The synthesis of L-proline derived tetraazamacrocyclic ligands of C2 symmetry via intramolecular ester aminolysis

Article abstract of DOI:10.1016/S0957-4166(01)00012-X

A convenient and efficient synthesis of enantiomerically pure 12-, 14-, and 16-membered tetraazamacrocyclic ligands, able to form complexes with transition metal cations, is discussed. Linear α,ω-aminoesters, prepared from L-proline, undergo intramolecular aminolysis to afford the corresponding macrocyclic amides in good yields.

Full text of DOI:10.1016/S0957-4166(01)00012-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 111–119
The synthesis of -proline derived tetraazamacrocyclic ligands of
L
C2 symmetry via intramolecular 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 28 November 2000; accepted 8 January 2001
Abstract—A convenient and efficient synthesis of enantiomerically pure 12-, 14-, and 16-membered tetraazamacrocyclic ligands,
able to form complexes with transition metal cations, is discussed. Linear a,v-aminoesters, prepared from L-proline, undergo
intramolecular aminolysis to afford the corresponding macrocyclic amides in good yields. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
respective racemates,11 or via the multicenter templated
condensation of chiral amines with ketones12).
There is a growing interest in the application of
polyazamacrocycles in transition metal coordination
processes, such as ion sequestration,1 biomimetic catal-
ysis,2 and biomedical uses,3 since they are effective
complexating agents.4 Among the polyazamacrocycles,
14-membered cyclam ring system (1,4,8,11-tetra-
azacyclotetradecane) and the 12-membered cyclen ring
system (1,4,7,10-tetraazacyclododecane) and their dioxo-
derivatives are of importance due to their ability to
form kinetically and thermodynamically stable com-
plexes with FeII, CoII, NiII, CuII, and PtII ions, and their
ability to stabilize high oxidation state metals.1,5 More-
over, certain complexes of NiII and FeII with cyclam
and its derivatives have been shown to catalyze organic
reactions such as alkene epoxidation,2,6,7 electrochemi-
cal epoxide carboxylation,8 and intramolecular reduc-
tive cyclization.9 As alkene oxidation processes such as
epoxidation, are associated with the formation of new
stereogenic centers, the use of optically active catalysts
is of interest. Exploiting a concept that the incorpora-
tion of functionalized side chains into a cyclam frame-
work may modify its coordination properties, Burrows
et al. have synthesized an enantiomerically pure cyclam
derivative using (S)-2,4-diaminobutyric acid,10 and sev-
Our recent communication reported a straightforward
route towards L
-proline derived cyclams,13 and detailed
an attractive methodology for the preparation of substi-
tuted cyclam 5b and its oxo- and dioxo-derivatives 6b
and 7b. The present work extends these studies on the
two other chiral tetraazamacrocycles: 5a based on the
1,5-dioxocyclen 12-membered ring, and 5c, its less com-
mon 16-membered analog (Scheme 1).
2. Results and discussion
N-Alkylation of
L-proline ester with the appropriate
N-Cbz-O-mesyl-aminoalcohols 1a–c afforded, respec-
tively, aminoesters 2a–c in good yields of 72–75%.
According to literature procedures compounds 1a14 and
1b15 are readily available from the corresponding
aminoalcohols. The unreported 1c was obtained from
N-Cbz-4-aminobutan-1-ol16 in analogous manner. In
the next step, N-alkylated
L
-prolines 3a–c were
obtained via saponification of esters 2a–c, and used in
subsequent reactions without further purification. The
amine protection was removed reductively from com-
pounds 2a–c (H2, Pd/C in methanolic HCl). In the
absence of hydrogen chloride upon hydrogenation of
2a, we observed rapid intramolecular ester aminolysis
leading to the bicyclic compound 8a (Scheme 2, 2a“
8a). Since we assumed that such an undesired process
could be expected for the other two Cbz-protected
aminoesters 2b and 2c, they were also hydrogenated in
the presence of hydrogen chloride.
eral 5,7-dioxocyclams, starting from
-valine and
-leucine7c (enantiomerically pure cyclam
L
-phenylalanine,7a
L
L
derivatives could also be obtained by resolution of
* Corresponding author. Tel.: +00 48 22 632 05 78; e-mail: jurczak
@icho.edu.pl
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00012-X

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i
Scheme 1. (a) L-Pro-OMe, Et3N, MeCN, rt then reflux; (b) H2O, reflux; (c) H2, Pd/C, HCl/MeOH; (d) 3, BuOCOCl, Et3N,
CH2Cl2, −20 to 0°C; (e) H2, Pd/C, MeOH; then NaOMe, MeOH, rt; or NaOH, MeOH, rt; or MeOH, 10 kbar, 50°C; (f) BMS,
THF, reflux, 4 h (6b) or 20 h (7b).
tion conditions. Originally,13 for the synthesis of chiral
Each of the aminoester hydrochlorides, obtained by
cyclam 5b we applied sodium methoxide in methanol
(procedure A) as a cyclization reagent (82% yield).
