Optically active tetraazamacrocycles analogous to cyclam

Article abstract of DOI:10.1016/S0957-4166(99)00232-3

The syntheses of enantiopure tetraazamacrocycles analogous to cyclam, (S,S)-3, (R,R)-3 and (S,S,S,S)-4, have been carried out. NMR and semiempirical studies of 3 have revealed that this compound presents a rigid conformation with C₂ symmetry, w

Full text of DOI:10.1016/S0957-4166(99)00232-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2515–2522
Optically active tetraazamacrocycles analogous to cyclam
Ignacio Alfonso, Covadonga Astorga, Francisca Rebolledo ∗ and Vicente Gotor ∗
Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 17 March 1999; revised 28 May 1999; accepted 7 June 1999
Abstract
The syntheses of enantiopure tetraazamacrocycles analogous to cyclam, (S,S)-3, (R,R)-3 and (S,S,S,S)-4, have
been carried out. NMR and semiempirical studies of 3 have revealed that this compound presents a rigid
conformation with C2 symmetry, which is stabilized by intramolecular bifurcated hydrogen bonds. Structural
studies for macrocycle 4 have shown that the presence of two cyclohexane rings of (S,S) configuration leads to the
loss of the D2 symmetry in solution, which is in agreement with the AM1 calculated structure. © 1999 Published
by Elsevier Science Ltd. All rights reserved.
1. Introduction
Cyclam (1,4,8,11-tetraazacyclotetradecane) is a useful and versatile macrocyclic tetraamine. Its ap-
plications and those of its derivatives cover a variety of fields such as coordination chemistry, catalysis,
biomimetic chemistry and medicine.1 For instance, some cyclam derivatives bearing functionalized side
chains at N and at C-6 have been used as bifunctional chelating agents for nuclear medicine applications.2
In addition, some dimers of cyclam exhibit potent inhibition of human immunodeficiency virus type 1
(HIV-1) and type 2 (HIV-2).3
On the other hand, the design of ligands possessing C2 symmetry has received much attention in
recent years.4 In particular, ligands bearing the (R,R)-cyclohexane-1,2-diamine unit have shown a high
efficiency in many asymmetric reactions.5 Moreover, this diamine has been used for the design of chiral
molecular receptors with applications in a variety of fields.6
Based on the broad spectrum of applications of both cyclam and optically active cyclohexane-1,2-
diamine, in this work we describe a simple approach to optically active cyclam analogues containing
trans-cyclohexane-1,2-diamine moieties in their structures.
∗
Corresponding authors. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00232-3

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2. Results and discussion
We have recently developed an efficient and simple method for the preparation of enantiopure (S,S)-
cyclohexane-1,2-diamine [(S,S)-1] and tetraamine (R,R)-2 by chemoenzymatic methodology.7 Following
the Richman–Atkins cyclization procedure,8,9 both of these compounds can be transformed into tetra-
azamacrocycles 3 and 4, analogous to cyclam (synthetic disconnections are outlined in Scheme 1). The
main step of these strategies involves coupling of tosylated di or polyamine with the adequate doubly
electrophilic reagent to complete the macrocyclic structure.
Scheme 1.
Synthesis of (S,S)-3 from (S,S)-1 (Scheme 1, route a) was accomplished in three steps, as shown
in Scheme 2. Tosylation of the dihydrochloride of (S,S)-1 with TsCl/K2CO3 in a diethyl ether–H2O
mixture gave (S,S)-5. The remaining portion of the macrocycle was constructed by N-alkylation of
ethylendiamine ditosylate with 3-bromopropan-1-ol, and subsequent transformation of the resulting diol
into the dimesylate 6.9,10 Coupling of (S,S)-5 with 6 in the presence of cesium carbonate in acetonitrile
afforded the macrocycle tetratosylate (S,S)-7, which was treated with 48% aqueous HBr and phenol to
give the tetrahydrobromide of the cyclam (S,S)-3.
Scheme 2. Reagents and conditions: (i) TsCl, K2CO3, Et2O/H2O (see lit.9); (ii) Cs2CO3, CH3CN; (iii) HBr (48%)/PhOH; (iv)
TsCl, K2CO3, THF/H2O (see lit.9); (v) Cs2CO3, CH3CN, then MsOCH2CH2OMs
Starting from tetraamine (R,R)-2 (Scheme 1, route b) as its tetrachlorhydrate salt,7 and applying the
same methodology, cyclam (R,R)-3·4HBr was obtained in 45% overall yield in three steps involving

