Chemoenzymatic syntheses of two optically active hexa-azamacrocycles

Article abstract of DOI:10.1016/S0957-4166(99)00010-5

Two optically active hexa-azamacrocycles with C₂ and D₂ symmetry, respectively, have been efficiently synthesized from the enzymatically prepared (R,R)-cyclohexane-1,2-diamine bis(amidoester) derivative (R,R)-4.

Full text of DOI:10.1016/S0957-4166(99)00010-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 367–374
Chemoenzymatic syntheses of two optically active hexa-
azamacrocycles
Ignacio Alfonso, Francisca Rebolledo ∗ and Vicente Gotor ∗
Departamento de Quimica Orgánica e Inorgánica, Universidad de Oviedo, E-33071 Oviedo, Spain
Received 23 November 1998; accepted 7 January 1999
Abstract
Two optically active hexa-azamacrocycles with C2 and D2 symmetry, respectively, have been efficiently synthe-
sized from the enzymatically prepared (R,R)-cyclohexane-1,2-diamine bis(amidoester) derivative (R,R)-4. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
The design and syntheses of organic receptor molecules capable of binding anionic species have wide
interest in chemical and biological fields.1 Several approaches are based on the use of protonated polyam-
monium macrocycles.2 These compounds display positively charged binding sites at neutral pH, and their
anion complexation properties have been extensively explored.3,4 Besides charge–charge interactions,
structural factors such as the cavity size of the macrocycle or the number of nitrogens play an important
role in their anion-binding features.3,5 Thus, protonated hexa- and hepta-azamacrocycles having from 18-
to 24-membered rings are excellent receptors for organic phosphates3a,4b,d and polycarboxylates,3b,c,4a,5
and some are involved in biological processes such as excitatory amino acids,6 nucleotides or nucleic
acids.7 However, despite the importance of chirality in living organisms, examples of suitable ligands for
the selective complexation of chiral anions are scarce.8 As far as we know, there is only one example in
which saphyrin-based receptors are used for molecular recognition of optically active dicarboxylates.9
Taking this into account, our purpose in this work has been the synthesis of two optically active 22-
membered ring macrocyclic polyamines (1a and 2a) bearing the chirality carrier (R,R)-cyclohexane-
1,2-diamine fragment. The efficiency of optically active trans-cyclohexane-1,2-diamine derivatives in
asymmetric syntheses,10 and as molecular receptors,11 is well documented.
∗
Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00010-5

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2. Results and discussion
Recently we have reported an easy and efficient method for the resolution of (ꢀ)-trans-cyclohexane-
1,2-diamine by Candida antarctica lipase (CAL) catalyzed aminolysis of dimethyl malonate.12 By
controlling the conversion extent, this method allowed us to prepare the enantiopure bis(amidoester)
(R,R)-4 (Scheme 1), which was used in this work as a starting material for the synthesis of 1a and 2a.
Scheme 1.
Transformation of (R,R)-4 into the azamacrocycles 1a and 2a was carried out following the procedure
outlined in Scheme 2, which mainly involves coupling the tosylated polyamine (R,R)-6 with a doubly
electrophilic reagent in the presence of a base. Compound (R,R)-6 was easily obtained from the
enantiopure bis(amidoester) (R,R)-4 as follows. Activated ester functions of (R,R)-4 were quantitatively
converted into amides by conventional ammonolysis (ammonia in methanol). Subsequent BH3/THF
reduction of the tetra-amide led to the tetra-amine (R,R)-5, which was isolated and used in the next
step as its tetrahydrochloride. Tosylation of (R,R)-5·4HCl with tosyl chloride (Scheme 2) was efficiently
carried out in a biphasic system formed by tetrahydrofuran and aqueous potassium carbonate. Other
attempts of tosylation of the free amine (R,R)-5 using pyridine or triethylamine in tetrahydrofuran or
dichloromethane afforded lower yields of (R,R)-6 (20–27% yield) and mixtures of partially tosylated
polyamines.
