Silanediol Anion Binding and Enantioselective Catalysis

Article abstract of DOI:10.1055/s-0037-1612217

Silanediols possess unique and complementary catalytic activity in reactions that are likely to proceed through anion binding. This article directly compares silanediols, thioureas, and squaramides in three separate anion-binding processes. The catalytic

Full text of DOI:10.1055/s-0037-1612217

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
feature
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J. W. Attard et al.
Feature
Synthesis
Silanediol Anion Binding and Enantioselective Catalysis
Jonathan W. Attarda
Kohei Osawab
Yong Guana
Jessica Hatta
Shin-ichi Kondob
Anita Mattson*a
O
O
O
O
H
OCH3
H
H3C CH3
O
Anion Binding
O
O
Catalyst
O
O
Comparison
H3CO
OCH3
NH
OCH3
H3CO
Anion Binding Catalysts
a Worcester Polytechnic Institute, Department of Chemistry
and Biochemistry, Worcester, MA 01609, USA
aemattson@wpi.edu
b Yamagata University, Department of Biochemical Engineer-
ing, Graduate School of Science and Engineering, Yonezawa,
Yamagata 992-8510, Japan
O
O
N
S
Ar
Ar
Si
N
H
N
H
N
H
O
H
O
H
H
Squaramide
Silanediol
Thiourea
Received: 11.01.2019
Chiral Silanediols in Anion Recognition
Accepted after revision: 14.01.2019
Published online: 12.03.2019
DOI: 10.1055/s-0037-1612217; Art ID: ss-2018-z0774-fa
O
O
–
H
H
O
O
H
H
Si
Si
*
*
Abstract Silanediols possess unique and complementary catalytic ac-
tivity in reactions that are likely to proceed through anion binding. This
article directly compares silanediols, thioureas, and squaramides in
three separate anion-binding processes. The catalytic abilities of select
members of each family are directly correlated to association con-
stants.
1: Silanediol
–
–
–
=
Cl , Br , AcO , TfO
R2
R2
R1
OH
OH
OH
=
Si
*
Si
OH
Key words anion recognition, enantioselective catalysis, thiourea, si-
lanediol, squaramide
1: Silanediol
R2
R1
R2
1a: R1 = H, R2 = H
1b: R1 = H, R2 = Ph
1c: R1 = 2-Naphthyl, R2 = H
The silanediol functional group, a silicon with two OH
groups bound to it, can host a variety of anions through hy-
drogen bonding interactions (Scheme 1).1 For instance,
seminal work in this area demonstrated that dinaphthyl si-
lanediols can host acetate, chloride, and bromide.2 The an-
ion recognition abilities of silanediols can be taken advan-
tage of in other areas of chemistry, such as sensing and ca-
talysis.3,4 Chiral BINOL-based silanediols (e.g., 1a–c, Scheme
1) have emerged as promising enantioselective anion-bind-
ing catalysts for addition reactions to isoquinolinium ions
and benzopyrylium ions.5,6
Scheme 1 Silanediols 1 can host anionic guests through hydrogen
bonding interactions
desired a better understanding of the roles of silanediols in
anion-binding catalysis. This article describes the results of
the direct comparison of silanediols, thioureas, and squara-
mides as (i) hosts in anion recognition and (ii) catalysts for
enantioselective reactions likely to involve anion-binding
catalysis.
In the context of anion-binding catalysis, silanediols can
offer an exclusive appeal. From a structural standpoint BI-
NOL-based silanediols stand out as anion-binding catalysts
because they are highly aromatic C2-symmetric dual O–H
hydrogen bond donors. In comparison, more common an-
ion-binding catalysts, such as (thio)ureas7 and squara-
mides,8 are N–H hydrogen bond donors that typically lack
C2-symmetry. Perhaps stemming from their unique struc-
tures, BINOL-based silanediols catalyze processes that are
complementary to the reactivity patterns observed with
the more traditional (thio)urea and squaramide catalysts.
Intrigued by the unique catalytic abilities of silanediols, we
The Discovery of Silanediols in Enantioselective An-
ion-Binding Catalysis
Chiral silanediols as enantioselective anion-binding cat-
alysts first emerged in the literature from our laboratory in
2013 (Scheme 2).6d Inspired by the impressive catalytic
abilities of (thio)ureas, in the early stages of our investiga-
tions it was hypothesized that silanediols would activate
ionic substrates through hydrogen bond recognition of the
anionic component (Scheme 2, eq 1). As a testing ground,
we chose to explore the feasibility of enantioselective si-
lanediol anion-binding catalysis in addition reactions of si-
lyl ketene acetals to N-acylisoquinolines, reactions that are
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
J. W. Attard et al.
Feature
Synthesis
Biographical Sketches
Jonathan Attard obtained his B.A.
in Chemistry and Physics from Whit-
tier college in 2010. He worked in in-
dustry for 6 years before beginning
his Ph.D. program, in 2016, at
Worcester Polytechnic Institute un-
der the guidance of Professor Anita
Mattson. His current research in-
volves enantioselective copper-cata-
lyzed reactions for the synthesis of
chromanone natural product ana-
logues.
Kohei Osawa obtained his B.A. in
Engineering from Yamagata Univer-
sity in 2014. He began his Ph.D. pro-
gram in 2014 and he is expecting to
complete his doctoral research on
anion recognition behavior and chi-
ral induction of biaryl-based bis-urea
derivatives with Professor Shin-ichi
Kondo in 2019 to obtain Ph.D. in En-
gineering from Yamagata University.
