Template effects in SN2 displacements for the preparation of pseudopeptidic macrocycles

Article abstract of DOI:10.1002/chem.201101416

Macrocyclisation reactions of C₂-symmetric pseudopeptides containing central pyridine-derived spacers are affected by the presence of different anions. The selection of the proper anion gives excellent results for the preparation of the corresp

Full text of DOI:10.1002/chem.201101416

FULL PAPER
DOI: 10.1002/chem.201101416
Template Effects in SN2 Displacements for the Preparation of Pseudopeptidic
Macrocycles
Vicente Martꢀ-Centelles, M. Isabel Burguete, and Santiago V. Luis*[a]
Abstract: Macrocyclisation reactions of
C2-symmetric pseudopeptides contain-
ing central pyridine-derived spacers are
affected by the presence of different
anions. The selection of the proper
anion gives excellent results for the
preparation of the corresponding mac-
rocyclic structures. Kinetic studies
show that the presence of those anions
enhances both the yield and the rate of
the reaction. Computational studies at
the B3LYP/6-31G* level have allowed
us to rationalise the experimental re-
sults. The obtained transition states
(TSs) show that the interaction be-
tween the anion and the open-chain
pseudopeptidic chain has a stabilising
effect. The anion stabilises the two TSs
involved: the first one, which involves
the formation of the initial bond be-
tween the two subunits and leads to an
open-chain intermediate, and the
second one, which precedes the forma-
tion of the cyclic structure. The opti-
mum anion (BrÀ when the central
spacer is derived from 2,6-bis(amino-
methyl)pyridine, is able to act as a tem-
plate, in that it forces the two ends of
the open-chain intermediate to ap-
proach each other by forming hydro-
gen bonds with the two amino acid
subunits present in the intermediate.
This stabilises the second TS to a great-
er extent than the first one, and thus,
favours macrocyclisation over the com-
peting oligomerisation reactions. The
computational calculations also al-
lowed us to predict the outcome of
new experiments. Accordingly, the syn-
thesis of the pseudopeptidic macrocy-
cle derived from 2,6-diaminopyridine
was not successful under the optimised
conditions previously used. Neverthe-
less, calculations predicted that in this
case ClÀ should be more efficient than
BrÀ, and this was subsequently experi-
mentally confirmed. Interestingly, the
presence of different substituents on
the constituent amino acids seems to
play a minor role in the overall pro-
cess.
Keywords: anions · macrocycles ·
pseudopeptides
·
supramolecular
chemistry · template effects
Introduction
anism for resistance towards proteases.[3,10] Thus, much at-
tention has been recently drawn to the preparation of mac-
rocyclic structures containing amino acids.[1,11] In most cases,
the preparation of those multifunctional molecules is limited
by the macrocyclisation step. This step needs to efficiently
compete with intermolecular dimerisation and oligomerisa-
tion processes, and can be kinetically or thermodynamically
controlled, depending on the irreversible or reversible
nature of the cyclisation reaction.[12] Entropic and enthalpic
factors contribute to achieve an adequate conformational ar-
rangement, leading to the desired regio- and stereochemis-
try.[13] For this purpose, complex synthetic routes need to be
devised. These require specifically designed protection and
deprotection steps, high-dilution techniques or specific pro-
tocols, such as ring-closing metatheses,[14] Ugi processes,[15]
click chemistry processes[16] or chemoenzymatic ap-
proaches.[17,18] Competing oligomerisation processes are, in
general, favoured by entropic factors. Thus, in successful
macrocyclisations, open-chain precursors are preorganised
in a folded conformation, in which the two reacting sites are
in proximity.[19] This arrangement, with the appropriate ori-
entation, provides an unencumbered trajectory of attack
and accelerates the intramolecular process, so that it be-
comes competitive with the intermolecular process.[20] In
recent years, we have been working on the preparation of
pseudopeptidic macrocycles, such as 1 and 2, which can be
Macrocyclic structures play an important role in nature. The
generation of a macrocyclic structure represents a simple
protocol that involves the preorganisation of a significant
number of functional groups with the appropriate disposi-
tion at the proper distance.[1] Many antibiotics, and in partic-
ular those that are able to act by inactivation of bacterial ri-
bosomes, contain macrolide structures.[2] In this regard, cy-
clopeptides have been shown to take part in important bio-
logical functions,[3] with the natural antibiotic vancomycin
being one of the earliest known examples of this kind of
compounds.[4] Many other important cyclopeptidic structures
include the hormone oxytocine,[5] the related neuropeptide
vasopressin,[5b] the antibiotics cyclosporine[6] and tyrocidine
A,[7] and some apoptosis-inducing cyclopeptides with antitu-
mour properties.[8] Their cyclic structure enhances their ac-
tivity,[9] their physicochemical stability and provides a mech-
[a] V. Martꢀ-Centelles, Prof. Dr. M. I. Burguete, Prof. Dr. S. V. Luis
Departament de Quꢀmica Inorgꢁnica i Orgꢁnica
Universitat Jaume I 12071 Castellꢂ (Spain)
Fax : (+34)964-728-214
E-mail: luiss@qio.uji.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101416.
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prepared from a common intermediate 3 (Figure 1). For
smaller [1+1] macrocycles 1, the successful reaction of 3
with a bis(bromomethyl)arene, is based on the preorganisa-
tion of the precursor 3, and that of the corresponding inter-
compounds. This was especially important when self-assem-
bly processes in solution or in the solid state were exam-
ined.[27–29] On the other hand, our initial studies on the cata-
lytic applications of those simple pseudopeptides, as well as
those of Dangel et al.,[30] suggested that the substitution of
an aliphatic spacer by an aromatic one can be an interesting
structural modification (Scheme 1).[31] Thus, taking into ac-
Figure 1. General representation of the macrocyclic and open-chain pseu-
dopeptidic structures.
