Cyclization of interlocked fumaramides into β-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket

Article abstract of DOI:10.1039/d0sc05757f

A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give β-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b) the polyamide macrocycle plays an important role not only as activating element but also as the stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes. This journal is

Full text of DOI:10.1039/d0sc05757f

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Cyclization of interlocked fumaramides into b-
lactams: experimental and computational
mechanistic assessment of the key intercomponent
proton transfer and the stereocontrolling active
pocket†
Cite this: DOI: 10.1039/d0sc05757f
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
a
a
Alberto Martinez-Cuezva, * Aurelia Pastor, * Marta Marin-Luna,
a
b
a
and Jose Berna *a
Carmen Diaz-Marin, Delia Bautista, Mateo Alajarin
A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides
to give b-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-
reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-
labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the
cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of
the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b)
the polyamide macrocycle plays an important role not only as activating element but also as the
stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the
adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes.
Received 19th October 2020
Accepted 10th November 2020
DOI: 10.1039/d0sc05757f
rsc.li/chemical-science
inhibiting the catalysis when the active site is shielded by the
1
. Introduction
39–44
macrocycle.
A rare exception to this rule, is the recent
The discovery and development of catalytic systems is one of the example described by Goldup and coworkers in which a mac-
1,2
most captivating challenges in chemistry. Enzymes, the most rocycle actively participates in a reaction occurring inside its
efficient known catalysts, control a vast number of biochemical cavity. In this particular case, the functionality of the thread is
3
45
processes occurring in living organisms. The high specicity dramatically altered by being prepared within the macrocycle.
exhibited by enzymes relies on their complex three-dimensional
In 2016 we reported the CsOH-promoted intramolecular
4
–7
structures, where the active site is located. In recent years, the cyclization of archetype N-benzylfumaramides 1a–c embedded
development of articial switchable catalysts has been the in the isophthalamide-based ring of a [2]rotaxane (Scheme 1,
object of deep study. These synthetic systems are able to control part (a)). In these processes, the corresponding interlocked b-
the rate, reaction pathway or stereochemical outcome of lactams trans-2a–c were isolated in almost quantitative yields as
a chemical process, triggered by a wide range of different single diastereoisomers. Note that the cyclization of the non-
46
8–15
external stimuli.
Interlocked molecules have become ideal interlocked fumaramide in the presence of CsOH (not shown)
candidates for this purpose due to their unique properties leads to a cis–trans mixture in poor yield. On the basis of these
16,17
derived from the presence of a mechanical bond
to a series of selective and/or stimuli-responsive catalysts.
giving rise results, we assumed that the interlocked polyamide macrocycle
18–38
must play a denitive activating role, making another exception
In most of the reported examples of switchable rotaxane- to the rule of interlocked systems in which the macrocycle-effect
based catalysts, the well-dened position of the macrocycle alters the reaction outcomes. Besides, the macrocycle exerts
along the thread allows to control the reaction rate, usually a protective role once the cyclization step has taken place. As
a result, the corresponding b-lactams trans-2a–c are isolated in
a
almost quantitative yields in spite of their high instability in
basic media. As a bonus, the extrusion of the chiral azetidinone
Department of Organic Chemistry, Faculty of Chemistry, University of Murcia,
Regional Campus of International Excellence “Campus Mare Nostrum”, 30100
Murcia, Spain. E-mail: amcuezva@um.es; aureliap@um.es; ppberna@um.es
threads (trans-3 in Scheme 1) through a thermal dethread-
b
47–49
ACTI, University of Murcia, 30100 Murcia, Spain
ing
completes an unusual method to obtain high value-
†
Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, kinetic data, X-ray ORTEP gures and NMR spectra
PDF).Computational data and cartesian coordinates (PDF).Crystallographic
50,51
added b-lactams.
By following a similar protocol we also
described a related cyclization of enantiopure interlocked N-a-
(
methylbenzylfumaramides, giving rise to enantioenriched
data for compound trans-8i (CIF). CCDC 2008919. For ESI and crystallographic
52
trans-b-lactams bearing a chiral quaternary atom.
data in CIF or other electronic format see DOI: 10.1039/d0sc05757f
This journal is © The Royal Society of Chemistry 2020
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a
Table 1 Synthesis of interlocked fumaramides 1a, 1d–i
a
3
Reaction conditions: (i) p-xylylenediamine, diacyl chloride, Et N,
ꢀ
b
46
CHCl , 25 C, 4 h. Reported in a previous reference.
