Asymmetric Ring-Opening of Donor-Acceptor Cyclopropanes with Primary Arylamines Catalyzed by a Chiral Heterobimetallic Catalyst

Article abstract of DOI:10.1021/acscatal.9b02523

An efficient catalytic asymmetric ring-opening reaction of donor-acceptor cyclopropanes with primary arylamines was developed. The reaction was achieved through the utilization of a chiral heterobimetallic catalyst, delivering a variety of chiral ?3-amino acid derivatives in up to 93% yield and 99% ee. Stereochemical experiments suggest a dominant role for kinetic resolution in this asymmetric process, which is supported by a computational study of the reaction coordinate. A class of chiral bimetallic Lewis acid catalysts formed through a ligand exchange/transmetalation process was introduced in this work. The symmetric structure of the bimetallic catalyst, i.e., Yb(OTf)₃-Yb[P]₃, was confirmed with X-ray crystallography.

Full text of DOI:10.1021/acscatal.9b02523

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Article
Asymmetric Ring-Opening of Donor-Acceptor Cyclopropanes with
Primary Arylamines Catalyzed by a Chiral Heterobimetallic Catalyst
Weiwei Luo, Zhicheng Sun, E.H. Nisala Fernando, Vladimir N. Nesterov, Thomas R. Cundari, and Hong Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02523 • Publication Date (Web): 30 Jul 2019
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Asymmetric Ring-Opening of Donor−Acceptor
Cyclopropanes with Primary Arylamines Catalyzed
by a Chiral Heterobimetallic Catalyst
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Weiwei Luo, Zhicheng Sun, E. H. Nisala Fernando, Vladimir N. Nesterov, Thomas R.
Cundari*, and Hong Wang*
Department of Chemistry, University of North Texas, Denton, TX 76203, United States
ABSTRACT An efficient catalytic asymmetric ring-opening reaction of donor-acceptor
cyclopropanes with primary arylamines was developed. The reaction was achieved
through the utilization of a chiral heterobimetallic catalyst, delivering a variety of chiral γ-
amino acid derivatives in up to 93% yield and 99% ee. Stereochemical experiments
suggest a dominant role for kinetic resolution in this asymmetric process, which is
supported by a computational study of the reaction coordinate. A class of chiral bimetallic
Lewis acid catalysts formed through a ligand exchange/transmetalation process was
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introduced in this work. The symmetric structure of the bimetallic catalyst, i.e., Yb(OTf)3-
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Yb[P]3, was confirmed with X-ray crystallography.
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KEYWORDS asymmetric catalysis, donor–acceptor cyclopropanes, heterobimetallic,
primary arylamines, ring-opening.
Chiral phosphoric acids (CPAs) play an important role in modern organocatalysis
owing to their high modifiability, ease of handling as well as their environmentally friendly
nature.1-2 In the evolution of chiral Brønsted acid catalysis, the combination of chiral
phosphoric acids with metal catalysts has emerged as a new and powerful strategy to
achieve enhanced acidity and flexibility of the catalytic systems.3 In general, combined
metal–phosphoric acid catalysis can be classified into the following types: relay catalysis,
binary acid catalysis, anion directed catalysis and phosphate metal catalysis (Type I - IV,
Figure 1).3e
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M2Xn
M1
O
O
O
O
P
O
O
+
M1 Ln
O
O
O
O
P
O
O
P
M1
H
n
M1 = Li, Na, Ca, M2 = Sc, In
Anion directed catalysis
III:
Relay catalysis
I:
Binary acid catalysis
II:
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*
*
O
O
O
O
M1
O
O
P
M2
O
Our work
M2Xn
O
M1
O
O
*
+
Xn
n
O
O
*
M1 = Y, Yb, M2 = Y, Yb
Bimetallic catalysis
Metal phospate catalysis
IV:
V:
Figure 1. Catalyst types derived from combining phosphoric acids with metals.
To further expand the utility of combined metal–phosphoric acid catalysis, we have
introduced a new class of chiral bimetallic Lewis acid catalyst (Type V, Figure 1).4a Current
asymmetric metal Lewis acid catalysis mainly relies on metal/chiral ligand approach.
