Conformationally biased selective alkylation of trans-cyclohexane-1,2- bis(sulfonamide) assisted by solvent-tuned protecting groups: Applications to the synthesis of a large optically active polyazamacrocycle

Article abstract of DOI:10.1002/ejoc.200600234

The selective alkylation of (R,R)-cyclohexane-1,2-bis(sulfonamide) with trityl bromoalkyl ethers has been studied in detail. The major formation of either mono- or dialkylated compounds clearly depends on the right combination of protecting groups and the

Full text of DOI:10.1002/ejoc.200600234

FULL PAPER
DOI: 10.1002/ejoc.200600234
Conformationally Biased Selective Alkylation of trans-Cyclohexane-1,2-
bis(sulfonamide) Assisted by Solvent-Tuned Protecting Groups: Applications to
the Synthesis of a Large Optically Active Polyazamacrocycle
Carmen Peña,[a] Ignacio Alfonso,[b] and Vicente Gotor*[a]
Dedicated to the memory of Professor Marcial Moreno-Mañas
Keywords: Protecting groups / Alkylation / Sulfonamides / Conformation analysis / Azamacrocycles
The selective alkylation of (R,R)-cyclohexane-1,2-bis(sulfon-
amide) with trityl bromoalkyl ethers has been studied in de-
tail. The major formation of either mono- or dialkylated com-
pounds clearly depends on the right combination of protect-
ing groups and the reaction solvent. An exhaustive study
suggests that this effect can be reasonably explained by the
conformational preferences of the monoalkylated com-
folded conformations in solution for all the tested examples.
Monte Carlo conformational searches supported this pro-
posal, showing a very good correlation between the fraction
of folded species and the selectivity towards monoalkylation.
Finally, tuning of the reaction conditions, leading to either
extended or folded conformations of the monoalkylated syn-
thetic intermediates, was exploited for the efficient synthesis
pounds, which also depend on the reaction medium, solvo- of a large optically active polyazamacrocycle.
phobic effects and weak intramolecular interactions. Struc-
tural analysis by NOE measurements showed the presence of
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
new synthetic methodologies for the mono- or dialkylation
of nonracemic trans-cyclohexane-1,2-bis(sulfonamide) 1.
During this ongoing research we found unexpected results
for the above-mentioned reaction.[13] Although the monoal-
kylation or monoprotection of cyclohexane-1,2-diamine is
not an easy task,[14] here we report an easily tunable meth-
odology for obtaining mono- or dialkylated bis(sulfon-
amide)s in high yields and selectivity depending on the reac-
tion conditions. We also decided to study this process in
depth in order to understand the factors affecting it and to
try to explain the observed behavior, which could be related
to the existence of either folded or extended conformations
of the monoalkylated intermediate. The possibility of ob-
taining monoalkylated derivatives is of great synthetic im-
portance as it would enable the preparation of unsymmetri-
cally substituted chiral ligands and synthons.[15] Related to
this and as an illustration of the potential utility of our
results, we applied the rationale of our synthetic methodol-
ogy to the preparation of a new enantiopure large polyaza-
macrocycle.
Introduction
Conformational preferences play an essential role in
chemistry[1] and biology.[2] The three-dimensional disposi-
tion of different residues, for instance, is the key factor in
the folding of biological macromolecules and, therefore, in
the active form of proteins and enzymes.[3] Usually the
spontaneous rearrangement into a given conformation is
promoted by the cooperative action of weak interactions
which work very distinctly depending on the environment.[4]
Thus, for instance, hydrophobic and hydrogen-bonding in-
teractions are essential for understanding the stability of the
DNA double helix,[5] the formation of some peptidic motifs
like α-helices[6] and β-sheets[7] or even the existence of lipid
bilayers in cell membranes.[8] Surprisingly, this interpret-
ation has not commonly been used to explain chemical re-
activity[9] even though conformational preferences could be
critical to the properties of a molecule. On the other hand,
following our studies devoted to the syntheses of new op-
tically active cyclic[10] and linear[11] polyamines and their
subsequent applications to chiral anion molecular recogni-
tion,[10c,12] we focused our efforts on the development of
Results and Discussion
[a] Departamento de Químca Orgánica e Inorgánica, Universidad
de Oviedo,
C/ Julián Clavería, s/n, 33071, Oviedo, Spain
[b] Departamento de Química Inorgánica y Orgánica, ESTCE,
Universidad Jaume I,
Selective Alkylation Reaction
In a preliminary communication,[13] we reported the ef-
fect of solvent polarity on the reaction of bis(sulfonamide)
Avd. Sos Baynat, s/n, 12071 Castellón, Spain
E-mail: vgs@fq.uniovi.es
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C. Peña, I. Alfonso, V. Gotor
1 with different trityl bromoalkyl ethers (Scheme 1). We Table 1. Selective alkylation of bis(sulfonamide) (R,R)-1.
FULL PAPER
found interesting trends in the alkylation of 1 with an excess
of the electrophile and by using potassium carbonate as a
base. The product distribution between the mono- and dial-
kylated final compounds depends dramatically on the reac-
tion conditions and, more precisely, on the solvent polarity.
Results shown in Table 1 highlight this trend. When the
process was carried out in dry acetonitrile, a very common
solvent for nucleophilic substitution, the reaction practi-
cally stopped after the monoalkylation step (Table 1, en-
tries 1–5). These results could initially be explained by the
steric hindrance between the Ts and Tr protecting groups.
Accordingly, for n = 0, alkylation occurred with only low
yields, the rest of the bis(sulfonamide) being recovered unre-
acted (ca. 50%). We extended the study to trityl bromoalkyl
ethers with different numbers of methylenes (n = 1–5). Sur-
prisingly, for all the examples tested, the reaction was also
highly selective (Ն85%) towards the formation of the
monoalkylated products, showing smooth variations in
yield with increasing lengths of the alkyl chain. These unex-
pected results suggest that the trityl protecting group is able
to prevent reaction on a remote NH center of the molecule
up to 12 bonds apart, which is quite remarkable considering
the length of the aliphatic spacer between the nitrogen
Sol-
vent
Yields
Yields
Selectivity[b]
Entry
n
R
2[a]
3[a]
2/3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
1
2
3
4
5
0
1
2
3
4
5
1
1
1
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OCPh3
OH
CH3CN 2a (20)
CH3CN 2b (70)
CH3CN 2c (80)
CH3CN 2d (75)
CH3CN 2e (67)
CH3CN 2f (75)
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
3a (4)
3b (11)
–
27:5:[68][c]
86:14
100:0
100:0
85:15
94:6
0:100
0:100
0:100
0:100
0:100
0:100
30:70
67:33
61:39
–
3e (12)
3f (5)
–
–
–
–
–
–
3a (80)
3b (72)
3c (77)
3d (79)
3e (80)
3f (82)
3g (50)
3g (30)
3h (28)
CH3CN 2g (21)
PhCH3 2g (60)
CH3CN 2h (44)
OH
Phthalimide
OCPh2-
(p-MeOC6H4)
16
1
CH3CN 2i (66)
3i (22)
75:25
[a] Isolated yields [%] after flash chromatography are given in pa-
rentheses. [b] Calculated from the isolated yields. [c] Value in brack-
ets corresponds to the percentage of recovered starting material
(50%).
