Enantioselective Formation of 2-Azetidinones by Ring-Assisted Cyclization of Interlocked N-(α-Methyl)benzyl Fumaramides

Article abstract of DOI:10.1002/anie.201803187

The synthesis of optically active interlocked and non-interlocked 2-azetidinones by intramolecular cyclization of N-(α-methyl)benzyl fumaramide [2]rotaxanes is described. Two different strategies of asymmetric induction were tested in which the chiral gro

Full text of DOI:10.1002/anie.201803187

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Accepted Article
Title: Enantioselective Formation of 2-Azetidinones by Ring-Assisted
Cyclization of Interlocked N-(α-Methyl)benzyl Fumaramides
Authors: Alberto Martinez-Cuezva, Delia Bautista, Mateo Alajarin, and
Jose Berna
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803187
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10.1002/anie.201803187
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Enantioselective Formation of 2-Azetidinones by Ring-Assisted
Cyclization of Interlocked N-(-Methyl)benzyl Fumaramides
Alberto Martinez-Cuezva,*[a] Delia Bautista,[b] Mateo Alajarin,[a] and Jose Berna,*[a]
Abstract: The synthesis of optically active interlocked and non-
interlocked 2-azetidinones by intramolecular cyclization of N-(-
methyl)benzyl fumaramide [2]rotaxanes is described. Two different
strategies of asymmetric induction were tested in which the chiral
group was located either proximal or distal to the reaction center of
the thread. During these experiments, an interesting equilibration
process inside the macrocyclic void occurred leading to the
cyclization through the (-methyl)benzyl carbon atom giving rise to
-lactams with a quaternary carbon atom in an enantio- and
diastereocontrolled manner. This cyclization also proceeds in
kinetically stable chiral pseudo[2]rotaxanes allowing further
dethreading to provide enantioenriched 3,4-disubstituted trans-2-
azetidinones. The stereochemical outcomes of the cyclizations
inside and outside the macrocycle showed notorious differences.
shielding of the threaded functions,[10a,14] in this case promoting
an unusual and disfavored 4-exo-trig ring closure. Herein we
report our efforts for achieving carbon-to-carbon chirality
induction from N-(-methyl)benzyl substituents to the carbon
atoms of the -lactam ring and its implementation to the
synthesis of enantioenriched 2-azetidinones.
Nature has always been a source of inspiration for the scientific
community. Many chemists have focused their efforts on
mimicking the catalytic behavior of enzymes.[1] The increase of
the reaction rates or the enhancement of the enantio- or
diastereoselectivities of natural processes are feasible by the
existence of active-site pockets constrained by the folding of the
protein. Thus, synthetic compounds having a restricted void or
matrix which could emulate the behavior of enzymes are highly
demanding.[2] Besides the use of highly confined
organocatalysts[3] or materials,[4] able to create the desirable
rigid space for the stabilization of the corresponding transition
states, self-assembled capsules,[5] molecular cages,[6] and
macrocycles,[7] are in the spotlight. These tailor-suited systems
can be easily tuned to enhance their catalytic features in a way
similar to other enzymatic structures.[8,9] The chemical activity of
mechanically interlocked molecules has been under intense
study in recent years.[10,11] The presence of the mechanical
bond[10a] infers particular chemical properties to these systems
that have been applied as selective and/or switchable catalysts
among others.[11]
Scheme 1. CsOH-catalyzed intramolecular cyclization of interlocked N-benzyl
fumaramides
To this end we first prepared enantioenriched pseudo-
[2]rotaxanes 3 and 4 bearing a single stereogenic carbon at one
of the N-substituents of the thread.[15,16,17] When these species
were submitted to
a one-pot CsOH-catalyzed cyclization-
dethreading process,[12] the non-interlocked trans-β-lactams 5
and 6 were obtained in good yields although in a disappointing
low diastereomeric ratios (1.3-1.4:1 approx.) (Scheme 2).[18]
Scheme 2. One-pot synthesis of the β-lactams 5 and 6. Reaction conditions: i)
Recently, we reported the intramolecular cyclization of N-
benzyl fumaramide [2]rotaxanes 1 (Scheme 1).[12] In that work,
we disclosed the role of the mechanical bond in a transformation
which occurs in a regio- and diastereoselective manner giving
interlocked 3,4-disubstituted trans 2-azetidinones 2 in high yields,
in contrast with the less efficient conversion carried out outside
the ring. The activating effect of the tetraamide macrocycle[13] in
these processes markedly contrasts with the habitual steric
CsOH, DMF, 25 °C; ii) HCl 1 M; iii) 100 °C, 24 h.