However, when combined with a chiral ligand, the activity of the metal Lewis acid often
decreases significantly. We considered developing a new type of chiral bimetallic Lewis
acid. This new type of chiral bimetallic catalysts could serve a complementary strategy to
the traditional metal/chiral ligand approach, opening up new opportunities in asymmetric
catalysis. Chiral phosphoric acids, i.e. binaphthyl phosphoric acids, appeared to be an
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ideal platform to serve the purpose. We speculated that a metal binaphthyl phosphate
would be able to bind another metal in one structural entity to form an unsymmetrical
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bimetallic
complex
(Scheme
1).
Interestingly,
an
unusual
ligand
exchange/transmetalation occurred, and a symmetrical bimetallic complex was formed
(Scheme 1). The bimetallic phosphate complex is expected to provide multi-binding sites
for the reacting substrates and required transition state, making it possible to better
control the stereoselectivity. Very importantly, the bimetallic nature of the catalyst may
possibly engender bifunctional activity of the catalyst, enabling reaction patterns and
activation modes different from those of other existing catalytic systems.4 This type of
bimetallic catalysts have shown much enhanced activity and/or enantioselectivity than
each individual metal salt.4 The easy accessibility and manipulability of this new type of
chiral bimetallic catalysts are expected to find broad applications in asymmetric catalysis.
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Scheme 1. Formation of chiral bimetallic catalysts.
Donor-acceptor (D-A) cyclopropanes serving as 1,3-dipolar synthons have received
increased attention in recent years.5-8 Ring-opening reaction of D-A cyclopropanes has
evolved into an effective strategy to assemble functionalized carbon scaffolds.
Asymmetric ring-opening reactions of D-A cyclopropanes with heteroatom nucleophiles
such as thiols, alcohols, water, amines, as well as acids have been developed (Scheme
2a).8d-h Among the nitrogen nucleophiles, functionalized allylic amines (mainly 2o amines)
pioneered by Tang group are routinely used in asymmetric ring-opening reactions of D-A
cyclopropanes.8d,e In contrast, there is only one single example of asymmetric ring-
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opening of cyclopropyl ketones with a secondary arylamine (i.e., N-methylaniline)
described by Feng and Liu (Scheme 2b).8g Asymmetric ring-opening reactions of D-A
cyclopropanes with primary arylamines, however, remains an open challenge in the
organic synthetic community. This is likely due to the following challenges: 1) As
compared with secondary amines, primary amine possesses more degree of freedom,
thus making it harder to control the stereoselectivity. 2) As compared with aliphatic
amines, the nucleophilicity of anilines is much lower, requiring stronger acid catalyst and
elevated temperatures to open the cyclopropane ring. It is more difficult to control the
stereoselectivity at higher temperature. 3) It is hard to stop the reaction at the ring-opening
stage as D-A cyclopropanes are 1,3-dipolar synthons. Further reaction of the resulting
secondary amine with the diester groups or another cyclopropane could happen to give
tertiary amine products.8g
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All reported asymmetric ring-opening reactions of donor-acceptor cyclopropanes are
based on chiral metal complexes of oxazolines or N,N’-dioxides.6-8 Both classes possess
limited binding sites for substrates. We decided to tackle this challenge reaction using the
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chiral bimetallic Lewis acid developed in our laboratory. Herein, the development of an
asymmetric ring-opening of D-A cyclopropanes with primary arylamines is reported. This
research not only offers new reaction patterns to be exploited for asymmetric synthesis,
but also provides insight into controlling factors in stereoselectivity, which are not well
understood. The syntheses developed could be used for the construction of many chiral
γ-amino acid derivatives and γ-lactams, which are important structural motifs for many
biologically active compounds.9
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a) Previous work (secondary amines)
R3 R4
In-TOX/Ni(II)
CO2R2
CO2R2
R3 R4
CO2R2
CO2R2
by Tang and Sun,
23 examples
up to 98% yield, 98% ee
N
N
H
R1
under N2
R1
R3, R4 = benzyl
or/and allyl
R2 = CH2 Bu
t
L-PiPr /
3 Sc(OTf)3
Ph
by Feng and Liu
1 example
97% yield, 97% ee
Ph
N
N
*
COPh
COPh
COPh
COPh
H
Ph
under N2
Ph
*
b) This work (primary amines)
CO2R2
*
O
O
Y
O
Ar
P
Yb[ ]3/Y(OTf)3
NH CO2R2
CO2R2
O
ArNH2
+
R1
CO2R2
Yb
O
O
R1
under air
*
+
Xn
O
O
Highlight:
Primary amines
*
New heterobimetallic catalysis
No inert atmosphere
Useful -amino acids and facile derivatization
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Scheme 2. Ring-opening reactions of D-A cyclopropanes with amines.