atoms and the Tr group. Regarding the selectivity of the processes, the corresponding dialkylated compound was ex-
process, dependence on the aliphatic methylenic length is clusively obtained in very good isolated yields and total
rather intriguing. Thus, if we compare the results of en- chemoselectivity (entries 7–12 in Table 1). The yield ob-
tries 1–3, we find that the selectivity towards the monoalky- tained is especially shocking for the shortest electrophile
lated compound increases with increasing length of the al- (entry 7), demonstrating the large effect of the reaction me-
kylating agent. The expected effect should be the reverse if dium on the accessibility of the free NH group of the
we just consider the steric hindrance between the Tr and Ts monoalkylated intermediate, even for the example in which
groups. In addition, although the selectivity is complete for the Ts and Tr groups are closest. However, the steric hin-
n = 2,3, it drops slightly for n = 4 and is partially recovered drance in the dialkylated derivatives is evidenced from the
for n = 5. This irregular behavior cannot be explained by broad signals displayed in the 1H NMR spectra, which sug-
simple consideration of the steric interactions between the gest the presence of dynamic conformational processes on
Ts and Tr groups as this effect would gradually be attenu- the NMR timescale. Thus, for the shortest derivative (R,R)-
ated when increasing the number of methylenic groups in 3a, the presence of different conformers in solution was ob-
the electrophile.
served by the splitting of the signals of the proton nuclei
in the proximity of the sulfonamide groups, which showed
typical coalescence behavior (n = 0, Tcoal = 323 K,
500 MHz, CDCl3).[16]
As we were intrigued by the effect of the Tr group in
different solvents, we have proposed a reasonable explana-
tion for these results. Considering the flexibility of aliphatic
linear chains and by comparing data gathered in Table 1,
we ruled out steric repulsion as the only source of this be-
havior. We then suspected that the conformation of the
monoalkylated sulfonamide (R,R)-2 could play an impor-
tant role in the reactivity of the second NH group. With the
alkyl chain in an extended conformation (I in Figure 1), the
Tr group would be far away from the second sulfonamide.
However, in a folded conformation (II), the aromatic rings
of the Ts and Tr groups would be close to each other. With
the bulky Tr group, this arrangement would protect the free
NH group in 2 from reaction with a second electrophile.
Thus, the steric effect of the trityl protecting group would
Scheme 1. Alkylation of bis(sulfonamide) (R,R)-1.
More interestingly, when the reaction was carried out in be operative exclusively through a folded conformation of
dry toluene, a solvent expected to be less suitable for SN2 the monoalkylated intermediate. Besides, this conforma-
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Selective Alkylation of trans-Cyclohexane-1,2-bis(sulfonamide)
FULL PAPER
tional equilibrium is expected to be highly dependent on the tioned rationale, the folded conformations of the monoalk-
polarity of the medium. Polar solvents (such as acetonitrile) ylated compound would be favorable in this case in a more
would favor folded conformers due to solvophobic effects, hydrophobic solvent, while solvation of the OH group in
while hydrophobic environments (such as toluene) would acetonitrile would favor extended structures. Another very
stabilize the extended form. This equilibrium based on the useful electrophile for the synthesis of polyamines,[18] N-(3-
polarity of the solvent used leads to a reasonable explana- bromopropyl)phthalimide, was also assayed, leading to
tion of our results.
lower selectivity towards monoalkylation than was ob-
served with Tr (entries 2 and 15), in good accordance with
its intermediate polarity. A final example, which supports
the need for the highly hydrophobic nature of the Tr group,
was obtained by using the slightly more polar p-methoxy-
phenyldiphenylmethyl-protected 3-bromopropanol (en-
try 16). Although the steric requirements of this group are
very similar to those of Tr, the selectivity towards the
monoalkylated derivative was slightly lower, which is in
agreement with its more efficient solvation in acetonitrile.
Additional experimental evidence for the existence of
folded conformations of the monoalkylated O-trityl deriva-
tives was obtained from 1D and 2D NOESY experi-
ments.[19] For instance, we obtained weak but measurable
NOE effects with (R,R)-2e between the ortho proton of the
Ts group of the alkylated sulfonamide and the methyl pro-
tons of the Ts group of the nonalkylated one (Figure 2). In
addition, this methyl group also shows NOE contacts with
the ortho protons of the Tr group. This would set the three
protecting groups at a distance of less than 5 Å,[20] support-
ing the existence of folded conformations of (R,R)-2e and
Figure 1. Proposed conformational equilibrium of the monoalkyl-
ated intermediate.
Some additional experiments were performed to obtain
more information about the variables affecting this reaction
and to try to validate our proposal. First of all, the use of
more reactive carbonates (such as Cs2CO3)[17] had a slight
effect on the reaction kinetics but not on the product distri-
butions, ruling out any ion-pairing effect on the selectivity.
Other sulfonamide-based protecting groups such as nitro-
benzenesulfonyl (Ns) or trimethylsilylethanesulfonyl (SES)
were also examined, but the corresponding cyclohexane de-
rivatives and the subsequent synthetic intermediates exhib-
ited many solubility and stability problems. In order to
check the effect of the conformational flexibility on this
process, we also carried out the reaction using ethylene-
bis(sulfonamide) 4 instead of the trans-cyclohexane moiety.
The cyclohexane-1,2-diamine structure is expected to preor-
ganize in a folded conformation whereas the ethylenedi-
amine motif would increase the conformational freedom.
Accordingly, when using ethylenebis(sulfonamide) 4 the re-
action in acetonitrile led to the exclusive formation of the
dialkylated derivative 5 in very good yields (ca. 80%,
Scheme 2). These results support the importance of the geo-
metrical restrictions of the cyclohexane structure, with the
system prefolding in solution.
Scheme 2.
Substitution of the Tr protecting group was also investi-
gated for one of the derivatives (n = 1). As the simplest
change, we carried out the reaction with the free bromo
alcohol both in acetonitrile and in toluene (entries 13 and
14 in Table 1). Although the chemoselectivity drops, a trend
was observed that is the reverse of the one displayed by the
highly nonpolar tritylated derivative. Thus, a small prefer-
ence for the formation of the dialkylated compound was
observed in acetonitrile, while the monoalkylated derivative
Figure 2. Selected NOE effects observed in the NOESY spectrum
was slightly preferred in toluene. Using the above-men- of (R,R)-2e (CD3CN, 500 MHz).
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C. Peña, I. Alfonso, V. Gotor
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also suggesting a syn disposition of the two Ts groups. The
overall effect would be a large steric hindrance around the
nonalkylated NH group. Similar results were obtained with
all the monoalkylated derivatives of the series.
With all this experimental evidence we have shown that
there is a synergistic effect between the preorganized con-
formation in solution, the bulky and hydrophobic Tr pro-
tecting group and the polarity of the solvent which ulti-
mately determines the selectivity of the alkylation process.
Under suitable reaction conditions the free NH group of
the monosubstituted intermediates can be protected. Thus,
the Tr residue of the alkylating agent can act as a protecting
group in acetonitrile, but its shielding effect can be elimin-
ated by simply changing the polarity of the medium. This
is an interesting example of solvophobic effects, with a ter-
minal group preventing the reaction at a remote center of
the molecule. From a synthetic point of view, this effect is
of interest because of the possibility of selectively obtaining
mono- or dialkylated bis(sulfonamide)s by simply changing
the solvent, in the same manner as a conventional protec-
tion/deprotection strategy. Concomitantly, suitable control
of the sequential alkylation reaction would allow unsym-
metrical substitution of the bis(sulfonamide) core. These
possibilities have been exploited in the efficient synthesis of
a large D4 symmetrical optically active polyazamacrocycle.
Figure 3. Side and upper views of superimposed conformations of
2f within an energy gap of 1 kcal/mol. Hydrogen atoms have been
omitted for clarity.