However, in the case of 4c, the cyclization reaction led
to a mixture of the desired product (S,S)-5c and its
meso-diastereoisomer (R,S)-5c (ca. 2:1, 78% yield, see
Table 1). In our opinion, the formation of the unde-
hydrogenation under acidic conditions, was condensed
with the appropriate, previously synthesized acid (3a–
c), to furnish corresponding amides 4a–c in a good
(75–90%) overall yield. After deprotection of the amino
group in amides 4a–c (H2, Pd/C in methanol), the
resulting aminoesters were submitted to macrocycliza-

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
113
Scheme 2. (a) H2, Pd/C, MeOH; (b) MeOH, 10 kbar, 50°C.
Table 1. Yields of bislactams under various macrocyclization conditions
Product
Procedure
A (NaOMe/MeOH, rt)
B (NaOH/MeOH, rt)
C (MeOH, 10 kbar/50°C)
5a
5b
5c
75%
82%
78%b
81%
80%
37%
48%a
66%
53%
a Accompanied by bicyclic side-product 8a.
b 2:1 mixture of (S,S)-5c:(S,R)-5c diastereoisomers (based on 1H NMR).
Figure 1. ORTEP view of compound 5a.
sired diastereoisomeric side-product (R,S)-5c should
not be attributed to epimerization of the rigid macro-
cyclic product 5c, but is presumably a result of a
partial epimerization of the substrate prior to its
cyclization caused by the strongly basic reaction condi-
tions. The absence of side products in the case of 5b
could be attributable to faster cyclization of its precur-
sor, which has only 12 atoms between reacting groups
as compared to 14 atoms in the case of the precursor
to 5c. Faster cyclization would shorten the exposure of
the precursor to epimerization conditions. To over-
come this problem other conditions which would pro-
mote cyclization reaction were investigated. Several
basic catalysts including organic bases (DBU, triethyl-
amine) and basic salts (TBAF, NaCN) were tried and
sodium hydroxide in methanol (procedure B) was
found to be the most effective base. Although for the
precursors 4b and 4c lower yields were observed com-
pared to the sodium methoxide promoted reactions, no
epimerization products were observed. Finally, as a
third cyclization procedure, high pressure conditions
were chosen. These reactions were carried out in
methanol at 50°C under 10 kbar pressure in a piston–
cylinder type apparatus17 (procedure C). Intramolecu-
lar aminolysis discussed earlier was also detected under
high pressure conditions (Scheme 2, 4a“8a). Although
the amide carbonyl group in 4a is definitely less elec-
trophilic than the ester carbonyl groups in both 2a and
4a, there is a strong preference for nucleophilic attack
leading to a six-membered ring. Yields of lactams 5a–c
for all three macrocyclization protocols are summarized
in Table 1.

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M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
The identity of ligands 5a–c was confirmed by X-ray
crystal structure analysis (Figs. 1–3).
antiomerically pure dioxo- (5b), monooxo- (6b), and
saturated cyclams derived from -proline were effec-
L
tively prepared. The method has been extended for
smaller (5a) and larger (5c) chiral macrocycles—5c
being to our knowledge the first 1,4,7,10-tetraaza-
cyclohexadecandione derivative reported to date. Three
distinct protocols for the macrocyclization reaction (4“
5), procedures A–C, have been developed. Employing
sodium hydroxide in methanol is the most general
procedure, both in terms of yield and enantiomeric
purity. Nonetheless the other two procedures offer bet-
ter performance in some particular cases. For example,
procedure A is most suited to the synthesis of 5b, whilst
procedure C gave the most efficient route to 5c. Thus
the procedures are complementary to one another. The
Reduction of 5b with BH3·Me2S complex7c over 4 hours
afforded the 2-oxocyclam 6b as a major product,
whereas exhaustive reduction of 5b with the same
reagent furnished the chiral cyclam 7b. In much the
same way this approach could be applied to com-
pounds 5a and 5c offering a convenient route to corre-
sponding analogs of 6b and 7b.
3. Conclusion
A synthetic pathway has been developed in which en-
Figure 2. ORTEP view of compound 5b.
Figure 3. ORTEP view of compound 5c.

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
115
methodology presented herein also offers an easy access
to 13- and 15-membered tetraazamacrocycles, which
can be synthesized via ‘mixed’ amides of type 4.
was transferred into a separatory funnel, washed with
0.5 M aq. HCl (50 mL), and satd aq. NaHCO3 (50
mL). The organic layer was dried (MgSO4), solvents
were evaporated and the solid residue was recrystallized
from CH2Cl2/hexanes, furnishing mesylate 1c (5.63 g,
The cyclams (5b–7b) served as chiral ligands for the
formation of NiII complexes,13 potentially useful as
chiral catalysts. Further investigations, including syn-
thesis of other more elaborated ligands of this type,
their complexes with transition metals and their use in
asymmetric catalysis are soon to be published.