Coupling of (R,R)-6 with the doubly electrophilic system, N,N0-ethylenebis-[3-(p-
toluenesulphonylamino)propyl methanesulphonate]† 13 bearing another fragment of the ring 1a,
was carried out with an excess of cesium carbonate in refluxing acetonitrile (a modification of the
Richmann–Atkins14 procedure). In these conditions the hexatosylated azamacrocycle (R,R)-1b was
obtained with a 73% yield after the purification by flash chromatography. Hydrolysis of the sulphonamide
functions of (R,R)-1b with 48% HBr and an excess of phenol yielded the desired hexa-azamacrocycle
†
N,N0-Ethylenebis[3-(p-toluenesulphonylamino)propyl methanesulphonate] was prepared from ethylenebis(sulphonamide)
following the same procedure as shown for (R,R)-10. Overall yield, 81%; mp 148–149°C, lit.13 mp 148–149°C. MS (EI) m/z
(rel. intensity): 485 (M+–Ts, 6), 320 (100). The spectral data are in accordance with literature values.13

I. Alfonso et al. / Tetrahedron: Asymmetry 10 (1999) 367–374
369
Scheme 2. Reagents and conditions: (i) NH3/MeOH; (ii) BH3/THF, reflux; (iii) TsCl, K2CO3, THF/H2O; (iv) Cs2CO3/CH3CN,
82°C then MsO(CH2)3TsN(CH2)2NTs(CH2)3OMs; (v) HBr(48%)/PhOH; (vi) Dowex, basic form, then 12 N HCl; (vii) 6 N
HCl, reflux; (viii) TsCl, K2CO3, Et2O/H2O; (ix) K2CO3/CH3CN, 3-bromopropan-1-ol; (x) MsCl/py, 0°C; (xi) Cs2CO3/CH3CN,
82°C
(R,R)-1a as its hexahydrobromic salt. In order to facilitate the purification of the macrocyclic salt,
bromide was changed to chloride by passing (R,R)-1a·6HBr through an anion exchanger and the
subsequent addition of concentrated HCl. The resulting (R,R)-1a·6HCl was easily recrystallized in an
ethanol–methanol mixture.
For the synthesis of the macrocycle (R,R,R,R)-2a, compound (R,R)-6 was coupled with (R,R)-10 in
a similar way as for (R,R)-1a. The electrophilic partner (R,R)-10 was also obtained from the bis(ami-
doester) (R,R)-4 as shown in Scheme 2. Acidic hydrolysis of (R,R)-4, followed by tosylation of the
resulting (R,R)-cyclohexane-1,2-diamine dihydrochloride (TsCl, diethyl ether/aqueous K2CO3) led to
the bis(sulphonamide) (R,R)-7. Alkylation of (R,R)-7 with 3-bromopropan-1-ol gave the diol (R,R)-8
with a moderate yield only (51%) even after a long reaction time (5 days). In this reaction, besides (R,R)-
8, the monoalkylated compound (R,R)-9 was isolated with a 20% yield. We have unsuccessfully tried
to improve the yield by changing the solvent and the base. Mesylation of (R,R)-8 was readily achieved
with mesyl chloride in pyridine at 0°C. Both the coupling of (R,R)-6 with (R,R)-10 and the subsequent
hydrolysis of the resulting sulphonamide (R,R,R,R)-2b were carried out in the same conditions as shown
previously for (R,R)-1a, obtaining compound (R,R,R,R)-2a·6HBr, which was also converted into the
corresponding hexahydrochloride to facilitate its purification.
Taking into account that the asymmetric centers do not participate in any reaction step, no racemization
is expected in these syntheses. Although 1H NMR spectra of (R,R)-1a and (R,R,R,R)-2a consist of broad
signals due to dynamic effects, 13C NMR spectra show ten and six signals, respectively, thus revealing
an effective C2 and D2 symmetry for each compound (see Experimental). These facts demonstrate that
in the above synthetic routes, epimerization of the chiral centers has not taken place, since epimerization

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would lead to the formation of cis/trans diastereomeric mixtures and so to an increase of the number of
signals in the 13C NMR spectra.