In order to compare trends depending on the methylenic
spacer length (n) the conformations within an energy gap
of 3 kcal/mol were considered and grouped into two fami-
lies. The first one contains the geometries with a completely
extended (all-anti) arrangement of the methylenic spacer
[–TsN–CH2–(CH2)n–CH2–O–] and the second those with at
least one gauche torsion angle in that moiety which are re-
garded as being folded. The numbers of total and folded
conformers for each compound determined using two dif-
ferent force fields are shown in Table 2. Accordingly, we
calculated the fraction of folded conformers, considering
the computed relative energies and following a Boltzmann
distribution. If we plot the fraction of folded conformers
obtained by Monte Carlo simulations versus the length of
the alkylating agent (n), a correlation with the monoalkyl-
ation selectivity can be found (Figure 4). The larger is the
fraction of folded species, the higher is the selectivity of the
monoalkylation reaction. Actually, the deviation from the
observed trend found experimentally for n = 4 is reflected
in this simple analysis (Figure 4). Modeling suggests that
the flexibility of the chain with n = 4 is less than for other
values of n (either shorter of longer) and therefore protects
NH less efficiently. Thus, the source of the observed selec-
tivity seems to be closely related to the conformational pref-
erences of the monoalkylated compound towards folded
conformers. As previously anticipated, the folded conform-
ers of 2a–f would set the aromatic rings of the protecting
groups preventing the second nucleophilic NH center from
a subsequent reaction to give the dialkylated species 3a–
f.[22]
Conformational Analysis by Molecular Modeling
As the explanation for the observed results seems to rely
on the conformational preferences of the corresponding
monoalkylated intermediates, we have also tried to support
our proposal by molecular modeling studies. In order to
obtain a global picture of the systems under study, as they
are supposed to be quite flexible, we subjected compounds
2a–f to Monte Carlo conformational searches without con-
straints. Two different force fields were used (MMFF and
MMFFaq). Although many local energy minima were ob-
tained, as expected in open-chain derivatives, some interest-
ing trends can be extracted. First of all, the trans-cyclohex-
ane moiety tends to retain the chair conformation, setting
the two sulfonamide groups in an equatorial disposition,
which is in agreement with the NMR spectroscopic data. A
representative example is shown in Figure 3 for the most
flexible compound (2f, n = 5). Superimposition of the low-
est-energy conformers within a 1 kcal/mol energy range
clearly shows how the cyclohexane moiety retains its con-
formation while the other parts of the molecule are sensibly
more flexible. Interestingly, the structure tends to locate
aromatic rings from all the protecting groups (Tr and both
Ts) in an averaged spatial proximity. Thus, many conform-
ers were obtained showing close contacts between the aro-
matic rings either in a face-to-face or edge-to-face fash-
ion.[21] These noncovalent weak interactions force the ali-
phatic alkyl chain to fold back over the Ts groups and even
the Ts groups to fold towards each other in a syn disposi-
Table 2. Number of total and folded conformations obtained by
Monte Carlo searches of 2a–f.
Compound (n) MMFF conformers
∆E Յ 3 kcal/mol
MMFFaq conformers
∆E Յ 3 kcal/mol
Total
Folded
Total
Folded
2a (0)
2b (1)
2c (2)
2d (3)
2e (4)
2f (5)
6
2
9
12
5
11
19
11
13
22
11
17
22
4
9
21
11
14
22
13
12
5
15
21
In addition, some differences are observed when compar-
tion. This disposition is in good agreement with the NOE ing the nonpolar (MMFF) and polar (MMFFaq) environ-
data.
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Selective Alkylation of trans-Cyclohexane-1,2-bis(sulfonamide)
FULL PAPER
a flexible extended nonhindered molecule, leading to the
efficient dialkylation reaction, as with the linear ethylene-
bis(sulfonamide) 4.
Synthesis of a Large Optically Active Polyazamacrocycle
Considering the results obtained and with the aim of
showing the synthetic applicability of this selective
alkylation process, we envisioned the synthesis of an
Figure 4. Plots of monoalkylation selectivity (squares) and fraction
of folded conformations obtained by Monte Carlo searches
(MMFF in circles and MMFFaq in triangles) versus the length of
the alkyl chain (n in Scheme 1).
optically
active
28-membered
polyazamacrocycle,
(R,R,R,R,R,R,R,R)-6 (Scheme 3). Related compounds have
been efficiently used for the enantioselective molecular re-
cognition of chiral anions of biological relevance in aque-
ous solution.[10c,12] The structure of the proposed receptor
would contain eight chiral centers in a D4 symmetrical ar-
rangement and also eight secondary amino groups which
would cause it to display a large positive charge density in
aqueous solution close to physiological pH. To prepare this
compound, a possible retrosynthetic analysis would be as
shown in Scheme 3, which requires the preparation of both
the monoalkylated (R,R)-2b and dialkylated (R,R)-3b deriv-
atives of bis(sulfonamide) (R,R)-1. In addition, consecutive
coupling between them has to be planned carefully using
the rationale described in the previous sections. This retro-
synthetic scheme exemplifies the power and practicality of
the methodology demonstrated in this paper.
though the fraction of folded species is very similar, greater
flexibility (larger number of conformations) is found as the
polarity of the medium increases. This can be interpreted
as an effect of stabilization of some conformers in polar
environments, which are not energetically accessible in the
absence of the compensatory effects of the solvent. More
interestingly, when comparing the global minima obtained
with and without the considered solvent, we found that the
minima derived from MMFFaq calculations present a more
hindered NH group than the one in the absence of solvent
effects. Figure 5 shows the CPK representation of a selected
example (n = 4). This structure presents a more compact
geometry than that of the minimum in vacuo, again sup-
porting our proposal. Note also that these folded structures
exhibited interatomic distances that are compatible with the
observed NOEs. In addition, we found very similar situa-
tions with the other compounds of the series.
Scheme 3.
Retrosynthetic
analysis
of
macrocycle
(R,R,R,R,R,R,R,R)-6 (R: protecting group, X: leaving group).
The conventional deprotection of Tr groups in (R,R)-3b
followed by mesylation of alcohol groups in (R,R)-3g af-
forded the doubly electrophilic compound (R,R)-7 in 60%
overall isolated yield (Scheme 4). Double nucleophilic coup-
ling of (R,R)-7 with two equivalents of (R,R)-2b led to com-
pound (R,R,R,R,R,R)-8, also in 60% yield after chromato-
graphic purification. According to our proposal, this pro-
Figure 5. Global minima obtained for 2e with MMFF (left) and
MMFFaq (right) force fields. An arrow points to he nonalkylated
NH and possible aryl–aryl interactions are highlighted with dashed
lines.
Consequently, the overall effect of a polar solvent would cess has to be performed in toluene, which favors the highly
be to fold the structure in a more compact and hindered solvated extended conformations of (R,R)-2b, allowing the
conformation, preventing the second alkylation reaction. second alkylation to proceed. Note that in the synthetic se-
On the other hand, in the presence of a hydrophobic and quence of (R,R)-1 to (R,R)-2b and then to (R,R,R,R,R,R)-
aromatic solvent, the aromatic rings of the protecting 8, the two sulfonamide groups of the starting material have
groups of the monoalkylated intermediate would be ef- been selectively and consecutively alkylated by simply
ficiently solvated, the bulkiness of the Tr group being inef- changing the solvent of the reaction, avoiding standard pro-
fective. Under these circumstances, the system behaves as tection/deprotection steps. This is a very clear illustration
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C. Peña, I. Alfonso, V. Gotor
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of the synthetic applicability of the studied reaction. Again,
a deprotection/mesylation sequence led to the conversion of
(R,R,R,R,R,R)-8 into (R,R,R,R,R,R)-10 with similar yields
to those obtained in the conversion of (R,R)-3b to (R,R)-7.
Cyclization of (R,R,R,R,R,R)-10 with (R,R)-1, promoted
by Cs2CO3 in acetonitrile, yielded the octatosylated macro-
cycle (R,R,R,R,R,R,R,R)-11 in a very good yield (74%). Al-
though NMR spectra with very broad signals were ob-
tained for (R,R,R,R,R,R,R,R)-11, consistent with reduced
conformational flexibility, its cyclic structure was clearly
demonstrated by ESI-TOF mass spectrometry, which
exhibited peaks corresponding to [11·Na2]2+ and [11·Na2 +
H2O]2+ at m/z = 947 and 956, respectively. This cyclization
process also led to a small amount of open-chain oligomers
1
(ca. 12%) which were detected in the crude H NMR and
ESI-MS spectra and were readily separated from the cyclic
compound by flash chromatography. Interestingly, when the
reaction was performed in toluene, a mixture of open-chain
oligomers was observed in both the 1H NMR and ESI-MS
spectra with no traces of the macrocycle being detected.