Scheme 1. Synthetic route for the preparation of pyridine-containing
pseudopeptidic macrocycles. General conditions for the macrocyclisation
reaction: acetonitrile as the solvent, the corresponding base (10 equiv),
TBAX (TBA=tetrabutylammonium, X=anion; 0.5 equiv) and 1,3-bis-
mediate afterwards. Derivatives of a,w-diamino alkanes,
adopt a U-turn folded conformation because of intramolecu-
lar interactions and solvophobic forces.[21] The synthesis of
larger [2+2] macrocycles 2 is accomplished by reaction of 3
with aromatic dialdehydes. When a chiral 1,2-cyclohexane
diamine is used as the spacer, proper preorganisation can be
achieved based on configurational traits and the match/mis-
match between the configuration of the diamine and that of
the amino acid determine the success of the macrocyclisa-
AHCTUNGTRENNG(UN bromomethyl)benzene (1 equiv). Bn=benzyl.
count previous studies into the use of different pyridine-con-
taining receptors (particularly polyazapyridinophanes) in
molecular recognition processes,[32,33] we selected structures
6 and 7 as our synthetic targets. For this purpose, the corre-
sponding open-chain pseudopeptides 4 and 5 were easily
prepared from 2,6-diaminopyridine and 2,6-bis(aminome-
thyl)pyridine. Compound 5 was prepared by reaction of the
diamine with the N-hydroxysuccinimide ester of the proper
amino acid, under the conditions previously reported for the
preparation of open-chain pseudopeptides containing ali-
phatic spacers (3).[21] In the case of 2,6-diaminopyridine, its
low reactivity required the activation of the corresponding
amino acid through the formation of a mixed anhydride of
ethyl chloroformate.[34] The macrocyclisation was then inves-
tigated under conditions similar to those used for the syn-
thesis of 1 from 3. Those conditions involved the use of ace-
tonitrile at reflux as the solvent, anhydrous K2CO3 as the
base and tetrabutylammonium bromide (TBABr; 0.5 equiv)
as the phase-transfer reagent. The use of TBABr (or other
TBAX salts) was required because most of the K2CO3 was
not dissolved. After 24 h, the expected product 7a (n=1,
R=CH2Ph) was isolated in 87% yield after the usual
workup. The formation of 6a (n=0, R=CH2Ph) could be
detected by MS, but the yield was so low that it could not
be isolated and purified. Careful analysis of the MS spectra
of the crude reaction mixture confirmed that the cyclisation
was not very efficient and that polymerisation/oligomerisa-
tion processes were prevalent. Thus, the MS spectra re-
vealed that along with the expected signal at m/z 585 [M+
H] for the macrocyclic compound 6a, important signals cor-
responding to the open-chain intermediate 8a (at m/z 586–
588 [M’+H]), and the successive open-chain oligomerisation
products 10a, 12a and 14a were also present. The identity
of the structures corresponding to those peaks was unequiv-
ocally identified by high-resolution (HR) MS and through
the isotopic pattern analysis of the corresponding clusters
tion.[22,23] When flexible spacers
( ACHTUNGTERN(NGUN CH2)n ) are used,
À
À
though, the use of an anionic template is imperative.[24] This
is an attractive strategy because one could select the specific
template best-suited for each macrocyclisation reac-
tion.[24,25,26] Nevertheless, the use of thermodynamic tem-
plates is only possible for reversible reactions (i.e., the
imine formation in the preparation of 2). Thus, this ap-
proach is unsuitable for macrocycle syntheses that involve
an irreversible cyclisation reaction (e.g., SN2 reactions).
Herein, we show how the use of anionic kinetic templates,
which preferentially stabilise the transition state (TS) of the
cyclisation step instead of that of the oligomerisation pro-
cess (increasing in kcyclisation/koligomerisation), is a useful tool for
optimising macrocyclisation.
A thorough computational
study has been carried out to understand this process and
the results obtained nicely agree with experimental data.
Moreover, the use of computational techniques has allowed
us to optimise template characteristics and determine the
conditions required for the synthesis of a very strained mac-
rocycle.
Results and Discussion
Most of our previous work with pseudopeptidic compounds
1–3 has been carried out using the general structure 3,
which was derived from 1,2-cyclohexane diamines or a,w-
aliphatic diamines. The conformational freedom provided by
À
À
the flexible
ACHTUNGTRENNUNG(CH2)n spacer and its easy sequential varia-
tion were useful for gaining insights into the role of the dif-
ferent structural elements on the properties of the resulting
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Template Effects in the Preparation of Pseudopeptidic Macrocycles
FULL PAPER
Figure 2. Experimental (bottom) and theoretical (top) isotopic patterns corresponding to the peaks for the different open-chain compounds obtained in
the attempted preparation of 6a: A) 6a, B) 8a, C) 16a, D) 14a, E) 12a, F) 10a.
(Figure 2). HRMS analysis also showed the presence of the
N-alkylated macrocycle 16a. This again confirmed that the
N-alkylation processes, not involving the formation of the
ring, efficiently compete with macrocyclisation (Scheme 2).
As for the synthesis of 7, we varied reaction conditions to
achieve optimal yields (Table 1). Interestingly, in the ab-
sence of a base (entry 7, Table 1) the maximum attainable
yield was 59%. This suggested that the molecules of 5 acted
as the base and neutralised the ammonium salts formed
after each N-alkylation. In good agreement with this, the
precipitation of the trihydrobromide salt of the bis-amino
amide was observed with the progress of the reaction. A
second observation was that the best yields were associated
with the presence of TBABr (entries 1 and 4, Table 1) and/
or K2CO3 (entry 1, Table 1). The presence of ClÀ or FÀ (en-
tries 5 and 6, Table 1) produced a significant decrease in the
yield. This is of particular relevance for the fluoride anion,
for which a large number of side products, most likely asso-
ciated with its behaviour as a strong base, were obtained.
Subsequently, we carried out a thorough kinetic analysis of
the macrocyclisation processes. For this, we developed an
HPLC protocol that allowed the separation and identifica-
tion of the main components of the reaction mixtures. Of
particular relevance for the kinetic analysis was the identifi-
cation of 5, 1,3-bis(bromomethyl)benzene and 7 (Scheme 2).
The open-chain intermediate 9 and some of the oligomeric
side products were also separated and identified (Figure 3).
The identity of each HPLC signal was assigned by compari-
son, when possible, with authentic samples and by a com-
plete HPLC–HRMS analysis of the corresponding mixtures.
Alternatively, the corresponding kinetics could also be fol-
lowed by NMR spectroscopy (amide, benzylic and methine
(stereogenic centre) protons were monitored (Figure 4)).
Evidently, the different reaction conditions not only affected
yields, but also, very significantly, the kinetics of the process
(Figure 5). The data for FÀ (entry 6 in Table 1) have not
been included in Figure 5 because the presence of a large
number of side products does not permit obtaining accurate
kinetic curves. For the sake of comparison, Figure 6 shows
the kinetic curves obtained at 258C under the conditions
shown in Table 1, entry 4, by using NMR spectroscopy.
