of signal intensities in the ESI-MS spectra ([L1 + M]+/[L2 + M]+)a
L1
L2
[L1 + Li+/L2 + Li+]
[L1 + Na+/L2 + Na+]
[L1 + K+/L2 + K+]
[L1 + Rb+/L2 + Rb+]
[L1 + Cs+/L2 + Cs+]
12a
12c
12f
12g
14
12b
12d
12e
12h
13
1.3
1.0
1.7
1.0
0.9
1.7
0.9
0.9
1.1
1.1
3.8
1.2
1.2
1.5
1.0
2.8
1.5
1.6
1.4
1.2
2.5
2.1
1.4
1.2
1.6
a The standard deviation is 10% of the listed number.
reduction of diester 10 with NaBH4 to appropriate diol
and following di-O-alkylation with bromoacetic acid
methyl ester. Macrocyclic bisamides 12b–d10 and 13,
1427 were synthesized previously.
O
O
O
O
O
N
H
H
H
O
O
H
H
4.2. ESI-MS experiments
O
O
HN
Mass spectrometric measurements were made on a
Quattro LC triple quadrupole mass spectrometer
equipped with an ESI source. The Harvard syringe
pump system ranged from 5.0 lL/min to 10.0 lL/min.
The needle potential for the methanol solution was set
to 3.0 kV for all experiments. Each spectrum taken
had an average of 25–30 scans and was acquired three
times for at least 180 s. All experimental conditions were
held constant throughout each series of experiments to
minimize the differences arising from inconsistencies in
ion formation or transmission.
O
13
O
O
O
O
O
N
H
H
O
O
H
HN
O
All solutions were prepared in 100% methanol. The
chloride salts were mixed in solution with the host of
interest to form the complexes studied. Host–guest solu-
tions containing a single host–multiple guest had a
14
Figure 2.
Table 4. Effect of regioisomerism on a complexation ability between two ligands toward one cation
Ligands
Ratios of signal intensities in the ESI-MS spectra ([L1 + M]+/[L2 + M]+)a
L1
L2
[L1 + Li+/L2 + Li+]
[L1 + Na+/L2 + Na+]
[L1 + K+/L2 + K+]
[L1 + Rb+/L2 + Rb+]
[L1 + Cs+/L2 + Cs+]
12f
12e
12d
12c
5.0
2.6
4.4
2.3
1.5
1.4
1.8
2.2
1.7
1.5
a The standard deviation is 10% of the listed number.
Table 5. Effect of presence of pyridine or benzene subunit on a complexation ability between two ligands toward one cation
Ligands
Ratios of signal intensities in the ESI-MS spectra ([L1 + M]+/[L2 + M]+)a
L1
L2
[L1 + Li+/L2 + Li+]
[L1 + Na+/L2 + Na+]
[L1 + K+/L2 + K+]
[L1 + Rb+/L2 + Rb+]
[L1 + Cs+/L2 + Cs+]
12d
12c
13
14
0.9
0.7
1.1
1.2
1.5
1.5
1.3
1.7
1.5
1.9
a The standard deviation is 10% of the listed number.

1944
M. M. Gruza et al. / Tetrahedron: Asymmetry 16 (2005) 1939–1946
concentration 1 · 10ꢀ5 M of each component. The solu-
tions containing two hosts and a single guest had a
concentration ratio of 10:10:1, where the hosts concen-
trations were 1 · 10ꢀ4 M for each host.
2.45 (s, 6H); 13C NMR (50 MHz, CDCl3), d: 144.8;
138.0; 132.9; 129.8; 129.6; 128.4; 127.9; 127.7; 79.6;
73.4; 69.7; 69.4; 69.1; 21.6; MS (HR ESI) m/z calcd for
C36H42O10S2Na [M+Na]+: 721.2117. Found: 721.2149.