He joined Professor Mattson’s cur-
rent research group from Nov 2017
to Jan 2018 as an international re-
searcher and worked on enantiose-
lective silanediol catalysis.
Yong Guan obtained his B.S. and
M.S. from Wuhan University in 2004
and 2006. He completed doctoral
research on construction of a vault-
ed biaryl ligand library for the aziridi-
nation reaction with Prof. William
Wulff and earned a Ph.D. in 2012
from Michigan State University. He
performed his postdoctoral research
with Prof. Christopher Douglas at
University of Minnesota on one-pot
Sonogashira coupling and regiose-
lective tetradehydro-Diels–Alder re-
action to synthesis rubicenes (2013–
2014), and with Prof. Steven
Townsend at Vanderbilt University
on metal-free synthesis of unsym-
metrical organoselenides and sele-
noglycosides (2015–2016). In 2017,
he joined Mattson group at Worces-
ter Polytechnic Institute as a post-
doctoral fellow. His current projects
are on asymmetric copper catalysis
and drug discovery.
Jessica Hatt is expecting to obtain
her B.S. in Chemistry from Worces-
ter Polytechnic Institute in 2020.
She joined Professor Mattson’s cur-
rent research group as an undergrad-
uate researcher in the fall of 2017.
Shin-ichi Kondo received his Ph.D.
from Kyoto University in 1995 under
the supervision of Professor Atsuy-
oshi Ohno. He became an assistant
professor at Ritsumeikan University
in 1995 and moved to Gunma Uni-
versity in 1996. In 2009, he became
an associate professor at Yamagata
University. Since 2012, he has been
a full professor at Yamagata Univer-
sity. His research interests include
molecular recognition, in particular
anion recognition chemistry, fluo-
rescence materials, and organosili-
con chemistry.
Anita Mattson obtained her B.S.
from Northern Michigan University
in 2002 where she conducted un-
dergraduate research with Frankie
Ann McCormick. She completed
doctoral research on thiazolium-
based N-heterocyclic carbene catal-
ysis with Prof. Karl Scheidt and
earned a Ph.D. in 2007 from North-
western University. After working on
a synthesis of hemibrevetoxin B as
an NIH NRSA postdoctoral fellow in
the Crimmins group at the Universi-
ty of North Carolina at Chapel Hill,
Anita began her independent career
in 2009 at the Ohio State University
(OSU). After being promoted to As-
sociate Professor with tenure at OSU
in 2015, she moved to Worcester
Polytechnic Institute in 2016. Anita’s
current research program blends her
love of organic catalyst design and
complex molecule synthesis with
drug discovery.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
J. W. Attard et al.
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Synthesis
known to benefit from (thio)urea anion-binding catalysis.7g
During our studies we were delighted to find that chiral, en-
antiopure BINOL-based silanediols influenced the addition
of silyl ketene acetals 3 to isoquinolinium ions generated in
situ from 2 giving rise to 4 in good yields and high levels of
enantiocontrol (Scheme 2, eq 2; up to 64% yield and 79%
ee). Based upon both prior hypotheses and data collected in
our laboratory, it is proposed that the silanediol is operating
to hydrogen bond to chloride to create chiral ion pair 5.
4-ones, oxygen heterocycles that are frequently found in
bioactive secondary metabolites.12 Prior to our studies, no
reports were present in the literature describing anion-
binding catalysis as a strategy to control the reactions of
chromenones via the in situ generation of 4-siloxybenzo-
pyrylium triflates.6b We hypothesized that silanediols could
activate benzopyrylium triflates via anion binding to gener-
ate a chiral ion pair and allow for the enantioselective
alkylation of chromenones.
The promise of silanediol-enabled control of chroma-
none functionalization was realized in the addition of silyl
ketene acetals to benzopyrylium ions, reactive oxygen het-
erocycles generated in situ from 6 and a suitable silyl tri-
flate (Scheme 3). Desirable products 8 were isolated in high
yield with decent levels of enantiocontrol in this first exam-
ple of an enantioselective functionalization of 4-siloxyben-
zopyrylium triflates. In a collaboration between the Kondo
and Mattson laboratories, data collected by fluorescence
spectroscopy suggests that the silanediol is able to host a
triflate anion through hydrogen bonding interactions.
Silanediol-Activation of Substrates
OH
Si
OH
Z
*
Y
H
(1)
Z
O
O
Y
X
Si
X
*
H
Silanediol-Catalyzed Additions to Isoquinolines
1b (20 mol%)
(2)
R1
R1
N
O
N
OTIPS
C(O)2R2
O
2
4
H3C
R2
Cl
O
OCH3
H3C
H3C
3
Silanediol-Catalyzed Additions to Chromanones
CH3
R2 = CH2CCl3
OCH3
i) TIPSOTf
O
O
O
39–64% yield
up to 79% ee
ii) 1c (20 mol%)
(3)
O
OTIPS
R
R
H3C
R1
O
OCH3
OCH3
6
8
N
O
H3C CH3
7
CH3
*
O
O
H
50–90% yield
up to 56% ee
O
R2
Si
Cl
5
H
OTIPS
O
Scheme 2 Silanediol activation of ion pairs (eq 1). The enantioselective
functionalization of isoquinolines with silanediol catalysis (eq 2).
