Stereocontrolled Synthesis of β-Lactams within [2]Rotaxanes: Showcasing the Chemical Consequences of the Mechanical Bond

Article abstract of DOI:10.1021/jacs.6b05581

The intramolecular cyclization of N-benzylfumaramide [2]rotaxanes is described. The mechanical bond of these substrates activates this transformation to proceed in high yields and in a regio- and diastereoselective manner, giving interlocked 3,4-disubstituted trans-azetidin-2-ones. This activation effect markedly differs from the more common shielding protection of threaded functions by the macrocycle, in this case promoting an unusual and disfavored 4-exo-trig ring closure. Kinetic and synthetic studies allowed us to delineate an advantageous approach toward β-lactams based on a two-step, one-pot protocol: an intramolecular ring closure followed by a thermally induced dethreading step. The advantages of carrying out this cyclization in the confined space of a benzylic amide macrocycle are attributed to its anchimeric assistance.

Full text of DOI:10.1021/jacs.6b05581

Subscriber access provided by The University of British Columbia Library
Communication
Stereocontrolled Synthesis of #-Lactams within [2]Rotaxanes: a
Showcase of the Chemical Consequences of the Mechanical Bond
Alberto Martinez Cuezva, Carmen Lopez-Leonardo, Delia Bautista, Mateo Alajarín, and José Berná
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05581 • Publication Date (Web): 29 Jun 2016
Downloaded from http://pubs.acs.org on July 2, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Stereocontrolled Synthesis of -Lactams within [2]Rotaxanes:
a Showcase of the Chemical Consequences of the Mechanical
Bond
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alberto Martinez-Cuezva,† Carmen Lopez-Leonardo,† Delia Bautista,‡ Mateo Alajarin,† Jose Berna*,†
†Departamento de Química Orgánica, Facultad de Química, Regional Campus of International Excellence "Campus Mare
Nostrum", Universidad de Murcia, E-30100 Murcia (Spain)
‡Sección Universitaria de Instrumentación Científica (SUIC), Servicio de Apoyo a la Investigación (SAI), Regional Campus
of International Excellence "Campus Mare Nostrum", Universidad de Murcia, E-30100 Murcia (Spain)
chemical consequences for carrying out this process in the
confined space of a macrocycle and the stereoselective synthesis
ABSTRACT: The intramolecular cyclization of N-benzyl
fumaramide [2]rotaxanes is described. The mechanical bond of
these substrates activates this transformation to proceed in high
yields and in a regio- and diastereoselective manner giving
interlocked 3,4-disubstituted trans azetidin-2-ones. This activation
effect markedly differs from the more common shielding
protection of threaded functions by the macrocycle, in this case
promoting an unusual and disfavored 4-exo-trig ring closure.
Kinetic and synthetic studies allowed us to delineate an
advantageous approach towards -lactams based on a two-step
one-pot protocol: an intramolecular ring closure followed by a
thermally-induced dethreading step. The advantages for carrying
out this cyclization in the confined space of a benzylic amide
macrocycle are attributed to its anchimeric assistance.
of -lactams through
a one-pot protocol based on an
intramolecular 4-exo-trig ring closure of an interlocked
fumaramide followed by a thermally-induced dethreading step
(Scheme 1c).
Scheme 1. Intramolecular 4-exo-trig Ring Closures of
Fumaramide Derivatives
The remarkable catalytic performance of the Nature’s
enzymes represents a stimulating source of inspiration.1 In fact,
the use of artificial hosts for transiently trapping compounds and
controlling its reactivity has always been an important challenge
for the chemists.2 In this regard, compounds having a void or
cavity such as self-assembled capsules,3 molecular cages4 and
macrocycles5 are vigorously investigated in this arena. Also, in
the last years, the govern of the chemical behavior of the entwined
components of mechanically interlocked compounds6,7 is being
explored with purposes such as the kinetic stabilization of the
encapsulated functionalities,8 the development of novel
configurable catalysts9 and the building of processive catalytic
interlocked systems.10
First, we assayed the intramolecular cyclization of the
rotaxane 2a, obtained from N,N,N’,N’-tetrabenzylfumaramide
(1a) acting as template, in DMF to exclusively afford the
interlocked -lactam trans-3a after a mild heating period of 6 h at
60 oC in DMF by using Cs2CO3 as base (Scheme 2).
