Interlocking the Catalyst: Thread versus Rotaxane-Mediated Enantiodivergent Michael Addition of Ketones to β-Nitrostyrene

Article abstract of DOI:10.1021/acs.orglett.9b01791

Fumaramide threads bearing one l-prolinamide fragment have been designed as templates for promoting the efficient formation of novel Leigh's [2]rotaxanes. Both threads and rotaxanes are shown to catalyze the asymmetric addition of ketones to β-nitrostyren

Full text of DOI:10.1021/acs.orglett.9b01791

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Interlocking the Catalyst: Thread versus Rotaxane-Mediated
Enantiodivergent Michael Addition of Ketones to β‑Nitrostyrene
,
†
§
‡
‡
̃
Alberto Martinez-Cuezva,* Marta Marin-Luna, Diego A. Alonso, Diego Ros-Niguez,
Mateo Alajarin,† and Jose Berna*
,†
†
Departamento de Química Organica, Facultad de Química, Regional Campus of International Excellence “Campus Mare Nostrum”,
́
Universidad de Murcia, E-30100 Murcia, Spain
§
Departamento de Química Organ
́
ica, Universidade de Vigo, Campus Lagoas-Marcosende, E-36310 Vigo, Spain
‡
Departamento Química Organ
́
ica e Instituto de Síntesis Organica, Facultad de Ciencias, Universidad de Alicante, E-03080 Alicante,
́
Spain
*
S Supporting Information
ABSTRACT: Fumaramide threads bearing one L-prolinamide
fragment have been designed as templates for promoting the
efficient formation of novel Leigh’s [2]rotaxanes. Both threads and
rotaxanes are shown to catalyze the asymmetric addition of ketones
to β-nitrostyrene in an enantio- and diastereoselective manner.
Interestingly, the enantioselective course of these processes is
reversed simply by changing from thread to rotaxane as catalyst.
DFT computations have allowed to rationalize the stereo-
divergence shown by the interlocked and noninterlocked catalysts.
ne of the most challenging issues in asymmetric catalysis
which the chemo- or the enantioselectivity of a selected
process is controlled and even enhanced due to the presence of
the mechanical bond.
O
is to obtain the two possible enantiomers of the desired
1
14
chiral products in a selected transformation. Most of the chiral
catalysts or ligands employed to access enantioenriched
systems are generally obtained from natural sources as a
Herein we describe the design and synthesis of a series of
chiral prolinamide-based threads incorporating a fumaramide-
ester template to allow their assembly into hydrogen-bonded
[2]rotaxanes. The threads and the corresponding rotaxanes
were employed as organocatalysts in the well-known
2
unique enantiomer. The synthesis of the alternative
enantiomer of the catalyst is not an easy task, usually requiring
several steps. To tackle this significant limitation, many
researchers have approached to methods of enantio- and/or
15
asymmetric Michael addition of ketones to β-nitrostyrene,
3
stereodivergent catalysis. Enantiodivergent approaches involve
aiming to detect remarkable alterations in their reactivity and/
or selectivity due to the presence of the mechanical bond.
Interestingly, a marked effect in the course of the process was
found, enabling to obtain both possible enantiomers in an
enantiodivergent approach just by picking either an interlocked
or noninterlocked system as catalyst.
a single enantiomer of the catalyst, which is able to catalyze a
process and access both enantiomers of the desired final
4
product just simply changing by the reaction conditions,
adding additives, or chemically tuning the catalyst structure.
5
6
Of particular interest is the recent design of switchable
molecular machines enabled to catalyze a chemical trans-
Having in mind the elegant reported works describing the
utilization of interlocked species as enhanced catalysts or
ligands, especially those in which the mechanical bond
7
formation in stereodivergent fashions.
In the last decades the synthesis and applications of
16
participates in the stabilization of the transition states, we
designed a pair of interlocked prolinamides (Figure 1). These
systems incorporate bulky groups at the end of their threads
which avoid the disassembly of the mechanically interlocked
compound. Both bear a fumaric fragment as a suitable template
able to ring around the hydrogen-bonded polyamide macro-
mechanically interlocked molecules has received increased
8
attention. Owing to the particular properties that the
9
mechanical bond endows to such systems, they have become
ideal candidates to be applied in different fields, remarking
1
0
their use as catalysts
or ligands in metal-catalyzed
1
1
processes. Switchable rotaxane-based catalysts, able to
change their catalytic activity (rate, chemoselective control,
activation mode), are available. Also specially selective, rigid
12
Received: May 22, 2019
1
3
and confined interlocked systems have been designed, by
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Finally, Boc deprotection of compounds 5a,b in the presence
of TFA yielded the prolinamide-based rotaxanes 6a,b,
1
quantitatively. An exhaustive H NMR analysis of thread 4a
and rotaxane 6a allowed us to acquire a precise idea about the
relative position of the macrocycle along the thread (Figure
18
S1). By comparison with reported examples, the displace-
ment of the proton signals of the thread after rotaxanation
indicates that the ring is located over the fumaramide binding
unit. In this scenario, the active site of the pyrrolidine core
remains available to participate in asymmetric reactions
catalyzed by the cyclic secondary amine. The photoisomeriza-
tion of 6a afforded the maleamide-based system Z-6a enabling
its use as catalyst (see the SI for further details).