R
*
O
O
H
H
Si
OTf
9
Silanediols as Enantioselective Anion-Binding Cata-
lysts
Examples of Other Anion-Binding Catalysts Explored:
The field of anion-binding catalysis is relatively new. It
was only in 2006 that Schreiner described the possibility
that hydrogen bond donor catalysts, specifically thioureas,
may operate to facilitate ionization.9 In 2007, Jacobsen and
co-workers intentionally applied chiral thioureas to influ-
ence an enantioselective intramolecular Pictet–Spangler re-
action via anion-binding catalysis.10 In the last ten years,
further investigations from a number of research teams
have supported the promise of anion-binding catalysis:
new families of catalysts are under development and im-
pressive reactivity patterns have been realized.11
Silanediols are a newer and rather unexplored family of
hydrogen bond donor anion-binding catalysts in compari-
son to the better-known (thio)ureas. Once we had success
in the enantioselective addition of silyl ketene acetals to
isoquinolinium ions – a known reactivity pattern – we be-
came interested in identifying useful, unique reactivity pat-
terns of enantioselective silanediol anion-binding catalysis.
Our attention first turned toward the enantioselective func-
tionalization of chromenones to generate 2-alkylchroman-
CF3
S
10 56% yield
racemic
N
N
H
CF3
H
HO
CF3
tBu
S
38% yield
racemic
11
12
N
N
H
N
H
CF3
O
CF3
O
O
24% yield
racemic
tBu
N
N
N
H
CF3
H
O
Scheme 3 Silanediol 1b as a catalyst for the addition of silyl ketene
acetals to 6 via proposed ion pair 9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
J. W. Attard et al.
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An important aspect of the ongoing work in our labora-
tories has identified the enantioselective functionalization
of in situ generated benzopyrylium ions with silanediol an-
ion-binding catalysis. In a direct comparison, it was found
that popular (thio)urea catalysts, such as 10 and 11,13 were
unable to control the facial selectivity of the addition of 7
(≡ 3) to 6. Likewise, squaramide 12,13 a hydrogen bond do-
nor recently reported to participate in triflate binding, pro-
vided only racemic product.8b
The distinctive catalytic abilities of silanediols triggered
us to consider further (i) additional catalytic processes that
may be unique to silanediols and (ii) what specific proper-
ties of the silanediol are responsible for its one-of-a-kind
catalytic performance.
yields (typically >90%) and with up to 86% enantiomeric ex-
cess. Although the mechanism of this process is still under
investigation, it is feasible that ion pair 16 is operating as a
key intermediate.6a
A brief survey of popular Lewis acid and dual hydrogen
bond donors led us to conclude that there is something
unique about the silanediol-Cu(OTf)2 catalyst system. Infe-
rior yields and enantiomeric excesses were obtained for
several other Lewis acids employed in the reaction system
(Table 1). Use of Cu(OTf)2 gave 15a in 92% yield with 72% ee
(Table 1, entry 1). While high yields of product were
achieved using Sc(OTf)3 and In(OTf)2, the enantiomeric ex-
cess never reached beyond 10% (entries 2 and 3). Both the
oxidation state of copper and the anion involved have huge
influences on the reaction: CuOTf afforded just 10% yield of
15a in 31% ee, while CuCl, CuI, and CuSO4 did not enable the
reaction to proceed (entries 4–6). BINOL-based silanediol
1a proved to be the best hydrogen bond donor in the pro-
cess. The addition of steric bulk to the silanediol scaffold,
such as BINOL-based silanediols 1b and 1c, resulted in steep
Silanediols and Lewis Acid Hybrid Anion-Binding
Catalysts
Encouraged by the development that silanediol-specific
catalytic outcomes are feasible, we sought to branch out
from the traditional anion-binding catalyst activation of
substrates. We reasoned that if silanediols can activate sub-
strates then they can likely activate other components of a
reaction system. For example, we hypothesized that silane-
diols could active Lewis acids thereby enabling the genera-
tion of hybrid anion-binding and Lewis acid catalyst sys-
tems that benefit from enhanced activity (13, Scheme 4).
Table 1 On the Unique Nature of Silanediol 1a-Cu(OTf)2 Hybrid Catalysisa
O
O
O
O
Lewis Acid (20 mol%)
HBD (20 mol%)
H3CO
OCH3
H3CO
OCH3
H
14a
15a
N
Silanediol-Activation of Lewis Acid Catalyst
*
HN
OH
Si
Cu(X)2
*
OH
(4)
OCH3
O
R
OCH3
O
R
O
H
H
Nu
*
O
Nu
O
Si
X
CuX
*
O
OCH3
OH
OH
OCH3
OCH3
13: Enhanced Lewis Acid
Si
OCH3
17
18
O
O
O
O
Cu(OTf)2 (20 mol%)
1a (20 mol%)
(5)
OCH3
15
H3CO
OCH3
H3CO
14
Entry
HBDb
Lewis acid
Yield (%)
ee (%)
H
N
*
R
R
R
HN
1
2
1a
1a
1a
1a
1a
1a
1b
1c
Cu(OTf)2
Sc(OTf)3
In(OTf)2
CuOTf
92
95
88
10
0
72
9
16–99% yield
up to 86% ee
R
3
10
31
–
OTf
Cu
4
O
O
R
Si
5
CuCl
O
H
O
H
H3CO
OCH3
6
CuSO4
0
–
7
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
76
14
0
13
6
O
16
Tf
8
Scheme 4 Silanediol-activated Lewis acid 13 as a catalyst for the addi-
tion of indoles to 14
9
10
11
12
17
18
–
10
11
12
13
0
–
10
28
25
10
To this end, our investigations led us to probe the effect
of BINOL-based silanediol 1a on Cu(OTf)2 in the addition of
indoles to alkylidene and arylidene malonates (14, Scheme
4, eq 5).6a We were delighted to find that the silanediol 1a
and Cu(OTf)2 cocatalyst system was effective in the addition
of indoles to 14, affording desirable products 15 in excellent
racemic
racemic
a See the experimental sections for details of the procedures.
b HBD: Hydrogen bond donor.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
J. W. Attard et al.
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declines in both yield and enantiomeric excess (entries 7
and 8). Attempts to use thiourea catalysts 10 and 11 pre-
vented the formation of product (entries 9 and 10). Low
yields and enantiomeric excesses of 15a were observed
with squaramide 12 operating as the cocatalyst (entry 11).