These results suggest that our interpretation of the solvent
effect is applicable not only to the alkylation of (R,R)-1 but
to the general behavior of conformationally preorganized
compounds. Besides, we realized that our rationale is in
very good agreement with the explanation proposed to ac-
count for the success of the Richman–Atkins procedure for
the synthesis of polyazamacrocycles.[23] As initially de-
scribed in the seminal paper on this reaction, the best com-
bination seems to be bulky hydrophobic protecting groups
Scheme 4. Synthesis of macrocycle (R,R,R,R,R,R,R,R)-6. Reagents
and conditions: a) TFA in CH2Cl2:MeOH; b) MsCl/NEt3 in
CH2Cl2 [60%, two steps from (R,R)-3b]; c) (R,R)-2b, Cs2CO3,
NBu4Cl cat., PhCH3 (60%); d) (R,R)-1, Cs2CO3, CH3CN, (74%);
e) HBr (aq.), PhOH, then NaOH with CH2Cl2 extraction and then
HCl (85%).
in very polar solvents. This situation would increase the drochloride salt by conventional basic/acidic extraction pro-
fraction of folded species of the open-chain intermediate, cedures (85% yield from 11). In this case, after cleavage of
entropically favoring the cyclization towards the final prod- the bulky Ts protecting groups, clean 1H and 13C NMR
uct. Finally, detosylation of (R,R,R,R,R,R,R,R)-11 with spectra were obtained for (R,R,R,R,R,R,R,R)-6 which ex-
aqueous HBr in the presence of PhOH yielded the free hibited signals compatible with a clear D4 symmetry in
macrocycle, which can be easily converted into the octahy- solution. This observation implies that no epimerization
Figure 6. Experimental (lower trace) and simulated (upper trace) ESI-TOF spectra of an aqueous solution of the octahydrochloride of
(R,R,R,R,R,R,R,R)-6, showing the base peak assigned to the [6·4H++Cl–]3+ species. A molecular model (Monte Carlo simulation with
MMFFaq minimizations) is also shown in CPK representation.
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FULL PAPER
General Procedure for the Monoalkylation Reaction: In a flask un-
der nitrogen, (R,R)-1 (2 mmol, 0.844 g) and anhydrous K2CO3
(2.76 g, 20 mmol) were suspended in dry CH3CN (12 mL) and the
mixture heated to 70 °C for half an hour. Then, the corresponding
electrophile (8 mmol) was added dropwise and the obtained mix-
ture stirred at 70 °C for 2 days (TLC: AcOEt/hexane, 3:2). After
that, the reaction was cooled to room temperature, acidified with
3  HCl (15 mL) and extracted with CH2Cl2. The combined or-
ganic layers were dried with Na2SO4 and the solvents evaporated
to dryness. The final product was isolated by flash chromatography
process happened during our synthetic procedure as a
change in the configuration of any chiral center of
(R,R,R,R,R,R,R,R)-6 would lead to a diastereomeric mix-
ture with lower symmetry which would be clearly detectable
in the NMR spectra by a larger number of anisochronic
nuclei.
The potential applications of this macrocycle in anion
recognition are evidenced in the ESI-TOF spectrum of
an aqueous solution of the octahydrochloride of
(R,R,R,R,R,R,R,R)-6, for which the base peak corresponds using the appropriate solvent mixture.
to the [6·4H+ + Cl–]3+ species (Figure 6).[24] Full isotopic
Compound (R,R)-2a: Yield 283 mg, 20%; white solid, m.p. 204–
207 °C. [α]2D0 = –15.8 (c = 0.41, CHCl ). IR (KBr): ν = 3058 cm–1.
analysis of accurate ESI-TOF experiments confirmed the
assignation, suggesting that the main species in aqueous
solution is the tetraprotonated chloride supramolecular
complex, in good agreement with the expected basicity of
6, its quaternary symmetry and very large cavity. Moreover,
molecular modeling studies suggest that the chloride anion
fits well inside the tetraprotonated macrocyclic cavity (see
inset in Figure 6). Experiments towards applications of this
receptor in chiral anion recognition are underway in our
laboratories and will be reported in due course.
˜
3
Rf = 0.31 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.71–1.74
(m, 8 H), 2.22–2.35 (m, 1 H), 2.40 (s, 3 H), 2.65–2.97 (m, 3 H),
3.13–3.34 (m, 2 H), 5.40 (d, J = 5.4 Hz, 1 H), 7.14 (d, J = 8.1 Hz,
2 H), 7.25–7.59 (m, 19 H), 7.82 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 21.5 (CH3), 23.9 (CH2),
25.2 (CH2), 30.8 (CH2), 35.1 (CH2), 41.7 (CH2), 53.3 (CH), 59.7
(CH), 62.1 (CH2), 86.5 (C), 126.6 (CH), 127.0 (CH), 127.3 (CH),
127.7 (CH), 128.4 (CH), 129.6 (CH), 129.6 (CH), 137.8 (C), 138.0
(C), 143.2 (C), 143.3 (C), 143.7 (C) ppm. MS (ESI): m/z (%) =
731.4 (40) [M + Na]+. C41H44N2O5S2 (708.4): C 69.46, H 6.26, N
3.95; found C 69.40, H 6.14, N 3.80.
Compound (R,R)-2b: Yield 1.01 g, 70%; white solid, m.p. 191–
196 °C. Rf = 0.31 (CH2Cl2). [α]2D0 = –31.2 (c = 0.95, CHCl3). IR
Conclusions
(KBr): ν = 3058 cm–1. 1H NMR (300 MHz, CDCl ): δ = 1.00–1.81
˜
3
The selective alkylation of cyclohexane-1,2-bis(sulfonamide) has
been studied in detail. The results obtained in solvents of different
polarity have been efficiently correlated with the conformational
preferences of the corresponding monoalkylated intermediates. Re-
actions carried out with different derivatives, NMR experiments
and molecular modeling are in agreement with the presence of
folded conformations in polar environments, in which the steric
effect of the terminal Tr group prevents subsequent reaction of the
nonalkylated sulfonamide. In more solvating media, more extended
conformers prevail and this protection effect no longer exists, lead-
ing to the final dialkylated compound. Thus, by simply changing
the solvent of the reaction, we can obtain either the mono- or dial-
kylated derivatives. Finally, this rationale has been used for the ef-
ficient synthesis of an enantiopure optically active large polyazam-
acrocycle.
(m, 10 H), 2.20 (s, 3 H), 2.44 (s, 3 H), 2.50–2.86 (m, 3 H), 2.89–
3.18 (m, 2 H), 3.24–3.48 (m, 1 H), 5.63 (d, J = 4.6 Hz, 1 H), 7.12–
7.49 (m, 19 H), 7.68 (d, J = 8.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 21.5 (CH3),
24.1 (CH2), 25.4 (CH2), 30.4 (CH2), 30.9 (CH2), 35.3 (CH2), 40.5
(CH2), 54.1 (CH), 60.1 (CH), 60.9 (CH2), 86.5 (C), 126.8 (CH),
127.1 (CH), 127.2 (CH), 127.8 (CH), 128.6 (CH), 129.6 (CH), 129.8
(CH), 137.9 (C), 138.2 (C), 142.9 (C), 143.5 (C), 143.9 (C) ppm.
MS (ESI): m/z (%) = 745.2 (100) [M + Na]+, 503.1 (70) [M + Na –
Tr]+. C42H46N2O5S2 (722.4): C 69.78, H 6.41, N 3.87; found C
69.65, H 6.53, N 3.54.
