The synthesis of L-proline derived hexaazamacrocyclic ligands of C3 symmetry via intramolecular methyl ester aminolysis

Article abstract of DOI:10.1016/S0957-4166(01)00068-4

A convenient synthesis of enantiomerically pure 18-, 21-, and 24-membered hexaaza-crown ligands is presented. Linear α,ω-aminoesters, prepared from L-proline, undergo intramolecular aminolysis to afford the corresponding 18-, 21-, and 24-membered macrocyc

Full text of DOI:10.1016/S0957-4166(01)00068-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 487–495
The synthesis of -proline derived hexaazamacrocyclic ligands of
L
C3 symmetry via intramolecular methyl ester aminolysis†
Micha*l Achmatowicza and Janusz Jurczaka,b,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
bDepartment of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw, Poland
Received 12 January 2001; accepted 9 February 2001
Abstract—A convenient synthesis of enantiomerically pure 18-, 21-, and 24-membered hexaaza-crown ligands is presented. Linear
a,v-aminoesters, prepared from
L-proline, undergo intramolecular aminolysis to afford the corresponding 18-, 21-, and
24-membered macrocyclic amides in satisfactory yields (42, 65, and 22%, respectively). These were subsequently transformed into
the title macrocyclic hexamines via exhaustive reduction with a borane–dimethylsulfide complex. X-Ray structures of two larger
macrocyclic amides are also presented. © 2001 Elsevier Science Ltd. All rights reserved.
are synthesised from enantiomerically pure (R,R)-cyclo-
hexane-1,2-diamine, as well as functionalised [18]aneN6
1. Introduction
obtained from L
-serine derived cyclic sulfamidate.7
Tetraazamacrocyclic compounds, such as cyclam
(1,4,8,11-tetraazacyclotetradecane) and its derivatives,
have been the subject of much interest mainly due to
their ability to bind transition metal ions.1 Their chiral
derivatives have also been synthesised and investi-
gated.2 Peraza-crown macrocycles with larger cavities
and higher numbers of donor nitrogen atoms are capa-
ble of accommodating more than one metal centre,
giving rise to the possibility of polynuclear macrocyclic
complex formation.3 Although larger macrocycles, pos-
sessing more than four in-ring nitrogen atoms, seem to
be equally interesting as ligands for transition metal
cations, they have attracted much less attention than
their smaller homologues.3–7 Among several reports on
unsubstituted hexadentate perazamacrocyclic ligands
We recently presented a convenient methodology for
the synthesis of -proline derived C2-symmetric tetra-
L
azamacrocyclic compounds via intramolecular methyl
ester aminolysis reactions.2g Prompted by these encour-
aging findings, we have investigated the possibility of
extending this approach to their C3-symmetric hexaaza
analogues. Herein, we present the results of these stud-
ies that led to the synthesis of chiral [18]aneN6,
[21]aneN6, as well as [24]aneN6, perazamacrocycles.
2. Results and discussion
and
their
metal
complexes,
i.e.
[18]aneN6
(1,4,7,10,13,16-hexaazacyclooctadecane),3b–d,4 [20]aneN6
Starting materials (1a–c and 2a–c) were synthesised
according to procedures given in our previous paper.2g
N-Cbz-Protected aminoesters 3a–c were obtained in
good yields (83–90%) by means of condensation of an
appropriate carboxylic acid derivative (1a–c) with an
amino compound (2a–c) using iso-butylchloroformate
as a dehydrating agent (Scheme 1). In the next step,
compounds 3a–c were quantitatively N-deprotected
under standard conditions (H2/Pd–C, methanol) to
afford the corresponding aminoesters 4a–c, which were
used as substrates for the subsequent macrocyclisation
reaction step. According to our previous investiga-
tions,2g we anticipated that methyl ester aminolysis with
4a–c in the absence of a catalyst would not be possible.
Several experiments proved this to be the case. Indeed,
(1,4,7,11,14,17-hexaazacycloicosane),3d,4a
[21]aneN6
(1,4,8,11,15,18-hexaazacyclohenicosane)5 and [24]aneN6
(1,5,9,13,17,21-hexaazacyclotetracosane),3a there are
only few chiral systems. To our best knowledge, the
only chiral hexaazamacrocycles reported to date are
[18]aneN6,5 and two [22]aneN6 based compounds6—all
* Corresponding author. Tel.: +00 48 22 632 05 78; e-mail: jurczak
@icho.edu.pl
†
Part III of the series ‘Chiral perazamacrocycles’; Part I, see: Ref. 2f;
Part II, see: Ref. 2g.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00068-4

488
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
i
Scheme 1. (a) BuOCOCl, Et3N, CH2Cl2, −20“0°C; (b) H2, Pd–C, MeOH; (c) 10 or 16 kbar, MeOH, 50°C; or NaOMe, MeOH,
rt; or NaOH, MeOH, rt; (d) BH3·Me2S, THF, reflux.
reactivity of the amino group towards the methyl ester
carbonyl function, which had to be improved.
aminoesters 4a–c did not react either intra- or inter-
molecularly when dissolved in a number of common
solvents, even at elevated temperatures. The only excep-
tion was DMF, which upon heating reacted with the
primary amine groups, affording N-formyl derivatives.