Scheme 2. Cyclization within Rotaxane 2aa
During the course of our investigations with amide-based
[2]rotaxanes11 we serendipitously found that the thermal treatment
of an interlocked N-benzylfumaramide in the presence of a base
cleanly produces an interlocked -lactam resulting from a formal
intramolecular Michael addition of a benzyl group of the axis to
the olefin. Interestingly, among the arsenal of methods to get -
lactams,12 this type of transformation has been barely reported.13
In this regard, Clayden and coworkers published an example of 4-
exo-trig cyclization of a benzyllithium fumaramide to exclusively
afford the cis -lactam in low yield (Scheme 1a).13a Almost a
decade after, Kawabata et al. described the conjugated addition of
axially chiral enolates generated from -amino acids to provide a
cis-trans mixture of -lactams (Scheme 1b).13b With these
precedents in mind we considered of interest to study the
cyclization of N-benzyl fumaramides within hydrogen bonded
[2]rotaxanes to yield interlocked -lactams. Herein we report the
aReaction conditions: (i) isophthaloyl dichloride, p-
xylylenediamine, Et3N, CHCl3, 2a, 36 %; (ii) Cs2CO3 (1 equiv),
DMF, 60 oC, 6 h, 3a, 99%.
In contrast with the symmetry of the aliphatic region of the 1H
NMR spectrum of the rotaxane 2a (Figure 1A), that of 3a displays
a complex set of signals corresponding to the three methylene AB
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 15
systems of the benzyl groups of the thread (in black) and the three
explored this transformation with the corresponding non-
interlocked substrate (Scheme 3).6a Even using an excess of
1
2
3
4
5
6
7
signals belonging to the 4-methylenecarboxamido azetidin-2-one
motif (in red) (Figure 1B). The coupling constant of 1.9 Hz for the
hydrogen at the position 4 of the lactam ring, Hb, of 3a lies in the
Cs2CO3, 1a remained unaltered after heating at temperatures
o
under 100 C for 24 h, probably due to the low basicity of each
benzylic protons.15 Total consumption of 1a requires an extended
1
range (1.5-2.2 Hz) reported for other trans -lactams14. H NMR
o
thermal treatment at 120 C for 7 days using 10 equiv of Cs2CO3
spectrum (Figure 1C) of the non-interlocked thread trans-4a (vide
infra) was compared with that of 3a showing an upfield shift of
the signals of the protons of the thread [e.g., (Hc) = 2.4 ppm]
due to the electronic currents of the benzylic amide macrocycle.
for obtaining the expected -lactams 4a in 45% yield as a
diastereomeric mixture in 2:1 ratio in favor of the trans isomer
along with a complex mixture of side products.
8
9
The broadness of the signals of the E, E’ methylene protons of
the macrocycle of 3a (Figure 1B) reveals an appreciable
intercomponent interaction with the thread despite of the branched
carbon chain connecting both hydrogen bond acceptor CO groups.
Indeed, in a separate experiment the rotaxane formation reaction
using the -lactam 4a as a template afforded the interlocked 3a in
8% yield (see Supporting Information).