1
98% yield) as colorless crystals; mp 34–36°C; H NMR
(500 MHz, CDCl3, 52°C, TMS): l=7.36–7.28 (m, 5H;
Ph), 5.10 (s, 2H; CH2Ph), 4.76 (bs, 1H; NH), 4.23 (t,
2H, J=6.3 Hz; OCH2), 3.24 (q, 2H, J=6.6 Hz; CH2N),
2.97 (s, 3H; CH3), 1.82–1.75 (m, 2H; CH2), 1.67–1.61
(m, 2H; CH2); 13C NMR (125 MHz, CDCl3, 52°C,
TMS): l=156.5, 136.7, 128.5, 128.1, 128.0, 69.3, 66.8,
40.5, 37.5, 26.5, 26.3; IR (KBr): w=3367, 3035, 2940,
1693, 1533, 1349, 1263, 1176 cm−1; MS (LSIMS HR)
calcd for [C13H20NO5S]+: 302.10622, found: 302.10542.
Anal. calcd for C13H19NO5S: C, 51.83; H, 6.31; N, 4.65.
Found: C, 51.69; H, 6.52; N, 4.69%.
4. Experimental
4.1. General methods
Melting points were determined on a Kofler hot-stage
apparatus with microscope and are uncorrected. Opti-
cal rotations were measured on a JASCO P 3010 polar-
4.3. General procedure for N-alkylation of L-proline
methyl ester
1
imeter using the sodium D line at 589 nm. H NMR
spectra were recorded on Bruker Avance 500 (500
MHz) and Varian Gemini AC-200 (200 MHz) spec-
trometers. Chemical shifts are given in ppm relative to
tetramethylsilane at l=0, with tetramethylsilane or the
residual non-deuterated solvent signal as internal stan-
dard. In addition to the conventional abbreviations for
multiplicity, the following have been used for first-order
spectra: m=multiplet, 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. 1H,1H-COSY and 1H,13C-HET-
COR experiments were carried out on some samples to
aid in the assignment of spectra. Infrared spectra were
run on Perkin–Elmer FT-IR Spectrum 2000 spec-
trophotometer. High resolution mass spectra (LSIMS
and EI) were recorded on Intectra AMD 604 spectrom-
eter. Electrospray (ESI) high resolution spectra were
recorded on Perseptive Biosystems Mariner (TOF) or
Sciex API 365 (triple quadrupole) spectrometers. Ele-
mental analyses (C, H, and N) were performed by the
‘in-house’ analytical service.
A solution of L-proline methyl ester (19.3 mmol, 2.50
g), freshly liberated from its hydrochloride, mesylate 1b
(19.3 mmol, 5.54 g), and triethylamine (1.0 equiv., 2.7
mL) in acetonitrile (10 mL) was kept overnight at room
temperature and then stirred at 50°C until the mesylate
1b was consumed (TLC). Solvents were evaporated and
the semi-solid residue was partitioned between ethyl
acetate (0.2 L) and water (25 mL). Organic layer was
then washed with water (25 mL), brine, and dried
(Na2SO4). Chromatographic purification of the crude
mixture (ethyl acetate/hexanes=7/3) afforded pure
Cbz-protected aminoester 2b in 72% yield (4.46 g) as an
oil. In the same manner, 2a (73% yield) and 2c (74%
yield) were prepared.
4.3.1. (2S)-N-(N%-(Benzyloxycarbonyl)-2%-aminoethyl))-
proline methyl ester 2a. A yellow oil; [h]2D0=−34.1 (c 1.0
1
in CHCl3); H NMR (200 MHz, CDCl3, 30°C, TMS):
l=7.45–7.27 (m, 5H; Ph), 5.70 (bs, 1H; NH), 5.12 (bs,
2H; CH2Ph), 3.70 (s, 3H; OCH3), 3.34–3.10 (m, 3H;
CH2, CHCO2), 2.86–2.58 (m, 2H; CH2), 2.48–2.34 (m,
1H; CHH), 2.26–1.74 (m, 5H; CHH, 2×CH2); 13C
NMR (50 MHz, CDCl3, 30°C, TMS): l=174.8, 156.4,
136.7, 128.3, 128.1, 127.8, 66.3, 65.5, 53.6, 53.2, 51.8,
39.6, 29.4, 23.4; IR (CHCl3): w=3418, 2955, 2823, 1715,
1512, 1456 cm−1; MS (EI HR, 70 eV) calcd for
[C16H22N2O4]+: 306.15796, found: 306.15780. Anal.
calcd for C16H22N2O4: C, 62.74; H, 7.19; N, 9.15.
Found: C, 62.57; H, 7.37; N, 9.03%.
