Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion

Article abstract of DOI:10.1021/jacs.6b00356

Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared. This premise, which is the crux of free energy relationships, exposes a challenging issue of identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity reversal is the result of a lone pair-π interaction between the substrate ligated boronic acid and the phosphate. On the basis of this proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid.

Full text of DOI:10.1021/jacs.6b00356

Article
pubs.acs.org/JACS
Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design
Reveals Structural Interplay between Achiral Directing Group and
Chiral Anion
Andrew J. Neel,†,∥ Anat Milo,‡,§,∥ Matthew S. Sigman,*,‡ and F. Dean Toste*,†
†Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
‡Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
§Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva, 84105, Israel
S
* Supporting Information
ABSTRACT: Enantioselectivity values represent relative rate
measurements that are sensitive to the structural features of
the substrates and catalysts interacting to produce them.
Therefore, well-designed enantioselectivity data sets are
information rich and can provide key insights regarding
specific molecular interactions. However, if the mechanism for
enantioselection varies throughout a data set, these values
cannot be easily compared. This premise, which is the crux of
free energy relationships, exposes a challenging issue of
identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem
in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing
groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key
enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these
outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted
aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids
resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity
reversal is the result of a lone pair-π interaction between the substrate ligated boronic acid and the phosphate. On the basis of this
proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92%
(S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid.
structural information regarding the mechanism of asymmetric
catalysis.
INTRODUCTION
■
The de novo design of chemo-, regio-, and stereoselective
catalysts remains an ongoing challenge in the field of organic
synthesis. In the case of enantioselective catalysis, a key issue is
the influence that catalyst and substrate structural features have
on product enantiomeric excess (ee) due to interactions at the
transition state (TS). This issue is exacerbated in situations
where seemingly minor perturbations to the catalyst or
substrate structure have a profound, and often nonintuitive,
influence on enantioselectivity. Conversely, this very feature
establishes the measurement of enantioselectivity as a powerful
mechanistic probe. Assuming that the conditions of the
Curtin−Hammett principle are satisfied,1 a product’s observed
enantioenrichment can be related to the free energy difference
between the competing diastereomeric TSs leading to either
enantiomer (ΔΔG‡ = −RT ln[(S)/(R)] in kcal/mol). Thus,
enantioselectivity represents a relative rate measurement that is
sensitive to the structural features of each reacting component.
Considered from this perspective, every selectivity value
obtained in the course of data collection bears specific
We recently reported a strategy to exploiting this wealth of
mechanistic information.2 Briefly, this approach involves (1)
preparing a catalyst and substrate library of systematically
perturbed structures, (2) identifying molecular descriptors that
could serve to quantify these structural changes, (3) correlating
these molecular descriptors with experimental selectivity
outcomes of each catalyst and substrate combination in the
data set, (4) developing mechanistic hypotheses on the basis of
the descriptors required for modeling, and (5) preparing
tailored catalysts or substrates to probe these hypotheses. Using
this approach, the key noncovalent interactions underlying
asymmetric induction3 were hypothesized, and consequently a
series of catalysts that leveraged these putative interactions to
improve selectivity over the entire data set were prepared and
validated.2
Received: January 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Although this strategy is general for the study of selective
reactions, it is predicated on the assumption that any variation
in selectivity stems from an analogous mechanism of
asymmetric induction for each data set member. If this
assumption is not valid for certain examples in the data set,
they cannot be directly compared. Classically, such changes in
mechanism have been revealed through changes in the slope of
univariate correlations (e.g., Hammett plots).4−23 However, in
cases where multivariate correlations are applied, these changes
become more challenging to identify, because the parameters
employed could serve to account for this variance.7 We became
interested in the question of how changes in mechanism could
be identified in such scenarios, as this would allow for further
generalization of our strategy that uses focused data sets to
elucidate the structural origins of enantioselectivity. Herein, we
demonstrate how data set design and organization enable the
rapid identification of mechanistic breaks that can be
subsequently confirmed experimentally. This approach allows
for valid comparisons to be made within a data set, resulting in
the identification of reasonable structural origins of enantiose-
lectivity under different mechanistic regimes. As a demon-
stration of the insight gained, we have rationally designed a
catalyst system capable of producing either enantiomer of a
chiral fluorinated product in high enantioselectivity using the
same enantiomer of chiral catalyst with a different achiral
additive.24−26
Recently, our group described the concept of chiral anion
phase transfer (CAPT) catalysis (Figure 1A).27−49 This strategy
relies on employing an insoluble cationic electrophile in a
nonpolar organic solvent, thus minimizing the unselective
background reaction with a soluble substrate. The electrophile
is solubilized through the action of a chiral, lipophilic, anionic
phosphate salt,50−54 ensuring that it is in a chiral environment
when it encounters the substrate in solution. This strategy has
proven successful for several electrophiles, including diazonium
salts,43,44,47 oxoammonium salts,36,38 and halogenating reagents
(Selectfluor along with its bromo and iodo analogues). With
respect to this latter reagent class, although a number of
examples have been reported by our group30−35,37,42 and
others,39−41,45,46,48,49 enantioselectivity has typically depended
on a preinstalled directing group to facilitate the interaction
between the substrate and phosphate catalyst in the
enantiodetermining step.
Figure 1. (A) Conceptual description of chiral anion phase transfer
catalysis. (B) Previously described enantioselective fluorination of
allylic alcohols combining a chiral phosphoric acid phase transfer
catalyst and a p-tolylboronic acid directing group. (C) Enantiose-
lectivity values obtained with different aryl BAs with (S)-TRIP.55
manner in which they interact at the TS to control
enantioselectivity in the fluorination of allylic alcohols.