Scheme 3. Intramolecular Michael Addition of N,N,N',N'-
Tetrabenzylfumaramide (1a)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The shorter reaction time of the intramolecular addition to the
interlocked Michael acceptor when compared with that of the
non-interlocked reactant contrasts with most of the reported
reactions on the axis of hydrogen bonded rotaxanes in which the
main effect lays on the kinetic stabilization of the threaded
function.6,8 Moreover, the high diastereoselectivity (>99:1), only
trans lactam is obtained, and the absence of reaction byproducts
(Scheme 2) are neat advantages of carrying out this process in the
inner of the benzylic amide macrocycle in comparison with the
same transformation on the isolated thread (Scheme 3). We next
examined further details of the conversion of 2a in trans-3a by
screening different reaction parameters such as temperature,
solvent, base and stoichiometry (Table 1 and Tables S1-5).
Whereas DMF or DMSO as solvents allow quantitative
conversions (Table 1), chloroform, acetonitrile and ethanol were
completely unproductive (see Table S3). The use of organic bases
(pyridine, piperidine, DIPEA or DBU) kept intact the substrate
(Table S2). Although different metal carbonates were assayed,
only cesium carbonate reached a full conversion, probably due to
its good solubility in polar solvents (Table 1, entries 1 and 2). We
found that metal hydroxides such as NaOH, KOH and CsOH also
achieved the complete cyclization of 3a (Table 1, entries 3-6), at
Figure 1. 1H NMR (400 MHz, CDCl3, 298K) spectra of: (A)
fumaramide [2]rotaxane 2a, (B) -lactam [2]rotaxane trans-3a
and (C) -lactam trans-4a. Letter assignments are in Scheme 2.
An X-ray analysis of a single crystal of 3a confirmed its
interlocked structure and the trans configuration of the
azetidinone ring (Figure 2). Whereas one of the isophthalamide
units establishes a bifurcated hydrogen bond with the CONBn2
carbonyl group of the thread through both NH amide protons, the
other isophthalamide moiety forms a strong hydrogen bond with
the -lactam carbonyl group although by means of only one of the
NH amide protons. The fourth amide group of the macrocycle
adopts now a transoid conformation, probably the ideal one for
enlarging the macrocyclic void and easing the accommodation of
the bulkier cyclic thread.
o
60 C, reducing the reaction time to 3 h. Remarkably, the use of
CsOH allows the complete reaction at room temperature in 6 h
(Table 1, entry 7) which contrasts with the failure of the
cyclization of 3a using Cs2CO3 as base under the same conditions
(Table 1, entry 8). Note that using CsOH as base in the cyclization
of non-interlocked fumaramide 1a led to a cis-trans mixture of 4a
in 51% yield after 3 days (Table S1).
Table 1. Intramolecular Cyclization of 2a Yielding the -
Lactam trans-3a
Entry Solventa Base (equiv.)
Temp (oC)
t (h) Conv (%)b
1
2
DMF
DMSO
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
Cs2CO3 (1)
Cs2CO3 (1)
CsOH (1)c
NaOH (1)
KOH (1)
CsOH (1)c
CsOH (1)c
Cs2CO3 (1)
CsOH (0.1)c
Cs2CO3 (0.1)
60
60
60
60
60
60
25
25
100
60
6
6
100
95
3
3
100
100
100
100
100
8
4
3
5
3
6
3
7
6
8
16
24
48
9
89
10
92
Figure 2. X-Ray structure of the [2]rotaxane 3a. Intramolecular
hydrogen-bond lengths [Å] (and angles [deg]): O11HN2 2.42
(161.6); O11HN3 2.23 (176.0); O12HN1 1.85 (166.3).
aThe reaction was carried out at 0.02 M scale. bDetermined by 1H
NMR of the crude reaction mixture. cCesium hydroxide was dried
prior to use by heating at 150 oC under vacuum.
Aimed to compare the effect of the mechanical bonding on the
outcome of the studied intramolecular conjugated addition we
2
ACS Paragon Plus Environment

Page 3 of 15
Journal of the American Chemical Society
Keeping in mind the interest in developing a synthetic strategy to
cases. In this vein, an electron withdrawing substituent such as p-
1
2
3
4
5
6
7
obtain non-interlocked azetidinones the result in entry 7 becomes
crucial as it would allow to carry out this transformation with
kinetically stable pseudorotaxanes (vide infra) which, after
dethreading,16 would set free the appealing four-membered cyclic
guest. Finally, it is also noteworthy that this conjugate addition
efficiently occurs by using catalytic amounts of base (Table 1,
entries 9 and 10) although after longer reaction times.