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the tetratosylation of (R,R)-2, the coupling of the resulting tetraamine tetratosylate with ethylenglycol
dimesylate to give (R,R)-7, and the removal of the tosyl groups (Scheme 2).
It is notable that no differences (reaction time and yield) were observed in the above cyclization steps.
Thus, starting from bis-sulphonamide (S,S)-5 or from the less hindered (R,R)-2 derived tetrasulphon-
amide, 65% of compound 7 was obtained after two days of reaction in both cases. This means that this
reaction is not influenced by the proximity of the cyclohexane ring to the reactive centres.
Synthesis of (S,S,S,S)-4 (Scheme 3) was carried out by coupling of tosylated diamine (S,S)-5 with the
electrophilic system (S,S)-8, this last being also obtained from (S,S)-5 as described for its enantiomer9
[alkylation of (S,S)-5 with 3-bromopropan-1-ol and mesylation of the resulting diol]. Cesium carbonate
promoted cyclization afforded the macrocycle tetratosylate (S,S,S,S)-9 in 64% yield after five days of
reaction. This longer reaction time compared with that found for the synthesis of both enantiomers of
7 might be due to the difficulty in coupling two (S,S)-trans-cyclohexane derivative fragments through
a favoured conformation. Removal of the tosyl groups of 9 with HBr/phenol yielded (S,S,S,S)-4, which
was isolated as its tetrahydrobromide.
Scheme 3. Reagents and conditions: (i) Cs2CO3, CH3CN; (ii) HBr (48%)/PhOH
The unprotonated species [(S,S)-3, (R,R)-3 and (S,S,S,S)-4] may be obtained by the addition of sodium
hydroxide to the aqueous solution of the corresponding tetrahydrobromide until pH=13, followed by
extraction with dichloromethane.
1H and 13C NMR spectra of (S,S)-3 and (R,R)-3 reveal an effective C2 symmetry for this compound
on the NMR time scale (Table 1).11 This fact demonstrates that in the above synthetic procedures,
racemization processes have not taken place since these would lead to cis/trans mixtures. Moreover,
1
the H NMR spectrum is in accordance with the trans configuration, as explained below. Chemical
inequivalence is shown for all the CH2 protons of both (6- and 14-membered) rings. As a general rule,
2
for each CH2 group the most deshielded proton shows a large coupling constant (assignable to JHH
)
and at least two small ones (assignable to two gauche couplings), whereas the most shielded proton
shows at least two large J values, which are assignable to 2JHH and to one anti-periplanar coupling. This
indicates the presence in solution of one conformer with axial and equatorial positions for all the protons
of the molecule, the most deshielded proton being the equatorial one.12 Of all the hydrogens attached to
carbons bearing amino groups, the highest field signal corresponds to H1, which is in agreement with an
axial position for H1 protons and, therefore, with a trans-diequatorial positioning of the amino groups.
Values of the coupling constants for the propylene unit (Table 1) are in accordance with the existence of
a pseudo-chair conformation for the 6-membered ring, built up at the expense of a strong intramolecular
hydrogen bond between nitrogen atoms. In addition, the ROESY spectrum of 3 shows a cross peak
between H2e and H6e, supporting the co-planarity between the 6- and 14-membered rings. With this
data, we propose a conformation as shown in Table 1.
The conformation obtained from the NMR analysis of 3 was optimized by the semiempirical molecular