Polar protic solvents, such as methanol, have been
suggested to play a crucial role in the formation of a
hydrogen-bonded, pre-organised structure, which, in
turn, promotes intramolecular ring closure over inter-
molecular reaction between a methyl ester and a pri-
mary amino group.8 Since both these functional groups
were present in substrates 4a–c, we anticipated similar
behaviour in methanol. The only drawback was the low
As previously demonstrated,2g this low reactivity can be
circumvented either by means of basic catalysis or by
use of high pressure reaction conditions. Investigations
into the use of sodium methoxide in methanol as a
basic catalyst in the macrocyclisation of 4a–c led to the
formation of the corresponding triamides 5a–c in good
yields of 42–65% (Table 1, entries 1–3). Unfortunately,
under such conditions, the desired (S,S,S)-5b (65%
yield; Table 1, entry 2) was accompanied by its (R,S,S)-
epimer formed in 5% yield and, in the case of

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
489
Table 1. Intramolecular ester aminolysis (4“5): yields of the triamides 5a–c under various macrocyclisation conditions
Entry
Triamide
Yield (%)
Reaction conditions
Reaction time (days)
1
2
3
4
5
6
7
8
5a
5b
5c
5a
5b
5c
5a
5a
5b
5b
5c
5a
5b
5c
5b
5b
42a
65b
60c
15
NaOCH3, CH3OH, rt
NaOCH3, CH3OH, rt
NaOCH3, CH3OH, rt
NaOH, CH3OH, rt
NaOH, CH3OH, rt
NaOH, CH3OH, rt
10 kbar, CH3OH, 50°C
10 kbar, CH3OH, 50°Cf
10 kbar, CH3OH, 50°C
10 kbar, CH3OH, 50°C
10 kbar, CH3OH, 50°C
16 kbar, CH3OH, 50°C
16 kbar, CH3OH, 50°C
16 kbar, CH3OH, 50°C
Bu4NOH, CH3OH, rt
DBU, CH3OH, rt
30
30
30
7
7
7
7
7
7
14
7
7
7
7
30
90
15
13
25d
23e
22
9
10
11
12
13
14
15
16
29
22
22g
25h
13i
39
36j
a Separated from the mixture of 5a:8a (1:1.2).
b (R,S,S)-5b (5% yield) was separated from the main (S,S,S)-5b diastereoisomer.
c Inseparable mixture of diastereoisomers.
d Separated from the mixture of 5a:8a (1:3.8).
e Separated from the mixture of 5a:7a:8a (1.1:1:5.6).
f iso-Propyl ester was used instead of the methyl ester 4a.
g Separated from the mixture of 5a:7a:8a (1.8:1:8).
h Separated from the mixture of 5b:7b (3.1:1).
i Separated from the mixture of 5c:7c (1:1).
j (R,S,S)-5b (6% yield) was separated from the main (S,S,S)-5b isomer.
be the system of choice in the preparation of smaller
12- to 16-membered macrocycles (with yields of up to
82%).2g However, its usefulness is limited to the smaller
ring compounds of up to about 16 in-ring atoms, for
which the rate of intramolecular aminolysis is relatively
fast when compared with competitive methyl ester
hydrolysis. The DBU promoted reaction was carried
out for 3 months affording (S,S,S)-5b (36% yield; Table
1, entry 16) accompanied by its (R,S,S)-epimer (6%
yield; Table 1, footnote j). An analogous reaction, using
tetrabutylammonium hydroxide, produced non-
epimerised (S,S,S)-5b in comparable yield of 39%
(Table 1, entry 15) after 1 month.
aminoester 5c, the reaction led to a complex mixture of
chromatographically inseparable diastereoisomers (60%
overall yield; Table 1, entry 3). In the case of the
macrocyclic triamide 5a (42% yield; Table 1, entry 1),
no epimerisation product was detected, but the yield of
the macrocycle 5a was lower compared to the larger
trilactams 5b and 5c. The lowered yield of 5a was
associated with the formation of the bicyclic lactam 8a
(Table 1, footnote a)—a product of a competitive
transamidation process involving attack by the amino
group on the amide carbonyl rather than on the ester
carbonyl group (Scheme 2).