3
inuence the course of the cyclization and the sense of diaster-
eocontrol. The global overview of the mechanism described herein
shows a detailed picture of the sequence of events at the molecular
level, which allows the assessment of a intercomponent proton
transfer and the stereocontrolling active pocket inside the macro-
cyclic counterpart as key features of these processes.
Scheme 1 Base-promoted intramolecular cyclization of interlocked
N,N-dibenzylfumaramides 1: (a) previously reported work and (b) novel
results included herein.
Despite the CsOH-promoted cyclization of interlocked
fumaramides has turned out an interesting tool for the dia-
stereoselective synthesis of b-lactams, the little knowledge
about the mechanism hinders further applications. With the
aim of inspiring further research, new insights of the cyclization
mode of [2]rotaxanes 1 are necessary to lead to a ne tuneable
2
. Results and discussion
2.1 Synthesis of the N-benzylfumaramide-based [2]rotaxanes
1d–i
design of our interlocked molecules without compromising The N,N-dibenzylfumaramide [2]rotaxanes 1d–i were prepared
5
3–55
their structural integrity and expand the synthesis to more following a well-established methodology
starting from N,N-
0
0
complex b-lactams.
dibenzyl-N ,N -dibutylfumaramide T1a as the effective template
46
Herein, we disclose the unravelling of the mechanism of the already utilized in the synthesis of 1a. Accordingly, [2]rotax-
base-promoted cyclization of interlocked fumaramides 1 through anes 1d–i bearing different polyamide rings were assembled
an exhaustive inspection tackled from three different but comple- through a ve-component reaction starting from T1a, p-xylyle-
mentary perspectives. First, a range of novel fumaramide [2]rotax- nediamine and the appropriate diacyl chloride in the presence
anes 1d–i (Table 1) differing in the structure and electronic features of Et N (Table 1). The interlocked fumaramides 1d–h were ob-
3
of the macrocyclic counterpart were synthesised to conduct tained in yields ranging 29–47%. However, the synthesis of the
a detailed structure-reactivity relationship analysis (Scheme 1, part adamantane-derived rotaxane 1i took place in a signicantly
(b)). This piece of research has revealed that diadamantyl-derived reduced yield (12%). The low yield in 1i could be tentatively
rotaxanes sparks the cyclization process, being possible to further explained in terms of the lower acidity of the NH hydrogen
enhance the scope of this transformation. Second, the KIE with atoms of the transient precursors of the macrocycle, thus
deuterium-labelled interlocked fumaramides was evaluated to decreasing the stability of the supramolecular complex previous
48,56
obtain some hints about the rate-determining step of the cyclization to the nal interlocked structure.
process. Third, despite the fact that computational analysis at DFT
level of interlocked molecules is challenging, we have conducted
2
.2 Synthesis of the interlocked b-lactams trans-2d–i
computational mechanistic studies, including the computing of the
possible intermediates, in order to gain a more detailed under-
standing of how interactions within the rotaxane structure might
The optimal reaction conditions for quantitively converting
rotaxane 1a into the interlocked b-lactam trans-2a had been
already settled in our previous studies (25 mM, 1 equiv. of
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ꢀ
46
CsOH, DMF, 25 C, 12 h). Unfortunately, we found that under delightfully isolated as single diastereoisomers regardless of the
the same reaction conditions the competitive dethreading of structure of the macrocycle.
the fumaramide containing rotaxanes 1d (R ¼ NO ), 1f (R ¼ Br)
2
and 1h (pyridine core) was also taking place in an important
2
.3 Structure-reactivity relationship study of the cyclization
extension, affording increasing amounts of T1a and the corre-
sponding macrocycle. The ability of related interlocked succi-
namide derivatives with electron-withdrawing groups at the
macrocycle to experience a fast dethreading process has been
of interlocked N-benzylfumaramides 1a–i: Hammett plots
We had previously observed that electron-withdrawing groups
attached to the para position of the N-benzyl groups of the
fumaramide thread accelerated the cyclization (Scheme 1).