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Table 1
1H NMR chemical shifts (ppm) and selected coupling constants (Hz) for 3a
orbital method AM1 (Fig. 1).13 Distances measured between adjacent nitrogen atoms (2.93–3.23 Å) are
close to the sum of the van der Waals radii of the nitrogens (3.1 Å) thus indicating the presence of
bifurcated hydrogen bonds,14 which stabilize the conformation. It must be pointed out that the inversion
of all the nitrogen atoms leads to an identical geometry by symmetry. In solution, this inversion is fast on
the NMR time scale and makes H-bonded and non-H-bonded amine protons indistinguishable. Moreover,
trace amounts of acid present in the CDCl3 could accelerate this process by protonation/deprotonation
sequences.
Figure 1. AM1 minimized structure of 3. Distances N–H···N (Å) are indicated. Distances (Å) between nitrogen atoms:
N1···N2, 2.931; N2···N3, 3.181; N3···N4, 3.018; N4···N1, 3.234
Because reactions involved in the syntheses of compounds 3 and 4 are similar, and taking into account
that the asymmetric centres do not participate in any reaction step, we assume that compound 4 does

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2519
not suffer epimerization of its stereogenic centres and (S,S,S,S)-4 is the only stereoisomer obtained.
1
The H NMR spectrum of (S,S,S,S)-4 recorded in CDCl3 at rt, consists of broad signals and its 13C
NMR spectrum shows 12 signals, suggesting dynamic effects and a loss of the symmetry in solution.
In order to demonstrate the existence of these effects, a temperature-dependent 13C NMR analysis was
carried out using DMSO-d6 as solvent. At rt the spectrum was similar to that obtained in CDCl3. When
the temperature was raised to 333 K, the range between 24 and 25 ppm was simplified, passing from
three broad signals to two sharper signals. At 373 K the spectrum consisted of five signals but some
of them were broad, meaning that a mixture of conformations was present. We have also carried out
a theoretical conformational analysis obtaining two minima with very similar energy (Fig. 2). Both
geometries present only one binary axis of symmetry and they differ in the conformation of the 14-
membered ring as a consequence of the different configuration of the nitrogen atoms. Results obtained
in the NMR experiments are in agreement with the presence of these conformations in solution.
Figure 2. AM1 minimized structures of (S,S,S,S)-4. Relative energies are indicated
In conclusion, efficient syntheses of both enantiomers of a C2-symmetrical cyclam derivative, (S,S)-
3 and (R,R)-3, and the macrocycle (S,S,S,S)-4, bearing (S,S)-cyclohexane-1,2-diamine moieties in their
structures, have been carried out. Results obtained from the structural analysis of this kind of macrocycle
should be of great interest for further applications of these compounds as chiral tools.
3. Experimental
All reagents were of commercial quality and were purchased from Aldrich Chemie. Solvents were
distilled over an adequate desiccant and stored under nitrogen. For column chromatography, Merck
silica gel 60/230–400 mesh was used. Melting points were taken using a Gallenkamp apparatus and
are uncorrected. Optical rotations were measured using a Perkin–Elmer 241 polarimeter. IR spectra were
1
recorded on a Perkin–Elmer 1720-X FT infrared spectrometer. H and 13C NMR spectra were obtained
on Bruker AMX-400 (1H 400 MHz and 13C 100 MHz), Bruker AC-300 (1H 300 MHz and 13C 75.5 MHz)
and Bruker AC-200 (1H 200 MHz and 13C 50.3 MHz) spectrometers, using TMS as internal standard.
Mass spectra were recorded on a Hewlett–Packard 5987 A spectrometer. Microanalyses were performed
on a Perkin–Elmer 240B elemental analyser.
For the theoretical calculations, a preliminary conformational searching was performed with the MMX
force field as implemented in PCMODEL program.15 The structures thus obtained were used as starting
geometries for the semiempirical AM1 level of theory in the Gaussian 94 program.13 They were fully

