Exchange Processes in Shibasaki's Rare Earth Alkali Metal BINOLate Frameworks and Their Relevance in Multifunctional Asymmetric Catalysis

Article abstract of DOI:10.1021/jacs.5b02201

Shibasaki's rare earth alkali metal BINOLate (REMB) catalysts (REMB; RE = Sc, Y, La - Lu; M = Li, Na, K; B = 1,1-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most successful enantioselective catalysts and have been employed in a broad range of mechanis

Full text of DOI:10.1021/jacs.5b02201

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Article
Exchange Processes in Shibasaki’s Rare Earth Alkali Metal BINOLate (REMB)
Frameworks and their Relevance in Multifunctional Asymmetric Catalysis
Jerome R. Robinson, Jun Gu, Patrick J. Carroll, Eric J. Schelter, and Patrick J Walsh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02201 • Publication Date (Web): 12 May 2015
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Journal of the American Chemical Society
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Exchange Processes in Shibasaki’s Rare Earth Alkali Metal BINO-
Late (REMB) Frameworks and their Relevance in Multifunctional
Asymmetric Catalysis
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a
a
a
a*
a*
Jerome R. Robinson, Jun Gu, Patrick J. Carroll, Eric J. Schelter, and Patrick J. Walsh
a – P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA
19104, United States
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
Supporting Information Placeholder
solved. These include: (1) Do the BINOLate ligands or alkali-
metal cations, M , undergo intra- or inter-molecular exchange
ABSTRACT: Shibasaki’s REMB catalysts (REMB; RE = Sc, Y,
La – Lu; M = Li, Na, K; B = 1,1-bi-2-naphtholate; RE/M/B =
1/3/3) are among the most successful enantioselective catalysts,
and have been employed in a broad range of mechanistically di-
verse reactions. Despite the phenomenal success of these cata-
lysts, several fundamental questions central to their reactivity
remain unresolved. Combined reactivity and spectroscopic studies
were undertaken to probe the identity of the active catalyst(s) in
Lewis-acid (LA) and Lewis-acid/Brønsted-base (LA/BB) cata-
lyzed reactions. Exchange spectroscopy provided a method to
obtain rates of ligand and alkali metal self-exchange in the RE/Li
frameworks, demonstrating the utility of this technique for prob-
ing solution dynamics of REMB catalysts. Isolation of the first
crystallographically characterized REMB complex with substrate
bound enabled stoichiometric and catalytic reactivity studies,
wherein we observed that substrate deprotonation by the catalyst
framework was necessary to achieve selectivity. Our spectroscop-
ic observations in LA/BB catalysis are inconsistent with previous
mechanistic proposals, which considered only tris(BINOLate)
species as active catalysts. These findings significantly expand
our understanding of the catalyst structure in these privileged
multifunctional frameworks and identify new directions for de-
velopment of new catalysts.
+
during catalysis and are these processes catalytically relevant? (2)
Do the BINOLate ligands dissociate in the presence of protic
substrates to generate metal complexes with less than three
BINOLate ligands coordinated? (3) What are the active species
generated during catalysis? Answers to these questions are criti-
cal to our understanding of these and other multifunctional cata-
lysts, and necessary for the rational design of improved catalysts.
Figure 1. Shibasaki’s REMB framework. RE = Sc, Y, La – Lu; M
1. Introduction
=
Li, Na, K; B = (S)-BINOLate; RE/M/B = 1/3/3.
Rare-earth catalysts continue to find great utility in asymmetric
catalysis, with Shibasaki’s rare-earth–alkali-metal heterobimetal-
To date, the reaction in which the structure of the active REMB
catalyst has been most thoroughly investigated was the Lewis-
1
lic complexes, [M (THF) ][(BINOLate) RE] (REMB; RE = Sc,
3
n
3
acid/Lewis-acid (LA/LA) catalyzed aza-Michael addition of O-
3
b, 4k, 5
Y, La–Lu; M = Li (1–RE), Na (2–RE), K (3–RE); B = 1,1ʹ-bi-2-
methylhydroxylamine to chalcone derivatives.
In this case, a
naphtholate; RE/M/B = 1/3/3; Figure 1) among the most enanti-
combination of NMR spectroscopy and rate studies was used to
characterize the likely active catalyst structure. Conversely, al-
most nothing is known about the active catalyst structure in Lew-
is-acid/Brønsted-base (LA/BB) catalyzed reactions, despite
LA/BB reactions constituting the vast majority (>90%) of report-
1f, g, 2
oselective and broadly applicable catalysts to date.
A key
attribute of this system is the diverse reactivity and selectivity
3
+
2a, b, 3
achieved through choice of RE and alkali metal.
Despite
the remarkable reactivity and selectivity of these heterobimetal-
lics, our understanding of these catalysts remains underdeveloped.
1
g, 2a-d, 3c-h
ed REMB catalyzed reactions.
Mass spectrometry has
3
b, c, 4
Significant advancements have been made with regard to the
state and solution characterization of
M (THF) ][(BINOLate) RE] complexes, which are the proposed
been commonly used to interrogate the structure of REMB
frameworks, however, these measurements to do not provide de-
finitive structural information due to the propensity of the ionic
solid
[
3
n
3
3b, 4a-k
species that enter the catalytic cycles.
The identities and
species of interest to undergo fragmentation even under mild ioni-
2a, b, 3c, 3e, 3g, 3i, 4l
structures of the active catalyst in operando, however, remain
largely unknown, leaving several fundamental questions unre-
zation conditions.
Essential qualitative and quanti-
tative information regarding elementary catalytic reaction steps,
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Journal of the American Chemical Society
Page 2 of 26
such as substrate deprotonation and ligand- and/or cation- ex-
emerged as a powerful tool to determine rates of chemical ex-
7
b,
8
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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5
6
change, have not been determined, which greatly limits the as-
sessment of viable catalytic species and cycles. As such, there is a
critical need to apply new spectroscopic techniques to study active
species in REMB asymmetric catalysis to contribute to our under-
standing of this important system.
change in a number of diverse systems,
including Li ex-
9
10
change in solution and solid states. Application of this tech-
nique requires that sufficient spectral resolution is achieved be-
7
b, 7d
tween analytes of interest.
To accomplish the requisite resolu-
tion for the study of 1–RE, we labeled otherwise chemically iden-
3+
tical compounds by using two different paramagnetic RE cati-
Herein we report combined spectroscopic and mechanistic in-
vestigations of the RE/Li frameworks to uncover attributes of the
active catalysts in Lewis-acid/Lewis-acid (LA/LA) and Lewis-
acid/Brønsted-base (LA/BB) catalyzed reactions. 2D NMR ex-
change spectroscopy (EXSY) was determined to be a powerful
technique for the study of these systems. Rates and activation
parameters of intermolecular self-exchange involving BINOLate
ons. Pr and Eu cations were chosen because the 1–Pr and 1–Eu
4e
complexes are isostructural, and have desirable NMR spectro-
scopic properties including relatively long relaxation times and
1
1
paramagnetic induced chemical shifts of opposite signs.