Higher concentrations are required to carry out the NMR
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S. V. Luis et al.
continually produced by the al-
kylating agent. For the initial
conditions (entry 1, Table 1)
the potential exchange be-
tween TBABr and (TBA)2CO3
accounted for the slower kinet-
ics observed at the beginning
of the reaction. As the process
progressed, the amount of BrÀ
increased and the kinetics of
the reaction gradually resem-
bled those of processes in
which BrÀ is the only anion
present. Similar kinetics were
observable for the conditions
given in Table 1, entries 2, 3
and 5. The consumption of 5a
in two different processes, N-
alkylation/macrocyclisation,
and its role as a base, led to a
rapid rate decrease when no
base was added (entry 7,
Table 1). No significant kinetic
effect was ascribed to ClÀ.
Thus, the BrÀ anion had a clear
catalytic effect on the macro-
cyclisation reaction, and poten-
tially a role as a kinetic anion
template, stabilising the TS
leading to the macrocycle.
Computational studies were
then carried out to shed light
on the issue. For this purpose,
the different stationary points
for the process under consider-
ation were fully optimised at the B3LYP/6-31G* level of
theory with the Gaussian 03 program.[35] For all cases, the
optimised structures were confirmed as true minima by an
Scheme 2. Overall reaction sequence including significant side reactions.
Table 1. Results obtained in the synthesis of 7 under different macrocyc-
lisation conditions.[a]
Entry
Solvent
Base
TBAX[b]
Yield [%][c]
[d]
1
2
3
4
5
6
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
K2CO3
Br
–
AcO
Br
Cl
F
93
82
69
96
DIPEA[e]
DIPEA[e]
DIPEA[e]
DIPEA[e]
DIPEA[e]
–
81
30[f]
58[g]
–
[a] All reactions were heated to reflux. [b] 0.5 equiv. [c] Determined by
HPLC from the crude reaction mixture. [d] Excess of solid anhydrous
salt. [e] DIPEA=diisopropylethylamine; 10 equiv of base were added.
[f] A very complex mixture was obtained. [g] Under those conditions the
triprotonated bis-aminoamide precipitated.
spectroscopy experiments because of an increased contribu-
tion from oligomerization processes. As seen in Figure 5, the
different reaction conditions assayed do not only affect the
yield of the reaction, but also, very significantly, the kinetics
of the process. Optimum results (in terms of kinetics and
final yields) were obtained with DIPEA as the base in the
presence of TBABr. This was attributed to the presence of
BrÀ at the beginning of the reaction and the fact that BrÀ is
Figure 3. HPLC chromatograms obtained from the reaction mixture
under the conditions considered in entry 2 of Table 1. Retention times:
7a 4.61 min, 1,3-bis(bromomethyl)benzene 5.29 min, 5a 6.15 min, mesity-
lene (internal standard) 7.64 min.
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Template Effects in the Preparation of Pseudopeptidic Macrocycles
FULL PAPER
mational analyses associated with the side chain. For proper
analysis of the role of different anions, we compared the rel-
ative activation energies of different reaction steps.
The two major steps in the process are shown in
Schemes 3 and 4. The first step involved the formation of in-
Figure 4. Kinetic analysis of the macrocyclisation process for the prepara-
tion of 7a under the conditions reported in entry 4 of Table 1 (258C).
a) d=7.80 ppm, amide NH of 7a. b) d=7.71 ppm, amide NH of 5a. c)
d=4.37 ppm. CH2 of 1,3-bis(bromomethyl)benzene. d) d=4.20 ppm,
CH2–pyridine of 5a. e) d=4.00 ppm, CH2–pyridine of 7a. Signals
marked with an asterisk correspond to DIPEA; signals marked with an
open circle correspond to TBA. Tetrakis(trimethylsilyl)silane was used as
the internal standard at d=0 ppm.
Scheme 3. Representation of the first step of the macrocyclisation process
that leads to the corresponding open-chain intermediates 8 and 9 in the
presence of XÀ.
Figure 5. Kinetic curves obtained by HPLC for the formation of 7a
under the different reaction conditions reported in Table 1. Data for
FÀ(entry 6, Table 1) were omitted because the large number of side prod-
ucts prevented accurate kinetic analysis.
termediate 9b, which, subsequently, cyclised in the second
step. An efficient anionic catalyst should, thus, selectively
reduce the activation energy of the cyclisation step more
than it reduces the activation energy of the first step. In this
approach, we assumed that the energy barriers for the dif-
ferent oligomerisation steps competing with the cyclisation
were very similar to that of the first step because they in-
volved a similar process and the presence of a given anion
produced an equal effect on them. The structures of reac-
tants, complexes of interaction of reactants (RIC), TSs, com-
plexes of interaction of products (PIC), and products were
optimised to obtain the corresponding reaction profiles. Ini-
tially, we carried out a potential energy surface (PES) calcu-
lation at the ONIOM (B3LYP/6-31G*:PM3) level of theory,
which allowed us to find the approximate TS geometry and
that of the other stationary points (Figure 7). The full opti-
misation of all the stationary points obtained from the PES
analysis was then carried out at the B3LYP/6-31G* level
(Figures 8 and 9). It was found that the anion was always ef-
ficiently bound in either of the TSs for the two reaction
steps. All of the anions seemed to act as templates in the TS
of the macrocyclisation step because supramolecular interac-
tions between the anion and the two amide fragments in 8b
enforced a closed conformation, which brought the reactive
sites in close proximity.[36] We then calculated the energy
Figure 6. Kinetic curves obtained by NMR spectroscopy at 258C for the
formation of 7a under the experimental conditions described in Table 1,
entry 4.
analysis of normal vibration modes. The alanine derivatives
5b, 7b and 9b were selected as models for the open-chain
precursor, the macrocyclic system and the intermediate, re-
spectively. This significantly reduced the number of atoms
relative to 5a, 7a, and 9a, and, accordingly, the calculation
time. Moreover, this eliminated the need to perform confor-
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S. V. Luis et al.
Figure 8. Fully optimised structures (B3LYP/6-31G*) for the TSs for the
first reaction step for the preparation of 7b in the presence of different
anions: a) none, b) BrÀ, c) ClÀ, d) FÀ, e) CO32À and f) AcOÀ.
Scheme 4. Representation of the second step of the macrocyclisation pro-
cess involving the formation of the macroring from the corresponding
open-chain intermediates 8 and 9 in the presence of XÀ.
Figure 9. Fully optimised structures (B3LYP/6-31G*) for the TSs for the
second reaction step for the preparation of 7b in the presence of differ-
ent anions: a) none, b) BrÀ, c) ClÀ, d) FÀ, e) CO32À and f) AcOÀ.
