Configuration Sampling With Five-Membered Atropisomeric P,N-Ligands

Article abstract of DOI:10.1002/anie.202102642

Here we report a strategy for the systematic variation of atropisomeric C₁-symmetric P,N ligands to incrementally change the position of the groups within the chiral pocket without modifying their steric parameters. More specifically, the effec

Full text of DOI:10.1002/anie.202102642

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How to cite:
International Edition: doi.org/10.1002/anie.202102642
German Edition: doi.org/10.1002/ange.202102642
Configuration Sampling
Configuration Sampling With Five-Membered Atropisomeric P,N-
Ligands
Gaurav Dahiya, Mukesh Pappoppula, and Aaron Aponick*
Abstract: Here we report a strategy for the systematic variation
of atropisomeric C1-symmetric P,N ligands to incrementally
change the position of the groups within the chiral pocket
without modifying their steric parameters. More specifically,
the effects of systematic modification of the nitrogen hetero-
cycle in atropisomeric C1-symmetric stack ligands have been
investigated in this study. The versatility and applicability of
this approach has been demonstrated in mechanistically
distinct catalytic enantioselective transformations, resulting in
the identification of a P,N-ligand for a highly enantioselective
synthesis of organoboranes.
E
nantioselective catalysis offers a powerful method for the
preparation of chiral molecules and methods development in
this area is continuous. Among the diverse spectrum of
catalysts, transition metal complexes have held a prominent
position, often relying on new ligand classes for advancement.
It is well known that subtle electronic and steric differences in
structure as well as minute conformational changes can
drastically influence reaction outcomes with regard to both
reactivity and selectivity.[1] Many of the most successful ligand
classes feature somewhat rigid chiral backbones with C2-
symmetry that reduces the number of degrees of freedom in
catalytic steps.[2] Of particular importance are C2-symmetric
bisphosphines such as BINAP.[3] As illustrated in Figure 1, the
atropisomeric biaryl backbone sets a “twist” that establishes
the chiral environment about the metal center by positioning
the aryl groups in an arrangement represented as a quadrant
diagram.[4] Modifications to the backbone can influence
catalysis in many ways, but one consequence is that changes
to the biaryl dihedral angle are transmitted to the chiral
environment about the metal-center and effectively change
the location of the aryl groups within the quadrants in the
stereodetermining transition state.[3b] Zhang has nicely dem-
onstrated this effect with systematic studies on TunePhos
ligands.[5]
Figure 1. Sampling chiral space in C1-symmetric atropisomeric P,N-
ligands.
ligands the pendant groups that define the chiral pocket can
be substituted to modulate their steric parameters, but one of
the key substituents (see R in Quinazolinap, Figure 1) is part
of the carbon backbone and identifying a ligand suitable for
a particular methodology can present a daunting challenge.
For example, Guiry reported utilizing axially chiral P,N-
ligands in the copper-catalyzed b-borylation of a,b-unsatu-
rated esters.[7] Although ligand modification effectively
changed the steric demand, low to moderate enantioselectiv-
ities were observed (Figure 1), the highest of which were
observed with the smallest R-group, R = H, in Quinap. It is
evident that the steric parameters are important, and
presumably the position of these groups is relatively constant
within this ligand family. Considering the differences between
atropisomeric C2- and C1-symmetric ligands, it occurred to us
that atropisomeric 5-membered heterocyclic ligands might
offer a platform to study the effect of changing the position of
the substituent on the ligand in addition to its size and this
may offer a selection of ligands with incremental changes
based on conformation/configuration. Shown schematically in
Figure 1, the axial chirality can be held constant in our stack
ligands[8] and the steric environment modified in an incre-
mental manner. This would allow for the phenyl group to be
In contrast, C1-ligands are also extremely successful and
P,N-ligands represent a class with broad utility.[6] Despite this,
the reduced symmetry and oftentimes inherent conforma-
tional flexibility makes it challenging to introduce incremen-
tal changes that parallel C2-ligands. With atropisomeric P,N-
[*] G. Dahiya, M. Pappoppula, Prof. A. Aponick
Florida Center for Heterocyclic Compounds & Department of
Chemistry, University of Florida
Gainesville, FL 32611 (USA)
E-mail: aponick@ufl.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102642.