0
1
2
3
4
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9
0
Effectively equimolar mixtures of 1–Pr and 1–Eu in THF–d
8
1
7
displayed well-resolved H and Li-NMR spectra corresponding
+
1
7
ligands and Li cations were determined using EXSY and found
to the two heterobimetallic frameworks. H and Li 2D EXSY
NMR experiments were performed at 300 K using several mixing
times, tmix (see Supporting Information). Appreciable rates of
to occur rapidly under catalytically relevant conditions. Our key
findings are that the associative nature of these processes disfavor
proposals of BINOLate dissociation to form coordinatively un-
+
–1
intermolecular exchange of both Li cations (20.5 s ) and BINO-
–
1
saturated
bis(BINOLate)
intermediates,
Late ligands (0.759 s ) were observed (Figures 2, 3, and Table 1).
[
Li (L) ][(BINOLate) RE(L) ] (L = solvent or substrate), as cata-
n
n
2
n
lytically active species in LA/LA catalyzed reactions.
In contrast, under LA/BB conditions, completely different cata-
lyst structures were observed from those in the LA/LA catalyzed
reactions. Isolation of the first crystallographically characterized
example of a REMB complex with substrate bound enabled stoi-
chiometric and catalytic reactivity studies, wherein we observed
that substrate deprotonation by the catalyst framework was neces-
sary to achieve selectivity. The dissociation of Li(BINOLate) was
observed spectroscopically, in coordinating solvent, for both non-
selective (Michael) and selective (Henry) reaction conditions. The
formation of bis(BINOLate) catalytic intermediates was implicat-
ed in those cases. Our spectroscopic observations stand in contrast
to the basic assumptions made in previous mechanistic proposals,
which considered that only tris(BINOLate) species were involved
during catalysis and redefines our understanding of the catalyst
structure in these important multifunctional frameworks.
1
7
Figure 2. Intermolecular exchange observed by H and Li 2D
EXSY NMR experiments. Bound solvents not shown for clarity.
2
. Results/Discussion
+
2.1 BINOLate and Li intermolecular self-exchange and
implications in Lewis-acid/Lewis-acid (LA/LA) catalysis
2
b, 3k
4g, 4j
Independently, Shibasaki
and Salvadori
determined that
intermolecular BINOL and BINOLate ligand exchange processes
occurred in select instances for REMB frameworks. Shibasaki and
coworkers demonstrated through H NMR spectroscopy, and
1
through observation of pronounced non-linear effects, that the
heterochiral and homochiral diastereomers, 1–Y(het) and 1–
Y(homo) respectively, underwent facile intermolecular BINOLate
ligand exchange under catalytically relevant conditions. Although
insightful for the origin of non-linear effects in the aza-Michael
reaction, the study did not attempt to quantify rates of ligand ex-
change. Using saturation transfer NMR experiments and near-
Infrared circular dichroism (NIR-CD), Salvadori and coworkers
observed intermolecular BINOLate/BINOL ligand exchange be-
tween 3–Yb and free (R)- or (S)-BINOL. However, due to the
poor spectral resolution in the exchange experiments, ligand ex-
change rates were only obtained in the case of 3–Yb(RRR) with
(
R)-BINOL. Notably, even less is known about the solution labil-
+
6
ity of M in these heterobimetallic frameworks, despite their
implication in the regulation of substrate activation and catalyst
structure.
would observe and quantify intermolecular BINOLate and Li
exchange in 1–RE complexes.
2
b, 2d, 3a, 3c, 4l
As such, we set out to develop a method that
+
+
We postulated that intermolecular BINOLate and M exchange
processes for [Li (THF) ][(BINOLate) RE(THF)]·THF (1–RE)
could be observed using two-dimensional exchange spectroscopy
3
4
3
7
1
7
(2D EXSY) using H- and Li-NMR. 2D EXSY NMR has
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Page 3 of 26
Journal of the American Chemical Society
–
3
–1
Figure 3. Representative 2D EXSY NMR spectra recorded for the
mixture of 1–Pr/1–Eu (13.1 / 14.6 mM) in THF–d at 300 K ob-
tion temperature, –20 °C, was 7.5  10 s . Both BINOLate and
+ 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
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1
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Li self-exchange proceeded at 10 -fold faster rates than the re-
8
1
–6
–1 3b, 4k, 5
serving: (A)
H
NMR (400 MHz, tmix
=
140 ms);
ported catalytic reaction, k = 2.8  10 M s ,
which indi-
7
■
= 1–Pr, ■ = 1–Eu and (B) Li NMR (126 MHz, t = 10 ms)
cated that these exchange processes were not rate determining in
catalysis and occurred with high frequency.
mix
Li = 1–Pr, Li = 1–Eu.
A
B
Notably, the activation parameters of the exchange processes
speak directly to viable catalytic intermediates. Formation of pro-
posed bis(BINOLate) RE species, [Li (L) ][(BINOLate) RE(L) ]
Table 1. Associated EXSY Rate Data and Activation Pa-
rameters for 1–Pr/1–Eu
x
n
2
n
(L = substrate or solvent, x = 1 or 2), would require a dissociative
‡
‡
‡
Exchange
Process
k
ΔH
ΔS
ΔG
BINOLate exchange; however, the self-exchange processes we
observed were associative in nature. Similar conclusions disfavor-
ing the possibility of BINOLate dissociation were reached from
the previous kinetics study where the reaction rate of the aza-
-1 a
-1 b
b
-1 b
(s ) (kcal mol )
(eu)
(kcal mol )
0
1
2
3
4
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0
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0
1–Pr  1–Eu
Michael reaction was found to be uninhibited upon addition of 1–
2
0.5
8.46
–101
15.7
+d
4k
Li
3 mol % Li (BINOLate) when using 1 mol% 1–Y as a catalyst.
2
c
(
20.7)
(7.73)
(–111)
(15.7)
Therefore, we propose that the active species under LA or LA/LA
2
b, 3k, 4b, 14
catalysis
would be substrate and solvent bound 1–RE
0
.759
14.8
–39.3
17.6
e
BINOLate
c
(Figure 4), sharing structural similarities to the recently reported
(0.899)
(13.8)
(–51.7)
(17.5)
4
a, 4d, e, 4h, i, 15
solid state X-ray structures.
1
–Eu  1–Pr
+d
Li
21.4
8.49
–100
15.6
c
(
22.3)
(7.66)
(–111)
(15.6)
0
.806
14.5
–42.9
17.6
e
BINOLate
c
(1.03)
(13.1)
(–60.7)
(17.4)
a – At 300 K, [1–Pr]/[1–Eu] = 15.0/14.6 mM. k values determined
using EXSYCalc. b – At 298 K. c – Values obtained in the pres-
ence of ~10 equiv chalcone / 1–RE. d – Values obtained at tmix
.5 ms. Additional tmix at 300 K can be found in Tables S5. e –
Values obtained from H at t = 140 ms. Additional values for H4
=
7
8
mix
Figure 4. Proposed and observed catalytic species involved in the
LA/LA catalyzed aza-Michael addition reaction. Boxes represent
open coordination sites
and H along with other t at 300 K can be found in Tables S1–3.
7
mix
+
Notably, Li cation exchange occurred ~27 times faster between 1–
+
Pr and 1–Eu than BINOLate exchange, indicative that Li ex-
2
.2 Investigation of Active Species Generated Under Lew-
change was not coupled to BINOLate exchange. Activation param-
+
is-acid/Brønsted-base (LA/BB) catalysis
eters for BINOLate and Li exchange were calculated using
1
2
The majority of reactions catalyzed by the REMB framework
are Lewis-acid/Brønsted-base (LA/BB) mediated, wherein a basic
EXSYCalc from variable temperature data collected between
73–330 K (Table 1, Figure S23 and S25). Both exchange process-
2
BINOLate ligand deprotonates the pro-nucleophile to activate the
es displayed large positive enthalpies of activation and large nega-
tive entropies of activation (Table 1), consistent with associative
1g, 2b-d, 3d-h, 16
substrate.