4.3. 2,3-Di-O-allyl-1,4-di-O-benzyl-L-threitol 5
4.6. 2,3-Bis-O-(2-phthalimidoethyl)-1,4-di-O-benzyl-L-
threitol 8
1,4-Di-O-benzyl-L-threitol (75 mmol), KOH (20 g), and
allyl bromide (33.3 mL, 0.4 mol, freshly distilled) were
added to anhydrous toluene (250 mL). The mixture
was stirred at 90 ꢁC for 24 h, then cooled, washed with
water, dried over Na2SO4 and concentrated. The result-
ing oil was purified by column chromatography, using
From diol 6: to a solution of diol 3 (3 mmol), phthali-
mide (1.06 g, 7.2 mmol) and triphenylphosphine (1.89,
7.2 mmol) in dry THF (30 mL), di-iso-propyl azadicarb-
oxylate (DIAD, 1.42 mL, 7.2 mmol) was added drop-
wise. The mixture was stirred at rt under argon for
3 days and the solvent evaporated. The crude oil was
chromatographed using hexane–AcOEt (3:2) as an elu-
ent to afford 8 as a colorless oil. Yield 82%.
hexane–AcOEt (8:2 ! 7:3) as an eluent to obtain 5 as
20
colorless oil. Yield 88%, ½aꢁ = +8.4 (c 2.12; CHCl3);
D
1H NMR (200 MHz, CDCl3), d: 7.36–7.26 (m, 10H,
–Ph); 6.00–5.80 (m, 2H, –CH@CH2); 5.29–5.08 (m,
4H, –CH@CH2); 4.51 (s, 4H); 4.24–3.94 (m, 4H);
3.77–3.50 (m, 6H); 13C NMR (50 MHz, CDCl3), d:
138.3; 135.3; 128.3; 127.6; 127.5; 116.9; 77.8; 73.4;
72.3; 69.8; MS (HR ESI) m/z calcd for C24H31O4
[M+H]+: 383.2222. Found: 383.2204.
From ditosylate 7: The compound was prepared accord-
ing to the literature procedure (procedure for com-
pounds 4 and 7) using ditosylate 4 instead of
dichlorides. Purification as described above. Yield
20
D
1
55%. ½aꢁ = ꢀ1.0 (c 4.5; CHCl3); H NMR (500 MHz,
CDCl3), d: 7.86–7.77 (AA0BB0/2, 4H, –NPht); 7.69–
7.62 (AA0BB0/2, 4H, –NPht); 7.30–7.16 (m, 10H, –Ph);
4.31 and 4.30 (2 · s, 4H); 3.95–3.81 (m, 6H); 3.81–3.74
(m, 6H); 3.65–3.60 (m, 6H); 3.57–3.51 (m, 2H); 3.46–
3.41 (m, 2H); 13C NMR (125 MHz, CDCl3), d: 168.2;
138.2; 133.8; 132.1; 129.5; 128.3; 127.5; 127.4;
123.2; 79.3; 73.2; 69.8; 67.8; 38.0; MS (HR ESI) m/z
calcd for C38H36N2O8Na [M+Na]+: 671.2369. Found:
671.2396.
4.4. 2,3-Bis-O-(2-hydroxyethyl)-1,4-di-O-benzyl-L-threi-
tol 6
Diallyl ether 5 (60 mmol) was dissolved in methanol
(400 mL), cooled to ꢀ78 ꢁC and ozone was passed
through the solution. When the solution turned blue,
ozone was passed for additional 30 min, followed by
oxygen for 30 min to remove the excess of ozone. To
the stirred solution, maintained below ꢀ21 ꢁC, a solu-
tion of sodium borohydride (10 g) in a mixture of meth-
anol–water (1:1, 150 mL) was added dropwise. The
mixture was stirred overnight at rt, then methanol was
distilled off, and water (100 mL) was added. The solu-
tion was extracted with chloroform several times and
the combined extracts was dried (MgSO4), filtered, and
concentrated, giving a colorless oil. The oil was chro-
4.7. 2,3-Bis-O-(2-aminoethyl)-1,4-di-O-benzyl-L-threitol 9
Diphthalimide 5 (1.5 mmol) was dissolved in warm eth-
anol (96%, 50 mL), to which hydrazine monohydrate
(1 mL) was added and the solution refluxed for 8 h. Eth-
anol was evaporated, the white residue dissolved in
aqueous sodium hydroxide (20%, 30 mL) and extracted
with CH2Cl2 (3 · 30 mL). The combined extracts were
washed with water (30 mL) and dried over Na2SO4.
The filtrate was evaporated to afford diamine 9 as a yel-
matographed using chloroform–methanol as an eluent.