With the aim of expressing quantitatively such structure-
reactivity relationship, we monitored the CsOH-promoted
cyclization of rotaxanes 1a–c by H NMR spectroscopy. The
cyclization of 1a in the presence of CsOH (1 equiv.) at 25 C in
DMF is illustrated in the stack plot of H NMR spectra depicted
in Fig. 1. As the reaction takes place, signals due to trans-2a
emerged (highlighted in green, for lettering see Table 2),
whereas the signals of the interlocked fumaramide 1a (marked
in red and blue) diminished. Next, similar experiments with [2]
rotaxanes 1b,c bearing Cl and MeO substituents at para position
of both N-benzyl groups, were carried out. Aer integrating the
specic resonances attributable to both reactant and reaction
product and tting the data to a rst order equation, we
calculated the respective rate constants (k) (Fig. 2a, for further
details see ESI†). The Hammett plot of log(k/k ) against the s
4
6
47
earlier reported. For this reason, the dethreading of rotaxanes
ꢀ
d–i in DMF-d at 25 C was monitored by H NMR spectroscopy
7
1
1
(see ESI for further details†) founding a half-life time 0.7 h for
1
1
d (R ¼ NO ), which showed to be the most prone to undergo
2
ꢀ
the disassembly process. By contrast, this parameter increased
1
t
until 190 h in the case of 1g (R ¼ Bu). The diadamantyl-derived
1
i did not show any dissociation aer long periods of time.
Due to this competitive pathway, the reaction conditions for
the cyclization of rotaxanes 1d–i needed to be individually
optimized (Table 2). All the experiments were carried out at
a 25 mM concentration of 1 except for the cyclization of 1g (R ¼
t
Bu), which was conducted at 10 mM as a consequence of its
lower solubility. Rotaxanes having electron-poor macrocycles
such as 1d (R ¼ NO ), 1f (R ¼ Br) and 1h (pyridine core)
2
demanded longer reaction times (24–48 h). In fact, the reaction
of 1d was extremely slow in the presence of 1 equiv. of CsOH,
thus favouring the dethreading process. For these rotaxanes the
presence of an excess of base (3 equiv.) was mandatory not only
to reach good conversions but, more importantly, to avoid the
undesired dethreading process. The cyclization worked out
1
a
p
constants of the X substituents at the benzylic groups of the
fumaramide moiety clearly demonstrates the linearity of the
2
correlation with r ¼ +3.85 (R ¼ 0.991) (Fig. 2b).
We next evaluated the inuence of the rings at the macro-
cycle (m-substituted benzene, pyridine, adamantane) on the
reaction rate. The conversions of the rotaxanes 1e–h into the
t
faster with rotaxanes 1g (R ¼ Bu, 10 h) and 1i (adamantane
core, 1 h). All the interlocked lactams trans-2d–i were
1
interlocked b-lactams trans-2e–i were monitored by H NMR,
a
Table 2 Base-promoted cyclization of rotaxanes 1a, 1d–i
Fig. 1 Kinetic experiment of the cyclization of 1a (DMF, 1 equiv. CsOH,
ꢀ
2
5 C, 25 mM). Signals referred to 1a are in red (thread) and light blue
(
macrocycle). Signals of the forming lactam trans-2a are in green. For
a
b
ꢀ
lettering see Table 2. Note that the signals referred to the macrocycle
Reaction conditions: (i) CsOH (1–3 equiv.), DMF (25 mM), 25 C.
Reported in a previous reference.
46
c
0
Reaction conducted under (E and E ) in trans-2a appeared as very broaden peaks, being difficult
diluted conditions (10 mM).
their observation at room temperature (see ESI for further details†).
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Fig. 2 Cyclization of rotaxanes 1a–c in the presence of CsOH (1
ꢀ
equiv.) at 25 C in DMF: (a) Plots of ln(c/c
o
) versus time for the
determination of the rate constants; (b) Hammett plot of log(k/k1a
against the substrate electronics (s ). The rate constant values are the
average of two independent measurements.
)
p
Fig. 3 Cyclization of rotaxanes 1a and 1e–i in the presence of CsOH (1
ꢀ
equiv.) at 25 C in DMF: (a) Plots of ln(c/c
o
) versus time for the
determination of the rate constants; (b) Hammett plot of log(k/k1a
against the substrate electronics (s ). The rate constant values are the
average of two independent measurements.