Despite the predominance of this class of
1
3
reactions, little is known about the active catalysts. Notably, it has
not been determined whether BINOLate ligands undergo com-
plete or partial ligand dissociation upon receiving a proton from
the pronucleophile (Figure 5). It has been proposed that RE com-
plexes are coordinated by three BINOLate ligands throughout
processes.
+
After obtaining rates for intermolecular BINOLate and Li cati-
on exchange, we were interested in establishing the relevance of
these processes to catalysis. The first reaction we interrogated was
3b, 4k, 5
the LA/LA mediated aza-Michael addition reaction (Eq 1).
LA/BB catalytic cycles, regardless of the pronucleophile or RE/M
Reaction kinetics and spectroscopic studies for the LA/LA cata-
lyzed aza-Michael addition were previously reported, allowing for
direct comparison of exchange processes to relevant reaction data.
Several key findings from the previous studies were that: (1) the
reaction showed a first order dependence on chalcone and catalyst
and a zero order dependence on O-methylhydroxylamine; (2) La–
Dy, Y REMB catalyzed the reaction with comparable rates and
1g, 2b-d, 3d-i, 16,17
combination used (Figure 5, A).
BINOLate ligand
dissociation and exchange for nucleophiles has been implicated
4g, 4j
by Salvadori and coworkers (Figure 5, B),
but there has been a
shortage of solution-phase evidence under catalytic conditions to
support these claims. To provide insight into the structure of the
active catalysts, we investigated two mechanistically distinct
LA/BB promoted transformations, the Michael and Henry reac-
selectivities; (3) the reaction rate was uninhibited by addition of
1g, 2a, b, 2d
3b, 4k
tions
Li (BINOLate).
2
Addition of 10 equiv chalcone per 1–RE produced negligible
+
differences in BINOLate and Li self-exchange rates in EXSY
2.2.1. Investigation of the Michael Reaction Promoted by 1–
RE. We began our studies focused on the enantioselective Mi-
experiments and activation parameters for self-exchange were
nearly identical to those obtained in the absence of chalcone (Ta-
ble 1). The extrapolated pseudo-first order rate constant for the
BINOLate self-exchange process at the catalytically relevant reac-
2
b
chael addition of malonates to cyclic enones (Eq 2). 1–RE (M =
Li) are often the most enantioselective catalysts of the REMB
frameworks, however, this particular Michael addition is a notable
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Journal of the American Chemical Society
Page 4 of 26
exception. Use of 10 mol % 1–La (M = Li) in THF reportedly
produced Michael adducts between cyclohexenone (CHO) and
1–Pr·2CHO included two molecules of coordinated CHO; one
CHO was bound at the Pr cation, while the other at a Li cation.
3
+
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dibenzylmalonate (DBM) in poor selectivity (2 % ee), whereas 2–
La (M = Na) showed high selectivity (85% ee). These differ-
ences in selectivity were not readily explained by solution binding
The bonding metrics for 1–Pr·2CHO were consistent with related
2
b
3+
+
4a, 4d, 15
+
Pr /Li REMB structures,
coordination at both Pr and Li cations was similar to the recent-
ly reported phosphine oxide adducts. Dissolving crystals of
and the observed Lewis-base
3
+
4
h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6. Thermal ellipsoid plot of 1–Pr·2CHO projected at the
3
0% probability level. Selected bond distances (Å): Pr(1)–O(1)
2.403(2), Pr(1)–O(2) 2.404(2), Pr(1)–O(3) 2.4603(18), Pr(1)–O(4)
2.414(2), Pr(1)–O(5) 2.365(2), Pr(1)–O(6) 2.3683(18), Pr(1)–
O(10) 2.525(2), Li(3)–O(9) 1.872(6), C(69)–O(9) 1.232(5), and
C(75)–O(10) 1.221(4).
1
–Pr·2CHO in the non-coordinating solvent toluene–d revealed
8
3
+
+
exchange of CHO between the Pr and three Li sites. Exhange
was fast on the NMR time-scale, as evidenced by a single Li
NMR resonance and two alkenyl resonances in the H NMR spec-
7
1
2
b, 4a,
tra (Figure S3, d-e). Consistent with previous binding studies,
4
d
the use of the coordinating solvent THF–d resulted in competi-
8
3
+
+
tive coordination of THF with CHO at the RE and Li cations
(
Figure S3, a-c).
Stoichiometric and Catalytic Reaction Studies. To establish the
species generated under LA/BB mediated reaction conditions we
first investigated the stoichiometric and catalytic reactivity of 1–
Pr·2CHO with dibenzylmalonate (DBM). We initiated our reac-
tivity studies with 1–Pr·2CHO in toluene–d , as the substrate
8
Figure 5. Proposed catalytic cycles of REMB (I) catalyzed
would not be displaced by competitive coordination of the NMR
solvent. Despite our observation that CHO rapidly exchanged
LA/BB reactions involving monomeric active species (A)
1g, 2b-d, 3d-i, 16 17
4g, 4j
RE/M/B = 1:3:3,
, and (B) RE/M/B = 1:2:2.
3
+
+
between Pr and Li cations in toluene–d at room temperature,
8
3
+
studies, which indicated that 1–RE binds CHO at the RE cation
more readily than 2–RE. Additional structural information could
inform on these subtleties, however, to date, crystallographic
characterization of an REMB framework with a substrate bound
has proven elusive. As such, we initiated our studies by isolating a
substrate-bound example, facilitated by our recent isolation of
CHO was bound to a chiral Lewis acid in either environment
(Figure S26). We postulated that addition of the preformed nucle-
–
ophile, DBM , would proceed with moderate levels of enantiose-
lectivity (Scheme 1). To our surprise, addition of two equiv
Li(DBM) to 1–Pr·2CHO in toluene formed the product, 3-
[bis(benzyloxycarbonyl)methyl]cyclohexenone, with only low
4
a, 4d, e, 4h, i, 15
seven-coordinate RE-neutral donor adducts.
Successful isolation of the first substrate-bound REMB com-
plex, [Li (THF)(Et O) (CHO)][(BINOLate) Pr(CHO)] (1–
3
2
2
3
Pr·2CHO, Figure 6), was accomplished by treating 1–Pr with ≥ 4
equiv CHO in diethyl ether solution followed by layering with
pentane (1:2 v/v; 86% crystalline yield). The use of weakly coor-
dinating solvent was critical for the isolation of 1–Pr·2CHO;
attempts to crystallize substrate bound examples of RE/M combi-
nations: RE = La, Pr; M = Li, Na, K using THF as the solvent
17
resulted in isolation of only the THF bound REMB compounds.
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Journal of the American Chemical Society
3
+
proximate to the Pr cation within an REMB framework would
1
5
1
2
3
4
5
6
7
8
9
be expected to show significant paramagnetic shifts.