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minimized without symmetry constraints and the frequencies analysis showed they were minima of
energy.
3.1. (S,S)-N,N0-(Cyclohexane-1,2-diyl)bis(p-toluenesulphonamide) (S,S)-5
The title compound was obtained from (S,S)-1 as described for its enantiomer (R,R)-5.9 90% Yield:
mp 180–181°C; [α]D20 −7.7 (c 0.56, CHCl3). The spectral data are in accordance with literature values.9
3.2. (1S,14S)-2,6,9,13-Tetrakis(p-toluenesulphonyl)-2,6,9,13-tetraazabicyclo[12.4.0]octadecane
(S,S)-7
Dry acetonitrile (30 mL) was added to a flask containing (S,S)-5 (423 mg, 1.0 mmol) and cesium
carbonate (3.23 g, 10.0 mmol) under a nitrogen atmosphere. The mixture was refluxed for 30 min and
then a solution of 6 (640 mg, 1.0 mmol) in dry acetonitrile (20 mL) was added dropwise. The reaction
mixture was kept at reflux for 2 days; after this time the solvent was removed and the residue was
subjected to column chromatography (ethyl acetate:hexane 1:1) to yield (S,S)-7 (565 mg, 65%) as a
20
1
white solid, mp 126–128°C; [α]D +18.3 (c 0.54, CHCl3). H NMR (CDCl3, 300 MHz) δ 0.70–1.10
(several m, 6H), 1.10–1.70 (several m, 4H), 2.27 (m, 12H), 2.75–3.90 (several m, 14H), 7.41 (m, 8H),
7.73 (m, 8H). HRMS (EI) m/z calcd for C35H47N4O6S3 (C42H54N4O8S4−Ts) 715.2658; found, 715.2661.
3.3. (1S,14S)-2,6,9,13-Tetraazabicyclo[12.4.0]octadecane tetrahydrobromide (S,S)-3·4HBr
Compound (S,S)-7 (422 mg, 0.5 mmol) and phenol (0.55 mL, 6.2 mmol) were dissolved in aqueous
48% HBr (6.6 mL), and the solution was heated at reflux for 4 days. Water and dichloromethane were
then added and the aqueous phase was repeatedly washed with dichloromethane. The organic layer was
discarded and the aqueous one was evaporated under reduced pressure. Recrystallization of the residue
from EtOH–48% aq. HBr yielded (S,S)-3·4HBr (272 mg, 94%) as a white solid, which was dried under
20
vacuum. Decomposition of the compound was observed when heated at 250°C. [α]D −20.7 (c 0.56,
H2O). 1H NMR (D2O, 200 MHz) δ 1.25–1.60 (bm, 6H), 1.75–1.60 (bm, 6H), 2.85–3.35 (bm, 14H). 13
C
NMR (D2O, 200 MHz) δ 21.7 (CH2), 22.3 (CH2), 26.5 (CH2), 41.1 (CH2), 43.0 (CH2), 44.3 (CH2), 54.9
(CH). MS (FAB+, NBA matrix) m/z (rel. intensity): 255 [(M+1)+, 100], 335 [(M+1+H79Br)+, 8], 337
[(M+1+H81Br)+, 8]. Anal. calcd for C14H34N4Br4: C, 29.09; H, 5.93; N, 9.69. Found: C, 28.71; H, 5.76;
N, 9.48. For the free amine 1H NMR data are collected in Table 1. 13C NMR (CDCl3, 100 MHz) δ 25.0
(C7), 29.3 (C3), 31.2 (C6), 47.9 (C2), 49.3 (C5), 50.7 (C4), 62.2 (C1).
3.4. (1R,14R)-2,6,9,13-Tetraazabicyclo[12.4.0]octadecane tetrahydrobromide (R,R)-3·4HBr
Dry acetonitrile (12 mL) was added to a flask containing the tetrasulphonamide derivative of (R,R)-
29 (338 mg, 0.4 mmol) and cesium carbonate (1.30 g, 4.0 mmol) under a nitrogen atmosphere. The
mixture was refluxed for 30 min and then a solution of ethylenglycol dimesylate (87.2 mg, 0.4 mmol)
in dry acetonitrile (8.0 mL) was added dropwise. The reaction mixture was kept at reflux for 2 days,
and the corresponding macrocycle tetratosylate (R,R)-7 (226 mg, 65%) was isolated using the same
procedure described for (S,S)-7. Hydrolysis of (R,R)-7 to (R,R)-3·4HBr was carried out following the
same procedure as for (S,S)-3·4HBr.