20
D
Yield 62%, ½aꢁ = +2.4 (c 2.0; CHCl3); 1H NMR
(500 MHz, CDCl3), d: 7.40–7.24 (m, 10H, –Ph); 4.52–
4.51 (2 · s, 4H); 3.90–3.45 (m, 14H); 3.21 (br s 2H,–
OH), 13C NMR (125 MHz, CDCl3), d: 137.6; 129.6;
128.5; 127.8; 79.7; 73.5; 73.0; 69.4; 62.2; MS (HR ESI)
m/z calcd for C22H30O6Na [M+Na]+: 413.1935. Found:
413.1933.
lowish oil, which was stored in a frigde. Yield >91%,
21
D
½aꢁ = +8.9 (c 2.05; CHCl3); 1H NMR (500 MHz,
CDCl3), d: 7.37–7.26 (m, 10H, –Ph); 4.50 (s, 4H);
3.72–3.63 (m, 6H); 3.57–3.50 (m, 4H); 2.87–2.77 (m,
4H); 1.66 (br s, 4H, –NH2); 13C NMR (125 MHz,
CDCl3), d: 138.0; 128.4; 127.7; 127.68; 78.9; 73.7; 73.4;
69.3; 42.1; MS (HR ESI) m/z calcd for C22H33N2O4
[M+H]+: 389.2440. Found: 389.2451.
4.5. 2,3-Bis-O-(2-p-toluenesulfonyloxyethyl)-1,4-di-O-
benzyl-L-threitol 7
Diol 6 (3 mmol) and tosyl chloride (12 mmol) were dis-
solved in anhydrous THF (30 mL), cooled to 0 ꢁC, and
KOH (0.7 g, 12 mmol) then added. The mixture was
stirred below 5 ꢁC for 2 h, and then at rt for 20 h. The
mixture was poured onto ice and the aqueous phase ex-
tracted (CH2Cl2, 3 · 30 mL). The combined extracts
were dried over MgSO4, filtered, and evaporated. The
4.8. General procedures for the syntheses of macrocycles
12
4.8.1. Method A (under high pressure). An equimolar
solution of dimethyl a,x-dicarboxylate (0.5 mmol) and
the appropriate a,x-diamine (0.5 mmol) in methanol
(5 mL) was charged into a Teflon ampoule, sealed,
placed in a high-pressure vessel filled with ligroin as a
transmission medium, and compressed (12 kbar) at
room temperature for 48 h. After decompression, the
reaction mixture was transferred quantitatively to a
round-bottomed flask and the solvent evaporated. The
obtained oil was purified by chromatography using hex-
23
D
ane–AcOEt (3:2) as an eluent. Yield 92%. ½aꢁ = +1.1 (c
1
2.3; CHCl3); H NMR (200 MHz, CDCl3), d: 7.78–7.74
(AA0BB0, 4H, J = 8.2); 7.23–7.38 (m, 10H, –Ph); 4.54–
4.36 (m, 4H); 4.09 (t, 4H, J = 5.0); 3.9–3.4 (m, 10H);

M. M. Gruza et al. / Tetrahedron: Asymmetry 16 (2005) 1939–1946
1945
residue was chromatographed on a silica gel column
using 0.5–3% mixtures of methanol in chloroform.
108.9; 80.1; 75.0; 74.6; 71.9; 70.8; 66.9; 39.0; 26.7; 25.3;
MS (HR EI) m/z calcd for C27H42O10N3 [M+H]+:
568.2870. Found: 568.2845; EA (%) calcd: C, 57.1; H,
7.3; N, 7.4. Found: C, 56.9; H, 7.0; N, 7.3.
4.8.2. Method B (in the presence of MeOꢀ). Sodium
(1 equiv) was added to a cooled (5 ꢁC) solution
(0.1 mol/L) of diester in dry methanol. Then an equal vol-
ume of a solution (0.1 mol/L) of diamine in dry methanol
was added. The mixture was left at rt over a period of sev-
eral days (monitored by TLC). Then the solvent was
evaporated and the residue was purified by column
chromatography using a gradient of toluene/chloroform,
chloroform and chloroform/methanol mixtures as eluent.
4.12. (13S, 14S)-13,14-Bis-benzyl-oxymethyl-3,9,12,15,
18,24-hexaoxa-6,12,30-triaza-bicyclo[24.3.1]triaconta-
1(29),26(30),27-triene-5,22-dione 12g
4.12.1. Method B. 8 days, 39%. Yellowish oil.
20
D
½aꢁ = +14.6 (c 1.0, CHCl3); 1H NMR (CDCl3), d:
8.08 (2H, br s –NHCO–), 7.67 (1H, t, J = 10.0), 7.32–
7.21 (12H, m), 4.69 (4H, s), 4.47 (4H, s), 4.09 (4H, s),
3.68–3.51 (22H, m). 13C NMR (CDCl3), d: 169.9,
157.1, 138.3, 137.9 (–Ph), 128.5 (–Ph), 127.8 (–Ph),
121.0, 79.1, 74.3, 73.5, 73.3, 70.8, 70.7, 69.9, 69.6, 38.9.