Both stoichiometric and catalytic (10 mol %) reactions per-
formed in toluene–d solutions promoted by 1–Pr or 1–Pr·2CHO
revealed the formation of new Pr /Li heterobimetallic species
together with a large amount of unreacted 1–Pr, as determined by
8
3
+
+
7
Li NMR (Figures S15 and S16). The formation of the new
3
+
+
Pr /Li heterobimetallic species was found to be reversible. Sev-
eral broadened paramagnetic resonances were observed upon
addition of DBM, however, at reaction completion 1–Pr was the
only observable paramagnetic species (Figures S16 and S17).
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
A key observation was that neither free external nucleophile,
Li(DBM), nor completely dissociated mono-lithiated BINOLate
ligand, Li(BINOLate), were observed by Li NMR during the
Scheme 1. Stoichiometric reactivity of 1–Pr·2CHO with
dibenzylmalonate (DBM, pronucleophile) or lithium diben-
zylmalonate (Li(DBM), preformed (external) nucleophile).
7
course of either the stoichiometric or catalytic reactions per-
formed in toluene. The absence of Li(DBM) or Li(BINOLate)
formed during the reaction was consistent with a structurally in-
tact complex formed upon deprotonation of DBM with 1–Pr. The
levels of enantiopurity (5% ee). In contrast, treatment of 1–
Pr·2CHO with 2 equiv of the pronucleophile, DBM, formed the
Michael adduct in 41% ee.
7
absence of the diamagnetic Li signals of Li(BINOLate) and
Li(DBM) could be due to excessive line broadening associated
The observed reactivity and selectivity clearly demonstrated the
multifunctional nature of the REMB catalysts. Simple LA coordi-
nation of the substrate does not provide an effective chiral envi-
ronment for a highly enantioselective conjugate addition between
an externally preformed malonate nucleophile to the coordinated
substrate, CHO. The pronucleophile must be deprotonated by the
catalyst to proceed selectively, and implies that the active catalyst
structure is different than that found in 1–Pr·2CHO.
+
+
with fast-exchange of these Li species with Pr/Li species. How-
ever, the spectroscopic observations were further corroborated by
independent control experiments. Use of 10 mol % Li(BINOLate)
or Li(DBM) effectively promoted racemic background reactions
at comparable rates to 1–Pr. Given these observations, the possi-
bility of forming large amounts of either Li(BINOLate) or
Li(DBM) during the reaction is unlikely, as Michael adducts from
stoichiometric and catalytic conditions were formed with moder-
ate levels of enantioselectivity. Therefore, we favor a proposed
catalytic cycle similar to that shown in Figure 5A.
Solvent choice is often an important parameter to optimize
catalyst performance for the REMB frameworks. Shibasaki and
coworkers observed high levels of enantioselectivity in the Mi-
chael reaction using non-coordinating solvent (CH Cl and tolu-
In contrast, a very different scenario was observed for the cata-
2
2
lytic reaction performed in THF–d . Addition of 10 equiv DBM to
ene) and low enantioselectivities using coordinating solvent
8
1
2
b, 3f, 16c
either 1–Pr or 1–Pr/CHO (1:10) resulted in a complex H-NMR
(THF).
They proposed that non-coordinating solvent disfa-
spectra with many new paramagnetic signals (Figures S9, S11,
vored formation of non-selective charge-separated salts. However,
no spectroscopic evidence was provided to support these pro-
posals. Considering these observations along with our previous
binding studies, we hypothesized that catalytic reactions per-
formed in THF would show lower levels of enantioselectivity due
to preferential and competitive coordination of solvent at the RE
cation.
7
and S14). The resulting Li NMR spectra of the catalytic reaction
proved more informative (Figure 7, B); it consisted of three major
species, Li , Li , and Li (67% of the total Li present), along with
A
B
C
~
six minor signals (Li –Li ; 33% of the total Li present). Notably,
D I
the relative concentration and number of resonances observed in
7
the Li NMR spectra were dependent on the concentration of 1–
Pr and DBM, where under the catalytically relevant concentra-
Use of 10 mol % of either 1–Pr or 1–Pr·2CHO in toluene fur-
nished active species of identical selectivities, where the catalytic
reaction proceeded with diminished levels of enantioselectivity
compared to the stoichiometric reaction (25% versus 40% ee).
Under rigorously anhydrous conditions, use of 10 mol % 1–Pr or
tions Li , Li , and Li were formed in a ~1:1.1:0.5 ratio, and
A
B
C
eleven other paramagnetic Li signals were observed (Figure S35).
Upon addition of CHO the spectra simplified to that displayed in
1
7
Figure 7B. H and Li spectroscopy indicated that the new hetero-
bimetallic species formed reversibly,
1
–Pr·2CHO as a catalyst in THF solvent resulted in a complete
reversal in enantioselectivity, where Michael adducts were fur-
nished in –25% ee. While the enantioselectivities obtained were
low, the unexpected reversal in catalyst facial selectivity suggest-
ed a change in catalyst structure associated with solvent choice
and prompted further spectroscopic investigation of salient reac-
1
8
tion conditions.
Spectroscopic Studies, Insight into the identity of the active
1
7
catalyst was probed by 1D and 2D H and Li NMR spectrosco-
pies. As depicted in the two mechanistic proposals shown in Fig-
ure 5, addition of the pronucleophile, DBM, to 1–Pr would be
–
expected to result in a deprotonation event, where either DBM
and BINOLate ligands could remain tightly associated to form
either six- or seven-coordinate RE complexes (Figure 5, A), or
–
DBM could exchange with one equiv of coordinated
7
Li(BINOLate) (Figure 5, B). We postulated that Li NMR reso-
3
+
3+
nances sensitized by a paramagnetic RE cation, namely Pr ,
would allow elimination of one of these mechanistic scenarios.
Dissociated Li(BINOLate) would be easily found in the diamag-
7
netic region of the Li-NMR spectrum, while lithium cations
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Journal of the American Chemical Society
Page 6 of 26
ligand exchange between Li and additional DBM or oligomeric
C
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
species with less than three BINOLate ligands per Pr cation. An-
other key spectroscopic observation supportive of our assignment
of Li and Li –Li was the ratio of Li :Li . If the reaction of 1–Pr
C
D
I
B
C
with DBM was the only source of Li(BINOLate)/Li(DBM), then
the expected ratio of Li :Li would be 1:1. However, the observed
B
C
2
:1 ratio was indicative that Li(BINOLate)/Li(DBM) was not
solely generated from 1–Pr.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 8. Major exchange processes and proposed species ob-
7
served by 2D Li-NMR EXSY experiment of 1–Pr/DBM (45.5
mM / 455 mM; tmix = 15 ms, 300 K). Bound solvents not shown.
7
Figure 7. Li-NMR spectra (155 MHz, THF–d ) taken of the
8
catalytic Michael reaction promoted by 1–Pr (41.7 mM, 10 mol
%) at various % conversion (A) 1–Pr (B) < 5% (C) 15% (D)
24% (E) 36% (F) 48% (G) 59% (H) 65%, (I) 95%. (J) Concentra-
tion of LiA (x, 1–Pr), Li (■, Li(BINOLate)), Li (○, 4–Pr) and
Li – Li from 0 – ~65% conversion of the catalytic Michael addi-
tion between CHO and DBM promoted by 10 mol % 1–Pr (41.7
B
C
D
I
7
Figure 9. 2D Li-NMR EXSY experiment of 1–Pr/DBM (45.5
7
mM) in THF as determined by Li-NMR. Lines are provided as
guides for the eye.
mM / 455 mM; tmix = 15 ms, 300 K).