Figure 1. Catalyst design: (a) noninterlocked prolinamide as thread;
(
b) interlocked prolinamide with a polyamide ring.
cycle. The relative position of the macrocycle and the active
site of the prolinamide backbone is crucial in this design. The
ring should be spatially close to the catalyst active site in order
to better control and stabilize the transition states of putative
processes by shielding one of the two faces where the
substrates can react and creating a more restricted pocket.
Importantly, this space should be large enough to allow the
substrates interact with the prolinamide, without inhibiting the
reaction or the catalyst turnover.
At this point, we were intrigued by the behavior of our
19
systems as chiral catalysts in the asymmetric Michael
addition of different ketones 7 to β-nitrostyrene 8. Initially,
we assayed dichloromethane as a noncompetitive solvent in
which the hydrogen-bonding network between the thread and
the macrocycle in the interlocked systems should remain
To approach this goal, we synthesized two prolinamide-
based rotaxanes differing in the degree of substitution at the
amide N atom (secondary or tertiary amide) (Scheme 1).
20
intact. The presence of an acid as additive, commonly
employed in this enamine-mediated transformations, other
solvents, and temperature were also tested (see Tables S1−
S4). Thus, we assayed the reaction between acetone 7a and β-
nitrostyrene 8 in the presence of catalytic amounts (10 mol %)
of the corresponding threads 4 and rotaxanes 6 (Table 1).
Scheme 1. Synthesis of Prolinamide-Based Threads 4a,b and
a
Rotaxanes 6a,b
Table 1. Asymmetric Michael Reaction between Acetone 7a
a
and β-Nitrostyrene 8
b
c
entry
catalyst
conversion (%)
er
config
1
2
3
4
4a
6a
4b
6b
4b
6b
5b
59
57
69:31
26:74
75:25
29:71
72:28
27:73
S
R
S
R
S
R
-
100
100
100
100
0
d
5
6
d
7
a
Reaction conditions: (i) EDCI, HOBt, amine (2,2-diphenylethyl-
a
Reaction conditions: nitrostyrene 8 (0.025 mmol), acetone 7a (0.25
mmol), CH Cl (100 μL), and catalyst (10 mol %) were stirred at 25
amine or dibenzylamine), DIPEA, CH Cl , 25 °C, overnight; (ii) (E)-
2
2
2
2
4
-((2,2-diphenylethyl)amino)-4-oxobut-2-enoic acid (S1), EDCI,
b
1
c
°C for 48 h. Determined by H NMR. Determined by chiral HPLC.
DMAP, CH Cl , 25 °C, overnight; (iii) TFA, CHCl , overnight;(iv)
2
2
3
d
Reaction conducted in the presence of 10 mol % of p-nitrobenzoic
p-xylylenediamine, isophthaloyl chloride, Et N, CHCl , 25 °C, 4 h.
3
3
acid.
Starting from the commercially available protected trans-4-
hydroxy-L-proline 1, the synthesis of the corresponding N-Boc-
protected threads 3a,b was accomplished. First, an amidation
reaction was carried out employing the suitable amine (2,2-
diphenylethylamine for 2a or dibenzylamine for 2b) in the
presence of the coupling system EDCI/HOBt. Then, an
esterification reaction between (E)-4-(2,2-diphenylethylami-
no)-4-oxobut-2-enoic acid (S1) and fragments 2a/2b provided
the corresponding protected threads 3a,b, which can be
deprotected in the presence of TFA to afford the catalytically
active threads 4a,b.
Thread 4b and rotaxane 6b having a tertiary amide attached to
the pyrrolidine core notably showed higher activities when
compared with 4a and 6a (with a secondary amide attached to
the pyrrolidine core), obtaining 100% conversion to the
Michael adduct 9a in 2 days (Table 1, compare entries 1, 2 and
3, 4).