HR ESIMS m/z calcd for C37H49N3O10 [M+Na]+:
718.3316. Found: 718.3329.
4.9. (7S,8S)-7,8-Bis(benzyloxymethyl)-6,9-dioxa-3,12,18-
triaza-bicyclo[12.3.1]octadeca-1(17),14(18),15-triene-
2,13-dione 12a
4.9.1. Method A: 38.7%; method B. 7 days, 42.0%.
24
D
1
Thick, yellowish oil; ½aꢁ = ꢀ28.8 (c 2.1; CHCl3); H
NMR (500 MHz, CDCl3), d: 8.89 (br m, 2H,
–NHCO–); 8.24 (d, J = 7.8, 2H); 8.03 (t, J = 7.8, 1H);
7.34–7.25 (m, 10H, –Ph); 4.47 (AB/2, J = 12.2, 2H);
4.42 (AB/2, J = 12.2, 2H); 3.90–3.84 (m, 2H); 3.84–
3.80 (m, 2H); 3.76–3.64 (m, 4H); 3.59–3.51 (m, 6H);
13C NMR (50 MHz, CDCl3), d: 162.5; 148.1; 139.4;
137.5; 128.4; 128.0; 127.9; 123.7; 78.7; 73.4; 67.3; 67.0;
38.7; MS (HR ESI) m/z calcd for C29H33N3O6Na
[M+Na]+: 542.2267. Found: 542.2262.
4.13. (13R, 14R)-13,14-Bis(2,2-dimethyl-[1,3]dioxalan-
4-yl)-3,9,12,15,18,24-hexaoxa-6,21,30-triaza-bicyclo-
[24.3.1]triaconta-1(29),26(30),27-triene-5,22-dione 12h
4.13.1. Method B. 7 days, 43%. Yellowish oil.
20
D
½aꢁ = +10.6 (c 1.0, CHCl3); 1H NMR (CDCl3), d:
8.19 (2H, br s –NHCO–), 7.76 (1H, t, J = 9.25), 7.27
(2H, m), 4.74 (4H, s), 4.23–3.91 (10H, m), 3.77–3.72
(4H, m), 3.55 (12H, m), 1.38 (6H, s), 1.31 (6H, s). 13C
NMR (CDCl3), d: 170.1, 157.2, 138.1, 121.1, 108.8,
80.6, 75.7, 74.4, 72.2, 70.9, 70.8, 70.0, 66.7, 38.9, 26.9,
25.5. HR ESIMS m/z calcd for C31H49N3O12
[M+Na]+: 678.3214. Found: 678.3220.
4.10. (10S,11S)-10,11-Bis(benzyloxymethyl)-3,9,12,18-
tetraoxa-6,15,24-triaza-bicyclo[18.3.1]tetracosa-
1(23),20(24),21-triene-5,16-dione 12e
4.10.1. Method A 14.1%; method B. 8 days, 30.0%.
24
D
Thick, yellowish oil. ½aꢁ = +2.2 (c 2.2; CHCl3). 1H
Acknowledgments
NMR (500 MHz, CDCl3), d: 7.71 (t, J = 7.8, 1H);
7.63 (br t, J = ꢂ 5.5, 2H, –NHCO–); 7.35–7.23 (m,
12H); 4.64 (AB/2, J = 11.2, 2H); 4.61 (AB/2, J = 11.2,
2H); 4.40 (AB/2, J = 12.2, 2H); 4.36 (AB/2, J = 12.1,
2H); 4.13 (AB/2, J = 15.6, 2H); 4.08 (AB/2, J = 15.6,
2H); 3.73–3.68 (m, 2H); 3.62–3.48 (m, 10H); 3.44–
3.36 (m, 2H); 13C NMR (50 MHz, CDCl3), d: 169.4;
156.3; 137.8; 137.5; 128.4; 127.7; 127.6; 122.2; 78.3;
74.5; 73.3; 70.8; 70.3; 69.1; 39.7; MS (ESI LR) m/z
calcd for C33H41N3O8Na [M+Na]+: 630.69. Found:
630.3.
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.
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