NMR exchange experiments performed in THF provided addi-
as 1–Pr was regenerated as the sole observable paramagnetic
signal at the conclusion of the catalytic reaction (Figure 7, I).
tional information on the solution behavior of the catalyst, 1–Pr.
7
2D Li EXSY NMR experiments performed on a solution of 1–
7
Pr/DBM (1:10) at 300 K (Figure 9) indicated that Li , Li , and
A
B
Located near 40 ppm in the Li-NMR spectrum (Figure 7, B),
Li was definitively assigned as 1–Pr (25%). A diamagnetic res-
Li underwent facile exchange with one another at rates (k = 5–
C
obs
A
-1
5
5 s ) comparable to the intermolecular exchange observed be-
tween 1–Pr/1–Eu (Table S10). Reversible ligand-exchange and
deprotonation was further corroborated through use of 2D
onance, Li , was assigned as a rapidly exchanging mixture of
B
19
Li(BINOLate) and Li(DBM), which was established through in-
dependent preparation and spectroscopic analysis of Li(DBM) and
Li (BINOLate) (n = 1 and 2; Figure S10). Observation of disso-
ciated Li(BINOLate) requires the formation of at least one new
RE heterobimetallic species with less than three coordinated
BINOLate ligands (Figure 8).
1
H
EXSY NMR. Exchange cross-peaks were observed for 1–Pr,
Li(BINOLate), DBM, and additional unidentified paramagnetic
species. Due to spectral overlap, analysis of exchange rates was
not possible (Figure S33).
n
The results of our reactivity and spectroscopic studies revise
previously proposed catalytic cycles and modes of action pro-
posed for 1–RE in catalysis. Our isolation of the first crystallo-
graphically characterized example of an REMB framework with
bound substrate enabled stoichoimetric and catalytic studies prob-
ing the identity of the active catalyst. Stoichiometric reactions
performed in toluene demonstrated the multifunctional nature of
1–Pr, where selectivity was only achieved when the active nucle-
ophile was generated upon deprotonation by 1–Pr. Choice of
coordinating or non-coordinating solvent favored distinctly differ-
ent species during catalysis. In toluene, dissociation of
Li(BINOLate) was not observed, which was consistent with pre-
Consistent with this conclusion, monitoring the addition of var-
ying equiv of DBM to 1–Pr by H and Li-NMR revealed con-
sumption of 1–Pr concomitant with growth of Li and the major
paramagnetic product, LiC (Figure S9). High concentrations of
DBM resulted in the growth of six additional minor Li signals
Li – Li ), consistent with these species originating from an acid-
base equilibria between 1–Pr and DBM. Accordingly, we have
tentatively assigned Li , the major Pr /Li heterobimetallic com-
plex, as either [Li (sol)][(BINOLate) Pr(DBM)], 4–Pr, or more
1
7
B
(
D I
3+
+
C
2
2
likely, oligomers containing the [Li (sol)][(BINOLate) Pr(DBM)]
moiety. We propose that the remaining six Li signals (Li – Li ;
Figure 7, B) to be products formed from further deprotonation and
2
2
7
D
I
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Journal of the American Chemical Society
viously proposed catalytic cycles as the one shown in Figure 5A.
gesting catalyst saturation was operative under the reaction condi-
tions.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In THF, reaction of 1–Pr and DBM resulted in the reversible
dissociation Li(BINOLate), as observed by 1D and 2D NMR
spectroscopy. These spectroscopic results were consistent with a
catalytic cycle similar to Figure 5B. While the observation of
Li(BINOLate) indirectly implied the formation of REMB com-
plexes with less than three coordinated BINOLate ligands during
the reaction, the definitive structural identification of the active
catalyst will require further mechanistic studies.
Additional insight into the catalytic intermediates formed in the
7
Henry reaction was gained by monitoring the reaction using Li
NMR (Figure 10, A–H, and 11 B). While the consumption of 1–
Pr was a zero order process, the kinetics associated with the for-
mation of additional Pr/Li and Li-containing species was more
complex. Five additional Li resonances grew in over the course of
the reaction (Li –Li ), where again Li corresponded to unreacted
A
F
A
2
.2.2 Investigation of the Henry Reaction promoted by 1–Pr.
1–Pr and Li was Li(BINOLate). While the new heterobimetallic
B
During our study of the Michael addition reaction we were in-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
trigued that 1–Pr was a highly selective catalyst for the Henry and
Aldol reactions, but showed poor selectivity in the Michael reac-
tion. We hypothesized that the observed selectivity differences
could be related to the acidity of the pronucleophile used. In Shi-
basaki’s seminal reports on the reactivity of chiral RE alkoxides,
poor selectivities and complete exchange of substrate for ligand
were observed using more acidic substrates. Similarly, our spec-
troscopic results on the acidic malonate pronucleophile, pK 15.9–
1
2
d
a
2
0
6.4 in DMSO, indicated that ligand exchange for substrate
occurred, resulting in a diverse Pr/Li speciation. With
Figure 11. (A) Concentration of 1–Pr (▲), cyclohexylcarboxal-
dehyde (CyCHO, ■), and (R)-1-cyclohexyl-2-nitroethan-1-ol
(CyNE, x) over the course of the catalytic Henry reaction by 1–Pr
7
Figure 10. Li NMR spectra (155 MHz, THF–d ) taken of the cata-
lytic Henry reaction promoted by 1–Pr (24.6 mM, 10 mol %) at
various % conversion (A) 1–Pr + CyCHO + H O (B) + CH NO
2
8
1
(24.6 mM, 10 mol %) as determined by H-NMR. Inset centered
2
3
2
(10 equiv); <1% (C) 7% (D) 12% (E) 19% (F) 22% (G) 32% (H)
on 1–Pr. R values presented next to linear fit. (B) Concentration
3
7% conversion. Li = 1–Pr; Li = Li(BINOLate).
of Li
(■; Li(BINOLate)), Li (●), Li (♦), Li (■), and Li (●)
B C D E F
A
B
with respect to time. Lines provided as guides for the eye.
these results in mind, we hypothesized that the less acidic nitro-
methane, pK 17.2 in DMSO, or acetophenone, pK 24.7 in
DMSO,
minimizing the concentration of off-cycle, less selective Pr/Li
species. To test our hypothesis, we turned our attention to the
catalytic enantioselective Henry reaction (Eq 3).
2
1
species could not be definitively assigned, the rates and relative
integrations of Li –Li (Figure 11, B) are informative in identify-
a
a
2
1
substrates would undergo deprotonation less readily,
C
F
ing the relevant species involved. There are two distinct processes
which occur during catalysis; one is the reaction of 1–Pr with
CH
NO to form Li(BINOLate), Li , and Li , while the other
3
2
C
D
process involves the formation of another heterobimetallic species
The catalytic Henry reaction between 1 equiv cyclohexanecar-
boxaldehyde (CyCHO) and 10 equiv nitromethane using 10 mol
%
THF–d furnished (R)-1-cyclohexyl-2-nitroethanol (CyNE) with
similar yields and selectivity (95% yield, 90% ee) as the original
+
(
Li and Li ) comprised of chemically inequivalent Li centers in
E F
2
2
a 2:1 ratio. In order to provide further insight into the species
generated in the Henry reaction and how the substrates interact
with the catalyst, we monitored the addition of varying equiva-
lents of CH NO to 1–Pr and 1–Pr/CyCHO/H O at RT (Figures
1–Pr and 30 mol % water at –40 °C (233 K) in THF or
8
.