BINOL (17) was also tested in the transformation and af-
forded racemic 15a in 28% yield, the same yield obtained as
the background rate of the reaction (entry 12). The impor-
tance of the silanediol functional group was supported with
the observation that dimethoxysilane 18 was unable to
control the absolute stereochemistry in the synthesis of 15a
(entry 13).
3.8 × 104 M–1 in toluene (Table 2, entry 1). The silanedi-
ol:triflate association constant in toluene was measured to
be 2.8 × 103 M–1 (entry 2). No association constant was de-
termined for the triflate in CHCl3 by UV/Vis spectroscopy
because the change in spectra upon the addition of TBAOTf
was too small.
Table 2 Association Constants Determined for 1a, 11, and 12 with
Chloride and Triflate (M–1
)
Entry
Host:Guest
UV/Vis
CHCl3
Toluene
Host:Guest Interactions of Silanediols
1
2
3
4
5
6
1a:Cl–
1.9 ± 0.22 × 103
3.8 ± 0.13 × 104
2.8 ± 0.40 × 103
7.9 ± 0.13 × 106
6.5 ± 0.27 × 104
>106
With the identification of a second reaction unique to
silanediols, our curiosity to better understand their anion-
binding properties grew stronger. Investigations were initi-
ated to explore the abilities of our chiral, BINOL-based si-
lanediol 1a to recognize chloride and triflate in two sol-
vents (e.g., chloroform and toluene) using UV/Vis spectros-
copy and nuclear magnetic resonance spectroscopy.
Under identical experimental conditions, the associa-
tion constants of thiourea 11 and squaramide 12 for both
chloride and triflate were also measured so as to be able to
compare anion-binding and catalysis of the three different
hydrogen bond donor families (Figures 1 and 2).
The association of silanediol 1a with both chloride and
triflate in chloroform and toluene was observed using
UV/Vis spectroscopy (Figure 1a and 1b and Supporting In-
formation). For example, plotting the change in absorbance
upon the addition of 0–5 equivalents of tetrabutylammoni-
um chloride (TBACl) and tetrabutylammonium triflate
(TBAOTf) at 262 nm generated the curves depicted in Figure
1b. From these data, the association constant for silanedi-
ol:chloride was determined to be 1.9 × 103 M–1 in CHCl3 and
1a:–OTf
11:Cl–
ND
1.8 ± 0.37 × 104
11:–OTf
12:Cl–
ND
7.6 ± 0.16 × 105
ND
12:–OTf
3.8 ± 0.04 × 105
ND: Not determined: The absorbance change was too small to accurately
determine the association constant.
Thiourea 11 and squaramide 12 were also found to rec-
ognize both chloride and triflate through UV/Vis titration
experiments (Figure 1c–f). A binding constant of 1.8 × 104
M–1 was extrapolated from the change in UV/Vis spectra
observed at 259 nm upon the addition of TBACl to thiourea
11 in CHCl3. Measuring of the binding constant in toluene
(Ka = 7.9 × 106 M–1) indicated a stronger host:guest interac-
tion relative to that observed in CHCl3 (Table 2, entry 3). The
association constant of squaramide 12 and chloride was
found to be 7.6 × 105 M–1 in CHCl3 and >106 M–1 in toluene
(entry 5). In the cases of both the thiourea 11 and squara-
Figure 1 UV/Vis titrations of silanediol 1a (a), thiourea 11 (c), and squaramide 12 (e) with TBACl in CHCl3. (b) Change in 262 nm when silanediol 1a
was titrated with [G] = TBACl and TBAOTf. (d) Change in 259 nm when thiourea 11 was titrated with [G] = TBACl and TBAOTf. (f) Change in 348 nm
when squaramide 12 was titrated with [G] = TBACl and TBAOTf.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
J. W. Attard et al.
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Figure 2 NMR titrations of silanediol 1a (a), thiourea 11 (c), and squaramide 12 (e) with TBAOTf in CDCl3. (b) Change in 2.33 ppm (OH) when silanediol
1a was titrated with [G] = TBACl and TBAOTf. (d) Change in 8.62 ppm (NH) when thiourea 11 was titrated with [G] = TBACl and TBAOTf. (f) Change in
9.78 ppm (NH) when squaramide 12 was titrated with [G] = TBACl and TBAOTf.
mide 12, the association constant found for triflate was
lower than that found for chloride (entries 3 and 5 vs en-
tries 4 and 6). In toluene, the association constant for 11:
–OTF was found to be 6.5 × 104 M–1 and 12:–OTF was found
to be 3.8 × 105 M–1 (entries 4 and 6, respectively). Similar to
the silanediol, the change in spectra was too small for both
thiourea 11 and squaramide 12 to accurately determine a
binding constant of triflate in CHCl3.
mide 12 generate improved enantiomeric excesses when
compared to the silanediol 1a, which has a lower associa-
tion constant.
