Goldberg Active Template Synthesis of a [2]Rotaxane Ligand for Asymmetric Transition-Metal Catalysis

Article abstract of DOI:10.1021/jacs.5b04726

We report on the active template synthesis of a [2]rotaxane through a Goldberg copper-catalyzed C-N bond forming reaction. A C₂-symmetric cyclohexyldiamine macrocycle directs the assembly of the rotaxane, which can subsequently serve as a ligan

Full text of DOI:10.1021/jacs.5b04726

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Communication
Goldberg Active Template Synthesis of a [2]Rotaxane
Ligand for Asymmetric Transition Metal Catalysis
Steven Hoekman, Matthew O Kitching, David A. Leigh, Marcus Papmeyer, and Diederik Roke
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Jun 2015
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Goldberg Active Template Synthesis of a [2]Rotaxane Ligand
for Asymmetric Transition Metal Catalysis
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Steven Hoekman, Matthew O. Kitching, David A. Leigh,* Marcus Papmeyer, and Diederik Roke
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
Supporting Information Placeholder
complex 2. Subsequently the anion is displaced by the stop-
ABSTRACT: We report on the active template synthesis of a
pered nucleophile 3, generating 4. Oxidative insertion into
[
2]rotaxane through a Goldberg copper-catalyzed C–N bond
the C–I bond of aryl iodide 5 should occur preferentially from
the other face of the macrocycle to give threaded Cu(III)
species 6. Reductive elimination should then liberate
forming reaction. A C -symmetric cyclohexyldiamine macro-
2
cycle directs the assembly of the rotaxane, which can subse-
quently serve as a ligand for enantioselective nickel-catalyzed
conjugate addition reactions. Rotaxanes are a previously un-
explored ligand architecture for asymmetric catalysis. We
find that the rotaxane gives improved enantioselectivity
compared to a non-interlocked ligand, at the expense of
longer reaction times.
[
2]rotaxane 7, concurrently regenerating Cu(I) allowing its
re-entry into the catalytic cycle. Reactions catalyzed by cop-
per ions not bound to 2, or coordinated outside of the cavity,
would produce the non-interlocked thread 8 instead.
H
N
H
N
O
N
H
N
H
Cu
X
H2N
2 3
Cs CO
The active metal template synthesis of rotaxanes utilizes
both a metal ion’s preferred coordination geometry (to direct
the assembly of a threaded intermediate) and its ability to
catalyze chemical reactions (to covalently capture the inter-
O
R
3
O
O
O
O
2
1
H
H
N
1
N
locked molecular architecture). Advantages of this approach
CsHCO3
CsX
Cu
O
R
compared to classical ‘passive’ metal template synthesis in-
clude that (i) the traditionally separate ‘threading’ and ‘cova-
lent capturing’ processes are combined in a single reaction,
and (ii) the metal catalyst can often turn over, meaning that
only sub-stoichiometric quantities of the template may be
Cu
X
HN
O
O
O
4
X = OAc or I
H
N
H
2
N
required. In addition, it is unnecessary to have a permanent
O
O
Cu
I
ligand set on the axle of the rotaxane in active template syn-
thesis, making it easier for rotaxanes to be designed that can
bind metal ions without saturating all of their coordination
R
O
N
H
R
O
O
R
5
I
O
O
O
3
sites. Furthermore, the orthogonal orientation of the
6
threaded components should embed a coordinated metal ion
within a binding pocket where the shape and surface topog-
raphy is well defined in all three dimensions. In principle,
these latter two features could be exploited to assemble well-
expressed chiral environments for catalysis. Here we report
on the synthesis and efficacy of the first rotaxane ligand em-
t
R = CH2CH2OC6H4C(4- BuC6H4)3
A
B
C
u
D
a
b
N
H
N
H
t
E
i
s
F
j
l
m
q
r
G
O
n
p
4
c
d
OH
O
O
e
ployed in asymmetric transition metal catalysis.
NH
f
h
o
k
O
O
O
O
To introduce asymmetry close to the metal center in a
target rotaxane ligand we searched for reactions that might
g
I
7
form rotaxanes with a chiral C -symmetric trans-N,N′-
2
dialkyl-1,2-cyclohexanediamine macrocycle, 1. Buchwald and
co-workers have described an effective strategy for the ami-
dation of aryl halides—the Goldberg reaction —employing a
Non-interlocked thread (8)
5
Scheme 1. Proposed Catalytic Cycle for the Goldberg
Active Metal Template Synthesis of [2]Rotaxane 7
from 1, 3, and 5.