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Scheme 1. Preliminary studies on ligand configuration sampling. See the Supporting Information for reaction conditions.
positioned towards the metal in A, away in C, and midway
with B. The ability to modify the chiral pocket in this manner
is somewhat unique to our ligands due to the 5-membered
imidazole/imidazoline moiety;[9] and, to the best of our
knowledge, no other atropisomeric ligands exist where the
same types of modifications and comparisons can be made.
At the outset, we would need to determine the potential
for this approach to be broadly applicable. In this regard,
different reactions were screened as a proof-of-concept and
we began by exploring copper-catalyzed enantioselective
alkynylation of silyloxybenzopyrylium ions to form 3 (Sche-
me 1a).[10] Ligands L1,[8e,h] L2,[8a] and L3[8e] (Scheme 1d)
should systematically change the position of the phenyl
groups in the chiral pocket while holding the identity of the
groups, and thus the inherent steric demand of these groups,
constant. In this reaction, our StackPhos ligand L2 proved
optimal and afforded 3 in 89% yield and 94% ee.[10] With
StackPhim L1, which would be predicted to be the most
hindered of these ligands, the product was obtained in 96%
yield but the selectivity was reduced to 74% ee. Interestingly,
moving the phenyl group further away with (Ra,R,R)-Stack-
Phim, ent-L3, the selectivity was 86% ee. It should be noted
that ent-L3 was used because it is prepared from the same
chiral diamine as L1. Opposite enantiomers of the product
were obtained using L1 and ent-L3, confirming that the chiral
axis dictates which enantiomer of product is formed. These
results support the idea that the backbone configuration is of
vital importance and that the position of the phenyl sub-
stituents serve as a fine-tuning element.
me 1b).[11] A significant increase in reactivity was observed as
the position of the phenyl group on the ligand was moved
from proximal to distal and L1 provided the chiral amine 4 in
16% yield, L2 in 80%, and ent-L3 in 78% yield. The
enantioselectivity also followed a similar trend, with 92%,
94%, and 96% ee and opposite enantiomers of 4 were
observed with L1 and ent-L3, again confirming the role of
axial chirality in controlling configuration. These results
suggest that this strategy could potentially be used to identify
ligands for transformations where the selectivity appears to
have reached a plateau after changing the steric parameters in
the typical manner and hopefully, understanding how to
overcome limitations would facilitate new advances with this
class of ligands.
Since utilizing stack ligands L1–L3 may offer an alter-
native tuning manifold, we decided to study the copper-
catalyzed enantioselective b-borylation highlighted in
Figure 1.[12] It should be noted that various ligand types
(bisphosphines: Josiphos,[13] QuinoxP*,[14] Taniaphos;[15]
NHCs;[16] and other planar chiral ligands[17]) are effective
here, but P,N-ligands have been less fruitful and this reaction
would offer a good stress test of the approach. Considering
these data, borylation of methyl cinnamate with B2pin2 was
selected for a configuration sampling screen (Scheme 1c). In
the event, (Sa,R,R)-StackPhim L1 gave 6a in 34% isolated
yield but in a mere À12% ee. With L2, the reactivity increased
to 46% but with no selectivity. Gratifyingly, a quite significant
improvement was observed when ent-L3 was employed and
the product was isolated in 78% yield and 91% ee. This
marked improvement with excellent enantioselectivity is
consistent with the notion that the placement of the sub-
Further experiments probing the ligand configuration
sampling effects centered on the A3-coupling reaction (Sche-
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Table 1: Substrate scope.[a]
stituents (phenyl groups in these ligands) can have a tremen-
dous impact, but the magnitude of the effect here was
unexpected. The increase in reactivity from L1 to L3 seems to
be related to sterics in the chiral pocket as L1 would be
predicted to be the most hindered and gives 6a in low yield,
while improvements are observed for L2 and ent-L3 where
the phenyl group would be further out. These results are
consistent with the idea that there is an optimal position for
the phenyl group that defines the chiral pocket, as outlined in
Figure 1, and that this small set of ligands can be used to
sample chiral space to overcome present limitations with
atropisomeric P,N-ligands such as this b-borylation reaction.