In typical circumstances, the N-alkyl amide carbonyl
group is a weak competitor when compared with the
methyl ester carbonyl group, both in terms of elec-
trophilicity and steric hindrance. However, in the case
of the aminoester 4a, there is a strong preference for
nucleophilic attack, which leads to a six-membered ring
and elimination of an 8a molecule (Scheme 2). A simi-
lar observation was made in connection with smaller
macrocycles having the same chiral subunit.2g The pos-
sibility of epimerisation, combined with the long reac-
tion time of 30 days, rendered catalysis by sodium
methoxide in methanol impractical for the synthesis of
trilactam 5c. Other basic additives, promoting methyl
ester aminolysis, were tested, including sodium and
tetrabutylammonium hydroxides, as well as 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU). Sodium hydroxide pro-
moted macrocyclisation reactions, after stirring for 1
week at room temperature, afforded trilactams 5a–c in
poor yields (13–15%; Table 1, entries 4–6). The sodium
hydroxide/methanol system has already been shown to
In order to improve both the yield and diastereoiso-
meric purity of products, we examined high pressure
conditions, which previously allowed transformation of
the similar a,v-aminoesters into macrocyclic amides
without basic additives and under neutral conditions.2g
Again, intramolecular methyl ester aminolysis was slow
and after 1 week at 50°C under 10 kbar pressure, the
desired products 5a–c were separated from starting
materials in only moderate yields (22–25%; Table 1,
entries 7–9 and 11). When the aminoester 4b was
allowed to react for 2 weeks, macrocycle 5b was
obtained in a better yield of 29% (Table 1, entry 10).
Although increasing the pressure from 10 to 16 kbar
had a negligible effect on the yield of 5a and 5b (see
Table 1, entries 12 and 13), the chemoselectivity of
attack by the amino group towards the ester and amide
functions was lowered substantially (Scheme 2). In all
cases (Table 1, entries 12–14) the macrocyclic triamides

490
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
Scheme 2. Possible intramolecular aminolysis of compounds 5a–c.
(see Section 4), indicating either a C3-symmetrical con-
formation in solution, or a rapid interchange between
their non-symmetrical conformations. On the other
hand, in the case of the triamide 5b, NMR spectra
recorded in CDCl3 at room temperature showed sepa-
rate signals from chemically equivalent nuclei, suggest-
ing that some of the hydrogen bonds present in solids
also exist in solutions.
5a–c were isolated from the mixture of products from
intramolecular aminolysis (Table 1, footnotes g–j;
Scheme 2). In the case of the largest macrocycle, 5c,
completing the reaction under a pressure of 16 kbar led
to a loss in selectivity and thence a substantial decrease
in yield to 13% in comparison to the reaction per-
formed under 10 kbar pressure, which afforded 5c in
22% yield (Table 1, entries 11 and 13).
Reduction of 5a and 5b with a large excess of borane–
dimethylsulfide complex in THF (Scheme 1) afforded
the title homochiral hexaaza-crown macrocycles
[18]aneN6 6a and [21]aneN6 6b in good yields of 85 and
70%, respectively. We were able to obtain compounds
5b and 5c as monocrystals suitable for X-ray analysis.
Although several attempts were made, no X-ray quality
crystals could be grown from the triamide 5a. The
relative flexibility of the macrocyclic rings of both 5b
and 5c allows the formation of intramolecular hydro-
gen bonds (Fig. 1, Table 2; Fig. 2, Table 3, respec-
tively), which induce a b-turn-like conformation in
some parts of the macro-rings. Such intramolecular
bonding interactions keep the molecules of triamides 5b
and 5c in ‘collapsed’ rather than C3-symmetrical con-
formations. 1H and 13C NMR spectra of 5a and 5c
recorded at room temperature in CDCl3 solution
showed averaged signals from all the homotopic nuclei
3. Conclusion
The present work was aimed at the synthesis of large,
enantiomerically pure hexaazamacrocycles using the
methodology previously shown2g to be effective for the
synthesis of their smaller tetraaza analogues. Although
the yields of the macrocyclisation reactions were not as
high as those of tetraazamacrocycles, which formed in
yields of up to 82%, the hexaaza-crown precursors 5a–c
were obtained in reasonable yields (22–65%). For the
efficient intramolecular aminolysis of such long, linear
a,v-aminoesters as 3a–c high pressure conditions (10
kbar) turned out to be the most general. An important
feature of the methodology presented (compared with
other large ring formation methods) is its facility. The
macrocyclisation reactions are performed with rela-
tively high concentrations of substrates (0.01–0.1 M) in
methanol with normal water content.

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
491
Figure 1. ORTEP view of compound 5b.
Table 2. Geometry of hydrogen bonds in compound 5b
ing the interaction of anions with triamides 5a–c and
the formation of transition metal complexes with lig-
ands of the type 6, are currently in progress.