Reaction 1
HBD (20 mol%)
N
O
N
OTIPS
NMR titration experiments were also used to analyze
the association of silanediol 1a, thiourea 11, and squara-
mide 12 to both the host chloride and triflate anions in
chloroform (Figure 2). In all cases, the introduction of TBACl
C(O)2R1
H3C
R1
Cl
O
H3C
H3C
O
OCH3
2a
4a
3
CH3
R1 = CH2CCl3
OCH3
1b: 50% yield; 79% ee
11: 49% yield; 82% ee
1
caused larger shifts in the H NMR spectra than TBAOTf.
Reaction 2
12: 42% yield; 86% ee
This data suggests that silanediol 1a, thiourea 11, and
squaramide 12 all operate as hosts of both chloride and tri-
flate, although they bind more strongly to chloride than tri-
flate (Figure 2).
With the collection of the association constant of both
chloride and triflate with our silanediol, thiourea, and
squaramide catalysts we correlated the association constant
to yield and enantiomeric excess in three reactions: (i) addi-
tions of silyl ketene acetals to isoquinolinium chlorides; (ii)
additions of silyl ketene acetals to benzopyrylium triflates;
and (iii) additions of indoles to cyclohexylidene malonate in
the presence of copper(II) triflate (Scheme 5).
O
O
HBD (20 mol%)
O
OTIPS
H3C
O
O
OCH3
OCH3
7
6a
8a
H3C CH3
CH3
1c: 76% yield; 39% ee
11: 38% yield; 0% ee
12: 24% yield; 0% ee
Reaction 3
O
O
O
O
Cu(OTf)2 (20 mol%)
HBD (20 mol%)
H3CO
OCH3
OCH3
cyc
H3CO
14a
H
15a
N
cyc
*
HN
In the first reaction, the addition of silyl ketene acetal 3
to 2a to generate 4a, plausibly proceeds through an isoquin-
olium chloride ion pair (Reaction 1, Scheme 5). This reac-
tion system allows us to directly study the effect of silane-
diols, thioures, and squaramides on ion pairs containing
chloride (Figure 3). There appears to be a clear correlation
of the strength of association to enantiomeric excess. Spe-
cifically, the more tightly bound thiourea 11 and squara-
1a: 93% yield; 72% ee
11: 0% yield; - ee
12: 10% yield; 10% ee
Scheme 5 Reactions 1–3 comparing silanediol 1a, thiourea 11, and
squaramide 12. Reaction 1: alkylation of isoquinoline with silyl ketene
acetal. Reaction 2: conjugate addition of silyl ketene acetal to chromen-
4-one. Reaction 3: Lewis acid catalyzed Friedel–Crafts alkylation of
indole with alkylidene malonate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
J. W. Attard et al.
Feature
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search program. This article describes the first direct com-
parison of silanediols, thioureas, and squaramides in three
separate reactions. It has also correlated the association
constant of each catalyst to enantiomeric excess in the
three processes. In the case of reactions involving chloride
ions there appears to be a trend that the stronger the
host:guest interaction is, the higher the enantiomeric ex-
cess. Alternatively, the silanediol uniquely enables enanti-
oselectivity in the two reactions involving triflate ion pairs
that are described herein despite the observation that its
binding constant to triflate is lower than both the squara-
mide and thiourea. Although the reasons for the unique re-
activity of silanediols remain uncertain there are additional
factors, such as undesired side reactions of the catalysts and
non-covalent interactions beyond just anion recognition
(e.g., pi-stacking), that may be important to consider. Ongo-
ing investigations in our laboratory are dedicated toward
better understanding and capitalizing on the unique role of
silanediols in enantioselective anion-binding catalysis.
Figure 3 Chloride association constant determined in CHCl3 correlated
to enantiomeric excess in the addition of silyl ketene acetals to isoquin-
olinium ions, Reaction 1 (R1)
The influence of silanediols, thioureas, and squaramides
on ion pairs containing triflate as the counterion can be
studied in Reactions 2 and 3 in Scheme 5. In these cases of
triflate ion pairs, the results are less predictable than in the
outcomes of the reactions with chloride ion pairs. It was ex-
perimentally determined that silanediol 1a recognizes tri-
flates more weakly than either the thiourea 11 or squara-
mide 12. However, in both the addition of silyl ketene acetal
7 (≡ 3) to the benzopyrylium triflate derived from 6a (Reac-
tion 2, Scheme 5) and the addition of indole to cyclohexyl-
methylene malonate 14a (Reaction 3, Scheme 5), the silane-
diol outperformed both thiourea 11 and squaramide 12 in
terms of enantiomeric excess and yield (Figure 4).
Toluene was purified by passage through a Pure Process Technology
solvent system prior to use. EtOAc and hexanes were used as received.
Toluene was dried over 4Å molecular sieves prior to use in the bind-
ing constant studies. CHCl3 was purified to remove any stabilizer and
distilled from CaH2 prior to use in the binding constant studies.
Cu(OTf)2 was dried at 100 °C under vacuum prior to use. Guest com-
pounds TBACl and TBAOTf were dried under vacuum and stored un-
der N2. The silanediol catalyst was prepared according to a literature
method.6d Thiourea 1114 and squaramide 128b were prepared accord-
ing to literature procedures. Indole was recrystallized from hexanes
prior to use. All other reagents were used directly as received from
the manufacturer, unless otherwise noted. Preparative silica gel chro-
matography was performed using SiliaFlash F60 silica gel (40–63 μm).