In conclusion, we have developed efficient syntheses of two optically active hexa-azamacrocycles
bearing one and two (R,R)-cyclohexane-1,2-diamine moieties in their structure, respectively. These
compounds, (R,R)-1a and (R,R,R,R)-2a, can be, in principle, good candidates for the chiral anion
complexation due to their structural characteristics: (i) they are both 22-membered rings, a convenient
size for the complexation of phosphates and polycarboxylates;3–5 (ii) they have six nitrogens forming
four propylene-1,3-diamine moieties. Azamacrocycles consisting of these groupings have increased their
protonation abilities at neutral or weakly acidic pH with respect to those azamacrocycles with ethylene-
1,2-diamine units;15 (iii) compound 1a presents C2 symmetry, whereas 2a possesses three C2 axes to
give it D2 overall symmetry. Studies of the protonation features of (R,R)-1a and (R,R,R,R)-2a, as well as
their chiral anion complexation properties, are currently in progress and will be reported elsewhere.
3. Experimental
All reagents were purchased from Aldrich Chemie. Solvents were distilled over an adequate desiccant
and stored under nitrogen. Precoated TLC plates silica gel 60 F254 from Merck were used, and for column
chromatography, Merck silica gel 60/230–400 mesh was used. Mps were taken using a Gallenkamp
apparatus and are uncorrected. Optical rotations were measured using a Perkin–Elmer 241 polarimeter.
IR spectra were recorded on a Perkin–Elmer 1720-X FT IR spectrometer. Mass spectra were recorded
on a Hewlett–Packard 5987 A spectrometer. Microanalyses were performed on a Perkin–Elmer 240B
elemental analyser. 1H and 13C NMR were obtained using a Bruker AC-300 (1H, 400 MHz and 13C, 75.5
MHz), a Bruker AC-200 (1H, 200 MHz and 13C, 50.3 MHz) or a Bruker AMX-400 (1H, 300 MHz and
13C, 100.7 MHz) spectrometer. For NMR spectra of (R,R)-1a·6HCl and (R,R,R,R)-2a·6HCl, samples
were dissolved in D2O and concentrated DCl was added until pD <2 to ensure the major existence of the
hexaprotonated species in solution.
3.1. (R,R)-N,N0-(Cyclohexane-1,2-diyl)bis(propane-1,3-diamine) tetrahydrochloride (R,R)-5·4HCl12
Bis(amidoester) (R,R)-4 (785 mg, 2.5 mmol) was added to a solution of NH3 in methanol (10%,
75 mL). After stirring at 7°C during 12 h, the solvent was removed and (R,R)-N,N0-(cyclohexane-1,2-
20
diyl)bis(2-carbamoylethanamide) was obtained quantitatively as a white solid; mp 252–253°C; [α]
D
+70.1 (c 0.65, H2O); IR (KBr) 3410, 3344, 3236, 3202, 1658, 1631 cm−1; H NMR (DMSO-d6, 300
1
MHz) δ (ppm) 1.31 (bd, J=4.9 Hz, 4H), 1.73 (bs, 2H), 1.90 (bs, 2H), 3.04 (bs, 4H), 3.61 (bs, 2H), 7,13
(bs, 2H, NH), 7.47 (bs, 2H, NH), 7.92 (bd, J=7.8 Hz, 4H). 13C NMR (DMSO-d6, 50 MHz) δ (ppm) 24.2
(CH2), 31.7 (CH2), 43.3 (CH2), 51.8 (CH), 166.8 (C), 168.9 (C). MS (EI) m/z (rel. intensity): 284 (M+, 5),
182 (100). A solution of BH3·THF (50 mL, 1 M) was added dropwise to a suspension of this tetra-amide
in tetrahydrofuran (100 mL) under nitrogen atmosphere. The obtained mixture was heated to reflux for
7 h. After this time, the reaction was treated at 0°C with 10 mL of water and evaporated to dryness. The
solid thus obtained was refluxed in 6 N HCl (100 mL) for 4 h, and then the water removed in vacuo.
The residue was dissolved in H2O, passed over Dowex 1 (basic form) and eluted with deionized water.