)
m
and their respective rate constants (k) estimated by tting of the
data to a rst order equation (Fig. 3a, further details in the
ESI†). All the experiments were carried out at a 25 mM
concentration of 1 and with 1 equiv. of base, except for the
revealed, by using a diadamantyl-based macrocycle. On the
contrary, electron-withdrawing groups at the N-benzylic group
of the thread favoured the intramolecular cyclization process (r
t
cyclization of 1g (R ¼ Bu), which was conducted at 10 mM due
57
to its lower solubility. Under these reaction conditions the
reaction of the 5-nitro-substituted rotaxane 1d was extremely
slow favouring the dethreading process. Therefore, 1d was
excluded from this study.
¼
+3.85). Signicantly, the latter r value tripled the rst,
revealing that the reaction is more sensitive to these substituent
58
effects.
As alluded to above, the kinetic data revealed that electron-
withdrawing groups at the benzene rings of the macrocycle
decelerate the process (Fig. 3a). Thus, poor conversions were 2.4 Study of kinetic isotopic effects (KIE) in the cyclization of
observed for the bromo-substituted rotaxane 1f and the dipyr- interlocked N-benzylfumaramides 1a and 4
idyl rotaxane 1h aer 8 h. Additionally, an appreciable amount
of dethreaded T1a was observed, which increased over time.
At this point, we decided to evaluate the KIE over the reaction
rate when the reference rotaxane 1a was labelled with deute-
Rotaxane 1e, with a methoxy group, reacted slightly slower than
the model substrate 1a. In contrast, the rate of converting
59
rium atoms at different positions. First, we compared the
cyclization rate of 1a and its labelled analog 1a-d (93% D)
2
t
rotaxane 1g, with an electron-releasing group ( Bu), was higher.
having two deuterium atoms at the olenic moiety of the
fumaramide fragment (Scheme 2). Similar rate constants for the
cyclization of both 1a and 1a-d were obtained (k ¼ 1.28 ꢁ
Interestingly, the reaction of the diadamantyl rotaxane 1i
experienced a 10-fold rate enhancement compared to that of the
2
1a
ꢂ4 ꢂ1
reference compound 1a (k1a ¼ 1.3 ꢁ 10
s
versus k1i ¼ 1.4 ꢁ
ꢂ4 ꢂ1
ꢂ4 ꢂ1
10
s
and k1a-d2 ¼ 1.27 ꢁ 10
s
), indicating that the
ꢂ3 ꢂ1
10
s , Fig. 3a). Plots of log(k/k1a) versus the s constants of
m
secondary KIE is negligible (see ESI for further details†). Having
the groups at the 5-position of the isophthaloyl group are shown
in mind the labelling degree of the starting material, a 97% of
D is retained in trans-2a-d (12 h of reaction time), while the D
1 2 2
labelling decreases to a 22% due to a progressive hydrogen-
deuterium exchange occurring under the basic reaction
conditions.
We next labelled the benzylic methylene group. For experi-
2
mental simplicity, we synthesised rotaxanes 4 and 4-d (Fig. 4a),
having a thread with one benzyl group and three n-butyl chains
in Fig. 3b. The data clearly tted to a linear correlation with
2
a negative value of r ¼ ꢂ1.24 (R ¼ 0.972).
In a nutshell, the analysis of the Hammett-plots shows that
electron-releasing groups at the macrocycle speed the forma-
tion of the interlocked b-lactams (r ¼ ꢂ1.24) indicating that the
latter substructure takes an active part in the transformation.
Moreover, an important enhancement of the reactivity is
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intramolecular aza-Michael reaction (IMAMR) of the formed
anion to the electrophilic C]C double bond of the thread.
However, to the light of the experimental results shown herein,
we presumed that a second alternative route should be also
considered, that involving the same initial step but followed by
the proton transfer from the benzyl group of the thread to the
macrocyclic anion. Thus, we scrutinized these two alternative
mechanistic pathways for the base-promoted cyclization of
interlocked N-benzylfumaramides 1 into b-lactams 2 at the
SMD(DMF)/DLPNO-CCSD(T)/ma-def2-SVP//wB97X-D/def2-SVP
theoretical level. For simplicity the [2]rotaxane 1j, featuring a N-
benzyl-N,N ,N -trimethylfumaramide thread, was selected as
a model structure. In this section we explain more in detail only
the mechanistic pathway of lowest energy, whereas the most
relevant steps of the not favoured mechanistic route are briey
summarized (see Fig. 5 and the ESI for a complete mechanistic
description†).