From this point, further condition optimization is still possible
and this strategy could be used prior to embarking on an
intensive ligand modification program whereby congeners
with a variety of different substituents with modified steric
and electronic properties are prepared and screened.
To this end, a brief optimization was undertaken and these
studies revealed that the proton source had significant impact
on the reactivity and enantioselectivity (see the Supporting
Information). It was found that toluene was beneficial, and
finally, an increase in the amount of boron reagent with
ethanol as an additive gave 6a in excellent yield (95%) and
enantioselectivity (96%), leading to the optimal conditions
shown in Scheme 1e. In the reactions screened above, based
on the absolute configuration of the products, we describe the
necessity of axial chirality and emphasize that the relative
placement of pendant substituents impacts the magnitude of
the observed selectivity. While L2 contains axial chirality but
not point chirality, a control experiment with point- but not
axial chirality is also central to our premise and a control
experiment with the optimized conditions was carried out
using L4 (no axial chirality) for direct comparison with ent-L3
(both axial and point chirality).[8e] With L4, 6a was obtained in
20% ee, which is in stark contrast to 96% ee with ent-L3
(Scheme 1e). These data indicate that, although the dihedral
angle is not constrained and L4 can assume a “twist”, axial
chirality is extremely important to achieve high enantiose-
lectivity whereby this constraint seems to fix the position of
substituents in L3 and this structural feature is extremely
important for enantioselectivity, thus differentiating these
ligands from more standard Phim-ligands such as L4.
With conditions established, the scope was explored, and
it was found that the reaction tolerates a variety of substitu-
ents on the b-substituent (Table 1). Electron donating- and
withdrawing- substituents and various halides produced 6b–f
in high yield and excellent enantioselectivities, all > 90% ee.
Ortho-, meta-, and para-alkyl substituents afforded 6g–i in
high enantioselectivities, 92% ee, 92% ee and 95% ee. The
reaction proceeded smoothly for heterocycles like furan and
thiophene, giving the corresponding products 6j and 6k in
high yield and ee. Fused ring systems were also compatible
yielding 6l and 6m in 91% ee and 90% ee, respectively. 6j and
6l were found to decompose during purification and were
oxidized to corresponding alcohols without purification. It
was demonstrated that Weinreb amide 6n, ketones 6o–q, and
alkene-bearing substrate 6r were also functional under the
reaction conditions, although the eeꢀs were slightly lower.
[a] Isolated yield. [b] Isolated yield of alcohol after oxidation. [c] 10 mol%
catalyst loading, 1.1 equiv of B2pin2, solvent=THF. [d] TFE instead of
EtOH.
Interestingly,
a reduction in enantioselectivity was
observed when the reaction conditions were applied to
a crotonate and 6s was obtained in 85% yield and 64% ee.
It should be noted that, in addition to an b-alkyl substituent,
6s contains a benzylic ester (as a chromophore for analysis).
6t was synthesized for a direct comparison with its methyl
counterpart and the high enantioselectivity (92% ee) suggests
that the b-aryl to b-alkyl switch has a dramatic impact on
selectivity. While the specific reaction is not the focus here,
ligand modification could also be explored as a next step that
could provide a complementary strategy for more extensive
optimization.
To further probe differences in selectivity imparted by
these ligands, an additional series of experiments was
performed using L1–L3 with the goal of examining a cascade
reaction building from the borylation.[18] As can be seen in
Scheme 2, the sequence involves borylation followed by an
aldol reaction, forging a new bond from the a-position to
a pendant aldehyde and resulting in the formation of the
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Scheme 2. Ligand screen for a tandem borylation aldol sequence.
indane 8 with three new stereocenters. While the diastereo-
selectivity in each of these reactions was reasonably high,
both the yield and ee trended upwards across the ligand set
and 8 was obtained in 72% yield with 90% ee using ent-L3.
These results suggest that the approach outlined in Figure 1
can be extended to complex systems and could be a useful
tool in developing new asymmetric transformations.