,
,
,
DꢀH···A
DꢀH (A)
H···A (A)
D···A (A)
DHA (°)
N2ꢀH2···N1
N2ꢀH2···N3
N4ꢀH4···O1
(x, y−1, z)
N6ꢀH6···N5
N6ꢀH6···O2
0.82
0.82
0.90
2.23
2.46
2.13
2.738
2.957
2.942
120
120
150
4. Experimental
0.94
0.94
2.17
2.37
2.707
3.094
116
134
4.1. General methods
Melting points were determined on a Kofler hot-stage
apparatus with a microscope and are uncorrected. Opti-
cal rotations were measured on a JASCO P 3010 polar-
imeter using the sodium D line at 589 nm. H NMR
spectra were recorded on a Bruker Avance 500 (500
Trilactams 5a–c, which were precursors for the title
hexaazamacrocycles, are very promising neutral hosts
for anions, since macrocyclic polyamides are known to
be able to bind such species.9 Further studies, concern-
1
Figure 2. ORTEP view of compound 5c.

492
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
Table 3. Geometry of hydrogen bonds in compound 5c
oration, the residue was purified by column chro-
matography (CH2Cl2/methanol=19/1) to afford pure
amide 3.
,
,
,
DꢀH···A
DꢀH (A)
H···A (A)
D···A (A)
DHA (°)
N2ꢀH2N···N3 0.74
2.45
2.00
2.745
2.843
107
167
N6ꢀH6N···O2
(x−1, y, z)
N2ꢀH2N···O3
0.86
0.73
4.2.1. (2S,11S,20S)-2,6-cyclo-11,15-cyclo-20,24-cyclo-
26 - (Benzyloxycarbonylamino) - 6,9,15,18,24 - pentaaza-
10,19-dioxohexacosanoic acid methyl ester 3a. Yield
83%; mp 77–78°C; [h]2D0=−99.6 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3, 30°C, TMS): l=7.64 (bs,
1H; CONH), 7.36–7.28 (m, 6H; CONH, Ph), 6.17 (bs,
1H; CO2NH), 5.15 (d, 1H, J=12.2 Hz; CHHPh), 5.05
(d, 1H, J=12.2 Hz; CHHPh), 3.67 (s, 3H; OCH3),
3.58–3.50 (m, 1H; NHCHH), 3.41–3.03 (m, 10H; 2×
CHCO, NHCHH, 2×NHCH2, NCH2, NCHH), 2.99–
2.90 (bs, 1H; CHCO), 2.84–2.69 (m, 3H; 3×NCHH),
2.58–2.41 (m, 3H; 3×NCHH), 2.38–2.20 (m, 3H;
NCH2, NCHH), 2.19–2.01 (m, 3H; CH2, CHH), 1.92–
1.65 (m, 15H; 7×CH2, CHH); 13C NMR (125 MHz,
CDCl3, 30°C, TMS): l=175.2, 174.6, 136.0, 128.4,
128.2, 128.0, 68.2, 68.1, 66.5, 65.7, 55.4, 54.9, 53.9,
53.7, 53.6, 53.2, 51.8, 40.2, 38.0, 37.7, 30.5, 30.3, 29.5,
24.2, 23.7, 23.5; IR (CHCl3): w=3355, 2981, 2955,
2883, 2817, 1715, 1659, 1523, 1455 cm−1; MS (EI HR):
calcd for [C30H46N6O6]+ 586.34788, found 586.34907.
2.27
2.24
2.891
2.757
144
116
N5ꢀH5N···N1 0.90
MHz) spectrometer. Chemical shifts are given in ppm
relative to tetramethylsilane at l=0, with tetra-
methylsilane or the residual non-deuterated solvent sig-
nal as internal standard. In addition to the
conventional abbreviations for multiplicity, the follow-
ing have been used for first-order spectra: m=multi-
plet, b=broad. 13C NMR spectra were recorded on
Bruker Avance 500 (125 MHz) and Varian Gemini
AC-200 (50 MHz) spectrometers and were proton
decoupled. H,1H-COSY and H,13C-HETCOR experi-
ments were carried out on some samples to aid in the
assignment of spectra. Infrared spectra were run on a
Perkin–Elmer FT-IR Spectrum 2000 spectrophotome-
ter. High-resolution mass spectra (LSIMS and EI) were
recorded on an Intectra AMD 604 spectrometer. Elec-
trospray (ESI) high-resolution spectra were recorded
on Perseptive Biosystems Mariner (TOF) or Sciex API
365 (triple quadrupole) spectrometers. Elemental analy-
ses (C, H, and N) were performed by the ‘in-house’
analytical service.
1
1
4.2.2. (2S,12S,22S)-2,6-cyclo-12,16-cyclo-22,26-cyclo-
29 - (Benzyloxycarbonylamino) - 6,10,16,20,26 - pentaaza-
11,21-dioxononanoic acid methyl ester 3b. Yield 90%; a
1
yellow oil; [h]2D0=−89.2 (c 1.0, CHCl3); H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.63 (bs, 1H; CONH),
7.43–7.28 (m, 6H; CONH, Ph), 5.31 (bs, 1H; CO2NH),
5.09 (bs, 2H; CH2Ph), 3.69 (s, 3H; OCH3), 3.47–3.39
(m, 1H; NHCHH), 3.36–3.29 (m, 1H; NHCHH), 3.27–
3.12 (m, 8H; CHCO2, 2×NHCHH, NHCH2, NCH2,
NCHH), 3.03–2.95 (m, 2H; 2×CHCO), 2.73 (dt, 1H,
J1=7.9 Hz, J2=12.0 Hz; NCHH), 2.67–2.56 (m, 2H;
NCH2), 2.46–2.35 (m, 3H; NCH2, NHH), 2.32–2.22
(m, 3H; NCH2, NHH), 2.19–2.06 (m, 3H; CH2, CHH),
1.94–1.61 (m, 15H; 7×CH2, CHH); 13C NMR (125
MHz, CDCl3, 30°C, TMS): l=174.9, 174.7, 174.6,
156.5, 136.7, 128.5, 128.1, 68.1, 68.0, 66.5, 66.6, 66.1,
53.9, 53.8, 53.4, 53.3, 52.9, 51.7, 39.1, 37.4, 36.8, 30.7,
30.6, 29.6, 29.3, 29.1, 28.6, 24.2, 23.2; IR (CHCl3):
w=3671, 3450, 3346, 2952, 2816, 1719, 1658, 1522,
1455 cm−1; MS (LSIMS HR): calcd for [C33H53N6O6]+
629.40265, found 629.40138.
Analytical TLC was carried out on commercially pre-
pared plates coated with 0.25 mm of self-indicating
Merck Kieselgel 60 F254 that were developed using
ninhydrin solution in a butanol/acetic acid mixture, in
addition to visualisation by UV and I2. Preparative
flash silica chromatography was performed using
Merck Kieselgel 60 (230–400 mesh). All reagents and
solvents were purified and dried as necessary according
to standard procedures.
4.2. General procedure for the amide bond formation
(1+2“3)
4.2.3. (2S,13S,24S)-2,6-cyclo-13,17-cyclo-24,28-cyclo-
32 - (Benzyloxycarbonylamino) - 6,11,17,22,28 - pentaaza-
12,23-dioxodotriacontanoic acid methyl ester 3c. Yield
86%; a yellow oil; [h]2D0=−73.7 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3, 30°C, TMS): l=7.40–7.29
(m, 6H; CONH, Ph), 5.09 (bs, 3H; CONH, CH2Ph),
3.71 (s, 3H; OCH3), 3.30–3.10 (m, 10H; 3×NHCH2,
NCH2, NCHH, CHCO), 3.02–2.96 (m, 2H; 2×
CHCO), 2.71 (m, 1H; NCHH), 2.62–2.54 (m, 2H;
NCH2), 2.47–2.36 (m, 3H; NCH2, NHH), 2.34–2.24
(m, 3H; NCH2, NHH), 2.19–2.04 (m, 3H; CH2, CHH),
1.95–1.42 (m, 21H; 10×CH2, CHH); 13C NMR (125
MHz, CDCl3, 30°C, TMS): l=174.9, 174.7, 156.4,
136.6, 128.5, 128.1, 67.9, 67.8, 66.6, 66.1, 55.7,
The N-Cbz-protected amino acid 12g (2.05 mmol) and
triethylamine (2.5 equiv., 0.70 mL) were dissolved in
dry CH2Cl2 (20 mL). The solution was cooled to −
20°C under argon and iso-butylchloroformate (0.27
mL, 2.1 mmol) was added dropwise. The reaction mix-
ture was stirred at −20°C for 1 h, and then at 0°C for
1 h. To this solution was added a solution of
aminoester 2 (see Ref. 2g, 2.03 mmol) in dry CH2Cl2
(15 mL) at 0°C. The reaction mixture was allowed to
warm to room temperature and stirred overnight, and
was then evaporated. The residue was dissolved in
ethyl acetate (0.10 L), washed with water (2×25 mL),
brine (25 mL) and dried (Na2SO4). After solvent evap-

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
493
55.6, 54.6, 53.9, 53.8, 53.4, 51.7, 40.9, 38.7, 38.6, 30.7,
30.6, 29.3, 28.0, 27.8, 27.7, 26.3, 26.2, 26.0, 24.2, 23.2;
IR (CHCl3): w=3453, 3344, 3007, 2947, 2868, 2814,
1721, 1659, 1521, 1455 cm−1; MS (EI HR): calcd for
[C36H58N6O6]+ 670.44178, found 670.44270.
4.3.4. (7S,17S,27S)-1,5,11,15,21,25-Hexaazatetracyclo-
[25.3.0.07,11.017,21]triacontane-6,16,26-trione 5b. Mp 151–
153°C; [h]2D0=−68.5 (c 1.9, CHCl3); 1H NMR (500
MHz, d8-toluene, 90°C, TMS): l=6.85 (bs, 3H; 3×
NH), 3.28–3.17 (m, 6H; 3×NHCH2), 2.91 (ddd, 3H,
J1=2.9 Hz, J2=7.0 Hz, J3=9.5 Hz; 3×NCHH), 2.86
(dd, 3H, J1=5.6 Hz, J2=9.3 Hz; 3×CHCO), 2.46 (dt,
3H, J1=7.6 Hz, J2=12.4 Hz; 3×NCHH), 2.21 (ddd,
3H, J1=5.7 Hz, J2=7.0 Hz, J3=12.5 Hz; 3×NCHH),
1.99 (dt, 3H, J1=7.0 Hz, J2=9.3 Hz; 3×NCHH), 1.94–
1.79 (m, 6H; 3×CH2), 1.58–1.38 (m, 12H; 6×CH2); 13C
NMR (125 MHz, d8-toluene, 90°C, TMS): l=173.6,
69.1, 55.2, 54.8, 38.0, 30.8, 30.4, 24.5; IR (CHCl3):
w=3341, 2948, 2821, 1660, 1518 cm−1; MS (EI HR):
calcd for [C24H42N6O3]+ 462.33184, found 462.33206.
Anal. calcd for C24H42N6O3: C, 62.34; H, 9.09; N,
18.18. Found: C, 62.06; H, 8.94; N, 18.26%.
4.3. Macrocyclisation procedures (3“4“5)
N-Cbz-Protected aminoesters 3a–c were subjected to
catalytic hydrogenation (H2 over 5% Pd–C in
methanol) affording aminoesters 4a–c, which were used
without further purification for subsequent macrocycli-
sation reactions.
4.3.1. Macrocyclisation reactions (4“5) promoted by
basic additives (NaOMe, NaOH, DBU, or TBAOH).
The following procedure for the macrocyclisation
employing sodium methoxide is representative for all
reactions promoted by basic additives. Aminoester 4
(1.87 mmol) was dissolved in NaONa solution in
methanol (0.4 M, 0.19 L), and allowed to stand at room
temperature for 30 days (for DBU and TBAOH pro-
moted reactions 10 equiv. of base were used). The
reaction mixture was neutralised with aq. HCl and
evaporated to dryness. The solid residue was dissolved
in water (20 mL) and extracted with CHCl3 (4×20 mL).
The combined chloroform extracts were dried (Na2SO4)
and the solvent was evaporated. Chromatographic
purification (CH2Cl2/methanol=9/1) followed by
recrystallisation from CH2Cl2/Et2O afforded the macro-
cyclic triamide 5 as colourless crystals.
4.3.5. (8S,19S,30S)-1,6,12,17,23,28-Hexaazatetracyclo-
[28.3.0.08,12.019,23]triacontane-7,18,29-trione 5c. Mp 151–
153°C; [h]2D0=−152 (c 0.50, CHCl3); 1H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.35 (bt, 3H, J=5.6 Hz;
3×NH), 3.50–3.42 (m, 3H; 3×NHCHH), 3.15 (dt, 3H,
J1=1.4 Hz, J2=7.8 Hz; 3×NCHH), 3.12–3.05 (m, 3H;
3×NHCHH), 3.01 (dd, 3H, J1=4.8 Hz, J2=10.1 Hz;
3×CHCO), 2.61 (dt, 3H, J1=7.6 Hz, J2=11.9 Hz;
3×NCHH), 2.49–2.43 (m, 3H; 3×NCHH), 2.32–2.25
(m, 3H; NCHH), 2.22–2.17 (m, 3H; 3×CHH), 1.88–
1.77 (m, 6H; 3×CHH, 3×CHH), 1.75–1.61 (m, 6H;
3×CHH, 3×CHH), 1.54–1.41 (m, 9H; 3×CH2, 3×
CHH); 13C NMR (125 MHz, CDCl3, 30°C, TMS):
l=174.7, 68.0, 55.6, 53.7, 38.6, 30.4, 27.9, 26.4, 24.2;
IR (CHCl3): w=3345, 2942, 2864, 2817, 1660, 1523,
1460 cm−1; MS (EI HR): calcd for [C27H48N6O3]+
504.37879, found 504.37919.
4.3.2. Macrocyclisation reactions (4“5) carried out
under high pressure conditions. A solution of the
aminoester 4 (0.409 mmol) in methanol (2.5 mL) was
added to a Teflon® ampoule, placed in a high-pressure
vessel filled with ligroin as a transmission medium and
compressed (10 kbar or 16 kbar) at 50°C for 7 days.
After decompression, the mixture was transferred quan-
titatively to a round-bottomed flask and the solvent was
evaporated. The crude product was purified by column
chromatography on silica (CH2Cl2/methanol=9/1), fol-
lowed by recrystallisation from CH2Cl2/Et2O, to afford
the macrocyclic triamide 5 as colourless crystals.
4.4. Reduction of the macrocyclic triamides (5“6)
4.4.1. (7S,17S,27S)-1,5,11,15,21,25-Hexaazatetracyclo-
[25.3.0.07,11.017,21]triacontane 6b. The following proce-
dure for amide reduction is representative. To a vigor-
ously stirred suspension of 5b (102 mg, 0.220 mmol) in
dry THF (10 mL) under argon, BH3·Me2S complex (10
M, 0.66 mL, 6.6 mmol) was added dropwise. For a
short period of time the reaction mixture turned into a
clear solution. The reaction mixture was then stirred at
reflux overnight (19 h), cooled to room temperature,
and a mixture of THF/water=4/1 (5 mL) was carefully
added. The mixture was evaporated to dryness. The
residue was taken up in aq. HCl (6 M, 10 mL) and
the suspension stirred under reflux until a clear
solution was seen (ca. 1 h). The mixture was eva-
porated to dryness and the solid residue was dissolved
in aq. NaOH (4 M, 5 mL) and extracted with CHCl3
(5×10 mL). The combined extracts were dried
(Na2SO4) and evaporated. Chromatographic purifica-
tion of the crude product (methanol/aq. NH3=9/1)
afforded the title compound (65 mg, 70% yield) as a
4.3.3. (6S,15S,24S)-1,4,10,13,19,22-Hexaazatetracyclo-
[22.3.0.06,10.015,19]heptacosane-5,14,23-trione 5a. Mp
1
224–225°C; [h]2D0=−149 (c 1.8, CHCl3); H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.43 (bs, 3H; 3×NH),
3.57–3.49 (m, 3H; 3×NHCHH), 3.29–3.22 (m, 3H; 3×
NHCHH), 3.16–3.08 (m, 6H; 3×NCHH, 3×CHCO),
2.89 (ddd, 3H, J1=4.8 Hz, J2=8.1 Hz, J3=12.7 Hz;
NCHH), 2.64 (dt, 3H, J1=5.1 Hz, J2=12.6 Hz; 3×
NCHH), 2.42 (dt, 3H, J1=9.5 Hz, J2=6.8 Hz; 3×
NCHH), 2.25–2.14 (m, 3H; 3×CHH), 1.94–1.87 (m,
3H; 3×CHH), 1.86–1.77 (m, 3H; 3×CHH), 1.74–1.63
(m, 3H; 3×CHH); 13C NMR (125 MHz, CDCl3, 30°C,
TMS): l=174.7, 67.9, 54.7, 54.1, 38.5, 30.1, 23.9; IR
(CHCl3): w=3347, 2822, 1663, 1524, 1450 cm−1; MS
(ESI HR): calcd for [C21H37N6O3]+ 421.2922, found
421.2914. Anal. calcd for C21H36N6O3: C, 60.00; H,
8.57; N, 20.00. Found: C, 59.75; H, 8.42; N, 19.77%.
1
colourless oil; [h]D20=−88.1 (c 0.57, CHCl3); H NMR
(500 MHz, CDCl3, 30°C, TMS): l=3.18–3.15 (m, 3H;
3×NCHH), 2.81 (dt, 3H, J1=8.1 Hz, J2=12.0 Hz;
3×NHCHH), 2.71–2.61 (m, 9H; 3×CHCH2NH, 3×
NCHH), 2.58–2.47 (m, 6H; 3×NCHH, 3×CH), 2.25

494
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 487–495
Table 4. Crystal data and structure refinement for com-
pounds 5b and 5c
4.5. X-Ray structure analysis of compounds 5b and 5c
X-Ray data for 5b were collected on a Nonius
MACH3, and on a KumaCCD diffractometer for 5c.
Data reduction was performed with the use of an
OpenMoleN system.10a Structures were solved with
direct methods SHELXS-8610b and refined with
SHELXL-97.10c Crystal data and details of structure
solution and refinement are summarised in Table 4.
5b
5c
Empirical formula
Formula weight
Temperature (K)
C24H42N6O3
462.64
293(2)
C27H48N6O3
504.71
293(2)
0.71073
Orthorhombic
P212121
9.0210(18)
9.6610(19)
32.156(6)
90
,
Wavelength (A)
1.54178
Monoclinic
P21
7.3420(10)
10.099(2)
17.338(3)
91.69(3)
1285.0(4)
2
Crystal system
Space group
,
a (A)
,
b (A)
Acknowledgements
,
c (A)
i (°)
Volume (A )
Z
3
,
2802.5(10)
4
1.196
This work was supported by the State Committee for
Scientific Research (Project 3T09A 127 15). The
authors wish to thank the Polish Science Foundation
for additional financial support. They are also indebted
to Dr. Agnieszka Szumna and Dr. Krzysztof Wozniak
for the X-ray structural analyses.
Calculated density
1.196
(Mg m−3
)
v (mm−1
F(000)
)
0.644
504
0.079
1104
q range (°)
Index ranges
2.55–74.28
05h59,
−125k50,
−215l521
1470/1366
[R(int)=0.0262]
3.39–20.00
−45h58,
−95k59,
−305l530
9752/2605
[R(int)=0.0762]
References
Reflections
collected/unique
Refinement method
Data/restraints/
parameters
1. Reviews: (a) Coordination Chemistry of Macrocyclic
Compounds; Melson, G. A., Ed.; Plenum: New York,
1979; (b) Hiraoka, M. Crown Compounds: Their Charac-
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41–49.
2. (a) Ito, H.; Fujita, J.; Torumi, K.; Ito, T. Bull. Chem.
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Espan˜a, E.; Micheloni, M.; Paoletti, P. Inorg. Chem.
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4. (a) Chandrasekhar, S.; Fortier, D. G.; McAuley, A.
Inorg. Chem. 1993, 32, 1424–1429 and references cited
therein; (b) Lloris, J. M.; Mart´ınez-Ma´n˜ez, R.; Pardo, T.;
Soto, J.; Padilla-Tosta, M. E. J. Chem. Soc., Dalton
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Keller, N.; Lance, M.; Vigner, J.-D. Acta Crystallogr.
1994, 50C, 52–54.
Full-matrix least-squares on F2
1366/1/350
2605/0/334
GooF
1.085
1.120
R indices [I\2|(I)] R1=0.0681,
wR2=0.1522
R1=0.0688,
wR2=0.1308
−5(4)
Absolute structure
parameter
−0.1(12)
Extinction coefficient 0.015(2)
0.0024(5)
0.211 and −0.183
Largest difference
0.247 and −0.219
peak and hole
−3
,
(e A
)
(dt, 3H, J1=5.7 Hz, J2=11.7 Hz; 3×NHCHH), 2.17–
2.09 (m, 3H; 3×NCHH), 1.90–1.88 (m, 3H; 3×CHH),
1.75–1.55 (m, 18H; 6×CH2, 3×CHH, 3×NH); 13C NMR
(125 MHz, CDCl3, 30°C, TMS): l=64.1, 54.4, 53.7,
53.6, 49.5, 29.3, 29.0, 23.3; IR (CHCl3): w=3278, 2949,
2879, 2811, 1603, 1462 cm−1; MS (ESI HR): calcd for
[C24H49N6]+ 421.40187, found 421.39984.
4.4.2.
(6S,15S,24S)-1,4,10,13,19,22-Hexaazatetra-
cyclo[22.3.0.06,10.015,19]heptacosane 6a. Yield 85%; a
1
colourless oil; [h]D20=−69.9 (c 0.57, CHCl3); H NMR
(500 MHz, CDCl3, 30°C, TMS): l=3.17–3.08 (m, 6H;
3×NCHH), 2.77 (dd, 3H, J1=4.4 Hz, J2=11.4 Hz;
3×CHCHHNH), 2.74–2.67 (m, 6H; 3×NHCH2), 2.64–
2.58 (m, 3H; 3×CH), 2.52 (dd, 3H, J1=6.1 Hz, J2=11.4
Hz; 3×CHCHHNH), 2.29 (dt, 3H, J1=4.5 Hz, J2=12.1
Hz; 3×NCHH), 2.26–2.10 (m, 6H; 3×NCHH, 3×NH),
1.90–1.83 (m, 3H; 3×CHCHH), 1.74–1.68 (m, 6H; 3×
CH2), 1.57–1.49 (m, 3H; 3×CHCHH); 13C NMR (125
MHz, CDCl3, 30°C, TMS): l=63.7, 54.5, 54.2, 53.6,
48.6, 28.9, 23.2; IR (CHCl3): w=3689, 3295, 2954, 2814,
1603, 1448 cm−1; MS (ESI HR): calcd for [C21H43N6]+
379.3544, found 379.3572.
5. Royer, D. J.; Grant, G. J.; Van Derveer, D. G.; Castillo,
M. J. Inorg. Chem. 1982, 21, 1902–1908.
6. Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron: Asym-
metry 1999, 10, 367–374.
7. Moon Kim, B.; Mog So, S. Tetrahedron: Asymmetry
1999, 40, 7687–7690.
8. Gryko, D. T.; Pia˛tek, P.; Pe˛cak, A.; Pa*lys, M.; Jurczak, J.

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Germany, 1986; (c) Sheldrick, G. M. SHELXL-97, Pro-
gram for Crystal Structures Refinement; University of
Go¨ttingen: Germany, 1997.
9. (a) Bisson, A. P.; Lynch, V. M.; Monahan, M.-K. C.;
Anslyn, E. V. Angew. Chem., Int. Ed. Engl. 1997, 36,
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10. (a) Nonius, B. V. OpenMoleN, Interactive Structure
.