RESULTS AND DISCUSSION
■
Control Experiments. Figure 2A depicts our proposed
mechanism for this transformation. Following anion metathesis
between phosphate A and Selectfluor, chiral, soluble ion pair B
encounters the condensation product (E) between allylic
alcohol C and BA D. A concerted or stepwise fluorination-
deprotonation sequence in the chiral environment of the
phosphate (G) affords enantioenriched allylic fluoride H and
phosphoric acid (PA) I, which can be regenerated to the anion
by an inorganic base. Prior to initiating our study of the
relationship between PA/BA structures and enantioselectivity,
we sought experimental evidence that BA monoester E was in
fact the species undergoing enantioselective fluorination under
catalytic conditions. Figure 2B summarizes the relevant results
using (S)-TRIP and p-tolylboronic acid as representative
reaction components. In the absence of (S)-TRIP, the yield
was greatly diminished (entry 2), supporting its role as a phase-
transfer catalyst. Omission of p-tolylboronic acid from the
reaction mixture somewhat restored the yield, but with a
complete loss of enantioselectivity (entry 3). However, a series
of NMR titration experiments demonstrated that under
relevant conditions, essentially all of alcohol 1 is associated
To address this limitation, it was recently demonstrated55
that simple allylic alcohols could be fluorinated56−63 with ee
values of up to 94% using aryl boronic acids (BAs) as traceless,
in situ directing groups (Figure 1B).64 The essential role of the
aryl BA for high enantioselectivity was underlined by the
formation of racemic product in its absence. However, it was
observed that enantioselectivity was highly dependent on the
structure of the aryl BA employed. For example, using (S)-
TRIP as the catalyst, simply changing from 3,5-dimethylphe-
nylboroinc acid to p-tolylboronic acid resulted in an 81%
change in ee (which, in this case, represents 1.0 kcal/mol,
Figure 1C). The notion that selectivity could be influenced to
such an extent by an achiral additive is intriguing in terms of the
structural underpinnings of this effect. We approached this
problem within the framework of our hypothesis that
enantioselectivity values can serve as sensitive mechanistic
probes that report on specific interactions between reacting
partners. Specifically, we anticipated that by designing a data set
in which the structural features of the aryl BA and phosphate
catalyst were systematically perturbed, we could ascertain the
B
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 2. (A) Proposed catalytic cycle for chiral PA catalyzed
enantioselective fluorination of allylic alcohols. (B) Control experi-
ments supporting p-tolylboronic acid’s role as a directing group. All
reactions were conducted on 0.1 mmol scale with respect to allylic
alcohol 1.
Figure 3. (A) Effect of boronic acid structure on enantioselectivity. All
reactions were conducted on 0.05 mmol scale with respect to allylic
alcohol 1. (B) Visualization of enantioselectivity range of 2 attainable
by variation of boronic acid structure.
with BA, either as the mono- (E) or bis-ester (F, see Supporting
Information for details), suggesting that this unselective
pathway is likely inoperative under catalytic conditions. Finally,
omission of molecular sieves resulted in an increased yield,
while enantioselectivity remained unaffected.65 The diminished
yield in the presence of molecular sieves likely arises from the
increased formation of BA bis-ester F under these dehydrating
conditions, which serves as an unreactive reservoir of alcohol 1.
Collectively, these data sufficiently demonstrate that monoester
E is likely the relevant species interacting with the chiral
phosphate in the enantiodetermining step of this reaction. The
remainder of our study was devoted to uncovering the nature of
this interaction within the relatively opaque region of the
catalytic cycle from E to G to yield H (Figure 2A).
Data set Design. Prior to designing a data set in which
both BA and phosphate structures were systematically
modified, we sought to establish the enantioselectivity range
accessible by changing only the achiral aryl BA. It was reasoned
that this approach would allow us to rapidly identify which BA
structural features most affected enantioselectivity, enabling the
effective design of a data set of catalysts and BAs. To this end,
21 commercially available aryl BAs were selected with
substituents that systematically spread the reaction space with
respect to both their steric and electronic profiles at the 2-, 3-,
4-, 2,6-, and 3,5- positions of the aryl ring (Figure 3A-B). (S)-
TRIP was selected as the catalyst for these studies, given its
ubiquity in the field of chiral PA/phosphate catalysis.66,67 Using
conditions slightly modified from those previously reported,65
the enantiomeric excess of 2 was measured using each of these
BAs with (S)-TRIP, resulting in values ranging from 66% ee of
the expected (S)-2, to 78% ee of the (R) enantiomer.
Remarkably, this represents a 2.2 kcal/mol range based solely
on the structure of the achiral BA (Figure 3B).
A notable structural effect is apparent from these data as well:
4-substituted phenyl BA derivatives lead to the (S) enantiomer
with the largest ee values, followed by their 2- and 3-substituted
counterparts, with 3,5-substituted derivatives resulting in the
highest enantioselectivities favoring the (R) enantiomer.
Having established this range, we turned to design a
complete data set in which both BA and phosphate structures
were perturbed (Figure 4A). To this end, eight BAs were
selected that evenly covered the range of enantioselectivities
representative of the different substitution patterns that were
C
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. (A) Enantioselectivity data obtained by variation of PA and BA substitution pattern. All reactions were conducted using 0.050 mmol 1,
0.065 mmol 3, 0.065 mmol Selectfluor, 0.200 mmol Na2HPO4, 0.005 mmol 4, and 40 mg MS 4Å in toluene (0.1 M). (B) Graphical representation of
BA structure−selectivity trends as a function of catalyst structure.
believed to influence selectivity (i.e., 2-, 4- and 3,5-substituted).
Simultaneously, eight phosphate catalysts were prepared with
variable substitution at the 3 and 3′ positions of the binaphthyl
backbone. Mesityl-substituted catalyst 4a was selected as a less-
encumbered version of TRIP (4b) to assess the potential role
of sterics within the 2,4,6-substitution pattern, while 2,6-(i-Pr)2-
Ph (4c), 2-i-Pr-Ph (4d), and 4-i-Pr-Ph (4e) substituted
catalysts were intended to serve as deconstructed derivatives
of TRIP to assess any potential isolated effects of these
positions. Finally, as the 3,5-disubstituted phenyl BAs 3m−3o
had been observed to afford inverted selectivity using TRIP as
the catalyst (Figure 3), 3,5-disubstituted catalysts 4g and 4h
were prepared to evaluate the possibility of shape comple-
mentarity between the BA and catalyst substituents.
D
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 5. Relationship between product and catalyst enantioselectivities for various BA-catalyst combinations: (A) 3b and 4b, (B) 3b and 4a, (C) 3b
and 4e, (D) 3o and 4b. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1.
Data Collection. With the appropriate libraries of
phosphate catalysts and BAs in hand, the enantioselective
outcome of each combination was measured with the goal of
producing correlations between the experimental values and
molecular parameters describing these structural varia-
tions.68−77 Figure 4A depicts the enantioselective outcome of
each BA-phosphate combination. It was anticipated that the
general trends observed using TRIP (Figure 3) would hold
across the series of catalysts (e.g., 4-substituted BAs would
display the highest propensity for one enantiomer, while 3,5-
disubstituted BAs would favor the other). We were therefore
surprised to observe that these trends were highly variable from
one catalyst to the next, even as a result of seemingly minor
structural changes. For example, the use of mesityl-substituted
catalyst (R)-4a resulted in the formation of (R)-2 as the major
enantiomer across the entire BA series, in contrast to the use of
structurally directly analogous (R)-TRIP (4b), which primarily
formed (S)-2 when used in combination with 3,5-disubstituted
phenyl BA derivatives. Additionally, the use of catalyst (R)-4e,
in which the ortho isopropyl groups of 4b have been removed,
afforded the enantiomeric product (S)-2 across the entire data
set. Figure 4B provides a method to visualize these data
simultaneously, where each line represents a BA and each x-axis
tick mark represents a catalyst aryl group. This visualization
scheme displays the same information contained in Figure 4A,
but in a manner that facilitates the identification of outliers and
stark trend breaks. For example, upon moving from left to right,
sharp breaks in the observed trends can be detected by distinct,
significant changes to enantioselectivity and a reordering of the
trend lines.