Cl at the ring of the benzyl units of 2g notably accelerated the
cyclization which ended in less than one hour. Note that this
behavior predetermines the regiochemical outcome of the
cyclization of 2h to exclusively yield the lactam 3h derived from
the addition of the p-chlorobenzyl anion (Scheme 4).
Scheme 4. Regiocontrolled Ring Closure within Rotaxane
2h
In order to study the scope of this intramolecular cyclization
we prepared a set of fumaramide-based rotaxanes differing in the
number of benzylic substituents and their organization at the
nitrogen atoms of the dicarboxamide. Electronic variations of the
substituents at the amido group were also examined by
introducing aryl groups with different electron donor or electron
withdrawing groups at the benzylic carbons of the axis. Rotaxanes
2b-g (Table 2) were obtained in 24-53% yields by five-component
clipping reactions using the respective fumaramides, in turn easily
prepared from fumaric acid derivatives (see Supp. Info. for
synthetic details). The intramolecular cyclizations of 2a-g were
carried out in the presence of cesium hydroxide to afford the
interlocked trans -lactams 3a-g in high yields (85-99%) (Table
2). Fumaramides 2b-2d having only one benzyl at the amide
group showed lower reaction rates than 2a and required an excess
of base to complete their cyclization.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rotaxanes 2d-2g, having one NBu2 terminus, can be
considered as kinetically stable pseudorotaxanes since under
appropriate thermal conditions these complexes dissociate into
their non-interlocked components.17 In fact, the half-life time of
2e in DMSO-d6 at 373 K is only 6 min (Figure S2). The release of
the thread through the Bu2N terminus of interlocked -lactams
3d-h is slower than that of its corresponding fumaramide
predecessors 2d-h. For instance, the half-life time of 3e in
DMSO-d6 at 373 K is 39 min (see Figure S3). The heating of
solutions of the pseudorotaxanes 3d-h in DMF extrude the
corresponding -lactams 5d-h in a quantitative manner (Table 3,
conditions i). Interestingly, both cyclization and dethreading steps
are able to consecutively occur in a one-pot protocol by
intercalating a neutralization step, thus enabling the direct
conversion of the fumaramide [2]rotaxanes into the corresponding
-lactams (Table 3, conditions ii).
Table 2. 4-Exo-trig Ring Closure of N-Benzyl
Fumaramides within [2]Rotaxanes 2a-ga
Table 3. Synthesis of the -Lactams 5d-ha,b
a Reaction conditions: i) 100 oC, 12 h; ii) CsOH, DMF, 20 oC, 24
h then adjusting pH ≈ 7 with aq 2N HCl and heating to 100 oC, 12
1
aComplete conversions were observed by H NMR. Yields refer
1
h. Quantitative conversions were observed by H NMR. Yields
refer to isolated pure compounds. bYields in brackets were
obtained by using the one-pot protocol.
to isolated pure compounds. For convenience, 2a and 3a are also
b
included herein. The lactam ring quantitative hydrolyzed giving
the interlocked 3-(phenylamino)propanoic acid derivative (see
Supp. Info.). cBased on the isolated hydrolysis compound.
In order to explain the role of the macrocycle in facilitating
the formation of the interlocked 2-azetidinones of this work we
propose these processes might be initiated by the initial
deprotonation of one of the four isophthalamide NH protons
(Scheme 5), reasonably the most acidic ones of the whole
supramolecule. This anion could then add to one of the sp2
carbons of the fumaramide thread in an intramolecular aza-
Michael reaction (IMAMR)18 generating an enolate capable to
internally abstract one of the nearby benzylic protons from the
dibenzylamido moieties. Then, the resulting carbanion
nucleophilically displaces the anchimeric assistant group19 to form
e
dCyclization finished in 12 h. A conversion of 90% required 5
equiv of CsOH and 48 h. fCyclization finished in 40 min.