Compound (R,R)-2c: Yield 1.18 g, 80%; white solid, m.p. 233–
235 °C. [α]2D0 = –37.9 (c = 0.43, CHCl ). IR (KBr): ν = 3058 cm–1.
˜
3
1
Rf = 0.42 (1.1% AcOEt/CH2Cl2). H NMR (300 MHz, CDCl3): δ
= 0.84–1.86 (m, 12 H), 2.34 (s, 3 H), 2.39 (s, 3 H), 2.74–3.08 (m, 2
H), 3.19–3.43 (m, 4 H), 5.71 (d, J = 4.2 Hz, 1 H), 7.08–7.53 (m, 19
H), 7.77 (d, J = 7.9 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 21.4 (CH3), 21.5 (CH3), 24.0 (CH2), 25.3 (CH2), 26.5 (CH2), 27.0
(CH2), 30.5 (CH2), 35.4 (CH2), 42.5 (CH2), 53.8 (CH), 59.8 (CH),
62.1 (CH2), 86.3 (C), 126.7 (CH), 126.9 (CH), 127.4 (CH), 127.7
(CH), 128.5 (CH), 129.5 (CH), 129.8 (CH), 137.9 (C), 138.0 (C),
142.8 (C), 143.4 (C), 144.1 (C) ppm. MS (ESI): m/z (%) = 581.3
(100) [M – Ts]+. C43H48N2O5S2 (736.4): C 70.08, H 6.56, N 3.80;
found C 70.23, 6.66, N 3.58.
Experimental Section
General: Reagents were purchased from Aldrich, Acros or Fluka
and used without further purification. Solvents were purified by
distillation with the appropriate drying agent. Specific rotations
were measured with a Perkin–Elmer 241 apparatus. Mass spectra
were performed with a HP-MS 1100 (ESI) or a MAT 95 (EI) spec-
trometer. NMR experiments were performed with a Bruker AC-
300, a Bruker AC-300 DPX or a Varian UNITY 500 spectrometer.
Molecular modeling calculations were performed using Spartan 04
software.[25] To obtain the energy minima, the conformer distribu-
tion calculation option available in Spartan 04 was used. With this
option, an exhaustive Monte Carlo search without constraints was
performed for every structure. The torsion angles were randomly
varied and the structures obtained fully optimized using either the
MMFF or MMFFaq force fields in separate runs. Thus, 100 energy
minima (for every run) within an energy gap of 10 kcal/mol were
generated. These structures were analyzed and ordered according
to the relative energy, with the repeated geometries being elimin-
ated.
Compound (R,R)-2d: Yield 1.13 g, 75%; white solid, m.p. 160–
162 °C. [α]2D0 = –26.7 (c = 0.39, CHCl ). IR (KBr): ν = 3058 cm–1.
˜
3
Rf = 0.31 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.93–1.74
(m, 14 H), 2.34 (s, 3 H), 2.41 (s, 3 H), 2.79–3.10 (m, 4 H), 3.19–
3.39 (m, 2 H), 5.63 (d, J = 4.2 Hz, 1 H), 7.08–7.49 (m, 19 H), 7.62
(d J = 8.3 Hz, 2 H), 7.80 (d, J = 8.3 Hz, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.4 (CH3), 23.8 (CH2), 24.0 (CH2), 25.3
(CH2), 29.3 (CH2), 29.9 (CH2), 30.6 (CH2), 35.2 (CH2), 42.8 (CH2),
54.0 (CH), 59.8 (CH), 63.2 (CH2), 86.2 (C), 126.7 (CH), 126.8
(CH), 127.1 (CH), 127.3 (CH), 127.6 (CH), 127.8 (CH), 128.5
(CH), 129.5 (CH), 129.7 (CH), 137.8 (C), 138.1 (C), 142.9 (C),
Eur. J. Org. Chem. 2006, 3887–3897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3893

C. Peña, I. Alfonso, V. Gotor
FULL PAPER
143.4 (C), 144.2 (C), 146.8 (C) ppm. MS (ESI): m/z (%) = 773.2
in dry toluene. A catalytic amount of tetrabutylammonium chloride
(40) [M + Na]+, 509.2 (100) [M – Tr]+. C44H50N2O5S2 (750.4): C was also added to increase the solubility of the inorganic salt in
70.37, H 6.71, N 3.73; found C 70.30, H 6.85, N 3.62.
toluene.
Compound (R,R)-2e: Yield 1.04 g, 67%; white solid, m.p. 91–94 °C.
Compound (R,R)-3a: Yield 1.59 g, 80%; white solid, m.p. 100–
[α]2D0 = –35.2 (c = 0.62, CHCl ). IR (KBr): ν = 3058 cm–1. R =
104 °C. [α]2D0 = –9.0 (c = 0.47, AcOEt). IR (KBr): ν = 3058 cm–1.
˜
˜
3
f
0.25 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.80–1.91 (m, 16
H), 2.36 (s, 3 H), 2.42 (s, 3 H), 2.93–3.24 (m, 4 H), 3.27–3.46 (m,
2 H), 5.71 (d, J = 4.6 Hz, 1 H), 7.14–7.63 (m, 19 H), 7.67(d, J =
8.5 Hz, 2 H), 7.83 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.6 (CH3), 24.2 (CH2), 25.5 (CH2), 25.7 (CH2), 27.0
(CH2), 30.1 (CH2), 30.7 (CH2), 35.4 (CH2), 43.0 (CH2), 54.2 (CH),
60.0 (CH), 63.5 (CH2), 87.2 (C), 126.9 (CH), 127.0 (CH), 127.5
(CH), 127.8 (CH), 128.8 (CH), 129.7 (CH), 129.9 (CH), 138.8 (C),
139.0 (C), 143.9 (C), 144.4 (C), 145.3 (C) ppm. MS (ESI): m/z (%)
= 787.2 (100) [M + Na]+. C45H52N2O5S2 (764.4): C 70.65, H 6.85,
N 3.66; found C 70.54, H 6.80, N 3.36.
Rf = 0.63 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.79–1.80
(m, 8 H), 2.40 (s, 6 H), 2.72–3.31 (m, 4 H), 3.32–3.67 (m, 3 H),
3.74–4.30 (m, 3 H), 6.80–8.17 (m, 38 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.4 (CH3), 25.0 (CH2), 31.8 (CH2), 43.3 (CH2), 57.5
(CH), 62.6 (CH2), 86.8 (C), 126.8 (CH), 127.1 (CH), 127.6 (CH),
128.5 (CH), 129.4 (CH), 138.7 (C), 142.7 (C), 143.9 (C) ppm. MS
(ESI): m/z (%) = 1017.2 (100) [M + Na]+. C62H62N2O6S2 (994.4):
C 74.73, H 6.48, N 2.60; found C 74.63, H 6.45, N 2.65.
Compound (R,R)-3b: Yield 1.47 g, 72%; white solid, m.p. 253–
256 °C. [α]2D0 = –33.2 (c = 0.25, CHCl ). IR (KBr): ν = 3058 cm–1.
˜
3
Rf = 0.63 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.10–1.42
(m, 2 H), 1.42–2.02 (m, 8 H), 2.02–2.24 (m, 2 H), 2.40 (s, 6 H),
2.84–3.53 (m, 8 H), 3.54–4.20 (m, 2 H), 6.90–7.61 (m, 34 H), 7.65–
7.97 (d, J = 8.1 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.3 (CH3), 25.3 (CH2), 30.6 (CH2), 31.8 (CH2), 42.0 (CH2), 58.4
(CH), 61.4 (CH2), 86.3 (C), 126.8 (CH), 127.3 (CH), 127.6 (CH),
128.5 (CH), 129.4 (CH), 138.5 (C), 142.7 (C), 144.1 (C) ppm. MS
(ESI): m/z (%) = 1023.3 (100) [M + 1]+. C64H66N2O6S2 (1022.7): C
75.11, H 6.50, N 2.74; found C 75.31, H 6.20, N 2.54.