The rst stage of both mechanisms is reasonably the
deprotonation of one amide function of the macrocycle, bearing
a priori the most acidic proton, to give the amidate INT0. Proton
transfer between oxygen and nitrogen acids and bases are
usually fast and, since four amide groups are embedded into the
macrocycle, the proton removal from 1j is also statistically fav-
oured. Thus, we presumed this proton transfer to be diffusion
controlled.
Scheme 2 CsOH-promoted intramolecular cyclization of interlocked
N,N-dibenzylfumaramide 1a-d (93% D).
2
0
0
as stoppers (threads T1b or T1b-d , see ESI for further
2
60
details†). The cyclization of both rotaxanes 4 and 4-d
2
(99% D)
needed 5 equiv. of CsOH in order to avoid the dethreading
46
1
phenomenon by speeding up the reaction. The H-NMR
monitoring allowed us to determine the respective rate
constants for the formation of the interlocked b-lactams
(Fig. 4b). Aer the cyclization, an 80% of the initial deuterium
was maintained in trans-5-d . The cyclization of the labelled 4-d
1
2
occurred slower than the non-deuterated one, indicating
a noticeable primary KIE (k /k
ꢃ 3) which implies that the
benzylic C–H(D) bond is broken during the rate-determining
H
D
61
step.
Amidate anion INT0 could evolve through two different
pathways: (A) acting as an internal base by abstraction of one
2.5 Computational study: a new mechanistic approach
A putative mechanism for the cyclization of interlocked N- benzylic proton of the thread thus leading to the carbanion
ꢂ1
benzylfumaramides in basic media was described in our INT1-A (+37.8 kJ mol ); or (B) adding to the electrophilic C]C
46,62
previous works.
We proposed therein that the resulting b- bond of the fumaramide via an intramolecular aza-Michael
lactams might be formed via a mechanism initiated by the reaction (IMAMR) to give a more energetic enolate anion
ꢂ1
deprotonation of the amide function of the ring followed by the INT1-B (+39.5 kJ mol ). Computational results predict that the
ꢂ1
transition structure TS1-A is 29.5 kJ mol lower in energy than
TS1-B, most likely due to the strained conformation that the
macrocycle must adopt in TS1-B in order to reach the alkene
moiety. The successive computed stationary points along path B
resulted all higher in energy than TS1-A, the rate-determining
transition state of pathway A. Thus, the former aza-Michael
proposal is a route non-competitive with the new revised
mechanism (see ESI for further details, Fig. S6†).
Following with path A, the resulting N-benzyl carbanion
could approach to the nearest Csp of the alkene moiety of the
2
fumaramide unit following two alternative trajectories, leading
to the diastereoisomeric enolates trans- and cis-INT2 (DGtrans--
ꢂ1
ꢂ1
INT2 ¼ +5.3 kJ mol and DGcis-INT2 ¼ +12.6 kJ mol ) in a 4-exo-
trig cyclization. Both enolates would be then internally proton-
ated by one of the amide functions of the macrocycle to give the
more stable amidates cis- and trans-INT3, with respective
ꢂ1
energies of ꢂ47.7 and ꢂ55.9 kJ mol , which would nally
transform into the interlocked b-lactams 2 by an external
protonation. Pleasantly, our simulations predict that cis-TS2 is
ꢂ1
higher in energy than trans-TS2 by +14.1 kJ mol a difference
that translates into a theoretical diastereoisomeric ratio higher
than 99 : 1 in favour of trans-INT2, in agreement with the
observed experimental diastereoselectivity (trans-2 were the
only reaction products).
Fig. 4 (a) Synthesis of interlocked b-lactams trans-5 and trans-5-d
1
;
(
b) plots of ln(c/c ) versus time for the determination of the rate
o
2
constants of the cyclizations of rotaxanes 4 and 4-d in the presence
of CsOH (5 equiv.) at room temperature in DMF.
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Fig. 5 Proposed mechanism for the formation of b-lactams trans-INT3 and cis-INT3 from the amidate INT0 at the SMD(DMF)/DLPNO-CCSD(T)/
ꢂ1
ma-def2-SVP//wB97X-D/def2-SVP theoretical level. Gibbs free energies are reported in kJ mol (1 atm and 298 K), relative to INT0. Path colours
refer to the alternative trajectories for the 4-exo-trig cyclization step: trans (red) and cis (blue).