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Racemic dimethyl 2-phenylcyclopropane-1,1-dicarboxylate (1a) and p-anisidine (2a)
were initially chosen as model substrates (Table 1). When either Y(OTf)3 or (R)-Yb[P]3
was used solely as the Lewis acid catalyst, only trace amounts of product were observed
(Table 1, entries 2 & 3). When Y(OTf)3 and (R)-Yb[P]3 were combined, a major product
was obtained (Table1, entry 9). This product turned out to be the desired ring-opening
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1
13
product 3a based on the analysis of its H and C NMR spectroscopic data and Mass
Spectrometry data. It should be noted that the occurrence of this reaction requires the
presence of both Y(OTf)3 and (R)-Yb[P]3. These data suggest a bifunctional nature of the
Y(OTf)3-Yb[P]3 catalyst in this reaction, highlighting a unique set of activity expected for
the bimetallic catalyst. Optimized reaction conditions were obtained after evaluating an
array of reaction parameters including solvents, temperature, and additives (Table S1-5
in SI). The primary conditions for the reaction of 1a (0.5 mmol) and 2a (0.1 mmol) involve
5 mol% of Y(OTf)3, 10 mol% of (R)-Yb[P]3 in m-xylene at 0 °C with addition of 5 µL of H2O
and 10 mg of 5 Å molecular sieves as additives, producing 3a in good yield and
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enantioselectivity (entry 1). The data demonstrate that both the metal phosphate (R)-
Yb[P]3 and metal salt Y(OTf)3 are crucial to this reaction. Replacement of (R)-Yb[P]3 with
(R)-Y[P]3 enhanced the yield, however, resulting in lower ee value (entry 4).
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The combination of Y(OTf)3 with (R)-HCPA (HCPA = 1,1′-binaphthyl-2,2′-diyl
hydrogenphosphate) resulted in higher ee values, however, the activity of the reaction
was much lower (entry 5). If a chiral Brønsted acid, i.e. (R)-HCPA, was used, the reaction
did not proceed (entry 6). When more Y(OTf)3 was used, yield of the reaction remained
similar, but enantioselectivity decreased moderately (entry 7). Replacing Y(OTf)3 with
YCl3 led to substantially lower yield (entry 8). These data suggest that this ring-opening
reaction cannot be easily catalysed by a simple Brønsted or Lewis acid. It is worthy of
mention that co-addition of water and molecular sieves as additives was crucial to obtain
higher enantioselectivity, albeit at the cost of activity.[10] If no additive was added, the
reaction gave 93% yield with 86% ee (entry 9). The addition of water significantly
enhanced the enantioselectivity, however, the activity also decreased significantly (entry
10, 57% yield, 92% ee). On the other hand, the addition of 5 Å molecular sieves without
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added H2O resulted in excellent conversion, but with much lower ee (entry 11). A
comparable result was achieved when increasing the reaction concentration (entry 12,
86% yield, 90% ee). It is speculated that water can mediate the interaction between the
substrate and the catalyst through hydrogen bonding and coordinating to the metal, and
molecular sieves serve to control the minor amount of water presence in the reaction. We
also screened other conditions such as other solvents and metals; the results are
compiled in SI (Table S1-5). The absolute configuration of 3a was established
unambiguously to be S by X-ray crystallographic analysis (Table 2, CCDC 1864175).11
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Table 1. Condition screening and optimization.a
Y(OTf)3 (5 mol%)
PMP
Ph
P
(R)-Yb[ ]3 (10 mol%)
NH CO2Me
CO2Me
CO2Me
CO2Me
PMPNH2
Ph
5 Å M.S., H2O
m-xylene, 0 oC, 4 d
1a
 -
2a
3a
"standard conditions"
O
O
O
HCPA
(R)-
: n = 1, X = H
P
O
X
P
(R)-Y[ ]3: n = 3, X = Y
P
(R)-Yb[ ]3: n = 3, X = Yb
n
Entry
1
variation from standard conditions
none
Yield (%)b ee (%)c
70 93
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2
without (R)-Yb[P]3
trace
trace
86
28
0
-
3
without Y(OTf)3
-
4
(R)-Y[P]3 instead of (R)-Yb[P]3
(R)-HCPA instead of (R)-Yb[P]3
(R)-HCPA instead of (R)-Yb[P]3/Y(OTf)3
7.5 mol% of Y(OTf)3
87
95
-
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75
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88
95
86
92
63
90
8
YCl3 instead of Y(OTf)3
without 5 Å M.S. and H2O
without 5 Å M.S.