Unfortunately, placing the stereogenic carbon proximal to the
benzylic carbon atom involved in the cyclization, both at the
same fumaramide N atom, prevented an effective chirality
induction. We next moved to the alternative distal approach, that
is locating the chiral inductor at the other terminus of the
fumaramide. Thus we next assayed the [2]rotaxane 7 bearing a
N,N-dibenzyl-N´,N´-bis((R)-1-phenylethyl)fumaramide as thread
incorporating a C2-chiral asymmetric inductor (Scheme 3). First,
the CsOH-promoted cyclization of 7 was carried out at room
temperature (Scheme 3, conditions i) affording a discouraging
1.6:1 mixture of two diastereoisomers, trans 9a and 9b.
Surprisingly, when the reaction was carried out at a rather
higher temperature (120 ºC) 7 yielded a completely different
product in high yield, the rotaxane 10, as resulting from the
cyclization of the thread through one of the chiral carbon atoms.
Rotaxane 10 was obtained as a single diastereoisomer in a
[a]
[b]
Dr. A. Martinez-Cuezva, Prof. Dr. M. Alajarin, Dr. J. Berna
Departamento de Química Orgánica, Facultad de Química,
Universidad de Murcia, E-30100 Murcia (Spain)
E-mail: amcuezva@um.es; ppberna@um.es
Dr. D. Bautista
SAI, Universidad de Murcia, E-30100 Murcia (Spain)
Supporting information for this article is given via a link at the end of
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10.1002/anie.201803187
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process involving the formation of a tetrasubstituted stereogenic
methylbenzyl)amino stopper than in 9 with a less sterically
demanding dibenzylamino group. Nevertheless, the cyclizations
leading to 10 and 11 are noticeable by involving one of the more
substituted benzylic carbon atoms of the thread as well by its
stereochemical course (retention of configuration).[15e,22] We
proposed some mechanistic proposals accounting for this latter
aspect which are based on our previous assumption concerning
the anchimeric assistance of the surrounding macrocycle.[12]
Thus, it might be explained by a rapid deprotonation/cyclization
with a concurrent disconnection of the assistant-ring precluding
the racemization at the chiral center[23] (Fig. S2, cycle A) or the
regioselective insertion of a stabilized carbene in the C-H bond
of a trisubstituted chiral carbon atom[24] (Fig. S2, cycle B). Other
alternative explanations based on radical pathways[25] were also
envisaged although seemed unlikely as result of our
experiments with TEMPO or in absence of light conditions (see
Schemes S6 and S7).
center from a trisubstituted one.[15b] The product 10 also formed
by heating the diastereomeric mixture
9 at the same
temperature (Scheme 3, conditions ii) in the presence of the
base.
In order to release the -lactams[26] from the interlocked
architecture we next replaced the dibenzylamino stopper of the
starting rotaxane 7 by a dibutylamino one for decreasing the
kinetic stability of the final interlocked ensemble, thus exploring
the reactivity of the pseudo[2]rotaxane 12 with a (E)-N,N-dibutyl-
Scheme 3. Synthesis of trans β-lactams 9-11. Reaction conditions i) CsOH (1
equiv.), DMF, 25 °C, 12 h; ii) CsOH (1 equiv.), DMF, 120 °C, 2 h.
N´,N´-bis((R)-1-phenylethyl)fumaramide
as
thread.