Compound (R,R)-2f: Yield 1.17 g, 75%; white solid, m.p. 52–54 °C.
[α]2D0 = –30.3 (c = 0.60, CHCl ). IR (KBr): ν = 3058 cm–1. R =
˜
3
f
0.30 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.76–1.91 (m, 18
H), 2.40 (s, 6 H), 2.91–3.17 (m, 4 H), 3.26–3.43 (m, 2 H), 5.75 (d,
J = 4.1 Hz, 1 H), 7.12–7.56 (m, 19 H), 7.68 (d, J = 8.3 Hz, 2 H),
7.83 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.2 (CH3), 23.8 (CH2), 25.1 (CH2), 26.0 (CH2), 26.7 (CH2), 28.6
(CH2), 29.7 (CH2), 29.8 (CH2), 30.3 (CH2), 35.0 (CH2), 42.7 (CH2),
53.8 (CH), 59.6 (CH), 63.2 (CH2), 86.0 (C), 126.5 (CH), 126.6
(CH), 126.9 (CH), 127.1 (CH), 127.4 (CH), 128.4 (CH), 129.4
(CH), 129.4 (C), 129.6 (C), 137.6 (C), 137.8 (C), 142.7 (C), 143.2
(C), 144.1 (C) ppm. MS (ESI): m/z (%) = 801.3 (45) [M + Na]+,
559.2 (100) [M + Na – Tr]+. C46H54N2O5S2 (778.4): C 70.92, H
6.99, N 3.60; found C 70.73, H 7.15, N 3.50.
Compound (R,R)-3c: Yield 1.62 g, 77%; white solid, m.p. 73–76 °C.
[α]2D0 = –11.8 (c = 0.58, AcOEt). IR (KBr): ν = 3058 cm–1. R =
˜
f
0.63 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.09–2.08 (m, 16
H), 2.36 (s, 6 H), 2.88–3.38 (m, 8 H), 3.87–4.13 (m, 2 H), 6.95–7.59
(m, 34 H), 7.59–7.78 (d, J = 7.9 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3 (CH3), 25.3 (CH2), 26.8 (CH2), 27.7 (CH2), 32.2
(CH2), 44.3 (CH2), 58.3 (CH), 62.8 (CH2), 86.1 (C), 126.6 (CH),
127.2 (CH), 127.5 (CH), 128.5 (CH), 129.3 (CH), 139.0 (C), 142.7
(C), 144.1 (C), 144.2 (C) ppm. MS (ESI): m/z (%) = 1073.3 (90) [M
+ 1 + Na]+. C66H70N2O6S2 (1050.4): C 75.40, H 6.71, N 2.66;
found C 75.55, H, 6.54, N 2.64.
Compound (R,R)-2h: Yield 536 mg, 44%; white solid, m.p. 79–
81 °C. [α]2D0 = –45.3 (c = 0.49, CHCl ). IR (KBr): ν = 1712 cm–1.
˜
3
1
Rf = 0.11 (CH2Cl2:AcOEt, 90:5). H NMR (300 MHz, CDCl3): δ
= 0.94–1.37 (m, 6 H), 1.37–2.03 (m, 3 H), 2.18–2.34 (m, 1 H), 2.41
(s, 3 H), 2.42 (s, 3 H), 2.48–2.81 (m, 2 H), 2.88–3.19 (m, 1 H), 3.19–
3.56 (m, 3 H), 5.56 (d, J = 4.4 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 4 H),
7.63 (d, J = 8.1 Hz, 2 H), 7.70–7.91 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.4 (CH3), 23.9 (CH2), 25.2 (CH2), 29.0
(CH2), 30.5 (CH2), 35.2 (CH2), 35.3 (CH2), 40.4 (CH2), 53.9 (CH),
59.9 (CH), 60.3 (CH2), 127.1 (CH), 129.6 (CH), 129.8 (CH), 131.7
(C), 134.0 (CH), 137.32 (C), 137.9 (C), 143.1 (C), 143.6 (C), 168.0
Compound (R,R)-3d: Yield 1.70 g, 79%; white solid, m.p. 71–75 °C.
[α]2D0 = –14.24 (c = 0.50, AcOEt). IR (KBr): ν = 3058 cm–1. R =
˜
f
0.63 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.05–1.98 (m, 20
H), 2.42 (s, 6 H), 2.86–3.33 (m, 8 H), 3.87–4.17 (m, 2 H), 7.10–7.69
(m, 34 H), 7.80 (d, J = 8.1 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3 (CH3), 24.2 (CH2), 25.3 (CH2), 29.5 (CH2), 29.9
(CH2), 32.3 (CH2), 44.4 (CH2), 58.4 (CH), 63.4 (CH2), 86.1 (C),
126.7 (CH), 127.2 (CH), 127.5 (CH), 128.5 (CH), 129.4 (CH), 129.3
(CH), 138.9 (C), 142.8 (C), 142.8 (C), 144.3 (C) ppm. MS (ESI):
m/z (%) = 1101.3 (20) [M + Na]+. C68H74N2O6S2 (1078.4): C 75.66,
H 6.91, N 2.60; found C 75.60, H 6.80, N 2.60.
(C) ppm. MS (ESI): m/z (%)
= 632.1 (100) [M +
Na]+.
C31H35N3O6S2 (609.1): C 61.06, H 5.79, N 6.89; found C 61.36, H
5.99, N 6.80.
Compound (R,R)-2i: Yield 993 mg, 66%; white solid, m.p. 82–
86 °C. [α]2D0 = –45.4 (c = 0.83, AcOEt). IR (KBr): ν = 3070 cm–1.
˜
Rf = 0.15 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.96–1.52
(m, 6 H), 1.52–1.82 (m, 4 H), 2.19 (s, 3 H), 2.42 (s, 3 H), 2.48–2.65
(m, 1 H), 2.65–2.85 (m, 2 H), 2.85–3.16 (m, 2 H), 3.31–3.46 (m, 1
H), 3.81 (s, 3 H), 5.69 (d, J = 4.4 Hz, NH), 6.9 (d, J = 8.9 Hz, 2
H), 7.10–7.55 (m, 16 H), 7.68 (d, J = 8.3 Hz, 2 H), 7.8 (d, J =
8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.1 (CH3),
21.3 (CH3), 23.9 (CH2), 25.1 (CH2), 30.2 (CH2), 30.6 (CH2), 35.0
(CH2), 40.3 (CH2), 55.0 (CH), 59.9 (CH), 60.5 (CH2), 86.0 (C),
112.9 (CH3), 126.6 (CH), 126.7 (CH), 127.6 (CH), 127.5 (CH),
128.1 (CH), 129.4 (CH), 127.7 (CH), 130.0 (CH), 135.4 (C), 137.6
(C), 137.4 (C), 142.8 (C), 143.3 (C), 142.2 (C), 144.3 (C), 158.4
(C) ppm. MS (ESI): m/z (%) = 997.7 (60) [M + Na]+, 776.32 (100)
[M + 1 + Na]+. C43H48N2O6S2 (752.3): C 68.59, H 6.43, N 3.72;
found C 68.42, H 6.65, N 3.50.
Compound (R,R)-3e: Yield 1.77 g, 80%; white solid, m.p. 74–77 °C.
[α]2D0 = –15.9 (c = 0.80, AcOEt). IR (KBr): ν = 3058 cm–1. R =
˜
f
0.63 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.07–1.96 (m, 24
H), 2.42 (s, 6 H), 2.82–3.28 (m, 8 H), 3.80–4.14 (m, 2 H), 7.07–7.63
(m, 34 H), 7.81 (d, J = 7.9 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3 (CH3), 25.4 (CH2), 25.8 (CH2), 27.3 (CH2), 27.3
(CH2), 29.9 (CH2), 32.3 (CH2), 44.4 (CH2), 58.4 (CH), 63.4 (CH2),
85.1 (C), 126.7 (CH), 127.3 (CH), 127.6 (CH), 127.8 (CH), 129.4
(CH), 138.9 (C), 142.8 (C), 144.4 (C) ppm. MS (ESI): m/z (%) =
1129.3 (40) [M + Na]+. C70H78N2O6S2 (1106.4): C 75.91, H 7.10,
N 2.53; found C 75.74, H 7.05, N 2.64.