The solution containing (R,R)-5 was acidified until pH=2 with conc. HCl. Evaporation of the solvent
yielded (R,R)-5·4HCl (767 mg, 82%), which was recrystallized from EtOH. 1H NMR (D2O, 300 MHz)
δ (ppm) 1.05 (bt, J=9.6 Hz, 2H), 1.53 (bs, 2H), 1.73 (bs, 2H), 2.09 (m, 4H), 2.22 (bd, J=12.7 Hz, 2H),
3.05 (t, J=12.7 Hz, 4H), 3.10 (m, 2H), 3.35 (m, 2H), 3.49 (m, 2H). 13C NMR (D2O, 75.5 MHz) δ (ppm)

I. Alfonso et al. / Tetrahedron: Asymmetry 10 (1999) 367–374
371
22.2 (CH2), 24.5 (CH2), 26.1 (CH2), 37.1 (CH2), 43.3 (CH2), 58.2 (CH). MS (FAB+, nitrobenzyl alcohol
matrix) m/z (rel. intensity): 229 [(M+1)+, 2]. Anal. calcd for C12H32Cl4N4: C, 38.51; H, 8.62; N, 14.97.
Found: C, 38.25; H, 8.97; N, 14.81.
3.2. (R,R)-N,N0-(Cyclohexane-1,2-diyl)-N,N0,N00,N000-tetrakis(p-toluenesulphonyl)bis(propane-1,3-
diamine) (R,R)-6
To a suspension of K2CO3 (19.6 g) in water (16 mL), THF (16 mL), (R,R)-5·4HCl (748 mg, 2.0
mmol) and p-toluenesulphonyl chloride (2.28 g, 12.0 mmol) were added. The resulting biphasic system
was vigorously stirred for 12 h. Water and ethyl acetate were then added to the mixture. The organic layer
was washed with 3 N HCl, dried with sodium sulphate, and evaporated to give (R,R)-5 in a 74% yield
20
D
after the flash chromatography (ethyl acetate:hexane, 1:1); mp 72–73°C; [α] −8.8 (c 0.51, CHCl3); IR
(Nujol) 3279 cm−1; 1H NMR (CD3CN, 300 MHz) δ (ppm) 1.09–1.40 (several m, 6H), 1.45–1.90 (several
m, 4H), 2.27 (s, 12H), 2.40–3.15 (several m, 12H), 5.40–5.70 (several m, 2H), 7.41 (m, 8H), 7.73 (m,
8H). MS (FAB+, glycerol matrix) m/z (rel. intensity): 845 [(M+1)+, 29], 844 (M+, 15), 689 [(M−Ts)+,
39]. Anal. calcd for C40H52N4O8S4: C, 56.87; H, 6.16; N, 6.63. Found: C, 56.78; H, 6.11; N, 6.34.
3.3. (R,R)-N,N0-(Cyclohexane-1,2-diyl)bis(p-toluenesulphonamide) (R,R)-7
6 N HCl (45 mL) was added to the bis(amidoester) (R,R)-4 (1.3 g, 4 mmol) and the mixture was heated
at 110°C for 3 h. The reaction mixture was then evaporated to dryness and the residue was recrystallized
from ethanol. The resulting (R,R)-cyclohexane-1,2-diamine dihydrochloride, obtained quantitatively, was
dissolved in a biphasic system formed by diethyl ether (16 mL) and a concentrated K2CO3 aqueous
solution (8.8 g of K2CO3 dissolved in 16 mL of water). An excess of p-toluenesulphonyl chloride (1.82
g, 9.6 mmol) was then added at room temperature and the mixture vigorously stirred for 12 h. The white
solid formed during this time was filtered, successively washed with water and hot hexane and dried to
20
give pure (R,R)-7 (1.52 g, 90% yield); mp 180–181°C; [α] +7.7 (c 0.56, CHCl3); IR (KBr) 3367 cm−1;
D
1H NMR (CDCl3, 300 MHz) δ (ppm) 1.10 (bs, 4H), 1.55 (bs, 2H), 1.83 (bs, 2H), 2.40 (bs, 6H), 2.73 (bs,
2H), 4.95 (bs, 2H, NH), 7.45 (d, J=8.0 Hz, 4H), 7.72 (d, J=8.0 Hz, 4H). 13C NMR (CDCl3, 50 MHz) δ
(ppm) 21.5 (CH3), 24.1 (CH2), 33.2 (CH2), 56.5 (CH), 127.1 (CH), 129.7 (CH), 136.9 (C), 143.5 (C).