We have interpreted these sharp breaks in the trends as being
indicative of a change in the mechanism of asymmetric
induction for certain phosphate-BA combinations. For this
reason, although our initial goal was the elucidation of the
relevant selectivity-determining interactions across the entire
data set through a multivariate correlation, the required models
would not necessarily account for these mechanistic breaks.
However, we reasoned that a mechanistic understanding of the
outliers would contextualize the remainder of the data, allowing
meaningful conclusions to be drawn regarding the structural
E
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
origins of selectivity. Because this data set had been designed to
cover a broad range of structure enantioselectivity relationships,
Figure 4 could serve as a guide for experimentally interrogating
regions of the data set that seemed distinctive. Specifically, we
were intrigued by the phenomenon that catalysts with the same
backbone chirality could deliver either enantiomer of 2 in
reasonably high ee. On the basis of the data in Figure 4, this
divergence in enantioselectivity appears to manifest itself in two
distinct respects: (1) by changing the catalyst substituent
(compare (R)-4e, containing a 4-i-Pr-Ph substituent, and (R)-
4b, containing a 2,4,6-(i-Pr)3-Ph substituent) and (2) by
holding the catalyst constant while changing the achiral BA
additive (compare 3b, 4-Me-Ph BA, with 3o, 3,5-(OMe)2-Ph
BA using (R)-4b as the catalyst). The ability of the described
approach to provide a systematic guide for focused outlier
identification steered our further studies toward selecting
particular experiments that would reveal the mechanistic
possibilities responsible for these observations.
evaluated in combination with this catalyst. Figure 6A shows
two Hammett plots correlating enantioselectivity to σpara that
include these results along with those from the original data set.
For a given substitution pattern (i.e., 3,5- or 4-), there is an
Nonlinear Effect Studies. The aforementioned inversions
of enantioselectivity are clearly indicative of a major change to
the structure of the enantiodetermining TS(s). Given the
doubly cationic nature of Selectfluor, we hypothesized that this
change may be related to the number of phosphate molecules
associated with Selectfluor (i.e., 1 or 2) during C−F bond
formation (B and G, Figure 2A), as this speciation could
conceivably be sensitive to the structure of the phosphate, BA
or both. To test this possibility, we conducted a series of
nonlinear effect (NLE) experiments78−101 using phosphate/BA
combinations from different regions of the original data set
hypothesized to function by unique mechanisms (vide supra).
As depicted in Figure 5A,B, using p-tolyl BA 3b, a linear
relationship was observed between catalyst and product ee
when using both (S)-4a and (S)-4b as catalysts, implicating
only a single phosphate in the enantiodetermining TS in each
of these scenarios. This result suggests that these two catalyst
are directly comparable and that the improvement from 65% ee
with 4b to 91% ee with the structurally analogous 4a is likely
geometric in origin. However, a significant positive NLE was
observed using (S)-4e as the catalyst with 3b (Figure 5C),
which is consistent with the involvement of multiple phosphate
species in the enantiodetermining TS.102 The reduced steric
profile proximal to the phosphate moiety in 4e lends credence
to the proposal that this catalyst is more likely to form a dimeric
salt compared with the bulkier 4b.103 Thus, we propose that the
selectivity reversal observed using catalyst 4e is a result of a
fundamentally different mechanism of asymmetric induction
when using this catalyst relative to the others in the data set.104
Intriguingly, a linear relationship between product and catalyst
ee was observed using 3,5-(OMe)2-substituted BA 3o with
catalyst 4b (Figure 5D), a combination that also afforded
product 2 with inverted enantioselectivity (−77% ee). This
result suggests that a single phosphate molecule is involved in
the enantiodetermining TS in this case and therefore, that the
origin of selectivity inversion for this particular phosphate/BA
combination is different than that of catalyst 4e (vide infra).
Examination of 4-iPr substituted catalyst 4e. As 4-i-Pr-
Ph substituted catalyst 4e likely operates via an alternative
mechanism, the enantioselectivity data collected using it cannot
be directly compared with those from the other catalysts in the
data set. However, we were interested in the source of the
significant variation (8 to −60% ee) in the data obtained using
this catalyst resulting from changes in BA structure. To obtain a
more complete representation, several additional BAs were
Figure 6. (A) Correlation between enantioselectivity of 2 (ΔΔG‡) and
σpara using catalyst 4e with various boronic acids. All reactions were
conducted on 0.05 mmol scale with respect to allylic alcohol 1. (B)
Reaction time course data for formation of 2 using 3n and 4e and (C)
3b and 4e. All reactions were conducted on 0.1 mmol scale with
respect to allylic alcohol 1.
F
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
excellent correlation between enantioselectivity (represented as
ΔΔG‡) and Hammett σpara values, with electron-rich BAs
generally affording higher enantioselectivities than electron-
poor examples. The 3,5-substituted BAs cannot be correlated
on the same plot as the 4-substituted BAs, yet independently,
both plots reveal robust linear free energy relationships with
electronic features of the BA substituent.105
́
Martinez-Aguirre and Yatsimirsky recently reported that, in
−
contrast to various other anions, H2PO4 tends to form Lewis
acid−Lewis base type tetrahedral adducts with aryl BAs.106
Furthermore, Tokunaga and co-workers have demonstrated the
increased electrophilicity of boron in electron poor aryl BAs by
studying the thermodynamics of boroxine hydrolysis as a
function of aryl substitution.107 On the basis of this precedent,
we propose that the sterically accessible phosphate moiety in 4e
is inhibited by the formation of a catalytically inactive covalent
adduct with electron poor BAs under the reaction conditions.
Therefore, the low enantioselectivities observed using electron
poor BAs reflect an inability of the phosphate to serve as a
phase transfer catalyst and thus to outcompete the unselective
background reaction. This hypothesis was probed further by
monitoring product formation in the presence and absence of
catalyst. As shown in Figure 6B, using 3,5-(CF3)2-substituted
BA 3n, fluorination occurred at nearly identical rates in the
presence and absence of catalyst 4e. However, using the more
electron rich 4-Me substituted 3b, a rate acceleration over the
uncatalyzed background reaction was observed in the presence
of catalyst (Figure 6C). Thus, we propose that although the
inverted sense of enantioselectivity using 4e presumably results
from the association of two chiral phosphates with Selectfluor,
the variation in enantioselectivity observed for this catalyst over
a set of BAs is predominantly electronic in origin, with electron
poor BAs acting as catalyst poisons.