Compound (R,R)-3f: Yield 1.86 g, 82%; white solid, m.p. 57–60 °C.
[α]2D0 = –18.6 (c = 0.60, CHCl ). IR (KBr): ν = 3058 cm–1. R =
˜
3
f
General Procedure for the Dialkylation Reaction: The reaction was
0.52 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.65–2.00 (m, 28
carried out following the procedure used for monoalkylation but
H), 2.41 (s, 6 H), 2.72–3.64 (m, 8 H), 3.73–4.06 (m, 2 H), 6.89–8.03
3894
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3887–3897

Selective Alkylation of trans-Cyclohexane-1,2-bis(sulfonamide)
(m, 38 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 25.4
FULL PAPER
General Procedure for the Mesylation Reaction: Mesyl chloride
(CH2), 26.1 (CH2), 27.4 (CH2), 29.0 (CH2), 29.9 (CH2), 32.3 (CH2), (0.105 mL, 1.35 mmol) was added dropwise to a solution of the
44.4 (CH2), 58.4 (CH), 63.5 (CH2), 86.2 (C), 126.7 (CH), 127.3 corresponding diol (0.4 mmol, 0.584 g) in dry CH2Cl2 (5 mL) and
(CH), 127.6 (CH), 128.6 (CH), 129.4 (CH), 138.9 (C), 142.8 (C), dry Et3N (0.2 mL, 1.43 mmol) at 0 °C. Once the starting diol had
144.4 (C) ppm. MS (ESI): m/z (%) = 979.6 (100) [M – Ts]+. been consumed (TLC monitoring) the solvent was evaporated and
C72H82N2O6S2 (1134.6): C 76.15, H 7.28, N 2.47; found C 76.05,
H 7.35, N 2.23.
the product purified by flash chromatography.
Compound (R,R)-7 showed the correct spectroscopic and analyti-
Compound (R,R)-3h: Yield 446 mg, 28%; white solid, m.p. 83–
cal data, as described previously.[10d]
85 °C. [α]2D0 = –45.87 (c = 0.92, CHCl ). IR (KBr): ν = 1711 cm–1.
˜
3
1
Rf = 0.13 (CH2Cl2/AcOEt, 90:5). H NMR (300 MHz, CDCl3): δ
Compound (R,R,R,R,R,R)-10: Yield 557 mg, 86%; white solid, m.p.
133–135 °C. [α]2D0 = –15.29 (c = 0.49, CHCl3). Rf = 0.31 (AcOEt/
hexane, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.70–1.68 (m, 27
H), 1.84–2.11 (m, 3 H), 2.11–2.55 (m, 20 H), 2.66–3.34 (m, 15 H),
3.56–4.44 (m, 10 H), 6.89–7.46 (m, 12 H), 7.46–7.95 (m, 12 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 24.7 (CH2), 24.9
(CH2), 25.1 (CH2), 29.8 (CH2), 30.1 (CH2), 30.2 (CH2), 30.5 (CH2),
36.9 (CH3), 40.8 (CH2), 41.5 (CH2), 58.3 (CH), 58.6 (CH), 59.3
(CH), 60.1 (CH2), 69.0 (2×CH2), 127.2 (CH), 129.4 (CH), 129.5
(CH), 129.6 (CH), 137.5 (C), 137.6 (C), 138.5 (C), 142.7 (C), 143.0
(C), 143.2 (C) ppm. MS (ESI): m/z (%) = 1639.2 (20) [M + H2O]+.
C74H102N6O18S8 (1618.5): C 54.86, H 6.35, N 5.19; found C 54.55,
H 6.20, N 5.05.
= 1.02–1.45 (m, 4 H), 1.47–1.78 (m, 5 H), 1.86–2.23 (m, 3 H), 2.37
(s, 6 H), 2.85–3.34 (m, 3 H), 3.41–3.69 (m, 4 H), 3.69–3.99 (m, 3
H), 7.21 (d, J = 8.1 Hz, 4 H), 7.63 (d, J = 8.0 Hz, 2 H),7.66–7.96
(m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 25.3
(CH2), 29.3 (CH2), 31.7 (CH2), 36.0 (CH2), 41.9 (CH2), 58.5 (CH),
123.1 (CH), 127.3 (CH), 129.6 (CH), 132.1 (C), 133.7 (CH), 138.0
(C), 143.1 (C), 168.3 (C) ppm. MS (ESI): m/z (%) = 819.0 (100) [M
+ Na]+. C42H44N4O8S2 (796.3): C 63.30, H 5.56, N 7.03; found C
63.15, H 5.64, N 7.15.
Compound (R,R)-3i: Yield 476 mg, 22%; white solid, m.p. 85–
87 °C. [α]2D0 = –28.36 (c = 0.46, AcOEt). IR (KBr): ν = 3070 cm–1.
˜
Rf = 0.35 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.09–2.26
(m, 12 H), 2.41 (s, 6 H), 2.83–3.48 (m, 8 H), 3.79 (s, 6 H), 3.94–
4.11 (m, 2 H), 6.90 (d, J = 8.8 Hz, 4 H), 7.03–7.56 (m, 28 H), 7.78
(d, J = 8.1 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4
(CH3), 25.3 (CH2), 30.7 (CH2), 31.8 (CH2), 42.0 (CH2), 55.1 (CH),
61.2 (CH2), 86.0 (C), 112.8 (CH3), 126.6 (CH), 127.3 (CH), 127.6
(CH), 128.3 (CH), 129.4 (CH), 130.2 (CH), 135.7 (C), 138.5 (C),
142.7 (C), 144.5 (C), 144.7 (C), 158.3 (C) ppm. MS (ESI): m/z (%)
= 1105.03 (20) [M + Na]+. C66H70N2O8S2 (1082.4): C 73.17, H
6.51, N 2.59; found C 73.02, H 6.70, N 2.38.
Coupling of (R,R)-7 with Two Equivalents of (R,R)-2b: Synthesis of
(R,R,R,R,R,R)-8: In a flask maintained under nitrogen, (R,R)-2b
(2.4 mmol, 1.73 g), Cs2CO3 (11.8 mmol, 3.85 g) and a catalytic
amount of tetrabutylammonium chloride were suspended in dry
toluene (72 mL). The mixture was stirred and heated at 70 °C for
half an hour and after that (R,R)-7 (1.2 mmol, 0.83 g) dissolved in
toluene (3 mL) was added dropwise. The reaction was stirred at
70 °C for 5 days, the solvent was evaporated and the product iso-
lated after chromatographic purification using 2.5% ethyl acetate
in CH2Cl2 as eluent to yield compound (R,R,R,R,R,R)-8. Yield
1.40 g, 60%; white solid, m.p. 208–211 °C. [α]2D0 = +26.8 (c = 0.46,
AcOEt). Rf = 0.88 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ =
0.90–1.93 (m, 28 H), 1.93–2.25 (m, 4 H), 2.44 (m, 18 H), 2.80–3.41
(m, 16 H), 3.68–4.15 (m, 6 H), 6.91–7.55 (m, 42 H), 7.55–7.95 (m,
12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 25.0
(2×CH2), 25.4 (CH2), 30.5 (CH2), 30.7 (CH2), 30.9 (CH2), 41.8
(2×CH2), 58.1(CH), 58.4 (CH), 58.9 (CH), 61.4 (2×CH2), 86.3
(C), 126.8 (CH), 127.3 (CH), 127.6 (CH), 128.6 (CH), 129.4 (CH),
138.3 (C), 138.6 (C), 138.9 (C), 142.7(C), 144.1 (C) ppm. MS (ESI):
m/z (%) = 997.7 (20) [M + 2Na]+, 1969.7 (10) [M + Na]+.