MS (FAB+, glycerol matrix) m/z (rel. intensity): 423 [(M+1)+, 100]. Anal. calcd for C20H26N2O4S2: C,
56.85; H, 6.20; N, 6.63. Found: C, 56.66; H, 6.05; N, 6.45.
3.4. (R,R)-N,N0-(Cyclohexane-1,2-diyl)bis-[3-(p-toluenesulphonylamino)propan-1-ol] (R,R)-8
(R,R)-Cyclohexane-1,2-diamine ditosylate [(R,R)-7] (844 mg, 2.0 mmol) and K2CO3 (2.76 g, 20
mmol) were suspended in dry acetonitrile (12 mL) and the mixture heated at 70°C for 30 min. 3-
bromopropan-1-ol (0.72 mL, 8.0 mmol) was then added dropwise. The reaction mixture was stirred
at 70°C until starting (R,R)-7 was not detected (TLC, ethyl acetate:hexane, 3:2). After 3 days aqueous 3
N HCl (15 mL) was added and the resulting mixture extracted with dichloromethane (3×15 mL). The
combined organic layers were dried and concentrated in vacuo to give a mixture of (R,R)-8 and (R,R)-9,
which was separated by flash chromatography using ethyl acetate:hexane (3:2) as eluent. (R,R)-8 was
20
isolated with 51% yield; mp 141–143°C; [α] +7.2 (c 0.58, CHCl3); IR (Nujol) 3138–3547 cm−1; 1H
D
NMR (CDCl3, 300 MHz) δ (ppm) 1.05–1.35 (m, 6H), 1.55 (bd, J=7.3 Hz, 2H), 2.25 (m, 4H), 2.45 (s,
6H), 2.99–3.09 (m, 2H), 3.28–3.38 (m, 2H), 3.55 (m, 2H), 3.75–3.90 (m, 4H), 7.31 (m, 4H), 7.72 (m,
4H). 13C NMR (CDCl3, 50 MHz) δ (ppm) 22.1 (CH3), 25.7 (CH2), 30.5 (CH2), 34.2 (CH2), 41.8 (CH2),

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60.5 (CH), 61.1 (CH2), 128.0 (CH), 130.4 (CH), 137.8 (C), 144.2 (C). MS (CI) m/z (rel. intensity): 539
[(M+1)+, 15], 383 [(M−Ts)+, 100]. Anal. calcd for C26H38N2O6S2: C, 57.96; H, 7.11; N, 5.20. Found:
C, 57.92; H, 7.43; N, 4.88.
3.5. (10R,20R)-N-(3-Hydroxypropyl)-N-[2-(p-toluenesulphonylamino)cyclohexyl]-p-toluenesulphona-
mide (R,R)-9
20
1
Yield, 20%; mp 178–180°C; [α] −11.7 (c 0.62, CHCl3); IR (Nujol) 3231, 3551 cm−1; H NMR
D
(CDCl3, 300 MHz) δ (ppm) 1.09–1.28 (m, 4H), 1.57–1.79 (m, 5H), 1.99 (m, 1H), 2.14 (m, 1H), 2.43 (s,
6H), 2.92 (m, 2H), 3.19 (m, 1H), 3.36 (m, 1H), 3.56 (m, 2H), 5.40 (d, J=4.4 Hz, 1H), 7.30 (m, 4H), 7.67
(m, 2H), 7.78 (m, 2H). 13C NMR (CDCl3, 50 MHz) δ (ppm) 21.4 (CH3), 23.8 (CH2), 25.1 (CH2), 29.7
(CH2), 32.9 (CH2), 34.6 (CH2), 40.1 (CH2), 54.2 (CH), 59.5 (CH2), 60.1 (CH), 126.6 (CH), 126.9 (CH),
129.5 (CH), 129.8 (CH), 137.2 (C), 138.4 (C), 143.1 (C), 143.6 (C). MS (EI) m/z (rel. intensity): 325
[(M−Ts)+, 80], 96 (100), 91 (84). Anal. calcd for C23H32N2O5S2: C, 57.47; H, 6.71; N, 5.83. Found: C,
57.26; H, 7.05; N, 5.69.