Further experiments were focused on gaining insight into
the selectivity differences between ligands using non-linear
effect studies. It is well-known that axially chiral P,N-ligands
typically exhibit strong non-linear behavior characteristic of
L2M2 catalysts.[19] To this end, a series of experiments using
mixtures of L1 and ent-L3 were performed. Strikingly, the
expected sigmoidal-shaped curve was not observed, and ent-
L3 outperformed L1 at every point a mixed system was
employed (Figure 2a). This strong nonlinear behavior sug-
gests that the catalyst formed from ent-L3 is much more
highly competent[20] and a 1:1 mixture of L1 and ent-L3 (0%
de) gave the product in the same ee as pure ent-L3.
Considering observations with other state-of-the-art atropi-
someric P,N-ligands,[19] the active catalyst may be higher
order, and this would complicate the central premise of this
work. To probe this, nonlinear effect studies were performed
using L3/ent-L3 (Figure 2b), but these data show a linear
correlation and suggest that a monomeric complex is the
active catalyst- a significant difference from the venerable
QUINAP-type ligands.
In this study, we report a strategy for the systematic
variation of atropisomeric C1-symmetric P,N-ligands to incre-
mentally change the position of the groups within the chiral
pocket without modifying the steric parameters inherent to
the substituents. The use of a small series of stack ligands as
probes to sample chiral space is demonstrated and applied to
mechanistically distinct reactions. This ligand chemotype
works well for alkyne addition reactions where the enantio-
selectivities varied from moderate to excellent, yet two
different ligands demonstrated the highest enantioselectiv-
ities despite their significant structural homology otherwise
(Scheme 1a,b). This range of substituent-conformation/con-
figuration variation exerts a significant influence over the
chiral pocket and, by exploiting these differences, a P,N-
ligand exhibiting high levels of enantioselectivity for the b-
Figure 2. a) NLE using StackPhim diastereomers L1 and ent-L3 (100%
de corresponds to pure ent-L3 and À100% de corresponds to pure
L1); b) NLE using the enantiomers L3 and ent-L3 of StackPhim (100%
ee corresponds to pure ent-L3). See SI for full details.
borylation of a,b-unsaturated esters was uncovered. Mecha-
nistic studies examining non-linear effects reveal a linear
correlation, suggesting that a monomeric catalyst is formed,
consistent with our M1L1 hypothesis in Figure 1. Remarkably,
two of the three ligands screened exhibited poor enantiose-
lectivity, while the third was very high, highlighting the idea
that these changes can facilitate the identification of suitable
ligands prior to extensive condition screening or ligand
modification, which could be used to access ligands that
sample the chiral space between those prepared here. In
a general sense, this set of P,N-ligands is predicted to be
a useful screen to assess the necessity of axial chirality and the
steric requirements for C1-symmetric atropisomeric P,N-
ligands, paralleling the type of screening that can be done
with their C2-symmetric counterparts. Further applications of
this approach are currently underway and will be reported in
due course.
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The authors thank the University of Florida and The National
Science Foundation (CHE-1900299) for their generous sup-
port of our programs. Mass spectrometry instrumentation was
supported by a grant from the National Institutes of Health
(S10 OD021758-01A1).
Conflict of Interest
[9] Strictly diastereomeric ligand sets have been studied previously.
For a recent example see: R. A. Arthurs, D. L. Hughes, C. J.
Richards, J. Org. Chem. 2020, 85, 4838 – 4847, and references
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The authors declare no conflict of interest.
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Keywords: atropisomers · borylation · configuration sampling ·
incremental change · stack ligands
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Manuscript received: February 21, 2021
Revised manuscript received: May 3, 2021
Accepted manuscript online: July 1, 2021
Version of record online: && &&, &&&&
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Communications
Configuration Sampling
G. Dahiya, M. Pappoppula,
A. Aponick*
&&&& — &&&&
Configuration Sampling With Five-
Membered Atropisomeric P,N-Ligands
The utility of a small series of atropiso-
meric, C1-symmetric P,N-ligands that
incrementally change the position of the
groups within the chiral pocket is
reported. This enables sampling of chiral
space without modifying the steric
parameters of the substituents. As
a demonstration of the utility, using this
small series of stack ligands, a P,N ligand
was identified for the enantioselective b-
borylation of Michael acceptors.
6
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