Analytical TLC was performed using Analtech 250 μm silica gel HLF
plates and visualized under UV 254 nm. All 1H NMR spectra were ac-
quired using a Bruker BioSpin 500 MHz Avance III Digital NMR spec-
trometer or JOEL ECA-500 (500 MHz) NMR spectrometer and cali-
brated using the solvent signal (CDCl3 7.26 ppm). Multiplicities were
determined using MNova software. All 13C NMR spectra were ac-
quired using a Bruker BioSpin 126 MHz Avance III Digital NMR spec-
trometer or Bruker Avance DPX 400 (100 MHz) and calibrated using
the solvent signal (CDCl3 77.16 ppm). IR spectra were acquired using a
Bruker Vertex 70 with an ATR accessory. High-resolution mass spec-
tra were acquired using an Agilent 6520 Q-TOF mass spectrometer.
Chiral HPLC analysis was performed using an Agilent 1260 equipped
with a diode array detector. Optical rotations were acquired on a Jasco
Digital Polarimeter with a 1 dm cell and a sodium lamp. UV/Vis spec-
trometry experiments were conducted using a Thermo Scientific Evo-
lution 3000 spectrometer or a Shimadzu UV-2500PC spectrometer
with 1 cm path length quartz cuvettes.
Figure 4 Triflate association constant, determined in toluene, correlat-
ed to enantiomeric excess in Reactions 2 and 3 (R2 and R3).
Conclusions
Anion-binding catalysis is emerging as an impressive
synthetic tool able to catalyze reactions that are inaccessi-
ble to more conventional types of catalysis. Several families
of enantioselective anion-binding catalysts are now avail-
able and it appears that there may be complementary reac-
tivity patterns between them. The identification of param-
eters able to aid in predicting which anion-binding catalyst
to choose in order to influence a desired reactivity pattern
would be an enormous advance in the field.
We have observed that silanediols can offer comple-
mentary reactivity patterns when compared to thioureas
and squaramides. The origin of the unique catalytic abilities
remains unknown and is a point of ongoing study in our re-
Compound 4a
An oven-dried 2-dram vial with screw top cap and septa was
equipped with a stir bar and flushed with N2. The vial was sealed and
covered further with parafilm. Isoquinoline (11.8 μL, 0.1 mmol, 1.0
equiv) was added via syringe, toluene (2 mL) was added and the solu-
tion was cooled to 0 °C. 2,2,2-Trichloroethyl chloroformate (15.0 mL,
0.22 mmol, 1.1 equiv) was added, the ice bath was removed, and the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
J. W. Attard et al.
Feature
Synthesis
solution was warmed to r.t. while stirring for 30 min. The cloudy sus-
pension was cooled to –78 °C. Anion-binding catalyst 1b (12.9 mg,
0.02 mmol, 0.2 equiv) was added as a solution in toluene followed by
the silyl ketene acetal 3 (38.8 mg, 0.15 mmol, 1.5 equiv). The reaction
vessel was transferred to a –78 °C acetone bath equipped with im-
mersion cooling coil and stirred for 40 h. The reaction was
quenched at –78 °C by the addition of NaOMe (0.2 mL, 0.5 M in
MeOH, 1.0 equiv) and then warmed to r.t. before filtration through a
short silica gel plug with EtOAc as the eluent. Removal of the solvent
in vacuo and subsequent purification via flash column chromatogra-
phy on silica gel (0:100 EtOAc/hexanes to 4:96 EtOAc/hexanes) af-
forded the title compound as a colorless oil; yield: 20.9 mg (0.051
HPLC: Chiralpak AD-H column; 98:2 (hexanes/i-PrOH), 1 mL/min, 254
nm; tR (minor) = 11.4 min, tR (major) = 13.8 min; e.r. = 30:70.
IR (neat): 2981, 2889, 1729, 1687, 1607, 1463, 1392, 1303, 1221,
1133, 1115, 1078, 990, 870, 764 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.88–7.86 (m, 1 H), 7.48–7.44 (m, 1 H),
7.01 (t, J = 7.2 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.64 (dd, J = 14, 2.4 Hz,
1 H), 3.73 (s, 3 H), 2.82–2.75 (m, 1 H), 2.62–2.58 (m, 1 H), 1.37 (s, 1 H),
1.28 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 192.3, 175.6, 161.7, 136.1, 127.1,
121.6, 120.9, 118.0, 81.8, 52.3, 46.3, 38.5, 20.9, 20.7.
HRMS (ESI): m/z calcd for C14H16O4Na [M + Na]+: 271.0941; found:
271.0934.
24
mmol, 51%); 3:1 mixture of carbamate rotamers by 1H NMR. [α]D
–24.5 (c 1.11, CHCl3).
HPLC: Chiralpak OD-H; 1% i-PrOH/99% hexane, 0.7 mL/min; tR (minor) =
12.8 min, tR (major) = 15.7 min.