The intramolecular cyclization of the interlocked fumaramides
2e-g also produced the corresponding 2-azetidinones 3e-g in
excellent yields (89-91%) but these reactions proceeded at
different rates depending on the acidity of the methylene protons
of the N-benzyl group (Figure S1). Thus the presence of donor
substituents, e.g. a methoxy group, on the benzyl groups of the
thread of 2f notably slowed down the transformation needing up
to 48 h for reaching conversions similar to those of unsubstituted
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 15
(2) (a) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen Piet,
the four-membered ring. The polar aprotic solvent, DMSO or
DMF, should play a key role in stabilizing the anionic interlocked
intermediates.
W. N. M. Chem. Soc. Rev. 2014, 43, 1734; (b) Zarra, S.; Wood, D. M.;
Roberts, D. A.; Nitschke, J. R. Chem. Soc. Rev. 2015, 44, 419; (c) Brown,
C. J.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Chem. Rev. 2015,
115, 3012; (d) Galan, A.; Ballester, P. Chem. Soc. Rev. 2016, 45, 1720.
(3) Yoshizawa, M.; Klosterman, J. K.; Fujita, M. Angew. Chem., Int.
Ed., 2009, 48, 3418.
(4) Rebek, J. Acc. Chem. Res., 2009, 42, 1660.
(5) (a) Breslow, R.; Dong, S. D. Chem. Rev. 1998, 98, 1997; (b)
Takahashi, K. Chem. Rev., 1998, 98, 2013. See also ref 2a.
(6) (a) Neal, E. A.; Goldup, S. M. Chem. Commun. 2014, 50, 5128; (b)
D’Souza, D. M.; Leigh, D. A.; Mottier, L.; Mullen, K. M.; Paolucci, F.;
Teat, S. J.; Zhang, S. J. Am. Chem. Soc. 2010, 132, 9465.; (c) Lahlali, H.;
Jobe, K.; Watkinson, M.; Goldup, S. M. Angew. Chem., Int. Ed. 2011, 50,
4151.
1
2
3
4
5
6
7
8
The vanishing of the double bond of the starting thread
through the herein proposed mechanism forecasts that the
cyclization of the Z isomer of 2a would also led to the trans -
lactam 3a as, indeed, it occurs (see Scheme S5). Additionally, the
ring closure of 1a using N,N’-bis(4-(benzamidomethyl)benzyl)-
isophthalamide as an open-chain surrogate of the benzylic amide
macrocycle (see Scheme S8) or the non-interlocked macrocycle
itself (see Scheme S9) inhibited the cyclization. Both results
further underpin the neighboring group participation of the
mechanically linked cyclic polyamide in this transformation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Xue, M.; Yang, Y.; Chi, X.; Yan, X.; Huang, F. Chem. Rev.
2015, 115, 7398; (b) Gil-Ramirez, G.; Leigh, D. A.; Stephens, A. J.
Angew. Chem., Int. Ed. 2015, 54, 6110.
(8) (a) Parham, A. H.; Windisch, B. B.; Vögtle, F. Eur. J. Org. Chem.
1999, 1233; (b) Ghosh, P.; Mermagen, O.; Schalley, C. A. Chem.
Commun. 2002, 2628; (c) Oku, T.; Furusho, Y.; Takata, T. Org. Lett.
2003, 5, 4923; (c) Leigh, D. A.; Perez, E. M. Chem. Commun. 2004, 2262;
(d) Winn, J.; Pinczewska, A.; Goldup, S. M. J. Am. Chem. Soc. 2013, 135,
13318.