This
structural modification excludes the possibility of using the
previous reaction conditions (120 ºC, DMF) due to the quick
dethreading of the fumaramide outside the ring. After an
optimization of the reaction conditions, the cyclization was
carried out at the lowest temperature allowing the -lactam
formation to occur (65 °C) inside the macrocycle and in the
presence of an excess of base (5 equiv) (Scheme 4). After 4
hours, two trans diastereoisomers were obtained in a 6:1 ratio,
both as single enantiomers. In this case, the cyclization of the
We determined the absolute configuration of the chiral
centers of the dibromo analogous 11, directly obtained in 92 %
yield by a CsOH-promoted cyclization of the corresponding
interlocked fumaramide 8 (see Scheme 3) by single-crystal X-
ray diffraction analysis (see Figure 1, CCDC: 1830131). The
structure of 11 unveiled that the cyclization, in which a
quaternary carbon is formed, occurred with retention of the
configuration at the reacting chiral stereocenter.[15b,19,20]
thread occurred with
a substantial percentage (15%) of
configurational inversion at the reacting stereocenter still with a
complete trans selectivity. We reasoned that the presence of the
less sterically-demanding two n-butyl groups of the thread would
allow a relative displacement of the macrocycle away from the
reactive center to decrease the steric congestion near the bulky
C2 chiral inductor thus proving the critical role of the ring not only
in the reactivity but also in the stereoselectivity. Rotaxanes 13
were dethreaded by heating at 120 ºC in DMF solution to
quantitatively yield the corresponding trans -lactams 14.
Figure 1. X-Ray structure of the [2]rotaxane 11. Intramolecular hydrogen-bond
lengths [Å] (and angles [deg]): O2HN5 2.09 (165); O1HN6 1.93 (166).
The reversibility of these cyclizations allows to rationalize the
conversion of 9 into 10 (see Scheme S5). Thus, by increasing
the temperature, the ring opening of the kinetically controlled
product, -lactams 9, should occur through a retro-Michael
addition21 followed by a second cyclization for leading to the
thermodynamically most stable interlocked -lactam 10. The
different stability of 9 and 10 is tentatively attributed to the
dissimilar repulsive non-bonding interactions between their
interlocked components, more severe in 10 having a bis(-
Scheme 4. Cyclization of the interlocked fumaramide 12 and synthesis of
trans β-lactams 14. Conditions: i) CsOH (5 equiv.), DMF, 65 °C, 4 h; ii) DMF,
120 °C, 4 h. The absolute configurations of the chiral carbons of 13 and 14
were assigned by comparison with those of 11.
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We next removed one of the two -methylbenzyl groups of
12 in order to minimize the displacement of the ring away from
the reactive center of the fumaramide and, more importantly, for
checking if the retention of the configuration at the reactive chiral
carbon is efficient enough for achieving a highly stereocontrolled
cyclization in a case in which the only stereocenter is the
reacting one. Therefore we assayed the intramolecular
cyclization in the pseudorotaxane 15, with three n-butyl and one
(S)--methylbenzyl groups as stoppers at the fumaramide
thread. A solution of 15 in DMF was heated in the presence of
an excess of base at 65 °C allowing its cyclization to
diastereoselectively provide the interlocked trans -lactam 16 in
72% yield (Scheme 5, conditions i).[27] The free trans--lactam
17 was quantitatively obtained after the habitual dethreading
process (Scheme 5, conditions ii).[28] Pleasantly, chiral HPLC
analysis of lactam 17 revealed that a highly enantioselective
cyclization had occurred (17, 93:7 e.r.). It is important to remark
that this level of stereocontrol is achieved at a relatively high
temperature.
Figure 2. 1H NMR spectra (400 MHz, CDCl3, 298 K) of a) N-(-
methyl)benzylfumaramide 18, b) N-(-methyl)benzylfumaramide [2]rotaxane
15, c) interlocked trans β-lactam 16, d) trans β-lactam 17, and e) trans and cis
β-lactam 17 obtained by cyclization of thread 18. Lettering as in Schemes 5
and 6.