Dimethyl 2-[Cyclohexyl(1H-indol-3-yl)methyl]malonate (15a)
Dimethyl cyclohexylidenemalonate (14a; 113 mg, 0.5 mmol, 1.0
equiv), Cu(OTf)2 (36 mg, 0.1 mmol, 0.2 equiv), trifluoroisopropanol
(22.6 μL, 0.25 mmol, 0.5 equiv), and toluene (5 mL) were added to a
20 mL screw top reaction vial with a Teflon-coated septum. The flask
was purged with dry N2 and the reaction mixture stirred for 15 min
or until a homogenous slurry was obtained. The reaction vial was
then cooled to –78 °C in a dry ice/acetone bath. Silanediol 1a stock
solution in toluene (2.4 mL of 0.05 M, 82 mg,15 0.24 mmol, 0.2 equiv)
and a solution of indole in toluene (2.6 mL 88 mg, 0.75 mmol, 1.5
equiv) were added dropwise to the reaction vial. The reaction vial was
transferred to a lab freezer (–28 °C) and stirred overnight. The reac-
tion was quenched with deionized H2O (2 mL), stirred for 10 min,
then extracted with EtOAc (3 × 10 mL), and the combined extracts
were dried (Na2SO4). Solvent was removed from the combined organ-
ic layers under vacuum to obtain the crude product. The crude prod-
uct was purified by silica gel column chromatography (eluent: 4:1
hexanes/EtOAc). The resulting material was purified further by silica
gel column chromatography (eluent: 100% CH2Cl2). After removal of
the solvent under vacuum, product 15a was obtained as an off-white
solid; yield: 159 mg (0.46 mmol, 93%; Rf = 0.25 (4:1 hexanes/EtOAc);
[α]D23 –9.1 (c 4.0, CH2Cl2).
IR (neat): 2991, 2924, 2357, 2343, 1724, 1717, 1627, 1448, 1374,
1322, 1225, 1128, 1046, 941 cm–1
.
1H NMR (400 MHz, CDCl3): δ (major rotamer) = 7.28–7.19 (m, 2 H),
7.10–6.95 (m, 2 H), 6.96 (d, J = 7.6 Hz, 1 H), 5.95 (d, J = 7.6 Hz, 1 H),
5.74 (s, 1 H), 4.97 (d, J = 12.0 Hz, 1 H), 4.70 (d, J = 12.0 Hz, 1 H), 3.64 (s,
3 H), 1.20 (s, 3 H), 1.12 (s, 3 H). δ (minor rotamer) = 6.05 (d, J = 7.6 Hz,
1 H), 5.79 (s, 1 H), 4.86 (s, 2 H), 3.61 (s, 3 H), 1.29 (s, 3 H), 1.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ (major rotamer) = 175.9, 152.3, 131.3,
128.4, 128.0, 127.2, 125.6, 124.9, 112.0, 95.2, 75.7, 60.9, 52.2, 50.3,
22.6, 21.5.
HRMS (ESI): m/z calcd for C17H18Cl3NO4Na [M + Na]+: 428.0199;
found: 428.0189.
Compound 8a
An 8 mL vial with stir bar was flame dried under vacuum, cooled to
r.t. under vacuum, and backfilled with argon gas. Chromone (6a; 14.6
mg, 0.1 mmol, 1 equiv) and 2,6-di-tert-butyl-4-methylpyridine (6.2
mg, 0.03 mmol, 0.3 equiv) were weighed out and placed in the vial.
The vial was then placed under vacuum again and backfilled with ar-
gon. Anhyd toluene (200 μL to make 0.5 M) was added to the vial.
Freshly distilled triisopropylsilyl trifluoromethanesulfonate (29.5 μL,
0.11 mmol, 1.1 equiv) was added via microliter syringe to the solution
and the vial was placed in a 60 °C oil bath for 1 h. After the reaction
time, the vial was cooled to r.t. and further diluted with toluene (1.3
mL). The vial was then cooled to –78 °C in an acetone/dry ice bath. Af-
ter an appropriate amount of time to allow the reaction to come to
temperature had passed, a solution of silanediol catalyst 1c (12.6 mg,
0.02 mmol, 0.2 equiv) in toluene (0.5 mL) was added slowly down the
side of the vial. The reaction mixture was stirred for 10 min before
addition of the silyl ketene acetal 7 (≡ 3) (125 μL of a 1 M solution in
toluene, 0.125 mmol, 1.25 equiv) slowly down the side of the vial. Af-
ter 4 h at –78 °C, the reaction was quenched with of aq 3 M HCl (200
μL, 6 equiv) at –78 °C. The solution was allowed to warm to r.t. over-
night. Then, the crude reaction mixture was extracted with EtOAc (5
mL), the organic layer was washed with H2O (5 mL), dried (Na2SO4),
and the solvent removed under vacuum. The crude mixture was then
dissolved in CDCl3 and 1,3,5-trimethoxybenzene was added as an in-
ternal standard for determining 1H NMR yield. The product was then
isolated by silica gel flash column chromatography (100% hexanes to
80/20 hexanes/EtOAc) or preparative TLC for HPLC analysis (80:20
hexanes/EtOAc solvent system). HPLC samples are occasionally fil-
tered through an alumina plug to remove any undesired silanol by-
products. The desired product 8a was prepared in 76% by 1H NMR
yield; [α]D23 13.0 (c 0.135, CHCl3).
HPLC: Chiralpak AS-H column (10% i-PrOH/hexanes, 1 mL/min, 225
nm); tR (minor) = 8.55 min, tR (major) = 23.80 min; 86.0:14.0 e.r.; 72%
ee.
IR (neat): 3413, 2926, 2853, 1755, 1726, 1457, 1431 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 8.03 (s, 1 H), 7.66 (ddt, J = 8.0, 1.5, 0.8
Hz, 1 H), 7.32 (dt, J = 8.0, 0.9 Hz, 1 H), 7.16 (ddd, J = 8.2, 7.0, 1.2 Hz, 1
H), 7.10 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 4.03 (d,
J = 10.8 Hz, 1 H), 3.78 (dd, J = 10.8, 4.9 Hz, 1 H), 3.73 (s, 3 H), 3.35 (s, 3
H), 1.78–1.55 (m, 6 H), 1.31–1.08 (m, 2 H), 1.02–0.81 (m, 3 H).