Isotopic Substitution Experiments. Having identified the
likely cause for the inverted enantioselectivity displayed by 4e,
we sought a sufficient explanation for the anomalous
enantioselectivity observed using 4b and 3,5-(OMe)2 sub-
stituted BA 3o (−78% ee, Figure 4). The absence of an NLE
(Figure 5D), indicated that a single phosphate was presumably
involved in this TS. This suggested that the inversion of
selectivity relative to 4-substituted BAs was likely due to specific
phosphate-BA interactions leading to a change in TS geometry.
To gain better insight into this region of the catalytic cycle,
substrate 1-d3 was prepared and subjected to the standard
reaction conditions with three different phosphate/BA
combinations. As demonstrated in Figure 7, the use of 4-Me
substituted BA 3b with both 4a and 4b afforded 2-d2 with
enantioselectivity nearly identical to that observed with its
protonated analogue. However, the combination of 3o and 4b
provided 2-d2 in −90% ee, a 13% ee (0.5 kcal/mol) increase
relative to 2. These results suggest that the cleavage of the C−
H bond is involved in the enantiodetermining TS in the latter
case, but not in the former. Figure 7B depicts a plausible
mechanistic explanation for this situation, in which a continuum
exists between two limiting scenarios: (1) irreversible,
enantiodetermining fluorination followed by rapid deprotona-
tion (pathway a) or (2) concerted enantiodetermining
fluorination-deprotonation (pathway b). The enantioselectivity
differences between the deuterated and protonated substrate
along this mechanistic continuum depend on the substituents
of the aryl BA, and are suggestive of a specific interaction
between the BA and catalyst in the latter of the two limiting
scenarios. The absence of an effect in the case of 3o with 4a
Figure 7. (A) Comparison of enantioselectivities of 2 and 2-d2 for
various BA and PA combinations. All reactions were conducted on
0.05 mmol scale with respect to allylic alcohol 1. (B) Plausible
mechanistic rationale for variable dependence of enantioselectivity on
isotopic substitution.
demonstrates that phosphate structure also plays a role in this
interaction. We thus focused our efforts on identifying the
nature of the specific interaction(s) that were presumably
responsible for the large inversion of enantioselectivity
observed using 3o with 4b.
Probing Direct Interaction. Inspection of our original data
set (Figure 4) revealed that 3,5-disubstituted BAs generally
resulted in inverted enantioselectivities when used in
combination with 4b, but this effect appeared particularly
pronounced with 3,5-(OMe)2-substituted boronic acid deriva-
tive 3o. In order to distinguish whether this marked effect using
3o was simply a result of its steric profile or was due to a direct
interaction with the methoxy substituent, hybrid 3-Me-5-OMe-
substituted phenyl BA derivative 3w was prepared and
evaluated under the standard reaction conditions using each
of the catalysts from the original data set. The resulting
enantioselectivities are presented in Figure 8A, alongside those
obtained using 3,5-(OMe)2 and 3,5-(Me)2 substituted deriva-
G
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
the alkyl substituent was held constant (R2 = Me), variation of
the alkoxy group (R1 = OEt, Oi-Pr, OBn) had a significant
impact on enantioselectivity, consistent with a structural
perturbation at this position disrupting the interaction
responsible for the observed inverted enantioselectivity.
Notably, 3-OMe substituted BA 3l also afforded inverted
enantioselectivity but to a lesser degree (−34% ee), suggesting
that while an interaction with the methoxy group is present, the
overall steric profile of the 3,5-substituted derivatives does play
a role. Finally, an intriguing dependence of the interaction in
question on catalyst structure was observed. Particularly notable
was the observation that mesityl-substituted catalyst 4a, which
possesses the same substitution pattern as 4b, did not furnish 2
with inverted selectivity when used in combination with BA 3o
(Figure 8A). However, an intermediate enantioselectivity value
was obtained using hybrid BA 3w compared with 3o and 3m
(55% ee vs 21 and 63% ee respectively), suggesting that the
putative direct interaction may be present, but attenuated.
On the basis of the following observations, we propose that a
lone pair-π interaction108−126 (Figure 8C) is attenuating
enantioselectivity: (1) our experiments isolated the interaction
to an alkoxy group at a specific position of the aryl BA, (2)
variation of this alkoxy group resulted in drastically altered
selectivity, and (3) subtle changes to the catalyst aryl ring had a
considerable impact on enantioselectivity. First discovered as a
stabilizing element for the conformation of Z-DNA (Figure
8C),118 the lone pair-π interaction entails an overlap between a
heteroatom lone pair and the face of an aromatic ring, and has
been demonstrated to be highly dependent on the geometries
of both interacting partners.127 Several studies have reported
the ability of this interaction to alter the overall geometries of
molecular complexes by acting in cooperation with other
noncovalent interactions such as hydrogen bond-
ing.115−117,119,122 Although lone pair-π interactions have been
implicated as stereocontrolling elements in asymmetric catalysis
computationally,125,126 our results serve as compelling exper-
imental support to this end.
We hypothesized that, if an interaction between a methoxy
lone pair in 3o and the catalyst aryl ring were important, then
control of the orientation of this ring might provide a means to
enhance it. Given the apparent trend moving from 4a to 4b, we
reasoned that a catalyst with bulkier substituents at the 2,4,6-
positions of its aryl rings may serve to reinforce the interaction
in question due to better overlap, perhaps owing to a change in
the torsional angle between the substituent and the binaphthyl
backbone. To this end, 2,4,6-(Cy)3-Ph substituted catalyst (R)-
TCYP (4i) was employed with 3o, furnishing (S)-2 in −92% ee
(Scheme 1). Using this same catalyst with the BA that gave the
largest positive enantioselectivity in the initial screen with TRIP
(4b) (4-i-Bu-substituted variant 3e), resulted in the formation
of (R)-2 in 77% ee. Thus, simply by making a subtle structural
change to an achiral additive, we are able to tune the
enantiomeric excess of fluorinated product 2 from 77% to
−92% (a ΔΔG‡ range of 3 kcal/mol) using the same chiral
catalyst 4i. We attribute this remarkable inversion of
enantioselectivity to a subtle, noncovalent interaction between
the achiral additive and the chiral catalyst.