copper catalyst bound to a cyclohexyldiamine ligand, and we
envisaged that this could be adapted for active template syn-
6
thesis (Scheme 1). In the proposed catalytic cycle, macrocy-
cle 1 co-ordinates the copper ion endotopically to generate
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6
We started our investigation of the Goldberg active metal
1b), a consequence of the threaded unsymmetrical axle ren-
dering the faces of the macrocycle inequivalent.
template rotaxane-forming reaction using conditions report-
6
ed by Buchwald and co-workers. A screen of reaction pa-
rameters found toluene to be the optimal solvent when
Cs CO was employed as the base, and Cu(OAc) was identi-
2
3
2
fied as the most effective copper source. We optimized these
conditions for [2]rotaxane formation (Table 1). Extending the
reaction time from 8 h to 20 h improved the yield of 7 from
6% to 15% (Table 1, entries 1 and 2). Increasing the reaction
concentration to 0.15 M, close to the limit of solubility of 3,
increased the rotaxane yield to 21% (Table 1, entry 3). While a
decrease in the loading of the copper catalyst (from 0.5 to 0.1
equiv.) slowed the reaction rate (Table 1, entry 4), higher
copper loadings reduced the amount of rotaxane 7 formed
0
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5
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7
8
9
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9
0
(
Table 1, entry 5), probably by increasing the rate of the non-
ligated-Cu(I)-catalyzed reaction to form 8. Using a higher
ratio of the axle components 3 and 5 to macrocycle 1 in-
creased the yield of [2]rotaxane to a synthetically viable 50 %
(
Table 1, entries 6–8).
Table 1. Optimization of [2]Rotaxane Synthesis by
a
Active Template Goldberg C–N Bond Formation.
entry Cu(OAc)2 time
temp conv. of rotaxane 7
b
(
equiv.)
(h)
(°C)
5 (%)
(
conv. %)
1
0.5
0.5
0.5
0.1
2
8
110
110
110
110
110
110
90
120
26
78
99
65
82
74
51
6
1
Figure 1. H NMR spectra (600 MHz, C D , 298 K) of a) mac-
6
6
2
20
20
20
20
48
48
15
15
21
14
11
rocycle 1, b) rotaxane 7, c) thread 8. The assignments corre-
spond to the lettering shown in Scheme 1.
c
3
c
4
c
5
Having established that the Goldberg reaction could be
used to prepare a chiral [2]rotaxane with an embedded metal
ion binding pocket with vacant coordination sites, our atten-
tion turned to evaluating the efficacy of 7 as a ligand in enan-
tioselective metal catalysis (Table 2). As a proof-of-concept,
we examined the well-studied metal-catalyzed enantioselec-
tive Michael addition of diethyl malonate (9) to trans-β-
c,d
6
0.5
0.5
0.9
51
51
c,d
7
c,e
8
f
99
57 (50 )
a
Performed with macrocycle 1 (1.0 equiv.), aryl amide 3 (1.5
equiv.), aryl iodide 5 (1.0 equiv.) and Cs CO (2 equiv.) in
2
3
7
8
b
nitrostyrene (10a). Evans has demonstrated the utility of
chiral cyclohexyldiamine ligands in NiBr -promoted variants
toluene (0.0725 M). Conversion to rotaxane 7 determined by
H NMR. 0.15 M concentration. Aryl amide 3 (4.5 equiv.),
aryl iodide 5 (4.0 equiv.) and Cs CO (8.0 equiv.). Performed
1
c
d
2
e
of this reaction to afford 11a, and we compared the effective-
ness of acyclic ligand 12 (Table 2, entry 1) and [2]rotaxane 7
(Table 2, entry 2) in this process. Pleasingly, both ligands
catalyzed the reaction between 9 and 10a. However, they
exhibited significant differences in catalytic behavior and
stereochemical outcome of the reaction. Although acyclic
ligand 12 facilitated rapid formation of 11a, only modest en-
antiomeric enrichment (68:32 er) was observed. In contrast,
despite more sluggish activity (10x longer reaction times than
for 12), [2]rotaxane 7 afforded product 11a in good yield
(>98% conversion) and enantioselectivity (93:7 er). This be-
havior is consistent with the rotaxane providing a much
more structurally defined 3D pocket for the metal ion and
substrate, improving the expression of chirality of the ligand
and reducing the degrees of freedom (in terms of confor-
mation and orientation) that the substrate can adopt upon
2
3
with aryl amide 3 (5.5 equiv.), aryl iodide 5 (5.0 equiv.) and
f
Cs CO (10 equiv.). Isolated yield.