Table 2. Gibbs energy barriers [kcalmolÀ1] for the first step of the reac-
tion from 5b.
2À
No cat. CO3
BrÀ
ClÀ
FÀ
Acetate
reactants–RIC
RIC–TS
TS–PIC
3.07 À139.86 À29.06 À21.40 À98.28 À27.38
25.80
À17.79
À2.09
13.18
À55.18 À24.17 À27.14 À26.53 À25.76
190.85 41.30 39.60 117.55 45.06
20.93
17.93
16.25
17.07
PIC–products
Table 3. Gibbs energy barriers [kcalmolÀ1] for the second step of the re-
action (cyclisation of 9b).
2À
No cat. CO3
BrÀ
ClÀ
FÀ
Acetate
Figure 7. PES of the macrocyclisation reaction at the ONIOM (B3LYP/6-
31G*:PM3 level of theory, in the absence of any additional anion, for the
transformation of 9b into 7b.
reactants–RIC
RIC–TS
TS–PIC
0.00 À137.67 À41.15 À36.42 À107.30 À41.22
31.76
À40.04
0.03
12.60
À51.39 À27.93 À18.49
168.21 42.41 26.90
18.42
19.77
20.23
À21.14 À21.14
99.96 33.34
20.77
PIC–products
barriers from the corresponding energy values of the opti-
mised structures of the different stationary points (Tables 2
and 3). In the associated energy profiles in Figures 10 and
11, it can be seen that all anions had a catalytic effect on
both reaction steps, reducing the values of the correspond-
ing RIC–TS free-energy barriers. In all cases, the catalytic
effect on the macrocyclisation step was more pronounced
than on the first step. This agreed with the template effect
observed for the structures of the different TSs. In the first
step, the most favourable effect was calculated for the
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Template Effects in the Preparation of Pseudopeptidic Macrocycles
FULL PAPER
2À
anion was CO3 with a difference of 6.54 kcalmolÀ1. All
other anions had much less pronounced favourable effects
(ClÀ: 4.12 kcalmolÀ1, AcOÀ: 2.26 kcalmolÀ1, FÀ: 1.98 kcal
molÀ1). The results obtained from the computational calcula-
tions were in excellent agreement with experimental obser-
vations. We obtained optimal results in the presence of
TBABr or K2CO3/TBABr, thus confirming the suggested
anion kinetic template effect. The computational results also
allowed us to justify why FÀ gave the worst results, and the
fact that the nature of the side chain of the amino acid origi-
nally used (phenyl alanine, alanine, valine) insignificantly af-
fected the process. Thus, when the corresponding cyclisa-
tions were carried out for the other C2 open-chain systems
(for the formation of macrocycles 7a and 7c) using the opti-
mised conditions (CH3CN, DIPEA, TBABr, at reflux) very
similar results were obtained in terms of both yields and ki-
netics (Figure 12).
Figure 10. Calculated energy profile for the first step of the reaction from
5b. The values for the RIC–TS barrier for each profile have been includ-
ed [kcalmolÀ1].
Figure 12. Kinetic curves for the formation of macrocyclic structures 7a–c
in CH3CN at reflux, using DIPEA as the base and TBABr (0.5 equiv).
A quantitative comparison between the experimental and
the computational data can be made through the calculation
of the corresponding experimental kinetic parameters. Dif-
ferent kinetic models can be proposed for the complex
system outlined in Scheme 2. Some simplifications need to
be made to obtain reliable results. We, thus, assumed that
the rate constants of the nucleophilic substitutions that gave
open-chain compounds were essentially identical (k1 =kp);
this is common for multistep processes.[37,38] This provided a
simple kinetic model to which the experimental kinetic data
were fit. The kinetic curves obtained with this model repro-
duced well the main features of the observed curves
(Figure 13). In this way, the corresponding kinetic parame-
ters could be calculated (Table 4). Although a perfect quan-
titative agreement between calculated and experimental pa-
rameters was not expected, the calculated kinetic parame-
ters displayed the same trends as those predicted by calcula-
tions. Thus, the bromide anion was the most efficient cata-
lyst. Taking into consideration the previous results, we
carried out identical calculations for the synthesis of 6. The
ultimate goal of this study was to define the conditions that
could allow the preparation of this elusive compound. The
simplest side chain (R=CH3) was again selected to facilitate
the calculations. The results from the computational calcula-
tions revealed some significant patterns (Figures 14, 15, 16,
Figure 11. Calculated energy profile for the second step of the reaction
(cyclisation of 9b). The values for the RIC–TS barrier for each profile
have been included [kcalmolÀ1].
2À
CO3
anion, which decreased the RIC–TS barrier by
12.62 kcalmolÀ1 relative to that obtained for the process in
the absence of anions. On the contrary, BrÀ was the anion
with the smallest effect for this step, reducing the corre-
sponding energy barrier by just 4.87 kcalmolÀ1. For the cycli-
2À
sation step, the CO3 anion was again the one to decrease
the RIC–TS energy barrier most efficiently (19.16 kcal
molÀ1), but in this case the second most effective catalyst
was BrÀ (13.34 kcalmolÀ1). We must bear in mind, however,
that the anions favouring the first step also favoured, in a
similar way, the oligomerisation processes competing with
the cyclisation. Thus, the overall catalytic effect produced by
a given anion was given by comparing the effects calculated
for the two steps. The most efficient catalyst for the forma-
tion of 7b should be the one favouring the second step rela-
tive to the first one. Thus, calculations showed that BrÀ was
the most efficient catalyst for the formation of the macrocy-
clic product: the difference between the decrease in the
RIC–TS energy barrier of the second step, relative to the
first step, was 8.47 kcalmolÀ1. The second most efficient
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S. V. Luis et al.
Figure 14. Fully optimised structures (B3LYP/6-31G*) for the TSs for the
first reaction step for the preparation of 6b in the presence of different
2À
anions: a) none, b) BrÀ, c) ClÀ, d) FÀ and e) CO3
.