3.6. (R,R)-N,N0-(Cyclohexane-1,2-diyl)bis-[3-(p-toluenesulphonylamino)propyl methanesulphonate]
(R,R)-10
Methanesulphonyl chloride (0.40 mL, 5.2 mmol) was added dropwise under nitrogen to a solution of
(R,R)-8 (700 mg, 1.3 mmol) in dry freshly distilled pyridine (3.9 mL). After stirring at 0°C for 1.5 h,
the mixture was treated with 3 N HCl (10 mL) and extracted with dichloromethane (3×20 mL). The
combined organic layers were dried and concentrated in vacuo yielding the product (R,R)-9 as a white
20
D
1
solid (822 mg, 91%), mp 137–139°C; [α] −17.3 (c 0.51, CHCl3). H NMR (CDCl3, 300 MHz) δ
(ppm) 1.05–1.40 (m, 6H), 1.55 (bs, 2H), 2.38 (m, 4H), 2.45 (s, 6H), 3.06 (s, 6H), 3.15 (m, 4H), 3.88
(m, 2H), 4.32 (m, 4H), 7.34 (m, 4H), 7.72 (m, 4H). 13C NMR (CDCl3, 50 MHz) δ (ppm) 21.4 (CH3),
25.0 (CH2), 29.9 (CH2), 30.1 (CH2), 37.1 (CH3), 40.9 (CH2), 59.6 (CH3), 69.2 (CH2), 127.2 (CH), 129.8
(CH), 137.0 (C), 143.6 (C). MS (FAB+, nitrobenzyl alcohol matrix) m/z (rel. intensity): 797 [(M+23)+,
67], 695 [(M+1)+, 56]. Anal. calcd for C28H42N2O10S4: C, 48.39; H, 6.09; N, 4.03. Found: C, 48.76; H,
5.94; N, 3.82.
3.7. General procedure for the cyclization reactions of (R,R)-6
Dry acetonitrile (30 mL) was added to a flask containing (R,R)-6 (844 mg, 1.0 mmol) and Cs2CO3
(3.26 g, 10.0 mmol) under a nitrogen atmosphere. The mixture was refluxed for 30 min, and then a
solution of the adequate electrophilic reagent (1.0 mmol) in dry acetonitrile (20 mL) was added dropwise.
The reaction mixture was kept to reflux for 2 days. After this time, the solvent was removed and the
residue was subjected to flash chromatography (ethyl acetate:hexane, 1:1) to yield the corresponding
tosylated azamacrocycle.
3.7.1. (R,R)-2,6,10,13,17,21-Hexakis(p-toluenesulphonyl)-2,6,10,13,17,21-hexaazabicyclo-
[20.4.0]hexaicosane (R,R)-1b
20
Yield, 73%, white solid; mp 110–112°C; [α] −20.9 (c 0.58, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
(ppm) 0.95–1.60 (several m, 8H), 1.70–2.25 (several m, 8H), 2.43 (m, 18H), 2.65–3.90 (several m, 22H),
7.31 (m, 12H), 7.73 (m, 12H). MS (FAB+, nitrobenzyl alcohol matrix) m/z (rel. intensity): 1293 [(M+1)+,

I. Alfonso et al. / Tetrahedron: Asymmetry 10 (1999) 367–374
373
2], 1137 [(M−Ts)+, 5]. Anal. calcd for C62H80N6O12S6: C, 57.56; H, 6.23; N, 6.49. Found: C, 57.48; H,
6.47; N, 6.11.