2
3
The rotaxane architecture of 7 was confirmed by mass spec-
trometry and NMR spectroscopy (see Supporting Infor-
1
mation). The H NMR spectra of [2]rotaxane 7 and its com-
ponents (1 and 8) also provided insight into the interactions
and relative positions of the components within the rotaxane
Figure 1). Resonances for protons associated with, or proxi-
(
mate to, the amide group of the axle (H , H and H ) are
k
l
j
shifted dramatically downfield in the rotaxane (Figure 1b)
compared to the non-interlocked thread (Figure 1c), with Hk
shifting nearly 3 ppm. This is indicative of the axle being held
in position by intercomponent hydrogen bonding between
the amide H-bond donor of the axle and the H-bond accep-
tor amines of the macrocycle. Several proton resonances for
9
binding to the catalytic center. However, burying the metal
ion deeper in the ligand structure apparently reduces its ac-
cessibility and availability for catalysis, increasing the reac-
tion time needed for full conversion to product.
the macrocycle are doubled in the rotaxane (e.g. H , Figure
G
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d
The substrate scope of the rotaxane-nickel-catalyzed reac-
tion was investigated (Table 3), with high levels of enantio-
meric enrichment obtained regardless of substitution pattern
Conversions determined by H NMR. Enantiomeric ratios
determined by HPLC using a Chiralpak IC column.
3
4
5
6
7
8
9
1
1
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(
11b-d) or electronic properties (11e,f) of the nitrostyrene
In conclusion, we have demonstrated that the Goldberg cop-
per-catalyzed amidation of an aryl iodide provides an effec-
employed.
tive means of introducing a C -symmetric chiral cyclohex-
2
Table 2. Ligand-Nickel-Catalyzed Enantioselective
yldiamine macrocycle into a [2]rotaxane architecture. Once
the rotaxane is assembled, the ligand remains active in pro-
moting asymmetric transition-metal-catalyzed reactions,
giving markedly higher enantioselectivities compared to a
non-interlocked analogue, albeit at the expense of signifi-
cantly longer reaction times.
Michael-Addition of Diethyl Malonate 9 and trans-β-
Nitrostyrene 10a.
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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0
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0
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8
9
0
Ligand (10 mol%)
O
O
NiBr2 (4.5 mol%)
NO2
2
EtO C
NO2
(
S)
Enzymes often perform asymmetric catalysis within deep
binding pockets of well-defined shape and surface topogra-
phy. It can be difficult to construct three-dimensional cavi-
ties in which the chirality is similarly well-expressed using
conventional small-molecule structures. The orthogonal ar-
rangement of the mechanically interlocked components of
rotaxanes, which can conveniently incorporate chiral C2-
symmetric (and other) macrocyclic ligands through active
template synthesis, offers an intriguing way of assembling
chiral three-dimensional binding pockets that have a ligated
transition metal ion with accessible coordination sites at the
core. Tuning of the structure of rotaxane ligand 7, by short-
ening the thread (to further restrict the freedom of move-
ment of the interlocked components) and varying the axle
constitution, is on-going in our laboratory.
EtO
OEt
PhMe, rt
CO2Et
9
10a
11a
b
c
ligand
time (d) conv. (%) er (S:R)
2
>98
68:32
Rotaxane 7
27
>98
93:7
a
Reaction conditions: 10a (1.0 equiv.), 9 (1.2 equiv.), ligand
b
(
10 mol%) and NiBr (4.5 mol%) in toluene (1 M) at rt. Reac-
2
1
c
tions were run to full conversion as determined by H NMR.
Enantiomeric ratios determined by HPLC using a Chiralpak
IC column. In the absence of NiBr , diamine 12 gives >98 %
conversion to 11a over 4 days with er 49:51 (consistent with
the diamine acting as a base, as with other amines in this
type of reaction ).
9
ASSOCIATED CONTENT
Supporting Information
2
8
b
Synthetic procedures, characterization data and catalysis
studies. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
Table 3. Scope of the Rotaxane-Nickel-Catalyzed En-
antioselective Michael-Addition of Diethyl Malonate
AUTHOR INFORMATION
a
Corresponding Author
9
and trans-β-Nitrostyrenes 10a-f.
David.Leigh@manchester.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This research was funded by the Engineering and Physical
Sciences Research Council (UK). We thank the EPSRC Na-
tional Mass Spectrometry Centre (Swansea, UK) for high-
resolution mass spectrometry, Evelyn Igunbor for her assis-
tance in the preparation of macrocycle 1 and Jack Beswick for
useful discussions.
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(9) The ability of 12 to confer enantioselectivity in the conjugate
addition increases at reduced ligand stoichiometry (e.g. 1:1) and
concentration. Rotaxane 7 is much less sensitive to changes in
these reaction parameters.
0
1
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8
9
0
1
2
3
4
5
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7
8
9
0
4
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(
2j,n
2d,f
2g,k
order rotaxanes, or to control the dynamics, and position
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