Figure 13. a) Variation of the concentration of the different species (mod-
elled according to the simplified kinetic mode defined in Scheme 2 with
k1 =kp) with time. g: [5a]; g: [1,3-bis(bromomethyl)benzene]; c:
[8a]; b: [7a]. Complete overlap of lines corresponding to the starting
materials is observed. The concentration of both the intermediate and
the oligomers is very low for the whole time span. b) Variation of the
concentration of the macrocyclic compound 7b (D) with time (under the
optimised conditions: DIPEA, TBABr, CH3CN at reflux); solid line:
curve obtained from the calculated k1 and k2 values, including standard
Figure 15. Fully optimised structures (B3LYP/6-31G*) for the TSs for the
second reaction for the preparation of 6b in the presence of different
2À
anions: a) none, b) BrÀ, c) ClÀ, d) FÀ and e) CO3
.
whereas a broader range was calculated for 6b (3.5–18 kcal
*
molÀ1). Overall, the presence of BrÀ and ClÀ favoured the
deviations (b); : experimental points. A perfect quantitative agree-
ment cannot be expected, but it can be seen how the calculat-
ed kinetic parameters display the same trends predicted by
calculations.
Table 4. Experimental kinetic parameters for the preparation of 7b under different
conditions.
°
°
Conditions
k1
k2
[minÀ1
DG1
[kcalmolÀ1
DG2
[kcalmolÀ1
DDG°
[a]
[mÀ1 minÀ1
]
G
]
]
]
[kcalmolÀ1
]
and 17, and Tables 5 and 6). As in the case of 7b,
we considered the relative DDG° values obtained
for both steps in the presence and in the absence
of the corresponding anion. The presence of
anions resulted in the reduction of the energy bar-
riers, as expected. Nevertheless, the effect of the
different anions on the cyclisation step was appre-
ciably smaller than in the case of 7b (for 7b DDG°
values ranged from 11 to 19 kcalmolÀ1, whereas
for 6b they ranged from 8.8 to 16.1 kcalmolÀ1).
Thus, the stabilisation of the TS through the pres-
ence of anions was about 3 kcalmolÀ1 less for 6b
than that for 7b. In the first step, however, DDG°
values for 7b were in the range of 5–12 kcalmolÀ1,
K2CO3/TBABr[b] 8.0Æ1.8
33800Æ100
0.8Æ0.5
22.31Æ0.16 16.42Æ0.03 À6.21Æ0.19
23.08Æ0.05 23.9Æ0.4 0.82Æ0.45
22.31Æ0.16 16.42Æ0.03 À5.89Æ0.19
DIPEA[b]
DIPEA/
TBABr[b]
DIPEA/
TBACl[b]
DIPEA/TBAA-
cO[b]
2.68Æ0.20
8.0Æ1.8
33800Æ100
2.80Æ0.17 2.234Æ0.010 23.05Æ0.04 23.21Æ0.10
0.16Æ0.07
2.18Æ0.11
3.8Æ0.6
2.47Æ0.17
6.6Æ1.6
7.9Æ0.6
°
0.170Æ0.023 22.84Æ0.11 25.02Æ0.10
No base, no
3091Æ13
43000Æ100
5.8Æ4.4
23.13Æ0.05 18.11Æ0.03 À5.02Æ0.08
22.45Æ0.16 16.25Æ0.03 À6.2Æ1.9
cat.[b]
DIPEA/
TBABr[c]
DIPEA/
TBABr[d]
22.32Æ0.05 22.5Æ0.5
0.18Æ0.55
[a] Calculated as DG2 ÀDG1°. [b] for 7a. [c] for 7b. [d] for 7c.
2416
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Chem. Eur. J. 2012, 18, 2409 – 2422

Template Effects in the Preparation of Pseudopeptidic Macrocycles
FULL PAPER
second step over the first one (4.46 and 5.79 kcalmolÀ1, re-
2À
spectively). On the contrary, the presence of FÀ or CO3
stabilised the TS of the first step better relative to the cycli-
sation TS (1.30 and 1.38 kcalmolÀ1). Except for ClÀ, those
values were less favourable for the second step than the
ones calculated for the preparation of 7b. Thus, the compu-
tational studies showed that the synthesis of smaller macro-
cycles (6) was less favourable than that of 7, and this al-
lowed us to rationalise our initial synthetic results. Addition-
ally, it was demonstrated that anions played different roles
in each synthetic process. For 6, we predicted that the small-
er ClÀ would have a more pronounced catalytic effect on
the macrocyclisation. This was in agreement with the exis-
tence of a kinetic template effect in which a specific anionic
template was best suited for each specific macrocyclisation
process. Based on those results, the use of TBACl/DIPEA in
CH3CN at reflux was expected to give the best results in the
synthesis of macrocycles 6. Accordingly, when the reaction
was carried out under those conditions and the precursor 4a
was used, the expected macrocycle 6a was isolated in 31%
yield. Interestingly, in this process the presence of RIC for
the cyclisation step was identified in the crude reaction mix-
ture in about 5–10% yields (see the Supporting Informa-
tion). Compound 6a was unequivocally identified by
HRMS. Nevertheless, the 1H NMR spectra of this com-
pound, taken under different conditions, always showed the
presence of complex, relatively broad signals with the ex-
pected chemical shifts. More significantly, the 13C NMR
spectra also showed the presence of more signals than those
expected for a compound such as 6a (with apparent C2 sym-
metry).[39] Even at 608C the improvement in the signals was
very limited (see the Supporting Information). Because the
chromatographic data, along with the MS and elemental
analyses data revealed the purity of the isolated compound,
Figure 16. Calculated energy profile for the first step of the reaction in
the preparation of 6b from 4b and 1,3-bis(bromomethyl)benzene in the
presence of different anions. The values for the RIC–TS barrier for each
profile have been included [kcalmolÀ1].
1
Figure 17. Calculated energy profile for the second step of the reaction in
the preparation of 6b from 4b and 1,3-bis(bromomethyl)benzene in the
presence of different anions. The values for the RIC–TS barrier for each
profile have been included [kcalmolÀ1].
the H NMR spectroscopy results were explained in terms
of the existence of several conformers interconverting very
slowly on the NMR timescale and/or the existence of a pre-
dominant rigid conformer not displaying the expected C2
symmetry. Conformational analysis of 6b at the B3LYP/6-
31G* level of theory was carried out to get a better under-
standing of this phenomenon. Calculations revealed the
presence of two conformers, separated by 2.49 kcalmolÀ1, as
the most stable ones (Figure 18). Both conformers had a
very strained macrocyclic ring. For the most stable confor-
mer, no C2 symmetry was present, whereas the second con-
Table 5. Calculated Gibbs energy barriers [kcalmolÀ1] for the first step
of the reaction in the preparation of 6b from 4b and 1,3-bis(bromome-
thyl)benzene in the presence of different anions.
2À
No cat.