2a, 23
3
2
2
report (Eq 3)
Unlike the Michael reaction and consistent with
S21-S25).
our hypothesis, introduction of the less acidic pronucleophile,
nitromethane, initially generated little Li(BINOLate) or other
Pr/Li species (Figure 10, B). The consumption of 1–Pr and Cy-
CHO showed a zero order rate dependence (Figure 11, A), sug-
Similar to the Michael reaction, increased concentration of pro-
nucleophile resulted in the generation of new heterobimetallic
species (Li
, Li , and Li ) and consumption of 1–Pr (Figure S22).
C
D E
Li and Li , 94 and –42 ppm respectively, were formed in a ~1:1
C
D
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Journal of the American Chemical Society
Page 8 of 26
ratio, whereas Li , –25 ppm, was only observable in trace
graphically characterized REMB framework with a substrate co-
E,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
amounts at the highest concentrations of CH NO . This was con-
ordinated enabled stoichiometric reactivity studies, which indicat-
ed that selective reactivity was only observed when the nucleo-
phile was generated through deprotonation by 1–Pr. Use of coor-
dinating solvent favored the dissociation of Li(BINOLate) during
catalysis, which was observed in both the catalytic Michael and
Henry reactions. Exchange between 1–Pr, Li(BINOLate), and
putative bis(BINOLate) species, 4–Pr, occurred readily at RT
with DBM as the pronucleophile. The implication of 4–Pr calls
previous mechanistic proposals for involvement of only the
tris(BINOLate) species in catalytic cycles (Figure 5, A) into ques-
tion. Our studies have shown that bis(BINOLate) or oligomeric
heterobimetallic species of this moiety are likely candidates for
catalytically active species, and that the active species generated
will likely vary significantly depending on the solvent and nucle-
ophile used. Our results clearly indicate that these reactions are
more mechanistically complex than originally assumed, and illus-
trate the need for further structural and mechanistic studies to
ascertain the true identity of the active catalysts.
3
2
sistent with the higher pKa of CH NO , which would require a
3
2
larger excess of CH NO to generate deprotonated nucleophile.
3
2
Li(BINOLate) was also generated, which was directly observed
1
1
using H-NMR. Li(BINOLate) was readily observable by H-
NMR, and was unequivocally confirmed by addition at the con-
clusion of the catalytic Henry reaction at RT (Figure S25). At RT,
+
Li cation exchange was fast on the NMR timescale for the cata-
lytic Henry reaction, and the characteristic diamagnetic Li signal
associated with Li(BINOLate) was not observed.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The presence of water can have a large effect on the stereose-
lectivity of REMB catalyzed reactions, yet the role of water is not
1
always well understood. H-NMR spectra recorded after the addi-
tion of H O (30 mol %) to 1–Pr (10 mol %) indicated coordina-
2
3
+
tion of H O to the Pr cation, even in the presence of one equiv
2
CyCHO (Figure S21). While reversible coordination of H O to
2
3
+
the RE in the REMB framework has been demonstrated in the
2a, 3b, 4e, 4k, 5
solid state and solution,
the result was surprising given
the strong preference of aldehyde coordination to a RE cation
4
a, 4d
ASSOCIATED CONTENT
Supporting Information
observed in previous anhydrous binding studies.
Evidence for
decomposition of 1–RE at higher H O levels (>10 equiv relative
2
1
x
to 1–RE) has been demonstrated, however, decomposition of the
catalyst is unlikely under the conditions investigated for the Henry
reaction.
Experimental details, NMR spectra, SFC chromatograms of race-
mic and enantioenriched product, and crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org,
Monitoring the catalytic reaction at RT performed with 1 equiv
CH NO provided additional insight into substrate catalyst inter-
3
2
actions. The heterobimetallic species generated from addition of
AUTHOR INFORMATION
CH NO to 1–Pr, Li and Li , were not observed when only one
3
2
C
D
equiv CH NO was used. On the other hand, addition of 10 equiv
Corresponding Author
3
2
CH NO resulted in an initial build-up followed by rapid con-
3
2
pwalsh@sas.upenn.edu, schelter@sas.upenn.edu
sumption of LiC and Li , consistent with their involvement as
D
active species in catalysis (Figure S24, B). Unlike the use of 10
equiv CH NO , only ~ 85% conversion could be attained using
Notes
3
2
The authors declare no competing financial interests.
one equiv of CH NO (Figure S23c). This observation suggests
3
2
that free/excess CH NO is needed for turnover. Additionally, the
3
2
ACKNOWLEDGMENT
other heterobimetallic species, Li , appears to builds up with ex-
E
cess CH NO without CyCHO to react with, and could likely
E.J.S. and P.J.W. acknowledge the University of Pennsylvania
and the NSF (CHE-1026553 and CHE-0840438 for an X-ray dif-
fractometer) for financial support of this work.
3
2
represent an off-cycle process.
In accordance with the observations from our spectroscopic
studies, we propose that the catalytic Henry reaction follows a
catalytic cycle similar to that found in Figure 5B. Evidence for the
dissociation of Li(BINOLate) was found under catalytic condi-
tions for the Henry reaction along with the addition of varying
REFERENCES
1
2
. Recent reviews: (a) Matsunaga, S.; Shibasaki, M., Chem. Commun.
014, 50, 1044-1057. (b) Averill, D. J.; Allen, M. J., Catal. Sci. Tech.
equivalents of CH NO to 1–Pr. We propose that Li /Li belong
3
2
C
D
2014, 4, 4129-4137. (c) Deng, Q.-H.; Melen, R. L.; Gade, L. H., Acc.
Chem. Res. 2014, 47, 3162-3173. (d) Kitanosono, T.; Kobayashi, S.,
Adv. Synth. Catal. 2013, 355, 3095-3118. (e) Ward, B. D.; Gade, L.
H., Chem. Commun. 2012, 48, 10587-10599. (f) Park, J.; Hong, S.,
Chem. Soc. Rev. 2012, 41, 6931-6943. (g) Shibasaki, M.; Kanai, M.;
Matsunaga, S.; Kumagai, N., Acc. Chem. Res. 2009, 42, 1117-1127.
Recent publications (2014-2015): (h) Li, W.; Tan, F.; Hao, X.; Wang,
G.; Tang, Y.; Liu, X.; Lin, L.; Feng, X., Angew. Chem. Int. Ed. 2015,
to the active heterobimetallic species, which is formed from the
reaction of 1–Pr with CH NO . While additional investigation
3
2
into the structure of the catalytic intermediates is needed and will
be the topic of future study, our results clearly indicated that lig-
and exchange between substrate and BINOLate occurs during the
course of the highly enantioselective Henry reaction.
5
4, 1608-1611. (i) Xiao, X.; Mei, H.; Chen, Q.; Zhao, X.; Lin, L.; Liu,
3. Conclusions
X.; Feng, X., Chem. Commun. 2015, 51, 580-583. (j) Cao, W.; Liu,
X.; Guo, J.; Lin, L.; Feng, X., Chem. Eur. J. 2015, 21, 1632-1636. (k)
Xia, Y.; Liu, X.; Zheng, H.; Lin, L.; Feng, X., Angew. Chem. Int. Ed.