Scheme 5. Enantioselective synthesis of β-lactam 17. Reaction conditions: i)
CsOH (5 equiv.), DMF, 65 °C, 2 h; ii) DMF, 120 °C, 4 h.
1
Figure 2 displays the stacked plot of the H NMR spectra of
(in purple) of the cyclization out of the ring, in sharp contrast with
the trans selective cyclization occurring inside of the macrocycle.
Chiral HPLC analysis of both diastereoisomers disclosed a
discrete enantioselectivity (74:26 e.r. for cis-17 and 80:20 e.r. for
trans-17). Intriguingly, the sense of the enantioselection in the
formation of trans-17 is opposite to that operating inside the ring,
the major (2R,3S) enantiomer in that case being now the minor
one.
In summary, the base-catalyzed intramolecular cyclization of
enantiopure -methylbenzyl fumaramides occurring inside the
cavity of a removable benzylic amide macrocycle, allows the
synthesis of 2-azetidinones with two contiguous chiral centers,
including a quaternary carbon, in a regio-, diastereo- and
enantio- controlled manner. Similar processes are shown also to
occur in non-interlocked fumaramides although under harsher
reaction conditions. The scenario in which this reaction is carried
out, inside or outside the ring cavity, deeply affect to the
reactivity and the stereocontrol of the process in the former case
avoiding the formation of one of the two possible cis/trans
diastereoisomers. Furthermore, an unprecedented, simple and
enantioselective cyclization yielding enantioenriched β–lactams
from easily available fumaramides has been uncovered for the
first time paving the way for future developments in related
syntheses of these relevant compounds.
the chiral fumaramide 18, the rotaxane 15, the interlocked trans
β-lactam 16 and the trans β-lactam 17. The comparison of the
spectra of the thread 18, as a 2:1 mixture of rotamers at 298 K in
CDCl3, and the rotaxane 15 disclosed the interlocked nature of
this latter species and the stabilization of the less sterically
crowded rotamer of the thread.[29] Interestingly, the splitting of
signals of the macrocycle (light blue) of 15 is ascribed to the
magnetically inequivalent isophthalamide units due to the
asymmetry of the thread 18. After cyclization, the corresponding
interlocked trans β-lactam 16 is obtained as
a single
diastereoisomer (green). Comparison of the spectra of the
rotaxane 16 and the non-interlocked 17, resulting from the
thermal dethreading step, shows a substantial shielding of the
signals of the -lactam core (He and Hf, green).
In stark contrast, the cyclization of the non-interlocked
fumaramide 18 under identical conditions required a significant
extension of the reaction time (6 h) to finally give a mixture of the
two cis and trans diastereoisomers (2:1 d.r.) in very low yield
(24%) accompanied by a number of byproducts (Scheme 6). A
quick inspection of the 1H NMR spectra of the mixture of lactams
in Figure 2e shows the cis diastereoisomer as the major product
Acknowledgements
We gratefully acknowledge the MINECO (CTQ2017-87231-P),
FEDER and Fundacion Seneca-CARM (Project 19240/PI/14)
for the financial support.
Scheme 6. Intramolecular cyclization of the -methylbenzyl fumaramide 18.
Reaction conditions: i) CsOH (5 equiv.), DMF, 65 °C, 2 h; ii) DMF, 120 °C, 4 h.
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Keywords: template synthesis • rotaxane • pseudorotaxane •
supramolecular chemistry • stereoselectivity
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afforded
a
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A. Martinez-Cuezva,* D. Bautista, M.
Alajarin, J. Berná,*
Page No. – Page No.
Enantioselective Formation of 2-
Azetidinones by Ring-Assisted
Cyclization of Interlocked N-(-
Methyl)benzyl Fumaramides
Mechanical Bond Effects. An unprecedented intramolecular cyclization through the
(-methyl)benzyl carbon atom of interlocked fumaramides gives rise to -lactams with
a quaternary carbon atom in an enantio- and diastereocontrolled manner. The
stereochemical consequences of the cyclizations inside and outside the ring exhibited
remarkable differences.
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