CO3
BrÀ
ClÀ
FÀ
reactants–RIC
RIC–TS
16.26
26.36
À124.51
8.59
À23.43
22.03
À20.38
22.84
À80.19
15.66
TS–PIC
PIC–products
À22.07
À65.41
À32.02
À19.50
À23.10
4.38
206.26
58.35
41.97
112.57
Table 6. Calculated Gibbs energy barriers [kcalmolÀ1] for the second
step of the reaction in the preparation of 6b from 4b and 1,3-bis(bromo-
methyl)benzene in the presence of different anions.
2À
No cat.
CO3
BrÀ
ClÀ
FÀ
reactants–RIC
RIC–TS
TS–PIC
0.00
28.40
À143.27
12.01
À41.83
19.61
À36.14
19.19
À103.97
19.00
Figure 18. Structures calculated (optimised at the B3LYP/6-31G* level of
theory in the gas phase) for the two most stable conformers of 6b.
a) Most stable conformer, non-C2 symmetric structure; b) second most
stable conformer, C2 symmetric structure.
À19.60
À55.83
À25.65
À24.96
À27.55
PIC–products
À11.81
184.08
44.86
38.91
109.51
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www.chemeurj.org
2417

S. V. Luis et al.
former displayed such symmetry. Contrary to what was ob-
served in the symmetric conformer, and in most peptidic
and pseudopeptidic systems, the most stable conformer con-
tained one strained cis amide bond, which seemed to strug-
gle to release some strain.[40] Thus, the presence of the asym-
metric structure as the most predominant conformer of 6b,
along with the presence of high interconversion barriers,
could explain the complexity of the NMR spectra. The UV-
visible and circular dichroism (CD) spectra of compounds
7a–c and for 6b were recorded. At the same time, the theo-
retical CD spectra were calculated computationally for the
two fully optimised structures (Figure 18).[41] Solvent effects
were taken into account with the use of the polarisable con-
tinuum model (PCM) methodology. Excellent agreement
between experimental and theoretical CD spectra (corre-
sponding to the minimum energy conformer) was observed
(Figure 19). It was evident that the two bands corresponding
to 6a and 7 in the UV spectrum overlapped at about
264 nm and were significantly split at 250 and 297 nm. Most
significantly, the CD of 6a not only displayed a very differ-
ent pattern (relative to 7) with a positive signal at 250 nm
and a negative one at 297 nm, but also more intense CD ef-
fects. This must be due to the higher degree of structural or-
ganisation of 6a.[24]
Conclusion
We clearly demonstrated that the presence of anions signifi-
cantly affected the course of macrocyclisation reactions in
pseudopeptides, peptides and related species, in which
supramolecular interactions between the selected anion and
the open-chain precursor existed at the TS. The appropriate
anionic species acted as a kinetic template that stabilised
the TS leading to the macrocyclic structure. Calculations at
the B3LYP/6-31G* level of theory enabled rationalisation of
those results and showed that the anions considered in this
study were able to stabilise the two TSs involved in the for-
mation of 7: the first one leading to the open-chain inter-
mediate 8 from 5, and the second one transforming 8 into 7.
The best anionic catalysts were those producing greater sta-
bilisation of the second TS than that of the first one. The
effect on the TSs of the competing oligomerisation side re-
actions and the TS of the transformation of 5 into 8 was sim-
ilar. In the transformation of 5 to 7, BrÀ was predicted to be
the most efficient template and this was in excellent agree-
ment with experimental results. The optimised structures of
the corresponding TSs for the macrocyclisation step re-
vealed how the anions acted as efficient templates for this
step by facilitating the approach between the two reactive
ends on 8: the anion interacted (electrostatically and
through hydrogen bonding) with the two pseudopeptidic
fragments. Thus, different anions should be the optimal ones
for macrocyclisation reactions involving macrocycles of dif-
ferent sizes. This was evidenced in the preparation of the
smaller macrocycle 6a, the synthesis of which was unsuc-
cessful under standard conditions. Computational calcula-
Figure 19. a) Experimental CD spectra for 6a (c, 0.215 mm in metha-
nol), and calculated CD spectra for the minimum energy conformer
(b, B3LYP/6-31G* PCM), and the second most stable conformer (d,
B3LYP/6-31G* PCM) of 6b. b) Experimental UV/Vis spectra. c) CD
spectra for compounds 7a (b), 7b (c), 7c (–··–··) and 6a (d).
tions revealed that the role of different anions as templates
was significantly different. In this case, the smaller ClÀ was
best suited to stabilise the TS of the macrocyclisation. Ac-
cordingly, the calculations predicted that the best conditions
for the synthesis of 6a involved the use of TBACl, instead
of TBABr. This has been experimentally confirmed. Thus,
when we used the predicted conditions (TBACl, DIPEA,
CH3CN at reflux) the expected macrocycle 6a could be iso-
lated in 30% yield. Structural analysis of this smaller macro-
cycle revealed that the high degree of strain in the structure
led to the loss of C2 symmetry in the minimum-energy con-
former and the existence of two different cis and trans
amide bonds.
2418
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Chem. Eur. J. 2012, 18, 2409 – 2422

Template Effects in the Preparation of Pseudopeptidic Macrocycles
FULL PAPER
evaporated under reduced pressure to give the crude product (0.919 g).
Purification of the product was carried out by flash column chromatogra-
phy on silica gel (50 g). CH2Cl2/methanol mixtures were used as the
mobile phase, containing a few drops of aqueous ammonia to prevent the
retention of amines on the column (from 100:0 to 90:3 v/v). The macro-
cycle 7a was obtained as a white solid (87%, 0.525 g, 1.22 mmol). M.p.
708C; [a]2D5 =70.54 (c=0.01 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
Experimental Section
NMR spectroscopy: NMR spectroscopy experiments were carried out
either on a Varian INOVA 500 spectrometer (500 MHz for 1H and
125 MHz for 13C) or a Varian MERCURY 300 spectrometer (300 MHz
for 1H and 75 MHz for 13C) at the SCIC (UJI). Chemical shifts are re-
ported in ppm from tetramethylsilane with the solvent resonance as the
internal standard. FTIR spectra were recorded by means of a Jasco FT/
IR-6200 with an attenuated total reflectance (ATR) adapter. Microanaly-
ses were performed on a CHN Euro EA 3000 elemental analyser. Mass
spectra were recorded by means of a Q-TOF Premier (Waters). Rotatory
power was determined by means of a Jasco DIP-100 digital polarimeter
(Na: 589 nm). Melting points were measured by means of a Melting
Points Stuart SMP10 apparatus. CD spectra were recorded on a Jasco J-
810 spectropolarimeter. Samples were prepared in a quartz cuvette of
1 cm path length and the measurement temperature was set to 258C.