Compound 5: This compound was obtained in acetonitrile follow-
ing the procedure used for the monoalkylation reaction. Yield
1
1.55 g, 80%; white solid, m.p. 181–183 °C. Rf = 0.63 (CH2Cl2). H
NMR (300 MHz, CDCl3): δ = 1.78–2.01 (m, 4 H), 2.43 (s, 6 H),
3.01–3.45 (m, 12 H), 7.07–7.91 (m, 38 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.4 (CH3), 29.3 (CH2), 47.3 (CH2), 48.2 (CH2), 60.7
(CH2), 86.5 (C), 126.9 (CH), 127.1 (CH), 127.7 (CH), 128.5 (CH),
129.6 (CH), 135.8 (C), 143.3 (C), 144.0 (C) ppm. MS (ESI): m/z
(%) = 992.2 (20) [M + Na]+. C60H60N2O6S2 (968.4): C 74.35, H
6.24, N 2.89; found C 74.50, H 6.40, N 2.75.
General Procedure for Tr Deprotection: The corresponding ditrityl-
ated compound (0.62 mmol, 1.2 g) was dissolved in dry CH2Cl2
(20 mL) then MeOH (12 mL) and trifluoroacetic acid (3.71 mmol,
0.275 mL) were added. The reaction mixture was stirred until the
starting material had disappeared (TLC monitoring). The crude
was evaporated and the final product purified by flash chromatog-
raphy.
C110H126N6O14S6 (1946.8): C 67.80, H 6.52, N 4.31; found C 67.60,
H 6.42, N 4.20.
Cyclization Reaction: Synthesis of (R,R,R,R,R,R)-11: In a flask
maintained under nitrogen, (R,R)-1 (0.215 mmol, 0.09 g) was dis-
solved in dry acetonitrile (7 mL) and CS2CO3 (2.1 mmol, 0.7 g) was
added and the mixture heated at 70 °C for half an hour. Then a
solution of (R,R,R,R,R,R)-10 (0.215 mmol, 0.314 g) in acetonitrile
was added dropwise and the resulting mixture stirred at 70 °C for
Compound (R,R)-3g showed the correct spectroscopic and analyti-
cal data.[10d]
Compound (R,R,R,R,R,R)-9: Yield 562 mg, 62%; white solid, m.p. 5 days. After this time, the solvent was evaporated and the macro-
123–125 °C. [α]2D0 = –1.50 (c = 0.55, CHCl3). Rf = 0.12 (AcOEt/
cyclic tosylated polyamine (R,R,R,R,R,R)-11 was purified by flash
hexane, 2:1). 1H NMR (300 MHz, CDCl3): δ = 0.83–1.63 (m, 22 chromatography using 7% ethyl acetate in dichloromethane as elu-
H), 1.83–2.17 (m, 10 H), 2.32 (s, 18 H), 2.45–2.70 (m, 2 H), 2.70– ent. Yield 294 mg, 74%; white solid, m.p. 210–212 °C. [α]2D0 = –9.3
3.27 (m, 11 H), 3.63–3.96 (m, 9 H), 6.89–7.38 (m, 12 H), 7.38–7.98
(c = 0.48, CHCl3). Rf = 0.14 (CH2Cl2/AcOEt, 7:1). 1H NMR
(300 MHz, CDCl3): δ = 0.99–1.74 (m, 32 H), 1.80–2.22 (m, 8 H),
(m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 24.7
(CH2), 25.0 (CH2), 29.8 (CH2), 30.2 (CH2), 30.5 (CH2), 33.3 (CH2), 2.29–2.45 (m, 21 H), 2.79–3.30 (m, 16 H), 3.76–4.08 (m, 8 H), 7.08–
40.8 (CH2), 40.6 (2×CH2), 58.3 (CH), 58.6 (CH), 59.3(CH), 60.2
(2×CH2), 127.1 (CH), 129.2 (CH), 129.3 (CH), 137.5 (C), 137.8
7.45 (m, 16 H), 7.58–8.00 (m, 16 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.3 (CH3), 25.0 (CH2), 30.7 (CH2), 41.7 (CH2),
(C), 138.4 (C), 142.5 (C), 142.8 (C) ppm. MS (ESI): m/z (%) = 58.3(CH), 127.3 (CH), 129.4 (CH), 138.7 (C), 142.6 (C) ppm. MS
2+
1484.7 (20) [M + Na]+. C72H98N4O14S6 (1462.6): C 59.07, H 6.75, (ESI-TOF): calcd. for C92H122N8O17S8Na2
N 5.74; found C 59.24, H 6.90, N 5.52.
([M
+ 2Na +
H2O]2+
,
100%): 956.3244; found 952.3236; calcd. for
Eur. J. Org. Chem. 2006, 3887–3897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3895

C. Peña, I. Alfonso, V. Gotor
FULL PAPER
C92H120N8O16S8Na2
947.3217.
([M + 2Na]2+
, 10%): 947.3191; found
2+
Soc. 2003, 125, 6677–6686; g) S. Otto, J. B. F. N. Engberts, Org.
Biomol. Chem. 2003, 1, 2809–2820.
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V. Gotor, Eur. J. Org. Chem. 2004, 1117–1127; c) I. Alfonso, F.
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Tetrahedron: Asymmetry 1999, 10, 2515–2522.
Detosylation Procedure: Synthesis of (R,R,R,R,R,R)-6: In a flask,
(R,R,R,R,R,R,R,R)-11 (0.1 mmol, 0.185 g), phenol (24.4 mg
0.259 mmol) and 48% aqueous HBr (2.6 mL) were mixed and
heated at 110 °C for 8 days. Then the reaction solvent was extracted
with CH2Cl2 and water and the organic layers discarded. The aque-
ous phase was basified with 1  NaOH and extracted again with
CH2Cl2 (3×15 mL). This organic fraction was dried and the sol-
vent evaporated to dryness. The resulting product was dissolved in
MeOH and acidified with concentrated HCl. The final title com-
pound was thus isolated as the octahydrochloride salt by
recrystallization. Yield 77 mg, 85%; pale yellow hygroscopic solid,
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decomposes without melting. [α] = –60.8 (c = 0.37, H2O). 1H
NMR (300 MHz, D2O): δ = 1.00–1.25 (m, 8 H), 1.25–1.50 (m, 8
20
Hg
H), 1.50–1.70 (m, 8 H), 1.85–2.15 (m, 16 H), 3.00 (m, 8 H), 3.22
(m, 8 H), 3.35 (m, 8 H) ppm. 13C NMR (75 MHz, D2O): δ = 21.5
(CH2), 22.9 (CH2), 25.4 (CH2), 42.7 (CH2), 57.6 (CH) ppm. MS
(ESI-TOF): calcd. for C36H76ClN8 ([M + 4H + Cl]3+, 100%):
3+
218.5294; found 218.5275.
Acknowledgments
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Financial support from the Spanish Ministerio de Educuación y
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Asturias (IB05-04) is grateful acknowledged. I. A. also thanks
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using varied mixing times, giving similar results. As suggested
by one referee, we have selected one example carried out in
CD3CN, although the 1H NMR spectrum shows a complicated
pattern due to the presence of a mixture of conformations in
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states that usually it is not the stabilities of the conformers that
determine the products, but rather their individual reaction
rates. Thus, products are often formed entirely from less stable
conformers. However, we tried to explain our experimental re-
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molecular mechanics analysis, our model reflects the trends ob-
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Eur. J. Org. Chem. 2006, 3887–3897

Selective Alkylation of trans-Cyclohexane-1,2-bis(sulfonamide)
FULL PAPER
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Received: March 16, 2006
Published Online: June 21, 2006
Eur. J. Org. Chem. 2006, 3887–3897
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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