Figure 8. (A) Comparison of enantioselectivity of 2 obtained using
hyrid BA 3w versus versus 3o and 3m as a function of catalyst
structure. (B) Effect of variation of alkyl vs alkoxy substituents for
various 3,5-disubstituted hybrid phenylboronic acid derivatives. All
reactions were conducted on 0.05 mmol scale with respect to allylic
alcohol 1. (C) Left: Qualitative depiction of lone pair-π interaction as a
stabilizing element for the structure of Z-DNA.108,109 Right:
Qualitative description of potential lone pair-π interaction between
BA and PA.
tives 3o and 3m respectively for comparison. With all catalysts
other than 4b, hybrid BA 3w afforded the fluorinated product
with enantioselectivity similar to that observed with 3,5-(Me)2
substituted variant 3m, suggesting that the BA steric profile is
the dominant factor governing enantioselectivity in these cases.
However, in combination with 4b, 3w behaved nearly
identically to 3,5-(OMe)2 substituted variant 3o, suggesting
the presence of a specific interaction between the BA methoxy
group and the aryl substituent of 4b, which is further supported
by the results provided in Figure 8B. Employing a series of
hybrid 3,5-disubstituted BAs, holding the alkoxy substituent
constant (R1 = OMe) while varying the second substituent (R2
= OMe, Me, CF3) displayed a minimal effect on enantiose-
lectivity. However, for the inverse set of experiments in which
Trend Analysis. Having gained sufficient insight regarding
several mechanistic regimes in the data set, we sought to
address our initial goal of producing multivariate correlations to
describe the catalyst-substrate enantioselectivity imparting
interactions (vide supra). Examination of Figure 4 revealed
that the catalysts that were the most sensitive to changes in the
H
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
symmetric substitution or any methoxy substituent (Figure
9E, blue) and those with 3-alkoxy-5-methyl substitution (Figure
9F, purple). In line with probing a putative lone pair-π
interaction, this subdivision keeps the alkoxy substituent
constant in one set and the alkyl substituent constant in the
other. Although these two models both contain the same
molecular descriptors (BA length, L, and catalyst torsion angle),
the correlation coefficients of each are slightly different, and the
former contains an interaction cross-term (consisting of the
infrared BA ring stretch (ν3)129 and catalyst torsion, Figure 9E).
This cross-term may be necessary to differentiate members of
this set containing a methoxy substituent from the other BAs,
as the former are presumed to undergo a direct interaction with
the catalyst. However, in the 3-alkoxy-5-methyl set (Figure 9F),
all of the BAs are presumed to undergo the same type of
interaction with the catalyst, and thus do not require this
additional interaction term. It is particularly intriguing that
catalyst torsion has the largest coefficient in both of these
models (Figure 9E and 9F), as these BAs are proposed to
undergo a direct interaction with the catalyst that is highly
geometry dependent. Because torsion is a major feature
differentiating catalyst 4a (2,4,6-(Me)3-Ph) from 4b and 4i
(2,4,6-(i-Pr)3-Ph and 2,4,6-(Cy)3-Ph respectively), this is also
consistent with the divergence in selectivity visibly noticeable in
Figure 9A. These results support the hypothesis that a direct,
noncovalent interaction controls enantioselectivity in a manner
that is greatly affected by the structures of both the BA and PA,
and is proposed to be directing the sizable inversion in
enantioselectivity.
Scheme 1. Inversion of Enantioselectivity of 2 Using Catalyst
4i Changing Only BA Structure
a
a
Reactions were conducted on 0.05 mmol scale with respect to allylic
alcohol 1.
BA structure were 4a (2,4,6-(Me)3-Ph, 3 to 90% ee), 4b (2,4,6-
(i-Pr)3-Ph, −78 to 66% ee), and 4e (4-(i-Pr)-Ph, −60 to 8%
ee). As previously discussed, catalyst 4e likely operates in a
mechanistically distinctive fashion and cannot be compared
directly with the others. The remainder of the catalysts tested
(4c, 4d, 4f−h) generally displayed ee values over a smaller
range indicating less sensitivity to the structure of the BA and
were therefore not considered for modeling purposes. Thus, 4a
and 4b were selected for modeling, along with their 2,4,6-
(Cy)3-Ph substituted analogue 4i. Figure 9A displays the
enantioselectivity trend for each catalyst as a function of BA
structure. The behavior of all three catalysts is clearly similar for
2- and 4- substituted BAs (Figure 9A, left), indicating the same
interactions are likely involved in determining selectivity in this
mechanistic region. However, upon moving to the 3,5-
substituted BAs (Figure 9A, right) there is a noticeable break
in the behavior of 4a relative to 4b and 4i demonstrating that
the latter two are behaving differently than 4a. Thus, to aid the
construction of correlations describing these trends, the data set
was initially divided according to the BA substitution pattern,
separating the 2- and 4- from 3,5-substituted aryl BAs (Figure
9B).
The first set, consisting of 2- and 4-substituted aryl BAs
(Figure 9B, light blue, Figure 9C), can be modeled using three
descriptors that are sensitive to the structures of the reactive
partners: the minimal and maximal width Sterimol128 steric
parameters (B1 and B5) describe the BA structure, and the
torsion angle between the binaphthyl backbone and 3,3′-
substituent describe the catalyst structure. As these are
normalized models (see Supporting Information for details),
the correlation coefficients denote the relative magnitude of
each effect. Thus, we propose that in this region of the data set,
the location of the BA substituent and the accessible
conformations of the catalyst aryl rings (represented by the
catalyst torsion parameter) dictate the geometry of their
interaction at the selectivity determining TS.
CONCLUSION
■
Often in the field of asymmetric catalysis, there exists an
infrequently acknowledged assumption that the trend observed
for a particular catalyst with several substrates will hold when
structurally analogous catalysts are tested. In fact, it is this line
of reasoning that generally drives standard optimization studies.
However, in many cases, this assumption does not prove valid.