1.89 (s, 2H), 2.74–2.90 (m, 2H), 3.27 (dd, 3J
3.57 (d, 3J(H,H)=12.4 Hz, 4H), 3.69 (d, 3J
(H,H)=12.6 Hz, 2H), 4.38 (d,
3J (H,H)=6.8, 15.4 Hz, 2H), 6.95 (d, 3J-
(H,H)=15.2 Hz, 2H), 4.78 (dd, J
ACHTUNGERTN(NUNG H,H)=2.9, 13.8 Hz, 2H),
A
ACHTUNGTRENNUNG
3
A
ACHTUNGTRENNUNG
AHCTUNGERTG(NNUN H,H)=6.6 Hz, 2H), 7.07–7.42 (m, 14H), 7.51–7.75 (m, 2H), 8.36 ppm (s,
2H); 13C NMR (75 MHz, CDCl3): d=39.1, 44.5, 53.1, 64.1, 121.6, 127.0,
127.4, 128.1, 128.6, 128.9, 129.3, 137.6, 137.9, 140.0, 156.4, 173.5 ppm; IR
(ATR): u˜ =3359, 3060, 3027, 2923, 2849, 1658, 1599, 1577, 1497,
1449 cmÀ1 HRMS (ESI-TOF): m/z calcd for C33H35N5O2 [M+H]+:
;
533.2917; found: 533.2917; elemental analysis calcd (%) for C33H35N5O2:
C 74.27, H 6.61, N 13.12; found: C 74.5, H 6.8, N 13.0.
General procedure for the preparation of the pseudopeptides: The start-
ing 2,6-bis(aminomethyl)pyridine was obtained from 2,6-bis(aminome-
thyl)pyridine hydrochloride (1.000 g, 4.78 mmol) by neutralisation with a
1:1 aqueous solution of NaOH. The resulting aqueous solution was ex-
tracted three times with chloroform; the organic phase was dried with an-
hydrous magnesium sulfate and evaporated in vacuo. The resulting yel-
lowish oil (0.420 g, 3.06 mmol) was dissolved in 1,2-dimethoxyethane
(25 mL) in a round-bottomed flask. Cbz-l-Phe-OSu (Cbz=carbobenzyl-
General procedure for the preparation of 4: Synthesis of 4a: Cbz-l-phe-
nylalanine-OH (22.150 g, 74 mmol) and triethylamine (10.3 mL,
74 mmol) were dissolved in dry THF (400 mL). The solution was cooled
to À58C and then ethylchloroformiate (7.3 mL, 74 mmol) was added to
the reaction flask and it was stirred for 30 min at À58C under a nitrogen
atmosphere. 2,6-Diaminopyridine (22.150 g, 74 mmol) was dissolved in
dry THF (25 mL) and added dropwise to the reaction flask in 15 min.
The reaction was stirred for 1 h at À58C under a nitrogen atmosphere.
After this period, the reaction was filtered and the solvent was evaporat-
ed under reduced pressure. The resulting foam was dissolved in ethyl ace-
tate (200 mL) and washed with water (3ꢄ50 mL), a saturated aqueous
solution of NaHCO3 (3ꢄ50 mL) and a saturated aqueous solution of
NaCl (3ꢄ50 mL). The organic phase was dried with MgSO4 and the sol-
vent was evaporated under reduced pressure. The crude product was pu-
rified by flash chromatography column on silica gel with hexane/ethyl
acetate (7:3) as the eluent. The product (4a) was obtained as a white
foam (57%, 14.050 g, 20.9 mmol). M.p. 109–1108C; [a]2D5 =50.5 (c=0.01
in DMSO); 1H NMR (500 MHz, CD3CN): d=9.64 (s, 2H), 7.92 (d, 3J-
ACHTUNGTRENNUNGoxy, Su=succinimidyl; 2.427 g, 6.12 mmol, 2 equiv) was dissolved in di-
methoxyethane (20 mL) and added to the reaction flask with a pipette. A
white precipitate was formed and the mixture was stirred at room tem-
perature for 20 h then heated to 508C for 6 h. After cooling, the white
precipitate was filtered, washed with cold water (50 mL) and a small
amount of methanol then dried under vacuum. The corresponding Cbz-
protected open-chain pseudopeptide was obtained as a white solid (90%,
3.855 g, 5.51 mmol).
Deprotection protocol: The resulting Cbz-protected pseudopeptide
(462 mg, 0.66 mmol) was placed in a 100 mL round-bottomed flask.
Then, HBr/AcOH (10 mL, 33%) was added. The resulting yellow solu-
tion was stirred under a nitrogen atmosphere for 1 h. The colourless final
solution was poured into a 250 mL beaker containing diethyl ether
(30 mL). The white precipitate formed was filtered and washed with di-
ethyl ether. The solid was redissolved in distilled water (30 mL). This
aqueous phase was washed twice with CHCl3 (10 mL). The aqueous
phase was basified with solid NaOH to a pH of 12–13 and then NaCl was
added until saturation. The aqueous solution was extracted three times
with CHCl3 (25 mL) and the organic phase was dried with anhydrous
MgSO4. The solvent was evaporated under reduced pressure and finally
dried in an oil vacuum pump to obtain a white solid (88%, 0.249 g,
0.58 mmol).
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(75 MHz, [D6]DMSO): d=174.6, 150.5, 141.2, 139.1, 130.0, 128.8, 126.9,
108.8, 57.3, 41.1 ppm; IR (ATR): u˜ =3292, 1637, 1533 cmÀ1; HRMS (ESI-
TOF): m/z calcd for C25H29N5O2 [M+H]+: 404.2087; found: 404.2091; el-
emental analysis calcd (%) for C25H29N5O2: C 69.58, H 6.77, N 16.23;
found: C 69.4, H 6.7, N 16.1.