2015, 54, 227-230. (l) Hashimoto, K.; Kumagai, N.; Shibasaki, M.,
Chem. Eur. J. 2015, 21, 4262-4266. (m) Hashimoto, K.; Kumagai, N.;
Shibasaki, M., Org. Lett. 2014, 16, 3496-3499. (n) Tamura, K.;
Kumagai, N.; Shibasaki, M., J. Org. Chem. 2014, 79, 3272-3278. (o)
Maudoux, N.; Roisnel, T.; Carpentier, J.-F.; Sarazin, Y.,
Organometallics 2014, 33, 5740-5748. (p) Wang, Z.; Yao, Q.; Kang,
T.; Feng, J.; Liu, X.; Lin, L.; Feng, X., Chem. Commun. 2014, 50,
4918-4920. (q) Song, G.; O, W. W. N.; Hou, Z., J. Am. Chem. Soc.
Shibasaki’s REMB frameworks are amongst the most enanti-
oselective catalysts discovered to date. However, 20 years after
their initial discovery their mechanism of action is still notunder-
stood. We have established through 2D EXSY NMR studies that
+
both Li cations and BINOLate ligands undergo self-exchange at
much faster rates than that of catalytic reactions. For LA and
LA/LA catalysis these self-exchange processes are associative in
nature, and exclude bis(BINOLate) species as active intermediates
in these catalytic cycles.
On the other hand in the presence of an acidic pronucleophile,
as is the case during LA/BB catalysis, a much different mechanis-
tic scenario was operative. Our isolation of the first crystallo-
2
014, 136, 12209-12212. (r) Qian, Q.; Tan, Y.; Zhao, B.; Feng, T.;
Shen, Q.; Yao, Y., Org. Lett. 2014, 16, 4516-4519. (s) Chen, W.; Lin,
L.; Cai, Y.; Xia, Y.; Cao, W.; Liu, X.; Feng, X., Chem. Commun.
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2
014, 50, 2161-2163. (t) Bai, S.; Liao, Y.; Lin, L.; Luo, W.; Liu, X.;
T.; Lesage, A.; Emsley, L.; Collet, A., J. Am. Chem. Soc. 2000, 122,
1171-1174. (h) Banci, L.; Bertini, I.; Briganti, F.; Luchinat, C.;
Scozzafava, A.; Oliver, M. V., Inorg. Chem. 1991, 30, 4517-4524. (i)
Dunand, F. A.; Aime, S.; Merbach, A. E., J. Am. Chem. Soc. 2000,
122, 1506-1512. (j) Aime, S.; Botta, M.; Ermondi, G., Inorg. Chem.
1992, 31, 4291-4299. (k) Willem, R., Prog. Nucl. Magn. Reson.
Spectrosc. 1988, 20, 1-94. (l) Heise, J. D.; Raftery, D.; Breedlove, B.
K.; Washington, J.; Kubiak, C. P., Organometallics 1998, 17, 4461-
4468.
9. (a) Arvidsson, P. I.; Ahlberg, P.; Hilmersson, G., Chem. Eur. J.
1999, 5, 1348-1354. (b) Hilmersson, G.; Malmros, B., Chem. Eur. J.
2001, 7, 337-341. (c) Li, D. Y.; Sun, C. Z.; Williard, P. G., J. Am.
Chem. Soc. 2008, 130, 11726-11736. (d) Pöppler, A.-C.; Meinholz,
M. M.; Faßhuber, H.; Lange, A.; John, M.; Stalke, D.,
Organometallics 2011, 31, 42-45. (e) Bauer, W.; Feigel, M.; Mueller,
G.; Schleyer, P. v. R., J. Am. Chem. Soc. 1988, 110, 6033-6046.
10. (a) Bottke, P.; Freude, D.; Wilkening, M., J. Phys. Chem. C 2013,
117, 8114-8119. (b) Davis, L. J. M.; Heinmaa, I.; Goward, G. R.,
Chem. Mater. 2009, 22, 769-775. (c) Cahill, L. S.; Chapman, R. P.;
Britten, J. F.; Goward, G. R., J. Phys. Chem. B 2006, 110, 7171-7177.
(d) Verhoeven, V. W. J.; de Schepper, I. M.; Nachtegaal, G.;
Kentgens, A. P. M.; Kelder, E. M.; Schoonman, J.; Mulder, F. M.,
Phys. Rev. Lett. 2001, 86, 4314-4317. (e) Nagel, R.; Groß, T. W.;
Günther, H.; Lutz, H. D., J. Solid State Chem. 2002, 165, 303-311.
11. (a) Cockerill, A. F.; Davies, G. L. O.; Harden, R. C.; Rackham, D.
M., Chem. Rev. 1973, 73, 553-588. (b) Peters, J. A.; Huskens, J.;
Raber, D. J., Prog. Nucl. Magn. Reson. Spectrosc. 1996, 28, 283-350.
12. Cobas, J. C.; Martin-Pastor, M. EXSYCalc, 1.0; Mestrelab
Research: Santiago De Compostela.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Feng, X., J. Org. Chem. 2014, 79, 10662-10668. (u) Zhou, L.; Liu,
X.; Ji, J.; Zhang, Y.; Wu, W.; Liu, Y.; Lin, L.; Feng, X., Org. Lett.
2
014, 16, 3938-3941. (v) Chu, Y.; Hao, X.; Lin, L.; Chen, W.; Li, W.;
Tan, F.; Liu, X.; Feng, X., Adv. Synth. Catal. 2014, 356, 2214-2218.
w) Hao, X.; Liu, X.; Li, W.; Tan, F.; Chu, Y.; Zhao, X.; Lin, L.;
(
Feng, X., Org. Lett. 2014, 16, 134-137. (x) Robinson, J. R.; Fan, X.;
Yadav, J.; Carroll, P. J.; Wooten, A. J.; Pericàs, M. A.; Schelter, E. J.;
Walsh, P. J., J. Am. Chem. Soc. 2014, 136, 8034-8041. (y) Robinson,
J. R.; Yadav, J.; Fan, X.; Stanton, G. R.; Schelter, E. J.; Pericàs, M.
A.; Walsh, P. J., Adv. Synth. Catal. 2014, 356, 1243-1254.
2
. (a) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
K.; Shibasaki, M., J. Am. Chem. Soc. 1993, 115, 10372-10373. (b)
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M., J. Am.
Chem. Soc. 1995, 117, 6194-6198. (c) Shibasaki, M.; Yoshikawa, N.,
Chem. Rev. 2002, 102, 2187-2209. (d) Shibasaki, M.; Sasai, H.; Arai,
T., Angew. Chem. Int. Ed. 1997, 36, 1237-1256. (e) Walsh, P. J.;
Kozlowski, M. C., Fundamentals of Asymmetric Catalysis. University
Science Books: Sausalito, CA, 2008; p 674.
3. (a) Sone, T.; Yamaguchi, A.; Matsunaga, S.; Shibasaki, M., J. Am.
Chem. Soc. 2008, 130, 10078-10079. (b) Yamagiwa, N.; Qin, H. B.;
Matsunaga, S.; Shibasaki, M., J. Am. Chem. Soc. 2005, 127, 13419-
1
3427. (c) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M., J.
Am. Chem. Soc. 2005, 127, 3413-3422. (d) Schlemminger, I.; Saida,
Y.; Groger, H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.;
Martens, J., J. Org. Chem. 2000, 65, 4818-4825. (e) Yoshikawa, N.;
Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M., J. Am. Chem.