˚
Aiming to shed light on the trajectory preference for the 4- structures, that of trans-TS2 being 0.1 A shorter. A chair-like
exo-trig cyclization step, responsible of the selective formation conformation of the macrocycle is observed in trans-TS2,
of the trans-2 interlocked lactams, both transition structures therefore keeping the four hydrogen bonds between the NH
trans-TS2 and cis-TS2 were analysed in detail (Fig. 6). The non- groups of the macrocycle and the two carbonyl units of the
covalent interactions established between the two components thread present in the starting rotaxane. In addition, the phenyl
of the [2]rotaxanes along with some other structural features group of the thread sets a stabilizing aromatic–aromatic inter-
justify the energy difference between the two transition states. action with one isophthalamide unit of the macrocycle (the
˚
The forming C–C bond distances are similar in both transition distance between the centroids of both rings is 3.72 A). On the
contrary, in cis-TS2 the thread adopts a tweaked conformation
hampering the formation of the fourth hydrogen bond and
forcing to the macrocycle to adopt a distorted conformation,
which translates into an energy penalty.
Thus, the energetically favourable mechanistic proposal
(path A) accounts for the active role of the macrocycle in the
cyclization process in two ways. First, the deprotonated mac-
rocycle acts as an activating element by internally removing one
proton from the N-benzyl group of the fumaramide thread
during the rate-determining step. And second, the steric
constraint imposed on the interlocked transition state cis-TS2 is
the stereo-differentiating element that controls the diaster-
eoselective outcome of the cyclization process. Accordingly, the
macrocycle offers an appropriate restricted environment where
the stereoselective cyclization takes place. In fact, the
Fig.
6 Computed transition structures trans-TS2 and cis-TS2.
Distances shown in Angstroms ( A˚ ). Selected hydrogen atoms are
hidden for clarity.
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cyclization of the noninterlocked thread T1a in the presence of systems. In fact, a control experiment of the stability was carried
CsOH leads to a cis–trans mixture of b-lactams in poor yield (see out with a rotaxane 1k, having the same macrocycle as 1a and
0 0
48
ESI for computational details, Fig. S7†).
N,N,N ,N -tetrabutylfumaramide as thread, that precludes the
The conned microenvironment governs the macrocycle– cyclization to occur. While the dethreading of this rotaxane in
ꢀ
thread interactions, in terms of the orientation and reactive DMF at 25 C takes place in a 15% of conversion in 24 h, the
conformation, thereby exerting control over the chemo-, regio, presence of CsOH (and the subsequent formation of the ami-
and stereoselectivity of the transformation and resulting in date anion) almost inhibits this process (5% with 1 equiv. of
much improved activity compared with that of the bulk solu- base, 2% with 3 equiv. of base, see Table S4†).
tion. As a matter of the fact, the mechanistic pathway A agrees
One last point to be settled for the sake of completeness is
well with our results above on the structure-reactivity relation- the role of the cesium base. As we detailed above, we observed
ships and kinetic isotopic effects. Thus, we proved that electron- that the usual amount of CsOH (1 equiv.) needed to be
withdrawing groups attached to the para position of the N- increased (3–5 equiv.) in order to avoid the dethreading of
benzyl groups of the fumaramide thread accelerated the cycli- rotaxanes either bearing electron-withdrawing substituents at
zation. Consistently, the Hammett plot of log(k/k1a) against the the macrocycle or with only one benzyl group at the extremes of
p
s constants affords a positive r value of +3.85 (Fig. 2b) the thread. Thus, 3 equiv. of CsOH instead of 1 equiv. approx-
reecting that electron-withdrawing groups stabilize the incip- imately tripled the reaction rate of 1a (see ESI for further details,
ient negative charge at the benzylic carbon by resonance effects. Fig. S2†).
On the other hand, electron-donating groups at the 5-position
Unfortunately, CsOH is not completely soluble in DMF
of the isophthaloyl groups of the macrocycle accelerated the under the reaction conditions and thus its concentration
cyclization step, with electron-withdrawing substituents acting cannot be accurately determined. Some authors have stated that
in the opposite direction (r ¼ ꢂ1.24, Fig. 3b). This fact can be cesium salts are nearly or completely dissociated in dipolar
rationalized as a consequence of the amidate anion acting as an aprotic solvents, such as DMSO or DMF, producing very reactive
63,64
internal base in the rate-determining step and the effect of “naked” anions.