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3.5. (S,S)-N,N0-(Cyclohexane-1,2-diyl)bis-[3-(p-toluenesulphonylamino)propyl methanesulphonate]
(S,S)-8
The title compound was obtained from (S,S)-1 as described for its enantiomer (R,R)-8.9 42% Yield: mp
20
138–140°C; [α]D +20.4 (c 0.25, CHCl3). The spectral data are in accordance with literature values.9
3.6. (1S,7S,12S,18S)-2,6,13,17-Tetrakis(p-toluenesulphonyl)-2,6,13,17-tetraazatricyclo[16.4.0.07,12 ]-
docosane (S,S,S,S)-9
Dry acetonitrile (45 mL) was added to a flask containing (S,S)-5 (633 mg, 1.5 mmol) and cesium
carbonate (4.89 g, 15.0 mmol) under a nitrogen atmosphere. The mixture was refluxed for 30 min and
then a solution of (S,S)-8 (1044 mg, 1.5 mmol) in dry acetonitrile (30 mL) was added dropwise. The
reaction mixture was kept at reflux for 5 days; after this time the solvent was removed and the residue
was subjected to column chromatography (ethyl acetate:hexane 2:3) to yield (S,S,S,S)-9 (875 mg, 64%)
20
1
as a foamy solid which was precipitated in hexane, mp 152–154°C; [α]D +28.5 (c 0.52, CHCl3). H
NMR (CDCl3, 300 MHz) δ 0.70–1.70 (several m, 14H), 1.80–2.20 (several m, 6H), 2.40 (m, 12H),
2.75–3.90 (several m, 12H), 7.41 (m, 8H), 7.73 (m, 8H). MS (FAB+, NBA matrix) m/z (rel. intensity):
947 [(M+Na)+, 25], 925 [(M+1)+, 13], 769 [(M−Ts)+, 18].
3.7. (1S,7S,12S,18S)-2,6,13,17-Tetraazatricyclo[16.4.0.07,12 ]docosane tetrahydrobromide
(S,S,S,S)-4·4HBr
Compound (S,S,S,S)-9 (750 mg, 0.81 mmol) and phenol (0.90 mL, 10.1 mmol) were dissolved in
aqueous 48% HBr (11 mL), and the solution was heated at reflux for 4 days. Water and dichloromethane
were then added and the aqueous phase was repeatedly washed with dichloromethane. The organic layer
was discarded and the aqueous one was evaporated under reduced pressure. Recrystallization of the
residue from EtOH–48% aq. HBr yielded (S,S,S,S)-4·4HBr (272 mg, 72%) as a white solid, which was
dried under vacuum. Decomposition of the compound was observed when heated at 160°C. [α]D20 +18.1
1
(c 0.53, H2O). H NMR (D2O, 300 MHz) δ 1.00 (bm, 4H), 1.22 (bm, 4H), 1.40 (bm, 4H), 1.70–2.10
(bm, 8H), 2.60–3.50 (bm, 12H). MS (FAB+, NBA matrix) m/z (rel. intensity): 309 [(M+1)+, 55], 389
[(M+1+H79Br)+, 12], 391 [(M+1+H81Br)+, 12]. 13C NMR of the free amine (S,S,S,S)-4 (DMSO-d6, 75
MHz, 373 K) δ 24.2 (CH2), 24.4 (CH2), 30.7 (CH2), 44.3 (CH2), 60.6 (CH).
Acknowledgements
This work was supported by the CICYT (BIO-98-0770). I.A. thanks the Ministerio de Educación y
Ciencia for a predoctoral fellowship.
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