9
93
57
92
86
10
11
12d
without H2O
0.5 mL of m-xylene
aStandard reaction conditions: 1a (0.5 mmol), 2a (0.1 mmol), Y(OTf)3 (5 mol%), (R)-
Yb[P]3 (10 mol%), 5 Å M.S. (10 mg), and H2O (5 µL) at 0 oC in m-xylene (1.0 mL) for 4
days. bIsolated yield. cDetermined by chiral-phase HPLC. dAverage of two runs.
With optimized conditions in hand (Table 1, entry 12), the generality of this protocol
for different substrates was investigated. To examine the scope of cyclopropanes, various
substituents at the 1- and 2- positions of the cyclopropane were tested (Table 2).
Changing the ester group from methyl to ethyl slightly increased the enantioselectivity,
but the reactivity decreased moderately (3a & 3b). The aryl substituent at the 2-position
of cyclopropane was investigated next. In general, meta-substituted phenyl groups (3d-j)
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displayed high reactivities and enantioselectivities (63-89% yields, and 82-97% ees).
Ortho-substituted phenyl group (3c) showed much lower reactivity and enantioselectivity,
likely due to both electronic and steric factors. For para-substituted phenyl group (3k), the
reactivity remained similar to that of meta-substituted phenyl groups, however, the
enantioselectivity decreased significantly (73% yield, 47% ee). For the meta substituents
on the 2-phenyl ring, electron-withdrawing groups (3f-j) gave higher enantioselectivities
and yields than electron-donating groups (3d-e). Meta-disubstituted phenyl groups (3l)
displayed inferior results as compared with their mono-substituted analogues (3g).
Thiophen-2-yl cyclopropane could also be employed as a substrate, leading to good yield
and enantioselectivity (3m, 79% yield, 85% ee). The scope of primary amines was also
explored. Importantly, substitution at different positions of the aniline nucleophile was well
tolerated. Aniline gave the ring-opening product (3n) in 64% yield and 92% ee. An
exception was dimethyl-4-phenylenediamine, which produced the ring-opening product
3w in lower yield (35%), but with excellent ee (99%); all other para-substituted anilines
with electron-rich substituents provided adducts with excellent yields and ee (3q-v). It is
notable that strongly electron-deficient 4-fluoroaniline was effective in this reaction,
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affording the ring-opening product in good yield and ee (3x, 61% yield, 93% ee). The
reactivity of 3-methylaniline (3p, 68% yield, 90% ee) is superior to 3-methoxyaniline (3o,
37% yield, 90% ee). Disubstituted anilines reacted smoothly with cyclopropanes under
the reaction conditions, forming
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Table 2. Substrate scope of the reaction.a-c
Y(OTf)3 (5 mol%)
Ar
P
(R)-Yb[ ]3 (10 mol%)
NH CO2R2
CO2R2
CO2R2
CO2R2
ArNH2
R1
R1
5 Å M.S., H2O
m-xylene, 0 oC
1
 -
2
3
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MeO
MeO
MeO
NH CO2Et
CO2Et
NH CO2Me
CO2Me
NH CO2Me
CO2Me
6
7
3a
3b
, 4 days
86% yield, 90% ee
, 4 days
69% yield, 91% ee
3c
, 4 days
35% yield, 67% ee
3a
8
9
MeO
MeO
MeO
MeO
MeO