In these instances, the rational design of a data set that takes the
structural variation of multiple reaction components into
account can greatly facilitate the identification of regions of
structural space where trends break down. We contend that
such regions signal potential changes in mechanism in a
manner analogous to a break in slope in a classical linear free
energy relationship. It is through an understanding of the
mechanistic underpinnings of these phenomena that the
remainder of the data set can be contextualized. Furthermore,
we contend that this approach facilitates the identification of
specific data set outliers that would be difficult to design de
novo, but which can be optimized once identified. Here, we
have demonstrated these principles using a data set of
enantioselectivities from an asymmetric BA-directed phos-
phate-catalyzed fluorination of allylic alcohols. We initially set
out to understand the structural underpinnings of enantiose-
lectivity by producing statistical models to describe the entire
data set. However, the recognition that multiple mechanistic
pathways may be operative called for a re-evaluation of our
strategy. Guided by a highly organized data set that was
designed according to geometric, steric, and electronic criteria,
we promptly recognized that not all of the values were directly
comparable, presumably due to differences in the mechanisms
of asymmetric induction. A series of mechanistic experiments
was conducted that shed light on the structural origins of these
effects, ultimately leading to a catalytic system capable of
Although a statistically robust model was identified for the
full set of 3,5-substituted BAs (Figure 9D, gray), in addition to
catalyst torsion, several BA steric parameters are required to
capture the possible TS geometries. Overall, this model seems
complex and reveals little regarding the interactions at the
origin of asymmetric induction. Thus, this set was further
subdivided according to substitution pattern: those with
I
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 9. (A) Graphical representation of catalyst structure-selectivity trends as a function of BA structure. (B) Enantioselectivity of 2 using catalysts
bearing 2,4,6-trisubstituted aryl substituents with various BAs. (C−F) Mathematical correlation of normalized catalyst and BA molecular descriptors
to enantioselectivity (ΔΔG‡) for 2- and 4-substituted aryl BAs (C), all 3,5-disubstituted aryl BAs (D), 3,5-disubstituted aryl BAs with symmetrical
substitution or a methoxy substituent (E), and 3-alkoxy-5-methyl substituted aryl BAs (F). All reactions were conducted on 0.05 mmol scales with
respect to allylic alcohol 1.
J
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(17) Bergon, M.; Calmon, J.-P. Tetrahedron Lett. 1981, 22 (10), 937.
(18) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104 (17),
4689.
(19) Meenakshisundaram, S.; Sockalingam, R. Collect. Czech. Chem.
Commun. 2001, 66 (6), 897.
(20) Um, I.-H.; Han, H.-J.; Ahn, J.-A.; Kang, S.; Buncel, E. J. Org.
Chem. 2002, 67 (24), 8475.
(21) Ravi, R.; Sanjeev, R.; Jagannadham, V. Int. J. Chem. Kinet. 2013,
producing either enantiomer of a chiral fluorinated building
block in high enantioselectivity. The insights gained in this
study can be generalized to countless situations in which
structural features of the catalysts and substrates may alter the
mechanism through which selectivity is induced. It is our
current goal to apply these approaches to new reaction
development, facilitating both a foundational guide to catalyst
design and a rapid identification of mechanistic outliers.
45 (12), 803.
(22) Jmaoui, I.; Boubaker, T.; Goumont, R. Int. J. Chem. Kinet. 2013,
45 (3), 152.
(23) Ciaccia, M.; Pilati, S.; Cacciapaglia, R.; Mandolini, L.; Di
Stefano, S. Org. Biomol. Chem. 2014, 12 (20), 3282.
(24) Lutz, F.; Igarashi, T.; Kawasaki, T.; Soai, K. J. Am. Chem. Soc.
2005, 127 (35), 12206.
(25) Lutz, F.; Igarashi, T.; Kinoshita, T.; Asahina, M.; Tsukiyama, K.;
Kawasaki, T.; Soai, K. J. Am. Chem. Soc. 2008, 130 (10), 2956.
(26) Holland, M. C.; Metternich, J. B.; Daniliuc, C.; Schweizer, W.
B.; Gilmour, R. Chem. - Eur. J. 2015, 21 (28), 10031.
(27) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4
(8), 603.
(28) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52 (2), 518.
(29) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52 (2),
534.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b00356.
■
S
Table of parameters. (XLSX)
Example model development script. (TXT)
Experimental and modeling details and characterization
data. (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*sigman@chem.utah.edu
*fdtoste@berkeley.edu
(30) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334 (6063), 1681.
(31) Phipps, R. J.; Hiramatsu, K.; Toste, F. D. J. Am. Chem. Soc. 2012,
134 (20), 8376.
(32) Wang, Y.-M.; Wu, J.; Hoong, C.; Rauniyar, V.; Toste, F. D. J.
Author Contributions
∥AJN and AM contributed equally.
Notes
The authors declare no competing financial interest.
Am. Chem. Soc. 2012, 134 (31), 12928.
(33) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew.
Chem., Int. Ed. 2012, 51 (38), 9684.
(34) Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135 (4), 1268.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-0749506 and CHE-1361296) and
the National Institute of General Medical Sciences (R01
GM104534) for partial support of this work. The support and
resources from the Center for High Performance Computing at
the University of Utah are gratefully acknowledged. Eiji
Yamamoto, Matt Larsen, Weiwei Zi, and Willie Wolf are
acknowledged for helpful discussions.
(35) Shunatona, H. P.; Fruh, N.; Wang, Y.-M.; Rauniyar, V.; Toste, F.
̈
D. Angew. Chem., Int. Ed. 2013, 52 (30), 7724.
(36) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem.
Soc. 2013, 135 (38), 14044.
(37) Wu, J.; Wang, Y.-M.; Drljevic, A.; Rauniyar, V.; Phipps, R. J.;
Toste, F. D. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (34), 13729.
(38) Lackner, A. D.; Samant, A. V.; Toste, F. D. J. Am. Chem. Soc.
2013, 135 (38), 14090.
(39) Liu, H.; Jiang, G.; Pan, X.; Wan, X.; Lai, Y.; Ma, D.; Xie, W. Org.
Lett. 2014, 16 (7), 1908.
REFERENCES
■
(1) Seeman, J. I. Chem. Rev. 1983, 83 (2), 83.
(2) Milo, A.; Neel, A. J.; Toste, F. D.; Sigman, M. S. Science 2015, 347
(6223), 737.
(3) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U. S. A.
2010, 107 (48), 20678.
(4) Jaffe, H. H. Chem. Rev. 1953, 53 (2), 191.
́
(5) Schreck, J. O. J. Chem. Educ. 1971, 48 (2), 103.
(40) Romanov-Michailidis, F.; Guen
Int. Ed. 2013, 52 (35), 9266.
(41) Romanov-Michailidis, F.; Guen
2013, 15 (22), 5890.
́
ee
́
, L.; Alexakis, A. Angew. Chem.,
, L.; Alexakis, A. Org. Lett.
́
ee
́
(42) Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136
(14), 5225.
(43) Nelson, H. M.; Reisberg, S. H.; Shunatona, H. P.; Patel, J. S.;
Toste, F. D. Angew. Chem., Int. Ed. 2014, 53 (22), 5600.
(44) Nelson, H. M.; Patel, J. S.; Shunatona, H. P.; Toste, F. D. Chem.
Sci. 2014, 6 (1), 170.
(6) Hoz, S.; Ben-Zion, M. J. Chem. Soc., Chem. Commun. 1980, 10,
453.