General procedure for the preparation of 6: Synthesis of 6a: Compound
4a (1.000 g, 2.478 mmol), TBACl (344 mg, 1.239 mmol) and DIPEA
(4.24 mL, 24.78 mmol) were placed in a round-bottomed flask and then
dry acetonitrile (600 mL) was added. The reaction mixture was heated
until all of the reactants were dissolved. Then, 1,3-bis(bromomethyl)ben-
zene (654 mg, 2.478 mmol) was dissolved in a small quantity of dry aceto-
nitrile and placed into the reaction flask and the reaction was heated at
reflux for 24 h under a nitrogen atmosphere. The reaction mixture was
then cooled and the solvent was evaporated under reduced pressure to
give the crude product as a foam. Purification of this product was carried
out by flash column chromatography on flash silica gel. CH2Cl2/methanol
mixtures were used as the mobile phase, containing a few drops of aque-
ous ammonia to prevent the retention of amines on the column (from
450:6 to 480:8 v/v). The macrocycle (6a) was obtained as a white solid
(31%, 393 mg, 0.777 mmol). M.p. 958C; [a]2D5 =À128.18 (c=0.01 in
CHCl3); 1H NMR (500 MHz, CDCl3) d=9.97–9.01 (m, 2H), 7.98 (m,
1H), 7.65 (m, 2H), 7.32—6.92 (m, 15H), 3.92—2.97 (m, 8H), 2.80 (m,
2H), 2.07 ppm (s, 3H); 13C NMR (125 MHz, CDCl3) d=172.9, 172.5,
172.4, 149.4, 149.1, 140.63, 140.57, 139.1, 139.0, 137.6, 137.0, 129.3, 129.1,
129.0, 128.8, 128.7, 127.7, 127.6, 127.1, 127.04, 126.97, 126.3, 109.5, 109.4,
107.8, 63.4, 56.9, 52.3, 40.6, 39.12, 39.07 ppm; IR (ATR): u˜ =3085, 3025,
2844, 1676, 1582, 1516, 1493, 1442, 1391, 1292, 1241 cmÀ1; HRMS (ESI-
TOF): m/z calcd for C31H31N5O2 [M+H]+: 506.2556; found: 506.2550; el-
emental analysis calcd (%) for C31H31N5O2 H2O: C 71.11, H 6.35, N
13.37; found: C 70.9, H 6.5, N 13.5.
Compound 5a: M.p. 109–1108C; [a]2D5 =69.88 (c=0.01 in CHCl3);
3
1H NMR (500 MHz, [D6]DMSO): d=8.43 (t, J
G
(t, 3J
2H), 4.31 (ddd, 3J
7.9 Hz, 2H), 2.95 (dd, 3J
R
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
8.0, 13.3 Hz, 2H), 1.75 ppm (s, 4H); 13C NMR (126 MHz, [D6]DMSO):
d=175.1, 158.2, 139.2, 137.6, 129.8, 128.6, 126.5, 119.3, 56.9, 44.3,
41.6 ppm; IR (ATR): u˜ =3363, 3351, 3293, 3062, 3031, 2916, 2852, 1637,
1591, 1577, 1531, 1494, 1459, 1415 cmÀ1; HRMS (ESI-TOF): m/z calcd for
C25H29N5O2 [M+H]+: 432.2400; found: 432.2396; elemental analysis
calcd (%) for C25H29N5O2: C 69.58, H 6.77, N 16.23; found: C 69.4, H 6.8,
N 16.4.
General procedure for the preparation of 7: Synthesis of 7a: Compound
5a (605 mg, 1.402 mmol), TBABr (226 mg, 0.701 mmol) and anhydrous
K2CO3 (1.937 g 14.02 mmol) were placed in a 250 mL round-bottomed
flask and then acetonitrile (200 mL) was added to obtain a final concen-
tration of 7 mm for 5a. The reaction mixture was heated until all of the
reactants, except potassium carbonate, were dissolved. Then, 1,3-bis(bro-
momethyl)benzene (370 mg, 1.402 mmol) was dissolved into
a small
quantity of dry acetonitrile and added to the reaction flask and the reac-
tion was heated at reflux for 24 h under a nitrogen atmosphere. The reac-
tion mixture was then cooled and filtered by gravity. The filtrate was
Chem. Eur. J. 2012, 18, 2409 – 2422
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2419

S. V. Luis et al.
Kinetic analysis of the cyclisation of 7 by HPLC: Experiments under dif-
ferent reaction conditions were carried out. In all cases, the solvent was
acetonitrile. Thus, for instance, bis-amidoamine 7a (49.3 mg,
0.187 mmol), DIPEA (320 mL, 1.870 mmol), TBABr (30.1 mg,
0.093 mmol) and mesitylene (25 mL), as the internal standard, were
placed in a round-bottomed flask equipped with a magnetic stirrer and a
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condenser under
a nitrogen atmosphere. Then, dry acetonitrile
(50.00 mL) was added and the system was heated to 81.68C. Afterwards,
1,3-bis(bromomethyl)benzene (49.3 mg, 0.187 mmol) was added to the re-
action mixture and this was assumed as the initial point of the reaction.
Aliquots were initially taken every 30 min and then every 1 h for a total
of 8 h. The aliquots were not further diluted. When K2CO3 was used as
the base, it was removed by filtration by means of a HPLC syringe filter.
The HPLC vials were rapidly cooled in an ice bath and the chromato-
gram was recorded immediately. The HPLC was equipped with a Proto-
nsil 120-5-C18 column with the detector adjusted at 210 nm. The volume
of injection was 0.5 mL. The mobile phase was acetonitrile/H2O (80:20)
and the flow was 1 mLminÀ1. The temperature was set at 358C and the
chromatogram was registered for 15 min.
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1
Kinetic analysis of the cyclisation of 7a by H NMR spectroscopy: In this
experiment tetrakis(trimethylsilyl)silane (0.056 equiv) was used as the in-
ternal standard. This allowed us to quantify the signals of the product
and the starting reactants. We performed the experiments directly in an
NMR tube at different temperatures, depending on the experiment (from
258C to 508C), using CD3CN (1.00 mL). The concentration of the start-
ing material was 7.5 mm. For this purpose, the bis-amidoamine catalyst,
base and internal standard were placed in a vial. Then CD3CN was
added and the reaction mixture was stirred and heated until a clear solu-
tion was obtained. The reaction mixture was transferred quantitatively to
an NMR tube. Then, the initial NMR spectrum was acquired. Then the
contents of the NMR tube were quantitatively transferred to a vial con-
taining 1,3-bis(bromomethyl)benzene, mixed and immediately transferred
back to the NMR tube. An NMR spectrum was acquired every 15 min at
least for 12 h.
Computational calculations: All structures where minimised by using the
Gaussian 03 program. All of the calculations were performed in the gas
phase. The nature of the minima was demonstrated by a normal mode of
vibration analysis. For TSs, one single negative eigenvalue was found,
corresponding to the reaction path involving the breaking and forming of
bonds. For the other structures all of the eigenvalues were positive.
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This work was supported by the Spanish Ministry of Science and Innova-
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