Soc. 1999, 121, 4168-4178. (f) Emori, E.; Arai, T.; Sasai, H.;
Shibasaki, M., J. Am. Chem. Soc. 1998, 120, 4043-4044. (g) Groger,
H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M., J.
Am. Chem. Soc. 1998, 120, 3089-3103. (h) Sasai, H.; Arai, S.; Tahara,
Y.; Shibasaki, M., J. Org. Chem. 1995, 60, 6656-6657. (i) Arai, T.;
Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M., Chem.
Eur. J. 1996, 2, 1368-1372.
13. (a) Jordan, R. B., Reaction Mechanisms of Inorganic and
Organometallic Systems. 2nd ed.; Oxford University Press: New
York, NY, 1998. (b) Asperger, S., Chemical Kinetics and Inorganic
Reaction Mechanisms. 2nd ed.; Kluwer Academic: New York, NY,
2003.
4
2
. (a) Wooten, A. J.; Carroll, P. J.; Walsh, P. J., J. Am. Chem. Soc.
008, 130, 7407-7419. (b) Wooten, A. J.; Salvi, L.; Carroll, P. J.;
14. Morita, T.; Arai, T.; Sasai, H.; Shibasaki, M., Tetrahedron:
Asymmetry 1998, 9, 1445-1450.
15. Robinson, J. R.; Booth, C. H.; Carroll, P. J.; Walsh, P. J.; Schelter,
E. J., Chem. Eur. J. 2013, 19, 5996-6004.
16. (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M., Angew.
Chem. Int. Ed. 2002, 41, 3636-3638. (b) Sasai, H.; Bougauchi, M.;
Arai, T.; Shibasaki, M., Tetrahedron Lett. 1997, 38, 2717-2720. (c)
Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M., Tetrahedron Lett. 1996,
37, 5561-5564. (d) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.;
Itoh, N.; Shibasaki, M., J. Org. Chem. 1995, 60, 7388-7389. (e) Sasai,
H.; Kim, W. S.; Suzuki, T.; Shibasaki, M.; Mitsuda, M.; Hasegawa,
J.; Ohashi, T., Tetrahedron Lett. 1994, 35, 6123-6126.
17. While full characterization was only undertaken for 1–Pr•2CHO,
other early RE’s could also be readily crystallized using identical
conditions.
18. It should be emphasized that the results of this Michael reaction
were obtained under rigorously anhydrous conditions. The original
work by Shibasaki and coworkers reported 2% ee for 1–La, however,
we have shown in a recent work (ref. 1x) that trace amounts of water
can have significant effects on the resulting stereoselectivity of the
Walsh, P. J., Adv. Synth. Catal. 2007, 349, 561-565. (c) Wooten, A.
J.; Carroll, P. J.; Walsh, P. J., Org. Lett. 2007, 9, 3359-3362. (d)
Wooten, A. J.; Carroll, P. J.; Walsh, P. J., Angew. Chem. Int. Ed.
2
006, 45, 2549-2552. (e) Aspinall, H. C.; Bickley, J. F.; Dwyer, J. L.
M.; Greeves, N.; Kelly, R. V.; Steiner, A., Organometallics 2000, 19,
416-5423. (f) Aspinall, H. C.; Dwyer, J. L. M.; Greeves, N.; Steiner,
5
A., Organometallics 1999, 18, 1366-1368. (g) Di Bari, L.; Lelli, M.;
Pintacuda, G.; Pescitelli, G.; Marchetti, F.; Salvadori, P., J. Am.
Chem. Soc. 2003, 125, 5549-5558. (h) Robinson, J. R.; Gordon, Z.;
Booth, C. H.; Carroll, P. J.; Walsh, P. J.; Schelter, E. J., J. Am. Chem.
Soc. 2013, 135, 19016-19024. (i) Robinson, J. R.; Carroll, P. J.;
Walsh, P. J.; Schelter, E. J., Angew. Chem. Int. Ed. 2012, 51, 10159-
1
0163. (j) Di Bari, L.; Lelli, M.; Salvadori, P., Chem. Eur. J. 2004,
10, 4594-4598. (k) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.,
Angew. Chem. Int. Ed. 2004, 43, 4493-4497. (l) Horiuchi, Y.;
Gnanadesikan, V.; Ohshima, T.; Masu, H.; Katagiri, K.; Sei, Y.;
Yamaguchi, K.; Shibasaki, M., Chem. Eur. J. 2005, 11, 5195-5204.
5
2
6
. Yamagiwa, N.; Matsunaga, S.; Shibasaki, M., J. Am. Chem. Soc.
003, 125, 16178-16179.
. Previous solution characterization has been limited to mass
product. .
19.
species, Li
+
Exchange was also observed between two of the minor Li
and Li
spectrometry. See references 2b, 2d, 3e, 4l.
. (a) Orrell, K. G., Two-Dimensional Methods of Monitoring
D
G
(Figure S35 and Table S10). Absence of
+
7
exchange of the remaining Li species was likely due to their
shortened relaxation times.
Exchange. In eMagRes, John Wiley & Sons, Ltd: 2007. (b) Perrin, C.
L.; Dwyer, T. J., Chem. Rev. 1990, 90, 935-967. (c) Jeener, J.; Meier,
B. H.; Bachmann, P.; Ernst, R. R., J. Chem. Phys. 1979, 71, 4546-
20. (a) Arnett, E. M.; Maroldo, S. G.; Schilling, S. L.; Harrelson, J.
A., J. Am. Chem. Soc. 1984, 106, 6759-6767. (b) Olmstead, W. N.;
Bordwell, F. G., J. Org. Chem. 1980, 45, 3299-3305.
21. Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R., J. Am. Chem. Soc. 1975, 97, 7006-
7014.
22. 30 mol % of water was used to ensure the best reproducibility of
observed catalyst performance. Previous reports introduced water
either through the synthesis of the catalyst or as an additive, ranging
from 30-1500 mol % (ref. 2a, 3c, 23)
4
553. (d) Coord. Chem. Rev. 1996, 150, 185-220.
8. (a) Babailov, S. P., Prog. Nucl. Magn. Reson. Spectrosc. 2008, 52,
-21. (b) Cahill, L. S.; Chapman, R. P.; Britten, J. F.; Goward, G. R.,
1
J. Phys. Chem. B 2006, 110, 7171-7177. (c) Pastor, A.; Martinez-
Viviente, E., Coord. Chem. Rev. 2008, 252, 2314-2345. (d) Kalverda,
A. P.; Salgado, J.; Dennison, C.; Canters, G. W., Biochemistry 1996,
3
5, 3085-3092. (e) Fischer, S.; Grootenhuis, P. D. J.; Groenen, L. C.;
Vanhoorn, W. P.; Vanveggel, F.; Reinhoudt, D. N.; Karplus, M., J.
Am. Chem. Soc. 1995, 117, 1611-1620. (f) Chen, M. C.; Roberts, J. A.
S.; Marks, T. J., J. Am. Chem. Soc. 2004, 126, 4605-4625. (g) Brotin,
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Tetrahedron Lett. 1993, 34, 2657-2660.
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81x254mm (96 x 96 DPI)
ACS Paragon Plus Environment

Page 23 of 26
Journal of the American Chemical Society
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54x381mm (96 x 96 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 26
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88x93mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 25 of 26
Journal of the American Chemical Society
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ACS Paragon Plus Environment