The lower conversions obtained with the systems 4a and 6a
could be due to the formation of a stable imidazolidinone
intermediate by reaction of the enamine with the nitrogen of
the pendant amide group, dramatically slowing the reaction
Both threads 3a,b own an amido-ester function which has
been previously utilized as hydrogen-bond acceptor in the
synthesis of polyamide-based rotaxanes although with a
21
rates. The use of p-nitrobenzoic acid as additive slightly
increases the er when 6b is employed (Table 1, entry 6). As we
expected, the reaction with the Boc-protected 5b was
unproductive, further proving the active participation of the
secondary amine as catalytic site in the deprotected systems
(Table 1, entry 7).
17
moderate templating ability. The [2]rotaxanes 5a,b were
obtained in reasonable yields (24−28%) by a five-component
reaction with p-xylylenediamine and isophthaloyl chloride in
the presence of Et N (see the Supporting Information).
3
B
DOI: 10.1021/acs.orglett.9b01791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The results obtained for acetone 7a were extended to the
use of cyclic ketones 7, which are prochiral and thus lead to the
formation of a second stereocenter in the process. The
conjugate additions of cyclohexanone 7b and cyclopentanone
7
c afforded the corresponding syn diastereoisomers as main
products regardless of the catalyst employed, although in
different diastereomeric ratios (Scheme 2). In the case of
Scheme 2. Enantiodivergent Michael Reaction of Ketones
a−c
7
a−c with β-Nitrostyrene 8
Figure 2. Nucleophilic attack of the enamine of (a) thread 4c′ and
(
b) rotaxane 6c′’ to the (E)-β-nitrostyrene (8). Energy differences,
⧧
ΔΔG
, between the two respective TSs are shown in kJ/mol.
Si−Re)
(
a
Distances and angles are shown in angstroms and degrees,
Reaction conditions: nitrostyrene 8 (0.025 mmol), ketone 7a−c
0.25 mmol), CH Cl (100 μL), p-nitrobenzoic acid (10 mol %), and
respectively. (c) Definition of d, θ, and Φ.
(
2
2
catalyst 4b or 6b (10 mol %) were stirred at 25 °C for 48 h (complete
b
1
conversion). Diastereomeric ratio (syn/anti) determined by
H
c
establishment of a hydrogen bond between the amide NH
group and the nitro group (1.99 Å) stabilizes both TS
structures, bringing near the electrostatically complementary
enamine and nitro N atoms (dN−N = 3.84 and 3.87 Å for
NMR. Enantiomeric ratio of the syn diastereoisomer (major)
determined by chiral HPLC.
adduct 9b, the diastereoselectivity increased when the
interlocked 6b was the catalyst if compared with the
unthreaded 4b (Scheme 2, 6b, 10:1 vs 4b, 4:1 dr). In contrast,
the dr was almost not affected by the presence of the
mechanical bond when cyclopentanone 7c was used. More
importantly, as initially occurred for adduct 9a, we were able to
obtain the two enantiomerically enriched syn diastereoisomers
TS4
and TS
, respectively). The gauche orientation
c′·Si8
4c′·Re8
between the phenyl group of the nitrostyrene and the double
bond of the enamine moiety (Φ = −57.3°) in TS favors
4
c′·Si8
22
an optimal trajectory of the reactants with a newly forming
C−C bond distance d = 2.2 Å and following a Burgi−Dunitz
̈
23
trajectory of θ = 107.5° very close to the ideal one. In
contrast, the antiperiplanar conformation (Φ = +2.0°) of
9
b,c as major byproducts just by rotaxanation of the catalyst.
TS
showing a new forming C−C bond distance d = 2.00
c′·Re8
Å counts with an approaching trajectory of the reactants θ =
114.4° far away from the optimal one.
4
To the best of our knowledge, this is the first time that the
presence or not of the mechanical bond at a catalyst backbone
is able to control the enantioselective course of a process by
accessing both enantiomers in an enantiodivergent fashion.
In order to rationalize the stereodivergence shown by the
interlocked and non-interlocked catalysts and its enantiose-
lective outcomes, we performed a DFT study of the reactions
using acetone (7a) as the carbonyl reactant. For computational
efficiency, we used as simplified models the enamine
intermediates 4c′ and 6c′ in which methyl groups replace
the stoppers of the experimental systems (Figure 2). The
transition structures for the Si- and Re-attack of both thread-
enamine 4c′ and rotaxane-enamine 6c′ over the two prochiral
faces of (E)-β-nitrostyrene (8) were computed at the
PCM(dichloromethane)/wB97XD/cc-pVDZ theoretical level
With rotaxane 6c′ as catalyst, the addition over the Re-face
of nitrostyrene is preferred by 7.3 kJ/mol with respect to the
Si-attack (Figure 2b). This preference is mainly attributed to
the NH···ONO hydrogen bond established in the gauche
conformation (Φ = +79.4°) of TS6
involving now one NH
group of the ring, which preorganizes the nucleophile−
c′·Re8,
electrophile pairing (d = 3.49 Å). In this structure, the
N−N
length of newly forming C−C bond d = 2.15 Å and the
approaching angle θ = 112.1° are close to the ideal ones. In
stark contrast, no hydrogen bonds linking both reactants are
present in the computed TS for the Si-attack TS6 , showing
c′·Si8
an antiperiplanar orientation between the phenyl and enamine
motifs (Φ = +175.9°), a d = 2.17 Å newly forming C−C bond
distance and a θ = 115.1° approaching trajectory.
(
Supporting Information). The TS4
transition state for the
c′·Si8
addition of 4c′ to the Si-face of the nitrostyrene, leading to
In conclusion, we have synthesized a series of interlocked
and noninterlocked prolinamides and evaluated their catalytic
activity in the Michael reaction between different ketones and
adduct (S)-9a was computed to be 7.0 kJ/mol lower in energy
than TS4
leading to (R)-9a (Re-attack) (Figure 2a). The
c′·Re8
C
DOI: 10.1021/acs.orglett.9b01791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
β-nitrostyrene. Interestingly, the mechanical bond deeply
affects the enantiocontrol of the process allowing an
enantiodivergent synthesis of γ-nitroketones. Starting from
the same chiral prolinamide backbone, both enantiomers of the
final products were accessed just by selecting the interlocked or
noninterlocked catalysts. A DFT study shows that with the
rotaxanes as catalysts the macrocycle plays a crucial role by
establishing a hydrogen bond with the electrophile in the TS,
thus favoring the attack of the nucleophile to the Si face of the
nitrostyrene. On the contrary, when the nude threads were
employed the enantioselective courses of these processes were
reversed as result of a different hydrogen bond between both
reactants now involving the NH group of the thread. These
examples could hopefully help to the future design of new
interlocked catalysts by placing anchoring units for reactants in
thread and ring, by means of which the mechanical bond could
be further exploited in the field of asymmetric synthesis.
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
mechanical bonding in catenanes and rotaxanes: isomerism,
modification, catalysis and molecular machines for synthesis. Chem.
Commun. 2014, 50, 5128−5142. (b) Lewis, J. E. M.; Galli, M.;
Goldup, S. M. Properties and emerging applications of mechanically
interlocked ligands. Chem. Commun. 2017, 53, 298−312. (c) Marti-
nez-Cuezva, A.; Bautista, D.; Alajarin, M.; Berna, J. Enantioselective
formation of 2-azetidinones by ring-assisted cyclization of interlocked
N-(α-methyl)benzyl fumaramides. Angew. Chem., Int. Ed. 2018, 57,
E-mail: amcuezva@um.es.
E-mail: ppberna@um.es.
ORCID
Alberto Martinez-Cuezva: 0000-0001-8093-7888
Diego A. Alonso: 0000-0002-9069-1188
Mateo Alajarin: 0000-0002-7112-5578
Jose Berna: 0000-0001-7775-3703
6563−6567. (d) Martinez-Cuezva, A.; Lopez-Leonardo, C.; Bautista,
D.; Alajarin, M.; Berna, J. Stereocontrolled synthesis of β-lactams
within [2]rotaxanes: showcasing the chemical consequences of the
mechanical bond. J. Am. Chem. Soc. 2016, 138, 8726−8729.
Notes
(10) (a) Thordarson, P.; Bijsterveld, E. J. A.; Rowan, A. E.; Nolte, R.
The authors declare no competing financial interest.
J. M. Epoxidation of polybutadiene by a topologically linked catalyst.
Nature 2003, 424, 915−918. (b) Berna, J.; Alajarin, M.; Orenes, R.-A.
Azodicarboxamides as template binding motifs for the building of
hydrogen-bonded molecular shuttles. J. Am. Chem. Soc. 2010, 132,
ACKNOWLEDGMENTS
■
This work was supported by the MINECO (CTQ2017-87231-
P and CTQ2015-66624-P) with joint financing by FEDER
́
Funds and Fundacion Seneca-CARM (Project 20811/PI/18).
A.M.-C. thanks MICINN for a Ramon y Cajal contract and
funding (RYC-2017-22700). M.M.L. thanks Xunta de Galicia
for her postdoctoral contract (ED418B 2016/166-0).
10741−10747. (c) Lewandowski, B.; De Bo, G.; Ward, J. W.;
Papmeyer, M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P. M. E.;
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DOI: 10.1021/acs.orglett.9b01791
Org. Lett. XXXX, XXX, XXX−XXX