13C NMR (CDCl3, 126 MHz): δ = 169.62, 168.96, 135.76, 128.42,
122.87, 121.85, 119.72, 119.41, 113.90, 111.02, 55.69, 52.64, 52.26,
42.04, 41.16, 32.33, 28.79, 26.68, 26.48, 26.32.
Determination of Association Constants
The association constant of the hosts (silanediol 1a, thiourea 11, and
squaramide 12) and guests (TBAOTf and TBACl) were determined by
UV/Vis spectroscopy. CHCl3 was purified to remove any stabilizers
and distilled from CaH2 prior to use. Toluene was dried over 4Å mo-
lecular sieves prior to use. Commercially available TBAOTf and TBACl
were dried under reduced pressure for 1 day prior to use. The titration
experiments were carried out with a host solution (3 mL, 1 × 10–5
in CHCl3) in a quartz cell and UV/Vis spectra recorded upon the addi-
tion of aliquots of the stock solution of guest ion in CHCl3 or toluene
with a microsyringe. The association constant was then calculated us-
M
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
J. W. Attard et al.
Feature
Synthesis
ing a self-written non-linear regression analysis program (see Sup-
porting Information for details). Each titration was repeated in tripli-
cate and the mean K11 was reported.
(6) For examples of silanediols plausibly involved in enantioselec-
tive anion-binding catalysis, see: (a) Guan, Y.; Attard, J. W.;
Visco, M. D.; Fisher, T. J.; Mattson, A. E. Chem. Eur. J. 2018, 24,
7123. (b) Hardman-Baldwin, A. M.; Visco, M. D.; Wieting, J. M.;
Stern, C.; Kondo, S.; Mattson, A. E. Org. Lett. 2016, 18, 2883.
(c) Wieting, J. M.; Fisher, T. J.; Schafer, A. G.; Visco, M. D.;
Galluci, J. C.; Mattson, A. E. Eur. J. Org. Chem. 2015, 525.
(d) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.; Mattson, A. E.
Angew. Chem. Int. Ed. 2013, 52, 11321.
(7) For select examples of processes plausibly proceeding through
thiourea anion binding catalysis, see: (a) Park, Y.; Harper, K. C.;
Kuhl, N.; Kwan, E. E.; Liu, R. Y.; Jacobsen, E. N. Science 2017, 355,
162. (b) Jarvis, C. L.; Hirschi, J. S.; Vetticatt, M. J.; Seidel, D.
Angew. Chem. Int. Ed. 2017, 56, 2670. (c) Kennedy, C. R.; Kehnerr,
D.; Rajapaksa, N. S.; Ford, D. D.; Park, Y.; Jacobsen, E. N. J. Am.
Chem. Soc. 2016, 138, 13525. (d) Zhao, C.; Chen, S. B.; Seidel, D.
J. Am. Chem. Soc. 2016, 138, 9053. (e) Reisman, S. E.; Doyle, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198. (f) De, C. K.;
Clauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060.
(g) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem. Int.
Ed. 2005, 44, 6700.
NMR Titrations
The NMR titration experiments were carried out with a host solution
(1 × 10–2 M) in CDCl3. NMR spectra were recorded upon the addition
of guest compound to the host solution. The guest compound was dis-
solved in the host working solution so as to maintain the concentra-
tion of host during the titration.
Funding Information
The National Science Foundation (1362030), the National Institutes of
Health (1R35GM12480401), and Worcester Polytechnic Institute
(WPI) are gratefully acknowledged for providing support for our stud-
ies. K.O. was supported by a fellowship from Yamagata University to
study in the Mattson laboratory to complete these investigations.
J.W.A. was supported by a WPI global scholars fellowship to complete
investigations in the Kondo laboratory. J.H. is grateful for a WPI Sum-
mer Undergraduate Research Fellowship that supported her contribu-
(8) For examples of plausible enantioselective squaramide anion
binding catalysis, see: (a) Wendlandt, A. E.; Vangal, P.; Jacobsen,
E. N. Nature 2018, 556, 447. (b) Banik, S. M.; Levina, A.; Hyde, A.
M.; Jacobsen, E. N. Science 2017, 358, 761. (c) Liu, R. Y.; Wasa,
M.; Jacobsen, E. N. Tetrahedron Lett. 2015, 56, 3428.
(9) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434.
(10) Raheem, I. T.; Thiara, P. V.; Peterson, E. A.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 13404.
tion to this project.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612217.
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(11) (a) Fischer, T.; Bamberger, J.; Gomez-Martinez, M.; Piekarski, D.
G.; Mancheno, O. Angew. Chem. Int. Ed. 2018, 57, in press; DOI:
10.1002/anie.201812031. (b) Fischer, T.; Duang, Q.-N.;
Mancheno, O. G. Chem. Eur. J. 2017, 23, 5983. (c) Mancheno, O.
G.; Asmus, S.; Zurro, M.; Fischer, T. Angew. Chem. Int. Ed. 2015,
54, 8823. (d) Zurro, M.; Asmus, S.; Beckendorf, S.; Muck-Licht-
enfeld, C.; Mancheno, O. G. J. Am. Chem. Soc. 2014, 136, 13999.
(e) Ohmatus, K.; Kiyokawa, M.; Ooi, T. J. Am. Chem. Soc. 2011,
133, 1307. (f) Ohmatsu, J.; Ando, Y.; Ooi, T. J. Am. Chem. Soc.
2013, 135, 18706.
References
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(13) Thiourea 11 and squaramide 12 were employed in these studies
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(14) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132,
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(15) Corrected for 5:1 silanediol:Et2O content.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I