Scheme 5. Proposed Mechanism for the 4-exo-trig Ring
Closure of Interlocked Fumaramides
(9) (a) Berna, J.; Alajarin, M.; Orenes, R.-A. J. Am. Chem. Soc. 2010,
132, 10741; (b) Blanco, V.; Carlone, A.; Hänni, K. D.; Leigh, D. A.;
Lewandowski, B. Angew. Chem., Int. Ed. 2012, 51, 5166; (c) Blanco, V.;
Leigh, D. A.; Marcos, V.; Morales-Serna, J. A.; Nussbaumer, A. L. J. Am.
Chem. Soc. 2014, 136, 4905; (d) Blanco, V.; Leigh, D. A.; Lewandowska,
U.; Lewandowski, B.; Marcos, V. J. Am. Chem. Soc. 2014, 136, 15775; (e)
Bordoli, R. J.; Goldup, S. M. J. Am. Chem. Soc. 2014, 136, 4817. (f)
Beswick, J.; Blanco, V.; De Bo, G.; Leigh, D. A.; Lewandowska, U.;
Lewandowski, B.; Mishiro, K. Chem. Sci. 2015, 6, 140; (g) Galli, M.;
Lewis, J. E. M.; Goldup, S. M. Angew. Chem., Int. Ed. 2015, 54, 13545.
(h) Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A. J. Am. Chem. Soc. 2016,
138, 1749.
(10) (a) Thordarson, P.; Bijsterveld, E. J. A.; Rowan, A. E.; Nolte, R. J.
M. Nature 2003, 424, 915; (b) Miyagawa, N.; Watanabe, M.; Matsuyama,
T.; Koyama, Y.; Moriuchi, T.; Hirao, T.; Furusho, Y.; Takata, T. Chem.
Commun. 2010, 46, 1920; (c) Takashima, Y.; Osaki, M.; Ishimaru, Y.;
Yamaguchi, H.; Harada, A. Angew. Chem., Int. Ed. 2011, 50, 7524; (d)
Lewandowski, B.; De Bo, G.; Ward, J. W.; Papmeyer, M.; Kuschel, S.;
Aldegunde, M. J.; Gramlich, P. M. E.; Heckmann, D.; Goldup, S. M.;
D’Souza, D. M.; Fernandes, A. E.; Leigh, D. A. Science 2013, 339, 189;
(e) van Dongen, S. F. M.; Clerx, J.; Nørgaard, K.; Bloemberg, T. G.;
Cornelissen, J. J. L. M.; Trakselis, M. A.; Nelson, S. W.; Benkovic, S. J.;
Rowan, A. E.; Nolte, R. J. M. Nat. Chem. 2013, 5, 945.
(11) (a) Berna, J.; Alajarin, M.; Marin-Rodriguez, C.; Franco-Pujante, C.
Chem. Sci. 2012, 3, 2314; (b) Berna, J.; Franco-Pujante, C.; Alajarín, M.
Org. Biomol. Chem. 2014, 12, 474; (c) Martinez-Cuezva, A.; Berna, J.;
Orenes, R.-A.; Pastor, A.; Alajarin, M. Angew. Chem. Int. Ed. 2014, 53,
6762; (d) Martinez-Cuezva, A.; Pastor, A.; Cioncoloni, G.; Orenes, R.-A.;
Alajarin, M.; Symes, M. D.; Berna, J. Chem. Sci. 2015, 6, 3087; (e)
Martinez-Cuezva, A.; Valero-Moya, S.; Alajarin, M.; Berna, J. Chem.
Commun. 2015, 51, 14501.
(12) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007,
107, 4437; (b) Pitts, C. R.; Lectka, T. Chem. Rev. 2014, 114, 7930.
(13) (a) Clayden, J.; Watson, D. W.; Chambers, M.; Sharp, M.; Park, T.