Thus, a close interaction between the
electron-donating groups increasing its basicity, favouring the cesium cation and the amidate anion is highly unlikely.
N-benzyl deprotonation. Finally, the substantial primary Nevertheless, our results apparently point to the deprotonation
isotopic effect observed in the cyclization of labelled 3-d (k /k
of the –CONH– fragments at the macrocycle being somewhat
ꢃ 3) is a strong evidence of the benzylic C–H bond being broken slower than expected, probably due to the intercomponent
in the rate-determining step. hydrogen bonds established between those NH protons and the
2
H
D
As we mentioned above rotaxane 1i, featuring two adamantyl carbonyl groups of the fumaramide thread.
fragments in the macrocycle, experiences the fastest cyclization.
In order to explain that, we considered that the torsional exi-
bility of the adamantyl core enables the proper orientation of
the amidate group, favouring the expeditious deprotonation of
56
2.6 Synthesis of interlocked trans b-lactams with less
sterically-hindered threads
the N-benzyl group of the thread. In that vein we computa- The extrusion of the chiral azetidinone threads from the inter-
tionally studied the conformational preference of a range of locked products trans-2 completes an unusual method to obtain
50,51
structurally simplied monoamidates 6 (Fig. 7). Interestingly, high value-added b-lactams
from N-benzylfumaramides
we found a relationship between the rates of the cyclization with the intermediacy of the interlocked species 1 and 2. In fact,
measured with the real interlocked fumaramides of comparable compounds trans-2 may be considered as kinetically stable
65
ꢀ
structures 1 and the degrees of exibility of the simplied pseudorotaxanes and their heating in DMF at 100 C for 12 h
amidate anions 6. Thus, the rotational barrier along the NCO– quantitatively yielded the respective dethreaded lactam trans-3
Ar bond increases in the following order: 6i 0 6g z 6a z 6e < (Scheme 3). Unfortunately, the deslipping of the Bu
2
N-
6f < 6d (see ESI for further details, Fig. S8–S14†) which parallels stoppered lactam from the diadamantyl rotaxane trans-2i did
the reactivity trend found with the real rotaxanes 1.
not occur even aer longer reaction times or higher tempera-
ꢀ
The formation of the amidate anion is also important in tures (up to 130 C).
order to maintain the structural integrity of the interlocked
With the aim of taking advantage of the fast cyclization
experienced by the diadamantyl-based rotaxane 1i, we envis-
aged that a less sterically hindered thread could expedite the
extrusion of the corresponding b-lactam. To explore this
possibility, we synthesised rotaxanes 7a and 7i, bearing
a dipropylamino-stoppered thread (T1c) in combination with
isophthaloyl- and adamantyl-derived macrocycles (Scheme 4).
48
When rotaxane 7a was submitted to the standard cycliza-
tion conditions the corresponding lactam trans-8a was appar-
ently not formed. Instead, only the dethreaded components T1c
and the polyamide macrocycle, poorly soluble in DMF, were
identied in the reaction mixture (Scheme 4, eqn (1)). In
contrast, rotaxane 7i, which is moderately insoluble in DMF
Fig.
7 Structures of the monoamidates 6a, 6d–g and 6i. The
conformational analysis was performed along the bonds coloured in
red.
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rotaxane 7i leads to the interlocked b-lactam trans-8i as a single
product (Fig. 8c). As a result of the thermal dethreading process,
only the signals of the b-lactam trans-9 are observed, with large
displacements to higher frequencies observed for the protons of
b c
the lactam core H , H as well as those of the methylene group
H
d
(Dd ¼ 1.04–1.90 ppm) (Fig. 8d, signals in green colour). In
contrast, the cyclization of the non-interlocked fumaramide T1c
gives a 2.9 : 1 mixture of diastereoisomeric b-lactams trans- and
cis-9 (Fig. 8e, signals of cis-9 in violet colour) besides other
minor compounds resulting from the decomposition of trans-
and cis-9 under the reaction conditions. The last result
demonstrates not only the protective function of the macro-
cycle, but also the denitive role of the mechanical bond
controlling the diastereoselectivity of the cyclization.
Scheme
3
Dethreading of interlocked lactams trans-2a, 2d–h.
ꢀ
Reaction conditions: (i) DMF, 12 h, 100 C. The different fragments in
the macrocycle are disclosed in Table 2.