3.7.2. (R,R,R,R)-2,6,10,13,17,21-Hexakis(p-toluenesulphonyl)-2,6,10,13,17,21-hexaazatricyclo-
[20.4.0.011,16] triacontane (R,R,R,R)-2b
20
Yield, 72%, white solid; mp 114–116°C; [α] −36.8 (c 0.56, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
δ (ppm) 0.95–1.60 (several m, 16H), 1.70–2.25 (several m, 8H), 2.43 (m, 18H), 2.65–3.90 (several m,
20H), 7.31 (m, 12H), 7.73 (m, 12H). MS (FAB+, nitrobenzyl alcohol matrix) m/z (rel. intensity): 1347
[(M+1)+, 2], 1191 [(M−Ts)+, 5]. Anal. calcd for C66H86N6O12S6: C, 58.81; H, 6.43; N, 6.23. Found: C,
58.90; H, 6.57; N, 5.95.
3.8. General procedure for the hydrolysis of the hexatosylated azamacrocycles
Hexatosylated azamacrocycle (0.7 mmol) and an excess of phenol (1.14 mL, 13 mmol) were dissolved
in 48% aqueous HBr (21 mL), and the solution was heated at reflux during 3 days. Water and dichlo-
romethane were then added and the aqueous layer was repeatedly washed with dichloromethane. The
organic layer was discarded and the aqueous layer was evaporated under reduced pressure. The residue
was dissolved in the minimum amount of water, passed over an anion exchanger (Dowex 1, basic form)
and eluted with deionized water until neutral pH. Concentrated HCl was added until pH ≤2 and the acid
solution was evaporated to dryness. The residue was recrystallized in a mixture of EtOH–MeOH yielding
the corresponding hexa-azamacrocycle hexahydrochloride as a white solid, which was dried in vacuo.
3.8.1. (R,R)-2,6,10,13,17,21-Hexaazabicyclo[20.4.0]hexaicosane hexahydrochloric salt (R,R)-1a·6HCl
20
D
1
Yield, 93%, decomposes at 250°C. [α] −16.1 (c 0.59, H2O); H NMR (D2O, 400 MHz) δ (ppm)
1.38 (m, 2H), 1.55–1.80 (bm, 4H), 2.05–2.45 (m, 10H), 3.10–3.52 (m, 16H), 3.55 (s, 4H), 3.64 (m, 4H).
13C NMR (D2O, 100 MHz) δ (ppm) 22.3 (CH2), 23.3 (CH2), 23.5 (CH2), 26.2 (CH2), 43.3 (CH2), 43.8
(CH2), 45.2 (CH2), 45.3 (CH2), 45.7 (CH2), 58.3 (CH). MS (FAB+, nitrobenzyl alcohol matrix) m/z (rel.
intensity): 369 [(M+1)+, 2]. Anal. calcd for C20H50N6Cl6: C, 40.89; H, 8.58; N, 14.31. Found: C, 40.72;
H, 8.38; N, 14.61.
3.8.2. (R,R,R,R)-2,6,10,13,17,21-Hexaazatricyclo[20.4.0.011,16 ]triacontane hexahydrochloric salt
(R,R,R,R)-2a·6HCl
20
D
1
Yield, 87%, decomposes at 245°C. [α] −55.6 (c 0.50, H2O); H NMR (D2O, 400 MHz) δ (ppm)
1.45 (m, 4H), 1.65 (bm, 4H), 1.85 (m, 4H), 2.25 (m, 8H), 2.33 (bd, J=11.0 Hz, 4H), 3.24 (m, 4H), 3.28
(t, J=8.0 Hz, 4H), 3.48 (m, 4H), 3.64 (m, 4H). 13C NMR (D2O, 100 MHz) δ (ppm) 22.1 (CH2), 23.5
(CH2), 26.1 (CH2), 43.3 (CH2), 45.3 (CH2), 58.2 (CH). MS (FAB+, nitrobenzyl alcohol matrix) m/z (rel.
intensity): 423 [(M+1)+, 2]. Anal. calcd for C24H56N6Cl6: C, 44.93; H, 8.80; N, 13.11. Found: C, 45.02;
H, 9.13; N, 12.81.
Acknowledgements
This work was supported by the CICYT (BIO-98-0770). I.A. thanks the Ministerio de Educación y
Ciencia for a predoctoral fellowship.

374
I. Alfonso et al. / Tetrahedron: Asymmetry 10 (1999) 367–374
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