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
Cl
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F
3d
, 4 days
79% yield, 83% ee
3e
3f
, 4 days
63% yield, 82% ee
, 6 days
81% yield, 89% ee
3g
, 6 days
81% yield, 93% ee
MeO
MeO
MeO
MeO
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
Br
F3
C
O2N
CO2Me
3j
, 4 days
3h
, 4 days
69% yield, 94% ee
3k
, 4 days
73% yield, 47% ee
3i
, 4 days
88% yield, 97% ee
89% yield, 97% ee
MeO
OMe
MeO
NH CO2Me
CO2Me
NH CO2Me
NH CO2Me
CO2Me
Cl
NH CO2Me
F3
C
CO2Me
F3
C
CO2Me
S
Cl
3l
3o
3n
, 4 days
37% yield, 90% ee
, 8 days
52% yield, 88% ee
, 4 days
64% yield, 92% ee
3m
, 4 days
79% yield, 85% ee
EtO
BnO
O
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
Br
F3
C
F3C
F3C
3p
, 6 days
3q
, 4 days
91% yield, 97% ee
3r
3s
, 4 days
70% yield, 97% ee
, 4 days
90% yield, 96% ee
68% yield, 90% ee
iPr
Et
N
NH CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
NH CO2Me
CO2Me
Br
F3
C
F3
C
F3C
CO2Me
3u
, 4 days
3t
3v
, 4 days
76% yield, 96% ee
, 6 days
3w
, 4 days
35% yield, 99% ee
86% yield, 96% ee
93% yield, 93% ee
OMe
O
O
F
MeO
NH CO2Me
NH CO2Me
NH CO2Me
NH CO2Me
F3C
F3C
Br
F3
C
CO2Me
CO2Me
CO2Me
CO2Me
3x
, 8 days
61% yield, 93% ee
3y
, 4 days
86% yield, 97% ee
3z
3aa
, 4 days
65% yield, 95% ee
, 4 days
70% yield, 96% ee
aStandard reaction conditions: 1 (0.5 mmol), 2 (0.1 mmol), (R)-Yb[P]3 (10 mol%),
Y(OTf)3 (5 mol%), 5 Å M.S. (10 mg), and H2O (5 µL) at 0 oC in m-xylene (0.5 mL). bIsolated
yield. cDetermined by chiral-phase HPLC.
the secondary amines in good yields with excellent enantioselectivities (3y-3aa, 65-86%
yield, 95-97% ee).
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To gain some mechanistic insight of this reaction, (R)- and (S)-isomers of 1a and 1k
were used as mechanistic probes. As shown in Table 3, stereospecific ring-openings
were observed for both the (R) and (S) enantiomers. It was found that an inconspicuous
rate preference was conferred for (R)-1a and (R)-1k, with unchanged ee for the recovered
cyclopropane. These data suggest a simple kinetic resolution rather than a dynamic
kinetic resolution process for the ring-opening reaction. As such, it is likely that an SN2-
type ring-opening primarily dominates the reaction.
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Table 3. Stereochemical Experiments.a
Y(OTf)3 (5 mol%)
PMP
Ar
P
(R)-Yb[ ]3 (10 mol%)
NH CO2Me
CO2Me
CO2Me
CO2Me
PMPNH2
Ar
1a
5 Å M.S., H2O
m-xylene, 0 oC
, Ar = C6H5
, Ar = 4-MeC6H4
2a
3
1k
Substrate
t (d)
Yield of 3 (%)b
ee of recovered 1
ee of 3 (%)c
(%)c
-30
96
(±)-1a
(R)-1a
(S)-1a
(±)-1k
2
2
2
5
25
77
38
25
91
98
-98
-15
-92
58
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(R)-1k
(S)-1k
6
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53
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98
99
-99
-99
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aReaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), Y(OTf)3 (5 mol%), (R)-Yb[P]3 (10
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o
b
mol%), 5 Å M.S. (10 mg), and H2O (5 µL) at 0 C in m-xylene (0.5 mL). Isolated yield.
cDetermined by chiral-phase HPLC.