Single crystals were obtained by slow diffusion of pentane
into a dichloroethane solution of rotaxane trans-8i. The X-ray
analysis conrmed the interlocked nature of trans-8i and the
relative conguration of the chiral atoms at the azetidinone ring
(Fig. 9). Interestingly, the diadamantyl-based macrocycle shows
a distorted chair-like conformation, different to that usually
66,67
found in isophthalamide-based systems.
One of the two
adamantanedicarboxamide units establishes bifurcated
hydrogen bonds of the NH protons with the carbonyl group at
the side-chain of the azetidinone, whereas the carbonyl group of
the b-lactam ring forms a hydrogen bond with only one of the
other NH protons of the macrocycle.
Scheme 4 Cyclization of rotaxanes 7a and 7i. Synthesis of the
a,b
a
unthreaded lactam trans-9.
Reaction conditions: (i) CsOH (1
ꢀ
ꢀ
equiv.), DMF, 12 h, 25 C; (ii) CsOH (1 equiv.), DMF, 30 min, 25 C; (iii)
DMF, 2 h, 100 C; (iv) CsOH (1 equiv.), DMF, 30 min, 25 C; then
neutralization with HCl 1 M (1 equiv.) and subsequent heating 2 h at
00 C; insets: (1) picture of the reaction vial at 0 min reaction time;
2) picture of the reaction vial after 30 min; yield obtained in the one-
ꢀ
ꢀ
ꢀ
b
1
c
(
pot procedure.
(Scheme 4, eqn (2), inset (1)), transformed in the presence of
base under more diluted conditions (10 mM) aer a short
period of time (30 min) into trans-8i, fully soluble in DMF, in
high yield (Scheme 4, eqn (2), inset (2)). The dethreading of
trans-8i to give the b-lactam trans-9 took place successfully by
ꢀ
heating at 100 C in DMF solution for 2 h. As we presumed,
a one-pot procedure quantitatively provided the desired azeti-
dinone trans-9 from the interlocked fumaramide 7i.
1
The H NMR spectra of the thread T1c, rotaxanes 7i and
trans-8i, the free lactam trans-9 and a mixture of lactams trans-
and cis-9 are stacked in Fig. 8. As expected, the protons of the
fumaramide function in the rotaxane 7i (H and H ) experience
1
Fig. 8 H NMR spectra (400 MHz, CDCl
3
, 298 K) of (a) N,N-dibenzyl-
b
c
0
0
N ,N -dipropylfumaramide T1c; (b) fumaramide-based [2]rotaxane 7i;
c) interlocked b-lactam trans-8i; (d) b-lactam trans-9; and (e) mixture
of b-lactams cis- and trans-9 obtained by cyclization of the thread T1c.
shis to higher eld (Dd ꢃ 1.54 ppm) due to the anisotropic
(
effect caused by the macrocycle (Fig. 9b, signals in red colour).
The highly diastereoselective CsOH-promoted cyclization of the Lettering as in Scheme 4.
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selectivity which nally leads to a regio- and diastereoselective
synthesis of b-lactams. The full understanding of this process
opens the door to the study of other transformations that could
occur in the cavity of a polyamide macrocycle, including the
development of the asymmetric version of this cyclization of
interlocked N-benzylfumaramides.
Conflicts of interest
There are no conicts to declare.
Fig. 9 X-ray structure of: (a) the [2]rotaxane trans-8i; (b) the thread of
Acknowledgements
[
2]rotaxane trans-8i (the macrocycle was removed for clarity). Intra-
molecular hydrogen-bond lengths [ A˚ ] (and angles [deg.]): O5HN1 2.19
164); O5HN4 2.34 (168); O6HN2 2.13 (164).
This work was supported by the MINECO and MICINN (project
CTQ2017-87231-P and RYC-2017-22700) and the Fundaci ´o n
Seneca-CARM (project 20811/PI/18). The authors gratefully
acknowledge the computer resources at Cibeles and the tech-
nical support provided by the Centro de Computaci ´o n Cient ´ı f-
ica-UAM (RES-QSB-2019-3-0012).
(
3. Conclusions
A precise inspection of the mechanism of the CsOH-promoted
cyclization of fumaramides embedded in the tetraamide ring
of a [2]rotaxane is presented. The mechanistic analysis has been Notes and references
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