(7) Sjostrom, M.; Wold, S.; Fredga, A.; Bonner, W. A.; Orn, U. Acta
̈
̈
̈
Chem. Scand. 1981, 35b, 537.
(45) Romanov-Michailidis, F.; Pupier, M.; Guen
́ ́
ee, L.; Alexakis, A.
(8) Jencks, W. P.; Brant, S. R.; Gandler, J. R.; Fendrich, G.;
Nakamura, C. J. Am. Chem. Soc. 1982, 104 (25), 7045.
(9) Williams, A. In New Comprehensive Biochemistry; Page, M. I., Ed.;
The Chemistry of Enzyme Action; Elsevier, 1984; Vol. 6, pp 127−201.
(10) Greig, I. R. Chem. Soc. Rev. 2010, 39 (6), 2272.
(11) Swain, C. G.; Langsdorf, W. P. J. Am. Chem. Soc. 1951, 73 (6),
2813.
(12) Anderson, B. M.; Jencks, W. P. J. Am. Chem. Soc. 1960, 82 (7),
1773.
(13) Hart, H.; Sedor, E. A. J. Am. Chem. Soc. 1967, 89 (10), 2342.
(14) Ta-Shma, R.; Rappoport, Z. J. Am. Chem. Soc. 1977, 99 (6),
1845.
Chem. Commun. 2014, 50 (88), 13461.
(46) Romanov-Michailidis, F.; Pupier, M.; Besnard, C.; Burgi, T.;
̈
Alexakis, A. Org. Lett. 2014, 16 (19), 4988.
(47) Nelson, H. M.; Williams, B. D.; Miro,
Chem. Soc. 2015, 137 (9), 3213.
́
J.; Toste, F. D. J. Am.
(48) Romanov-Michailidis, F.; Romanova-Michaelides, M.; Pupier,
M.; Alexakis, A. Chem. - Eur. J. 2015, 21 (14), 5561.
(49) Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.;
Hamashima, Y. J. Am. Chem. Soc. 2015, 137 (32), 10132.
(50) Akiyama, T. Chem. Rev. 2007, 107 (12), 5744.
(51) Terada, M. Synthesis 2010, 2010 (12), 1929.
(52) Terada, M. Curr. Org. Chem. 2011, 15 (13), 2227.
(53) Mori, K.; Akiyama, T. In Comprehensive Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH Verlag GmbH & Co.
KGaA, 2013; pp 289−314.
(15) Young, P. R.; Jencks, W. P. J. Am. Chem. Soc. 1979, 101 (12),
3288.
(16) Stein, A. R.; Tencer, M.; Moffatt, E. A.; Dawe, R.; Sweet, J. J.
Org. Chem. 1980, 45 (17), 3539.
K
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(54) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014,
114 (18), 9047.
(86) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc.
1998, 120 (38), 9800.
(55) Zi, W.; Wang, Y.-M.; Toste, F. D. J. Am. Chem. Soc. 2014, 136
(87) Chen, Y. K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc. 2001,
(37), 12864.
123 (22), 5378.
(56) Bobbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006, 4 (11),
2065.
(88) Noyori, R.; Suga, S.; Oka, H.; Kitamura, M. Chem. Rec. 2001, 1
(2), 85.
(57) Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. J. Fluorine
(89) Buono, F.; Walsh, P. J.; Blackmond, D. G. J. Am. Chem. Soc.
Chem. 2007, 128 (5), 469.
2002, 124 (46), 13652.
(58) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108 (9), PR1.
(59) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X. Chem.
Soc. Rev. 2010, 39 (2), 558.
(90) Oestreich, M.; Rendler, S. Angew. Chem., Int. Ed. 2005, 44 (11),
1661.
(91) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005,
(60) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal.
2010, 352 (16), 2708.
44 (25), 3881.
̌
(92) Portada, T.; Roje, M.; Hamersa
2005, 46 (35), 5957.
(93) Dziedzic, P.; Zou, W.; Ibrahem, I.; Sunden
Tetrahedron Lett. 2006, 47 (37), 6657.
(94) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am.
Chem. Soc. 2007, 129 (7), 2130.
̌
k, Z.; Zinic,
́
M. Tetrahedron Lett.
(61) Valero, G.; Companyo,
2018.
́
X.; Rios, R. Chem. - Eur. J. 2011, 17 (7),
́
, H.; Cordova, A.
́
(62) Ye, Z.; Zhao, G. Chimia 2011, 65 (12), 902.
(63) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015,
115 (2), 826.
(64) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130
(1), 46.
(95) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007,
129 (49), 15398.
(65) (a) Although reaction rates were qualitatively greater in the
absence of activated molecular sieves, sieves were included in the
standard reaction conditions as their presence generally resulted in
more reproducible enantioselectivities. Additionally, toluene was used
as the only solvent for operational simplicity. See Supporting
Information for details. (b) For the entirety of this article, we have
defined the result in Figure 1B as the standard enantioselectivity (i.e.,
the (S)-catalyst affords the (S)-product). On the basis of this
convention, the predominant formation of the (R)-product was
considered “negative” when using the (S)-catalyst. Similarly, if use of
the (R)-catalyst results in the (S) enantiomer as the major product,
this result is considered “negative”. This convention was opted as it
better alerts the reader to the fact that the enantioselectivity inversion
is independent of the catalyst enantiomer used (as opposed to the (R)
and (S) terminology).
(66) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44 (45), 7424.
(67) Tiago Menezes Correia, J. Synlett 2015, 26 (03), 416.
(68) Miller, J. J.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47 (4),
771.
(69) Gustafson, J. L.; Sigman, M. S.; Miller, S. J. Org. Lett. 2010, 12
(12), 2794.
(96) Gelalcha, F. G.; Anilkumar, G.; Tse, M. K.; Bruckner, A.; Beller,
M. Chem. - Eur. J. 2008, 14 (25), 7687.
̈
(97) El-Hamdouni, N.; Companyo,
Eur. J. 2010, 16 (4), 1142.
́
X.; Rios, R.; Moyano, A. Chem. -
(98) Li, N.; Chen, X.-H.; Zhou, S.-M.; Luo, S.-W.; Song, J.; Ren, L.;
Gong, L.-Z. Angew. Chem., Int. Ed. 2010, 49 (36), 6378.
(99) Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Angew. Chem.,
Int. Ed. 2013, 52 (7), 2027.
(100) Wang, H.-Y.; Zhang, K.; Zheng, C.-W.; Chai, Z.; Cao, D.-D.;
Zhang, J.-X.; Zhao, G. Angew. Chem., Int. Ed. 2015, 54 (6), 1775.