In order to further understand the reaction profile, the relationship between the ee
value of (R)-Yb[P]3 and that of product (3h) was studied through mixing different ratios of
(R)-Yb[P]3 and
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Figure 2. Identification of bimetallic catalyst.
(S)-Yb[P]3 (Figure 2a). A linear effect was observed, suggesting that the main catalytic
active species should be highly uniform. While attempts to grow single crystals for the
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heterobimetallic catalyst Y(OTf)3-Yb[P]3 were not successful, single crystals suitable for
X-ray diffraction studies were obtained for the homobimetallic catalyst Yb(OTf)3-Yb[P]3
from 1,4-dioxane/hexane (Figure 2b, CCDC 1888132).[11] X-ray crystallographic analysis
revealed a symmetrical binuclear metal complex with the two metals sharing four bridged
phosphate ligands. It appears that transmetalation between Yb(OTf)3 and (R)-Yb[P]3
occurred, resulting in the formation of the symmetrical binuclear metal complex. This
structure is consistent with a Y(OTf)3-Y[P]3 (Y2[P]4) complex described previously by our
group.4a It should be noted that the structures of these bimetallic complexes represent
new coordination chemistry for rare earth metals.
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Considering that rare earth metals have similar coordination chemistry and Lewis
acidities, several chiral bimetallic complexes composed of different metal ions and chiral
phosphates were prepared. The catalytic properties of these bimetallic complexes were
investigated at room temperature using simple kinetic resolution between 2.0 equivalent
of rac-1i and 1.0 equivalent of 2a (Table 4). The Sc3+ ion is the smallest (and hence most
Lewis acidic) rare earth metal cation (Z/r3; Z = charge and r = ionic radius).12a The
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corresponding Sc(OTf)3-Sc[P]3 showed moderate reactivity and no enantioselective
induction (entry 1). These results indicate that bimetallic complex (R)-Sc2[P]4 did not form,
and a background reaction dominated the process. La3+ ion is the largest lanthanide
trication. Similar to Sc(OTf)3-Sc[P]3, La(OTf)3-La[P]3 produced a racemic product 3i in
very low yield (entry 2). Although the ee of product is low, (R)-Ce2[P]4 displayed increased
enantioselectivity (entry 3). Sm3+ cation, whose ionic radius is about 0.958 Å, was also
examined. The corresponding Sm2[P]4 complex afforded the product in 54% yield with
77% ee (entry 4). Yttrium and ytterbium phosphate complexes were compared (entries 5
& 6). (R)-Yb2[P]4 was superior to (R)-Y2[P]4, which is consistent with the results obtained
earlier in this work. Although Lu3+ is smaller than Yb3+, the Lewis acidity of the former is
weaker due to its incomplete 4f orbital.[12a] As it turned out, (R)-Lu2[P]4 gave the product
in moderate yield with high enantioselectivity (entry 7). The ee values of the recovered
cyclopropane were measured for each experiment, and the selectivity factors were
calculated based on these values (Table 4). (R)-Yb2[P]4 displayed highest selectivity
factor followed by (R)-Y2[P]4. Based on these data, a trend was identified: bimetallic
complexes with decreasing ionic radius within a certain range (1.032 Å to 0.868 Å) give
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rise to increasing enantiomeric control (entries 2-7). We speculate that a rare-earth metal
ion with too small radius, such as Sc3+, will not go through ligand exchange with the
corresponding metal phosphate to form the bimetallic complex due to the structural
confinement of metal phosphate, for example (R)-Sc[P]3. On the other hand, for metals
that can form the bimetallic compounds, the enantioselectivity of the bimetallic catalyst
increases with a decrease of the metal ionic radius due to the tighter coordination sphere of
the bimetallic complexes.
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Table 4. Test of bimetallic catalyst.a
M(OTf)3 (5 mol%)
PMP
NH CO2Me
P
(R)-M[ ]3 (10 mol%)
CO2Me
CO2Me
F3C
F3C
PMPNH2
CO2Me
m-xylene, rt
2 days
1i
2a
3i
Entry Cat.
rM3+ (Å) Yield (%)b ee of recovered 1i ee of 3i sd
(%)c
n.d
n.d
n.d
(%)c
1
2
3
(R)-Sc2[P]4 0.754
(R)-La2[P]4 1.032
(R)-Ce2[P]4 1.01
36
14
4
1
-
-
-
0
10
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(R)-
0.958
0.900
54
32
77
11
Sm2[P]4
5
6
7
(R)-Y2[P]4
80
70
53
48
56
39
82
92
81
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(R)-Yb2[P]4 0.868
(R)-Lu2[P]4 0.861
aReaction conditions: 1i (0.2 mmol), 2a (0.1 mmol), M(OTf)3 (5 mol%), (R)-M[P]3 (10
mol%), at room temperature in m-xylene (1.0 mL). bIsolated yield. cDetermined by chiral-
phase HPLC. dSelectivity factors (s), calculated according to the following equation: s =
ln[(1 − C)(1 − ee1)]/ln[(1 − C)(1 + ee1)], C = (ee1)/(ee1 + ee3).
To further understand the selectivity and reactivity of the bimetallic catalyst, the
electronic structure and selectivity of Yb(OTf)3-Yb[P]3 complex was studied
computationally with two-layer ONIOM (B3LYP:UFF) for geometry optimization followed
by single-point calculations with m-xylene solvation at 0 °C. Since Y(OTf)3-Y[P]3 and
Yb(OTf)3-Yb[P]3 showed similar activity and enantioselectivity for this ring-opening
reaction, the X-ray crystallographic data for Yb(OTf)3-Yb[P]3 were used in our initial guess
for the geometry of Y(OTf)3-Yb[P]3 catalyst through substituting one Yb with Y in the
crystal structure. Y(III) and Yb(III) are expected to have similar lability due to their similar
charge-to-size ratios. The calculations were based on the reaction of substrates (±)-1a
and p-anisidine. It is speculated that 1a binds to one of the metals of the bimetallic
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Y(OTf)3-Yb[P]3 catalyst and is thus activated. Calculations reveal that the binding of (R)-
1a with Yb is about 3–6 kcal/mol lower than the other three possible bindings, i.e., (S)-1a-
Yb, (R)-1a-Y and (S)-1a-Y. Ligand substitution for (R)-1a-Yb is favored energetically by -
10.1 kcal/mol (see SI). Transition state calculations suggest that the anticlockwise
conformations (TSYbS) is the most favored than the clockwise (TSYR and TSYbR)
conformations (Figure 3). The free energy difference (ΔΔG‡) between TSYbR and TSYbS
is 2.0 kcal/mol. Boltzmann analysis of the calculated TSs (TSYbR and TSYbS) predicts
enantiomeric excess of 95% at the experimental temperature of 0 °C, which is close to
the experimental ee value of 90% (3a). When (±)-1a binds to the catalytic center, steric
clashing between (S)-1a and BINOL phosphate blocks the anisidine C that is the site of
attack on the cyclopropane ring, leading to a distortion of the catalyst in the transition
state. Optimized geometries indicate that TSYbR is more distorted than TSYbS. The most
favored transition state TSYbS leads (R)-reactant to (S)-intermediate with S configuration
at the chiral carbon, which is consistent with the absolute configuration of product 3a
identified with X-ray crystallography. Hence, both experimental and computational data
support that this ring-opening reaction of cyclopropane with arylamine is through a two-
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step SN2/proton transfer mechanism, and the SN2 reaction is the rate- and enantio-
determining step of the overall reaction.
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Figure 3. Free energy surface (in kcal/mol) modelled with SN2 (TSM±) and proton transfer
(PTM±) transition states, M=Y or Yb for R- and S-enantiomers.
To further highlight the prospect of this reaction, transformations of the ring-opening
product 3a (Scheme 3) were investigated. Triester 4a was easily obtained from 3a in
85% yield with 93% ee. Allylation product 4b and methylation product 4c were generated
readily at the malonate moiety of 3a without any loss of enantioselectivity.
Decarboxylation of 3a was difficult, requiring higher temperature and resulting in γ-amino
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acid 4d with low yield. This is likely due to the presence of the amino group in 3a.
Subsequent cyclization of 4d with NaH gave optically active γ-lactam 4e in moderate yield
with 96% ee.
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PMP
PMP
t
NH CO2Me
CO2Me
NH CO2 Bu
CO2Me
CO2Me
Boc2O, DMAP, Et3N
CH2Cl2, rt, 3 h
4a
3a
, 93% ee
85% yield, 93% ee
R X
PMP
PMP
NH Me
NH
PMP
NaHMDS
NaHMDS
CO2Me
CO2Me
NH CO2Me
CO2Me
, 93% ee
CO2Me
CO2Me
THF, rt
2 h
THF, rt
14 h
4b
29% yield, 95% ee
4c
71% yield, 93% ee
3a
PMP
PMP
NH CO2Me
CO2Me
NH
LiCl, H2O
NaH, THF
reflux, 12 h
O
N
PMP
CO2Me
DMSO
130 oC, 2 h
4e
52% yield, 96% ee
4d
28% yield, 95% ee
3a
, 93% ee
Scheme 3. Versatile synthetic transformations.
In summary, an efficient enantioselective ring-opening reaction of donor-acceptor
cyclopropanes with primary arylamines has been successfully developed through a novel
chiral heterobimetallic Lewis acid catalyst. These bimetallic catalysts displayed
bifunctional catalytic properties, which enabled this difficult reaction to occur with ease.
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Our study has shown that the enantioselectivity of these rare-earth bimetallic catalysts is
closely related to the size of the metal ions. Stereochemical experiments suggest that this
asymmetric ring-opening reaction can be ascribed to kinetic resolution and that a SN2-
type of ring-opening primarily dominates the process. Computational studies support the
primary role of kinetic resolution in this asymmetric synthesis. An X-ray crystal structure
was obtained for Yb(OTf)3-Yb[P]3, revealing a symmetrical Yb-Yb center bridged with four
chiral phosphate ligands which represents new coordination chemistry for rare earth
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metals. These data further confirm the occurrence of
a
novel ligand
exchange/transmetalation process in the formation of the bimetallic complex. The utility
of the ring-opening products (chiral γ-amino acid derivatives) has also been demonstrated
through useful organic transformations. The extension of these bimetallic complexes to
other group of metals and the exploitation of these chiral bimetallic Lewis acid catalysts
in other organic transformations are underway.
ASSOCIATED CONTENT
AUTHOR INFORMATION
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Corresponding Author
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* hong.wang@unt.edu, * thomas.cundari@unt.edu
ORCID
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Weiwei Luo: 0000-0002-1962-7714
Hong Wang: 0000-0001-7947-2083
Thomas R. Cundari: 0000-0003-1822-6473
Notes
The authors declare no competing financial interest.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental procedures, 1H and 13 C NMR and other characterization data, single
crystal X-ray analysis, computational methods.
Crystallographic data for (R)-Yb2[P]4 complex (CIF), Crystallographic data for 3a (CIF).
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ACKNOWLEDGMENT
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We acknowledge the National Science Foundation MRI Program (CHE-1726652) and the
University of North Texas for supporting the acquisition of the Rigaku XtaLAB Synergy-S
X-ray diffractometer. We thank Dr. Guido Verbeck and the Laboratory for Imaging Mass
Spectrometry at the University of North Texas for Mass Spectrometry data. WL is grateful
for University of North Texas for providing financial support. Z. S. and T. R. C. thank the
support of the U.S. Department of Energy, Office of Science, Basic Energy Science,
Catalysis Science Program under award DE-FG02-03ER15387. Z. S. and T. R. C. also
acknowledge the National Science Foundation for their support of the UNT Chemistry
CASCaM high performance computing facility through Grant CHE-1531468.
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REFERENCES
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Acid Catalyst for Asymmetric Synthesis. Aldrichimica Acta 2008, 41, 31–39. (c) Terada,
M. Binaphthol-Derived Phosphoric Acid as A Versatile Catalyst for Enantioselective
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Carbon–Carbon Bond Forming Reactions. Chem. Commun. 2008, 4097–4112. (d)
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Phosphates. Chem. Rev. 2014, 114, 9047–9153.
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(2) For seminal works, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.
Enantioselective Mannich-Type Reaction Catalyzed by A Chiral Brønsted Acid. Angew.
Chem. Int. Ed. 2004, 43, 1566–1568. (b) Uraguchi, D.; Terada, M. Chiral Brønsted Acid-
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