Analytical TLC was carried out on commercially pre-
pared plates coated with 0.25 mm of self-indicating
Merck Kieselgel 60 F254 and were developed using
ninhydrine solution in butanol/acetic acid mixture, in
addition to visualization 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. N-(Benzyloxycarbonyl)-O-(methanesulphonyl)-
aminobutanol 1c
4.3.2. (2S)-N-(N%-(Benzyloxycarbonyl)-3%-aminopropyl))-
proline methyl ester 2b. A yellow oil; [h]2D0=−62.3 (c
1.43 in CHCl3); 1H NMR (500 MHz, CDCl3, 30°C,
TMS): l=7.37–7.26 (m, 5H; Ph), 5.89 (bs, 1H; NH),
5.11 (bs, 2H; CH2Ph), 3.69 (s, 3H; OCH3), 3.36–3.25
(m, 2H; CH2NH), 3.18–3.12 (m, 2H; NCHH, CHCO2),
2.80–2.78 (m, 1H; NCHH), 2.46–2.39 (m, 1H; NCHH),
2.24 (dAB, 1H, JAB=8.5 Hz, lAB=16.9 Hz; NCHH),
2.15–2.06 (m, 1H; CHH), 1.94–1.75 (m, 3H; CHH,
Cbz-Protected 4-aminobutanol (19.1 mmol, 4.26 g) and
triethylamine (3.0 mL, 1.1 equiv.) were dissolved in dry
CH2Cl2 (100 mL), placed in a cooling bath, and
methanesulphonyl anhydride (1.1 equiv., 3.76 g) was
added in a few portions with vigorous stirring. The
reaction was completed after the last portion of the
anhydride had been added (TLC). The reaction mixture

116
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
CH2), 1.71–1.61 (m, 2H; CH2); 13C NMR (125 MHz,
CDCl3, 30°C, TMS): l=174.8, 156.6, 137.0, 128.5,
127.8, 66.3, 66.1, 52.9, 52.6, 51.8, 39.5, 29.3, 27.8, 23.2;
IR (CHCl3): w=3451, 3349, 2954, 2813, 1714, 1517,
1438 cm−1; MS (EI HR, 70 eV) calcd for [C17H24N2O4]+:
320.17361, found: 320.17479.
2.97 (m, 2H; 2×CHCO), 2.94–2.81 (m, 2H; NHCHH,
NCHH), 2.72 (dt, 1H, J1=3.0 Hz, J2=12.6 Hz;
NCHH), 2.54 (dt, 1H, J1=3.7 Hz, J2=12.4 Hz;
NCHH), 2.35–2.26 (m, 2H; NCHH, NCHH), 2.22–
2.11 (m, 1H; CHH), 2.10–2.00 (m, 2H; NCHH, CHH),
1.85–1.60 (m, 6H; 2×CHH, 2×CH2); 13C NMR (125
MHz, CDCl3, 30°C, TMS): l=174.9, 174.7, 157.1,
136.9, 128.4, 128.3, 128.1, 67.8, 66.5, 66.2, 55.2, 54.8,
53.4, 53.1, 51.8, 40.1, 37.2, 30.4, 29.5, 24.1, 22.9; IR
(CHCl3): w=3360, 2884, 2816, 1714, 1655, 1526, 1439
cm−1; MS (EI HR, 70 eV) calcd for [C23H34N4O5]+:
446.25292, found: 446.25212. Anal. calcd for
C23H34N4O5·0.5H2O: C, 60.66; H, 7.69; N, 12.31.
Found: C, 60.86; H, 7.64; N, 12.27%.
4.3.3. (2S)-N-(N%-(Benzyloxycarbonyl)-4%-aminobutyl))-
proline methyl ester 2c. A yellow oil; [h]2D0=−44.3 (c 1.0
1
in CHCl3); H NMR (500 MHz, CDCl3, 46°C, TMS):
l=7.35–7.26 (m, 5H; Ph), 5.18 (bs, 1H; NH), 5.09 (bs,
2H; CH2Ph), 3.68 (s, 3H; OCH3), 3.24–3.08 (m, 4H;
CH2NH, NCHH, CHCO2), 2.70–2.63 (m, 1H;
NCHH), 2.44–2.37 (m, 1H; NCHH), 2.36–2.29 (m, 1H;
NCHH), 2.12–2.02 (m, 1H; CHH), 1.94–1.73 (m, 3H;
CHH, CH2), 1.60–1.48 (m, 4H; 2×CH2); 13C NMR (125
MHz, CDCl3, 46°C, TMS): l=174.6, 156.5, 136.9,
128.4, 128.0, 127.9, 66.6, 66.0, 54.5, 53.3, 51.5, 41.0,
29.3, 27.8, 26.0, 23.2; IR (CHCl3): w=3453, 2953, 2813,
1720, 1516, 1455, 1438 cm−1; MS (LSIMS HR) calcd
for [C18H27N2O4]+: 335.19708, found: 335.19565.
4.4.2. (2S,12S)-2,6-Cyclo-12,16-cyclo-19-(benzyloxycar-
bonylamino)-6,10,16-triaza-11-oxononadecanoic acid me-
thyl ester 4b. A yellow oil; [h]2D0=−71.8 (c 1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3, 30°C, TMS):
l=7.61 (bs, 1H; CONH), 7.37–7.28 (m, 5H; Ph), 5.23
(bs, 1H; CO2NH), 5.09 (bs, 2H; CH2Ph), 3.67 (s, 3H;
OCH3), 3.43–3.36 (m, 1H; NHCHH), 3.32–3.19 (m,
3H; NHCH2, NHCHH), 3.18–3.11 (m, 3H; CHCO2,
NCH2), 2.99 (dd, 1H, J1=5.0 Hz, J2=9.9 Hz; CHCO),
2.74 (dt, 1H, J1=7.9 Hz, J2=12.0 Hz; NCHH), 2.69–
2.60 (m, 1H; NCHH), 2.45–2.37 (m, 2H; NCH2), 2.31–
2.23 (m, 2H; NCH2), 2.18–2.06 (m, 2H; CH2), 1.98–1.62
(m, 10H; 5×CH2); 13C NMR (125 MHz, CDCl3, 30°C,
TMS): l=174.7, 174.6, 156.5, 136.7, 128.4, 128.0, 68.1,
66.5, 66.1, 53.9, 53.2, 53.0, 51.7, 39.1, 37.3, 30.5, 29.2,
28.6, 24.0, 23.1; IR (CHCl3): w=3451, 3348, 2953, 2815,
1719, 1658, 1520, 1455 cm−1; MS (LSIMS HR) calcd
for [C25H39N4O5]+: 475.29205, found: 475.29123.
4.4. General procedure for amide bond formation
A mixture of N-(benzyloxycarbonyl) aminoester 2a
(2.17 g, 7.10 mmol) and water (0.10 L) was vigorously
stirred while refluxed until saponification was complete
(TLC). Water was evaporated, followed by azeotropic
water removal with dichloromethane (three times)
affording crude N-(benzyloxycarbonyl) amino acid 3a
(2.1 g) which was used for condensation reaction with-
out further purification. The amino acid 3a (2.1 g, 7.1
mmol) and triethylamine (4 equiv., 4.0 mL) were dis-
solved in dry CH2Cl2 (70 mL). The solution was cooled
to −20°C under argon and iso-butylchloroformate (0.93
mL, 7.15 mmol) was added dropwise. The reaction
mixture was stirred at −20°C for 1 hour, and then at
0°C for an additional 1 hour. A solution of aminoester
hydrochloride (7.20 mmol, 1.50 g) [prepared in parallel
4.4.3. (2S,13S)-2,6-Cyclo-13,17-cyclo-21-(benzyloxycar-
bonylamino)-6,11,17-triaza-12-oxoheneicosanoic acid me-
thyl ester 4c. A yellow oil; [h]2D0=−70.5 (c 1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3, 30°C, TMS):
l=7.39–7.29 (m, 5H; Ph), 5.22 (bs, 1H; CO2NH), 5.09
(bs, 2H; CH2Ph), 3.69 (s, 3H; OCH3), 3.32–3.08 (m,
6H), 3.00 (dd, 1H, J1=4.7 Hz, J2=10.1 Hz; CHCO),
2.70–2.63 (m, 1H), 2.61–2.53 (m, 1H), 2.47–2.23 (m,
4H), 2.18–2.02 (m, 2H), 1.99–1.43 (m, 15H); 13C NMR
(125 MHz, CDCl3, 30°C, TMS): l=174.9, 174.8, 156.5,
136.6, 128.5, 128.1, 128.0, 67.9, 66.5, 66.2, 55.7, 54.8,
53.8, 53.5, 51.7, 40.9, 38.6, 30.6, 29.3, 28.0, 27.6, 26.3,
26.1, 24.2, 23.1; IR (CHCl3): w=3453, 3348, 2948, 2867,
2814, 1719, 1658, 1520, 1456, 1438 cm−1; MS (LSIMS
HR) calcd for [C27H43N4O5]+: 503.32335, found:
503.32445. Anal. calcd for C27H42N4O5·0.5H2O: C,
63.41; H, 8.41; N, 10.96. Found: C, 63.40; H, 8.69; N,
10.78%.
by
hydrogenolysis
of
N-(benzyloxycarbonyl)
aminoester 2a (7.20 mmol, 2.20 g) in methanolic hydro-
gen chloride (ca. 0.1 M, 8 mmol) over 5% Pd/C] was
added in dry CH2Cl2 (25 mL) at 0°C. The reaction
mixture was allowed to warm up and was kept at room
temperature overnight. Solvents were evaporated, and
the residue was taken up in ethyl acetate (0.20 L),
washed with water (2×50 mL), brine (50 mL) and dried
(Na2SO4). After solvent evaporation the residue was
purified by column chromatography (CH2Cl2/
methanol=19/1) to afford pure amide 4a (2.56 g, 85%
yield) as an oil. Amides 4b (90% yield) and 4c (75%
yield) were obtained analogously.
4.4.1. (2S,11S)-2,6-Cyclo-11,15-cyclo-17-(benzyloxycar-
bonylamino)-6,9,15-triaza-10-oxoheptadecanoic acid me-
thyl ester 4a. A yellow wax; [h]2D0=−70.6 (c 1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3, 30°C, TMS):
l=7.78 (bs, 1H; CONH), 7.37–7.28 (m, 5H; Ph), 6.50
(bs, 1H; CO2NH), 5.18 (d, 1H, J=12.1 Hz; CHHPh),
5.03 (d, 1H, J=12.1 Hz; CHHPh), 3.62 (s, 3H; OCH3),
3.58–3.47 (m, 2H; 2×NHCHH), 3.37–3.31 (m, 1H;
NCHH), 3.22–3.11 (m, 2H; NHCHH, NCHH), 3.08–
4.5. Macrocyclization procedures
N-Cbz-Protected aminoesters 4a–c were subjected to
catalytic hydrogenation (H2 over Pd/C in methanol)
prior to cyclization reactions. Each of the following
procedures (A–C) are exemplified by the preparation of
one of the macrocyclic bisamides (5b, 5a, and 5c,
respectively).

M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
117
4.5.1. Procedure A. The aminoester (1.53 g, 4.5 mmol),
obtained from 4b, was dissolved in 0.4 M sodium
methoxide methanolic solution (0.45 L) and allowed to
stand at room temperature for 28 days. After neutral-
ization with hydrogen chloride in methanol, the solvent
was evaporated, and the solid residue was extracted
with CH2Cl2. The combined extracts were passed
through a short Celite plug and the solvent was evapo-
rated. The crude product was purified by column chro-
matography (CH2Cl2/methanol=19/1), and finally
recrystallized from CH2Cl2/Et2O to afford the macro-
cyclic bislactam 5b (1.14 g, 82% yield).
(m, 2H; CHH), 2.45–2.39 (m, 2H; CHH), 2.27–2.17 (m,
4H; 4×CHH), 1.95–1.60 (m, 10H; 2×CHH, 4×CH2);
13C NMR (125 MHz, CDCl3, 30°C, TMS): l=174.5,
69.5, 54.0, 53.1, 38.2, 30.3, 26.3, 24.0; IR (CHCl3):
w=3334, 2820, 1660, 1528 cm−1; MS (EI HR, 70 eV)
calcd for [C16H28N4O2]+: 308.22123, found: 308.22126.
Anal. calcd for C16H28N4O2: C, 62.3; H, 9.09; N, 18.1.
Found: C, 62.2; H, 9.01; N, 18.1%.
4.5.6. (8S,19S)-1,6,12,18-Tetraazatricyclo[17.3.0.08,12]-
docosane-7,18-dione 5c. Colorless needles; mp 163–
1
165°C; [h]2D0=−165 (c 0.41 in CHCl3); H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.50 (bs, 2H; 2×NH),
3.65–3.57 (m, 2H; 2×NHCHH), 3.25–3.19 (m, 2H; 2×
NCHH), 3.03 (dd, 2H, J1=4.7 Hz, J2=10.1 Hz; 2×
CH), 2.98–2.91 (m, 2H; 2×NHCHH), 2.55–2.45 (m,
4H; 2×NCH2), 2.35–2.29 (m, 2H; 2×NHCHH), 2.21–
2.13 (m, 2H; 2×CHH), 1.86–1.43 (m, 14H; 2×CHH,
6×CH2); 13C NMR (125 MHz, CDCl3, 30°C, TMS):
l=175.0, 68.0, 55.8, 54.5, 37.9, 30.4, 27.6, 27.2, 24.4;
IR (KBr): w=3303, 2944, 2867, 2780, 1652, 1520, 1457
cm−1; MS (ESI HR, CH3OH) calcd for [C18H33N4O2]+:
337.2598, found: 337.2623. Anal. calcd for C18H32N4O2:
C, 64.29; H, 9.52; N, 16.67. Found: C, 64.58; H, 9.51;
N, 16.39%.
4.5.2. Procedure B. The aminoester (593 mg, 1.90
mmol), obtained from 4a, was dissolved in 0.5 M
NaOH solution in methanol (0.20 L), and allowed to
stand at room temperature for 6 days. The reaction
mixture was neutralized with aq. HCl and evaporated
to dryness. The solid residue was dissolved in water (20
mL) and extracted with CHCl3 (4×20 mL). The com-
bined chloroform extracts were dried (Na2SO4) and the
solvent was evaporated. Chromatographic purification
(CH2Cl2/methanol=19/1), followed by recrystallization
from CH2Cl2/hexanes, afforded the macrocyclic bislac-
tam 5a (430 mg, 81% yield).
4.5.3. Procedure C. A solution of the aminoester (144
mg, 0.391 mmol), obtained from 4c, in methanol (2.5
mL) was filled into a Teflon® ampule, placed in a
high-pressure vessel filled with ligroin as a transmission
medium and compressed at 10 kbar and 50°C for 7
days. After decompression, the mixture was transferred
quantitatively to a round-bottomed flask and the sol-
vent was evaporated. The crude product was purified
by column chromatography on silica (CH2Cl2/
methanol=19/1), followed by recrystallization from
CH2Cl2/hexanes, to afford the macrocyclic bislactam 5c
(70 mg, 53% yield).
4.6. Reduction of dioxocyclam 5b
4.6.1. (7S,17S)-1,5,11,15-Tetraazatricyclo[15.3.0.07,11]-
icosane-6-one 6b. To a vigorously stirred suspension of
5b (102 mg, 0.331 mmol) in dry THF (10 mL), under
argon, BH3·Me2S complex in THF (ꢀ10 M, 2.0 mmol,
0.20 mL) was added dropwise. The reaction mixture
was then stirred at reflux for 4 h. The mixture was
cooled to room temperature and a mixture of THF/
water=4/1 was carefully added (3 mL) and the solvents
were evaporated to dryness. The resulting solid was
taken up in 6 M aq. HCl (10 mL) and a suspension was
stirred at reflux until the mixture turned clear (ca. 25
min.). The solvents were then evaporated to dryness,
the solid residue was dissolved in 4 M aq. NaOH (5
mL) and extracted with CHCl3 (5×10 mL). The com-
bined extracts were dried (Na2SO4) and the solvents
were evaporated. Chromatographic separation of the
post-reaction mixture (CH2Cl2/methanol=9/1) afforded
the unreacted substrate 5b (18 mg) and title compound
(46 mg, 57% yield calculated on converted substrate) as
a colorless oil; [h]D20=−66.5 (c 0.66 in CHCl3); 1H NMR
(500 MHz, CDCl3, 30°C, TMS): l=8.50 (br. s, 1H;
CONH), 3.89–3.81 (m, 1H; CHH), 3.64–3.28 (m, 2H;
NH, CHH), 3.22 (t, 1H; J=7.5 Hz; CHH), 3.09–3.01
(m, 2H; 2×CHH), 2.98 (dt, 1H, J1=9.2 Hz, J2=2.9 Hz;
CHH), 2.88 (dd, 1H, J1=6.5 Hz, J2=9.6 Hz; CH),
2.84–2.76 (m, 2H; CHH, CHH), 2.70 (dd, 1H, J1=2.6
Hz, J2=11.6 Hz; CHH), 2.66–2.61 (m, 1H; CH), 2.60–
2.51 (m, 2H; 2×CHH), 2.47–2.40 (m, 1H; CHH), 2.27–
2.10 (m, 3H; 2×CHH, CHH), 2.06–1.96 (m, 2H; CHH,
CHH), 1.95–1.59 (m, 9H; 2×CHH, 2×CH2, CHH,
CH2); 13C NMR (125 MHz, CDCl3, 30°C, TMS): l=
174.3, 70.3, 63.9, 56.7, 56.1, 54.5, 53.1, 52.5, 51.9, 39.9,
30.5, 27.9, 26.5, 26.4, 24.4, 23.5; IR (CHCl3): w=3289,
2971, 2949, 2879, 2812, 1651, 1526, 1464, 1146,
4.5.4. (6S,15S)-1,4,10,13-Tetraazatricyclo[13.3.0.06,10]-
octadecane-5,14-dione 5a. Colorless needles; mp 153–
155°C; [h]2D0=−183 (c 1.0 in CHCl3); 1H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.60 (bd, 2H, J=8.2
Hz; 2×NH), 3.79–3.73 (ddt, 2H, J1=3.3 Hz, J1=9.5
Hz, J1=17.1 Hz; 2×NHCHH), 3.37–3.32 (m, 2H; 2×
NCHH), 3.12 (dd, 2H, J1=5.4 Hz, J2=10.4 Hz; 2×
CHCO), 2.91 (ddt, 2H, J1=2.8 Hz, J1=10.5 Hz,
J1=13.5 Hz; 2×NHCHH), 2.69–2.58 (m, 4H; 2×
NCH2), 2.35 (m, 2H; 2×NCHH), 2.27–2.17 (m, 2H;
2×CHH), 1.93–1.81 (m, 6H; 2×CHH, 2×CH2); 13C
NMR (125 MHz, CDCl3, 30°C, TMS): l=174.4, 68.4,
56.4, 53.7, 37.1, 30.2, 24.7; IR (KBr): w=3305, 2947,
2800, 1658, 1534, 1440 cm−1; MS (EI HR, 70 eV) calcd
for [C14H24N4O2]+: 280.18993, found: 280.19006. Anal.
calcd for C14H24N4O2: C, 60.00; H, 8.57; N, 20.00.
Found: C, 59.78; H, 8.52; N, 20.03%.
4.5.5. (7S,17S)-1,5,11,15-Tetraazatricyclo[15.3.0.07,11]-
icosane-6,16-dione 5b. Colorless needles; mp 250°C
1
(decomp.); [h]2D0=−182 (c 1.0 in CHCl3); H NMR (500
MHz, CDCl3, 30°C, TMS): l=7.78 (bs, 2H; 2×NH),
3.41–3.35 (m, 4H; 2×CH2), 3.24–3.19 (m, 2H; 2×CHH),
2.98 (dd, 2H, J1=5.7 Hz, J2=9.9 Hz; 2×CH), 2.87–2.80

118
M. Achmatowicz, J. Jurczak / Tetrahedron: Asymmetry 12 (2001) 111–119
Table 2. Crystal data and structure refinement for compounds 5a–c
Identification code
5a
5b
5c
Empirical formula
Formula weight
Temperature (K)
C14H24N4O2
280.37
293(2)
C16H28N4O2
308.42
293(2)
C18H32N4O2
336.48
293(2)
,
Wavelength (A)
1.54178
Monoclinic
P21
1.54178
Monoclinic
P21
1.54178
Monoclinic
C2
Crystal system
Space group
,
a (A)
11.842(1)
10.284(1)
13.127(1)
103.930(7)
1551.6(2)
4
1.200
0.664
608
5.078(1)
19.230(4)
9.107(2)
105.16(3)
858.3(3)
2
1.193
0.642
20.403(5)
5.2552(5)
17.862(2)
104.42(1)
1854.9(5)
4
1.205
0.634
736
,
b (A)
,
c (A)
i (°)
Volume (A )
3
,
Z
Calculated density (Mg m−3
)
v (mm−1
F(000)
)
336
q Range (°)
Index ranges
3.85–64.62
05h513, −125k50,
−155l514
1580/1505 [R(int)=0.0243]
4.60–73.80
05h56, −235k50,
−115l510
1663/1491 [R(int)=0.0277]
Full-matrix least-squares on F2
1491/1/232
4.48–66.21
05h523, −65k50,
−205l520
1331/1291 [R(int)=0.0354]
Reflections collected/unique
Refinement method
Data/restraints/parameters
GooF
1505/1/378
0.946
1291/1/226
1.076
0.913
R indices [I\2|(I)]
Absolute structure parameter
Extinction coefficient
R1=0.0537, wR2=0.1305
0.1(8)
0.0045(8)
R1=0.0846, wR2=0.1664
0.3(5)
0.93(6)
R1=0.0866, wR2=0.2162
0.4(1)
0.020(2)
Largest difference peak and hole
0.159 and −0.176
0.360 and −0.505
0.237 and −0.266
−3
,
(e A
)
1129 cm−1; MS (EI HR, 70 eV) calcd for [C16H30N4O]+:
294.24196, found: 294.24148.
4.7. X-Ray structure analysis of compounds 5a–c
X-Ray data were collected on a Nonius MACH3 four-
circle diffractometer using the EXPRESS procedure.18
The ꢀ–2q scanning mode was applied. Unit cell parame-
ters were obtained by refinement of 25, 15, and 25
reflections in the q-range 21.0–41.3, 18.7–23.3, and
20.9–43.2° for compounds 5a–c, respectively. Data
reduction was performed with the use of an OpenMoleN
system.19 Structures were solved with direct methods
using the SHELXS-8620 program and refined with
SHELXL-97.21 Crystal data and details of structure
solution and refinement are shown in Table 2.
4.6.2. (7S,17S)-1,5,11,15-Tetraazatricyclo[15.3.0.07,11]-
icosane 7b. To a vigorously stirred suspension of 5b (101
mg, 0.328 mmol) in dry THF (10 mL), under argon
atmosphere, BH3·Me2S complex in THF (ꢀ10 M, 6.4
mmol, 0.64 mL) was added dropwise. The reaction
mixture was then stirred at reflux for 20 h. It was cooled
to room temperature, a mixture of THF/water=4/1 was
carefully added (5 mL) and solvents were evaporated to
dryness. The resulting solid was taken up in 6 M aq. HCl
(10 mL) and a suspension was stirred at reflux until a
mixture became a clear solution (ca. 1 h). Solvents were
then evaporated to dryness, the solid residue was dis-
solved in 4 M aq. NaOH (6.5 mL) and extracted with
CHCl3 (5×10 mL). Combined extracts were dried
(Na2SO4) and solvents were evaporated. Chromato-
graphic purification of the crude product (methanol/aq.
NH3=19/1) afforded title compound (70 mg, 75% yield)
Acknowledgements
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 addi-
tional financial support. We are also indebted to
Agnieszka Szumna for X-ray structures analyses.
1
as a colorless oil; [h]2D0=−56.5 (c 0.60 in CHCl3); H
NMR (500 MHz, CDCl3, 30°C, TMS): l=3.35–3.30 (m,
2H; 2×CHH), 2.94–2.88 (m, 2H; 2×CHH), 2.84 (dt, 2H,
J1=2.6 Hz, J2=12.6 Hz; 2×CHH), 2.67–2.63 (m, 4H;
2×CH2), 2.54 (dt, 2H; J1=1.9 Hz, J2=11.0 Hz; 2×CHH),
2.49–2.43 (m, 2H; 2×CH), 2.39–2.34 (m, 2H, 2×CHH),
2.06–1.91 (m, 6H; 2×CH2, 2×CHH), 1.83–1.58 (m, 8H;
2×CHH, 2×CH2, 2×CHH); 13C NMR (125 MHz, CDCl3,
30°C, TMS): l=64.2, 56.4, 54.3, 52.3, 51.9, 27.6, 27.3,
24.1; IR (CHCl3): w=3272, 2946, 2877, 2802, 1458, 1357,
1133 cm−1; MS (EI HR, 70 eV) calcd for [C16H32N4]+:
280.26270, found: 280.26180.
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