Chem. Commun. 2003, 2582; (b) Yoshimura, T.; Takuwa, M.; Tomohara,
K.; Uyama, M.; Hayashi, K.; Yang, P.; Hyakutake, R.; Sasamori, T.;
Tokitoh, N.; Kawabata, T. Chem. Eur. J. 2012, 18, 15330.
(14) (a) Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org. Chem. 2005, 70,
334; (b) Zhang, Z.; Liu, Y.; Ling, L.; Li, Y.; Dong, Y.; Gong, M.; Zhao,
X.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 4330.
(15) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
(16) Asakawa, M.; Ashton, P. R.; Ballardini, R.; Balzani, V.;
Bělohradský, M.; Gandolfi, M. T.; Kocian, O.; Prodi, L.; Raymo, F. M.;
Stoddart, J. F.; Venturi, M. J. Am. Chem. Soc. 1997, 119, 302.
(17) Martinez-Cuezva, A.; Rodrigues, L. V.; Navarro, C.; Carro-Guillen,
F.; Buriol, L.; Frizzo, C. P.; Martins, M. A. P.; Alajarin, M.; Berna, J. J.
Org. Chem. 2015, 80, 10049.
(18) (a) Sánchez-Roselló, M.; Aceña, J. L.; Simón-Fuentes, A.; del Po-
zo, C. Chem. Soc. Rev., 2014, 43, 7430; (b) Lebrun, S.; Sallio, R.; Dubois,
M.; Agbossou-Niedercorn, F.; Deniau, E.; Michon, C. Eur. J. Org. Chem.
2015, 1995.
(19) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12928.
The base-catalyzed intramolecular Michael addition of -
benzyl fumaramides ocurring inside the cavity of a removable
benzylic amide macrocycle, built from two isophtalamide units
connected by two p-xylylene linkers, benefits of the activating
and stereodirecting effects of the mechanical bond. These
transformations taking place in a confined space proceeded
without the formation of byproducts, at higher reaction rates than
those of the non-interlocked fumaramides and in a regio- and
diastereoselective manner.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data for all new
compounds, kinetics measurements, and full crystallographic
details of 3a including CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ppberna@um.es
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported by the MINECO (CTQ2014-56887-P)
with joint financing by FEDER Funds from the European Union,
and Fundacion Seneca-CARM (Project 19240/PI/14). A.M.-C.
also thanks the MINECO (Contract No. FPDI-2013-16623) for his
postdoctoral contract.
REFERENCES
(1) (a) Stimulating Concepts in Chemistry (eds F. Vögtle, J. F. Stoddart
and M. Shibasaki), Wiley-VCH, Weinheim, Germany.
4
ACS Paragon Plus Environment

Page 5 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Intramolecular 4-exo-trig Ring Closures of Fumaramide Derivatives
78x45mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 7 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Cyclization within Rotaxane 2aa
74x33mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. 1H NMR (400 MHz, CDCl3, 298 K) spectra of: (A) fumaramide [2]rotaxane 2a, (B) β-lactam
[2]rotaxane trans-3a and (C) β-lactam trans-4a. Letter assignments are in Scheme 2.
70x86mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 9 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. X-Ray structure of the [2]rotaxane 3a. Intramolecular hydrogen-bond lengths [Å] (and angles
[deg]): O11HN2 2.42 (161.6); O11HN3 2.23 (176.0); O12HN1 1.85 (166.3).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Intramolecular Michael Addition of N,N,N\',N\'-Tetrabenzylfumaramide (1a)
83x15mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 11 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. 4-Exo-trig Ring Closure of N-Benzyl Fumaramides within [2]Rotaxanes 2a-ga
70x89mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Regiocontrolled Ring Closure within Rotaxane 2h
84x30mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 13 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Synthesis of the β-Lactams 5d-ha,b
69x51mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Proposed Mechanism for the 4-exo-trig Ring Closure of Interlocked Fumaramides
80x67mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 15 of 15
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TABLE OF CONTENTS
84x34mm (144 x 144 DPI)
ACS Paragon Plus Environment