(101) Tanaka, K.; Iwashita, T.; Yoshida, E.; Ishikawa, T.; Otuka, S.;
Urbanczyk-Lipkowska, Z.; Takahashi, H. Chem. Commun. 2015, 51
(37), 7907.
(102) For further support of this claim, see the Supporting
Information.
(103) A significant positive nonlinear effect was also observed using
4e and o-tolylboronic acid (3p). See the Supporting Information for
details.
(104) Despite its formally “positive” enantioselectivity with p-
tolylboronic acid (3b), Ph-substituted catalyst 4f displayed a nonlinear
effect, as anticipated given its lack of steric bulk proximal to the
phosphate moiety. For a more complete discussion of this experiment,
see the Supporting Information.
(105) It should also be noted that for both of the BA subsets, σ-para
values correlate with selectivity, indicating that asymmetric induction
throughout either set is governed by a substantial resonance
component (σ-meta values were not well-correlated, see Supporting
Information for details).
(70) Jensen, K. H.; Sigman, M. S. J. Org. Chem. 2010, 75 (21), 7194.
(71) Harper, K. C.; Sigman, M. S. Proc. Natl. Acad. Sci. U. S. A. 2011,
108, 2179.
(72) Harper, K. C.; Sigman, M. S. Science 2011, 333 (6051), 1875.
(73) Harper, K. C.; Bess, E. N.; Sigman, M. S. Nat. Chem. 2012, 4
(5), 366.
(74) Harper, K. C.; Sigman, M. S. J. Org. Chem. 2013, 78 (7), 2813.
(75) Harper, K. C.; Vilardi, S. C.; Sigman, M. S. J. Am. Chem. Soc.
2013, 135 (7), 2482.
(76) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6 (2), 1355.
(77) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem.
Soc. 2015, 137 (23), 7290.
(106) Martínez-Aguirre, M. A.; Yatsimirsky, A. K. J. Org. Chem. 2015,
80 (10), 4985.
(107) Tokunaga, Y.; Ueno, H.; Shimomura, Y.; Seo, T. Heterocycles
2002, 57 (5), 787.
(108) Egli, M.; Sarkhel, S. Acc. Chem. Res. 2007, 40 (3), 197.
(109) Singh, S. K.; Das, A. Phys. Chem. Chem. Phys. 2015, 17 (15),
9596.
(78) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108 (9), 2353.
(79) Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H.
B. J. Am. Chem. Soc. 1994, 116 (21), 9430.
(110) Gallivan, J. P.; Dougherty, D. A. Org. Lett. 1999, 1 (1), 103.
(111) Grimme, S. J. Comput. Chem. 2004, 25 (12), 1463.
(112) Amicangelo, J. C.; Gung, B. W.; Irwin, D. G.; Romano, N. C.
Phys. Chem. Chem. Phys. 2008, 10 (19), 2695.
(80) Kagan, H. B.; Girard, C.; Guillaneux, D.; Rainford, D.; Samuel,
(113) Jain, A.; Ramanathan, V.; Sankararamakrishnan, R. Protein Sci.
O.; Zhang, S. Y.; Zhao, S. H.; Ciglic, M. I.; Haugg, M.; Trabesinger-
2009, 18 (3), 595.
Ruf, N.; Weinhold, E. G. Acta Chem. Scand. 1996, 50, 345.
̈
(114) Yang, T.; An, J.-J.; Wang, X.; Wu, D.-Y.; Chen, W.; Fossey, J. S.
Phys. Chem. Chem. Phys. 2012, 14 (30), 10747.
(115) Singh, S. K.; Kumar, S.; Das, A. Phys. Chem. Chem. Phys. 2014,
(81) Heller, D.; Drexler, H.-J.; Fischer, C.; Buschmann, H.; Baumann,
W.; Heller, B. Angew. Chem., Int. Ed. 2000, 39 (3), 495.
(82) Kagan, H. B. Adv. Synth. Catal. 2001, 343 (3), 227.
(83) Kagan, H. B. Synlett 2001, 2001 (Special Issue), 888.
(84) Klussmann, M.; Mathew, S. P.; Iwamura, H.; Wells, D. H.;
Armstrong, A.; Blackmond, D. G. Angew. Chem. 2006, 118 (47), 8157.
(85) Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew. Chem., Int.
Ed. 2009, 48 (3), 456.
16 (19), 8819.
(116) Mondal, S. I.; Dey, A.; Sen, S.; Patwari, G. N.; Ghosh, D. Phys.
Chem. Chem. Phys. 2014, 17 (1), 434.
(117) Ao, M.-Z.; Tao, Z.; Liu, H.-X.; Wu, D.-Y.; Wang, X. Comput.
Theor. Chem. 2015, 1064, 25.
L
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(118) Egli, M.; Gessner, R. V. Proc. Natl. Acad. Sci. U. S. A. 1995, 92
(1), 180.
(119) Korenaga, T.; Tanaka, H.; Ema, T.; Sakai, T. J. Fluorine Chem.
2003, 122 (2), 201.
(120) Gung, B. W.; Xue, X.; Reich, H. J. J. Org. Chem. 2005, 70 (18),
7232.
(121) Gung, B. W.; Zou, Y.; Xu, Z.; Amicangelo, J. C.; Irwin, D. G.;
Ma, S.; Zhou, H.-C. J. Org. Chem. 2008, 73 (2), 689.
(122) Korenaga, T.; Shoji, T.; Onoue, K.; Sakai, T. Chem. Commun.
2009, 31, 4678.
(123) Nijamudheen, A.; Jose, D.; Shine, A.; Datta, A. J. Phys. Chem.
Lett. 2012, 3 (11), 1493.
(124) Pavlakos, I.; Arif, T.; Aliev, A. E.; Motherwell, W. B.; Tizzard,
G. J.; Coles, S. J. Angew. Chem., Int. Ed. 2015, 54 (28), 8169.
(125) Duarte, V. C. M.; Faustino, H.; Alves, M. J.; Gil Fortes, A.;
Micaelo, N. Tetrahedron: Asymmetry 2013, 24 (18), 1063.
(126) Reddi, Y.; Sunoj, R. B. ACS Catal. 2015, 5 (3), 1596.
(127) Mooibroek, T. J.; Gamez, P.; Reedijk, J. CrystEngComm 2008,
10 (11), 1501.
(128) Verloop, A.; Hoogenstraaten, W.; Tipker, J. In Drug Design;
Ariens, E. J., Ed.; Medicinal Chemistry: A Series of Monographs;
̈
Academic Press: Amsterdam, 1976; Vol. 11, Part G, pp 165−207.
(129) Milo, A.; Bess, E. N.; Sigman, M. S. Nature 2014, 507 (7491),
210.
M
DOI: 10.1021/jacs.6b00356
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX