Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer

Article abstract of DOI:10.1021/jacs.6b11367

Enantioselective 1,1-diarylation of terminal alkenes enabled by the combination of Pd catalysis with a chiral anion phase transfer (CAPT) strategy is reported herein. The reaction of substituted benzyl acrylates with aryldiazonium salts and arylboronic acids gave the corresponding 3,3-diarylpropanoates in moderate to good yields with high enantioselectivies (up to 98:2 er). Substituents on the benzyl acrylate and CAPT catalyst significantly affect the enantioselectivity, and multidimensional parametrization identified correlations suggesting structural origins for the high stereocontrol.

Full text of DOI:10.1021/jacs.6b11367

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Communication
Development and Analysis of a Pd(0)-Catalyzed Enantioselective
1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase-Transfer
Eiji Yamamoto, Margaret J Hilton, Manuel Orlandi, Vaneet Saini, F. Dean Toste, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11367 • Publication Date (Web): 22 Nov 2016
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Eiji Yamamoto,†‡⁑Margaret J. Hilton,†⁑Manuel Orlandi,† Vaneet Saini,†‖ F. Dean Toste§ and Matthew
S. Sigman†*
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†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, USA.
§Department of Chemistry, University of California, Berkeley, California 94720, United States
Chemical Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United
States
Supporting Information Placeholder
ABSTRACT: The enantioselective 1,1-diarylation of terminal
alkenes is reported herein enabled by the combination of palla-
dium catalysis with a chiral anion phase-transfer strategy. The
reaction of substituted benzyl acrylates with aryldiazonium
salts and arylboronic acids gave the corresponding 3,3-diaryl
propanoates in moderate to good yields and high enantioselec-
tivies (up to 98:2 er). Substituents on the benzyl acrylate and
chiral anion phase-transfer catalyst significantly affect the en-
antioselectivity, and multidimensional parameterization identi-
fied correlations suggesting structural origins for high stere-
ocontrol.
From the perspective of molecular diversity and step economy,
palladium-catalyzed difunctionalization reactions of alkenes are a
powerful synthetic tool,1 providing rapid access to complex build-
ing blocks, such as the 1,1-diarylalkane motif that is widespread in
numerous natural products and pharmaceuticals.2 In fact, a high-
throughput screen of 1,1-diarylmethines synthesized in our group
led to the identification of a compound, C-6, that is selectively ac-
tive against chemo-resistant breast cancers (Scheme 1a).3 In addi-
tion, compounds containing a 1,1-diarylmethine stereogenic center
are present in a number of drug targets, like CDP8402b and SB-
2096702c (Scheme 1a). Accordingly, developing synthetic methods
to access these compounds in a modular and stereocontrolled man-
ner is of great importance, particularly to accelerate the screening
process and structure-activity relationship studies in drug discovery.
In this context, our group has focused on the development of
Pd(0)-catalyzed three-component coupling of terminal alkenes, ar-
ylboronic acids, and aryldiazonium salts or alkenyl triflates to con-
struct 1,1-difunctionalized products (Scheme 1b).4 Despite the sig-
nificance of enantioenriched 1,1-diarylalkanes, the enantioselec-
Scheme 1. Relevance and overview of the enantioselective 1,1-
difunctionalization of alkenes
tive three-component coupling reaction has remained elusive, since
the desired process is suppressed in the presence of common P- or
N-based chiral ligands.4b To address this problem, the Toste group
recently reported the Pd(0)-catalyzed enantioselective 1,1-aryl-
borylation of terminal alkenes using a chiral anion phase-transfer
(CAPT) strategy (Scheme 1c).5 We envisioned that this approach
would translate well to the enantioselective 1,1-diarylation of al-
kenes due to the similarity in proposed mechanisms. However, the
use of arylboronic acids in place of B2pin2 was projected to involve
several additional complications, including solubility issues as well
as the potential for direct interactions with the chiral anion.6
Mechanistically, the crucial step in the CAPT approach is the
formation of a soluble chiral ion pair between the chiral phosphate
anion and an aryldiazonium cation from the corresponding tetra-
fluoroborate salt that is insoluble under the reaction conditions
(Scheme 1d). Oxidative addition of this chiral ion pair by Pd(0)
generates cationic Pd-aryl intermediate A that, assuming the chiral
anion remains associated, underdoes an enantioselective migratory
insertion of the acrylate alkene, generating Pd-alkyl B. In order to
form the 1,1-diarylated product, the catalyst migrates to C1 via β-
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hydride elimination to form alkene C followed by reinsertion to
scriptors to the reaction outcome.8 As a result, an excellent correla-
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give intermediate D. Stabilized as a π-benzyl species, D undergoes
transmetallation with the second coupling partner and reductive
elimination, releasing the product. Herein, we present the develop-
ment of an enantioselective 1,1-diarylation of benzyl acrylates
providing 3,3-diarylpropanates7 in high enantioselectivity using a
CAPT approach (Scheme 1d). The determination of the best chiral
anion and substrate combination was enabled and analyzed using a
multi-dimensional parameterization8 tactic revealing key insight
into potential remote noncovalent interactions responsible for ef-
fective asymmetric catalysis.
tion was established, relating the measured enantioselectivity to
three parameters derived from a phosphate model system (4, Figure
1). As mentioned previously, chiral anions with 2,6-disubstituted
aryl groups resulted in enhanced enantioselectivity, and in general,
larger dihedral angles (α) correlate with higher enantioselectivity
(Table 1 and Figure S4, R2 = 0.78). The appearance of this term, α,
in the multivariate model reinforces the significance of the arene’s
orientation towards the phosphate group, conceivably allowing for
stabilizing noncovalent interactions with the substrates. Addition-
ally, the symmetric P=O stretch or vPOsy could describe the effect
of the aryl ring substituents on the phosphate’s interaction with the
diazonium and/or palladium counterions. Finally, Sterimol param-
eter B1meta represents the minimum width of the meta-substituents
of the arenes, suggesting substituent size at this position impacts
enantioselectivity.10 While this strategy revealed a potentially pre-
dictive model that could identify a more selective CAPT catalyst,
an inherent limitation concerns the synthetic effort and accessibility
required to examine any predictions. Therefore, we selected the
best-performing chiral anion (2l) in terms of er and redirected our
efforts towards evaluating another modular component in the reac-
tion: the benzyl acrylate substrate.
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Our efforts towards applying this CAPT strategy in an enantiose-
lective 1,1-diarylation reaction were initiated with the examination
of several common BINOL-based chiral phosphoric acids9 (2), in
addition to 1a as substrate and phenyldiazonium salt and 4-hydrox-
yphenyl boronic acid as coupling partners (Table 1). By increasing
the torsion of the aryl groups in 2 with substituents at the 2- and
2,6-positions, a significant increase in er was observed compared
to 3,5- or 4-substituted catalysts (2a-f), all of which also returned
low yields of the desired product (3a). In agreement with this ob-
servation, increasing the size of the substituents at the 2,4,6-posi-
tions from methyl (2i) to isopropyl (2j) to cyclohexyl (2k) led to
increasing er values as well as increased yields. Finally, the ex-
tended π-system, 9-anthracenyl (2l), afforded the highest enanti-
oselectivity although slightly lower yields were observed due to a
higher percentage of traditional Heck product formation. Control
experiments demonstrated that no desired product was observed
when hexane was used as solvent (entry 13), and lower enantiose-
lectivity resulted when the reaction was conducted in THF, in
which the diazonium salt is soluble (entry 14).
Table 1. Evaluation of Chiral Anion Phase-Transfer
(CAPT) catalysts and solventsa
Figure 1. Multidimensional Correlation of Chiral Anion Parame-
ters with Enantioselectivity.
Aligning with our goals to not only optimize this reaction but
also understand the influences on enantioselectivity, benzyl acry-
lates provided an exciting advantage in that a diverse library could
easily be generated from the corresponding benzyl alcohols for a
broad survey of substituent effects. Therefore, a set of substituted
benzyl acrylates was designed to include electron-withdrawing and
–donating substitutions in single, multiple and varying positions
(Figure 2a,b). After evaluating a number of these benzyl acrylates
in combination with phosphate 2l, a significant effect of both the
substituents’ identity and position on the arene was revealed (a
range of ~2 kcal/mol). As the benzyl group is distal from the site of
reaction, these non-intuitive observations support our hypothesis
that attractive noncovalent interactions between the benzyl group
and the chiral anion are controlling elements in the stereodefining
step. The use of substrates 1d (2-OMe), 1f (3,5-Me2), and 1g (3-
Me) with electron-donating substituents resulted in similar levels
of enantioselectivities to that of benzyl acrylate 1a. Conversely,
several additional electron-donating substitutions and two ex-
tended-π systems (1h 2-Naph, 1i 3-OMe, 1k 1-Naph, 1m 3,5-
(OMe)2, 1n 3,4,5-(OMe)3) exhibited higher enantioselectivities
compared to 1a. Adding a substituent at the 4-position did not have
a significant effect on the enantiodetermining step (compare 1m
and 1n). Finally, good to excellent enantioselectivities were ob-
served when electron-deficient substrates were used (1j 3,5-F2, 1l
2-CF3, 1o 3-NO2, 1p 3,5-(CF3)2, 1q 3,5-Cl2, or 1r 3,5-Br2). Seren-
dipitously, both 1q and 1r resulted in the highest enantioselectivity
(98:2 er). In contrast, substrates 1b (2,6-Cl2) and 1c (2,4,6-F3),
which contain electronegative atoms at the 2,6 positions, provided
the desired product in the lowest er values, emphasizing the posi-
tional requirement of a electron withdrawing group on enantiose-
lectivity and thus highlighting the potential for noncovalent inter-
actions between the benzyl group and the CAPT catalyst. In order
aReactions were performed on 0.1 mmol scale of 1a in solvent (2
mL) at 20 °C for 20 h and were repeated twice. bYields were deter-
mined by 1H NMR of the crude reaction mixture using an internal
standard. cEnantiomeric ratios were determined by SFC. dTorsion
(α) was calculated using phosphate model system 4.
In order to gain further insight into the effect of the chiral anion
substitution pattern on enantioselectivity and perhaps predict a
more selective CAPT catalyst, we applied our multidimensional pa-
rameterization technique, which correlates relevant molecular de-
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to understand these diverse effects, additional studies were initiated,
stacking interaction.15 Additional detailed studies are underway to
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focusing on relating the substituents effects to the observed enanti-
oselectivities.
elucidate the subtle effects on enantioselectivity in this complex
system and to identify specific attractive interactions.
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Table 2. Examination of the aryl diazonium salt and boronic
acid scope.
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Figure 2. Evaluation and Correlation of Benzyl Acrylate Substitu-
ent Effects on Enantioselectivity.
The same multidimensional parameterization technique was ap-
plied to correlate various molecular descriptors of the benzyl acry-
lates to the measured enantioselectivity. During this process, we
observed a trend between the average NBO charge of the atoms at
the 2,6-positions and the measured ∆∆G‡ values (Figure 2c).11 Due
to the significant difference in charge between a halogen and a hy-
drogen, we were not surprised to observe that substrates 1b and 1c
are outliers in this simple relationship. Nonetheless, this insight
could suggest that the 2,6-hydrogens themselves play a role in cat-
alyst recognition, and electron-deficient hydrogens lead to a more
selective process.12 Although this parameter could solely represent
the electronic contribution from the benzyl acrylates’ substituents,
it was also a significant term in the multivariate model, supporting
its descriptive power of the benzyl acrylate’s effect on enantiose-
lectivity (1b, 1c, and 1e were removed from the training set, Figure
2d). Combining NBO26H (average NBO charge of the 2,6-hydro-
gens11) with three additional terms, two stretching frequencies and
the acrylate’s mean polarizability, provided an excellent correlation
between the measured and predicted ∆∆G‡ values. As IR vibrations
are sensitive to changes in electronic nature and mass, νring 3 and
νCH2 scissor likely account for these effects resulting from the various
benzyl groups’ substituents.13 Finally, we have previously used po-
larizability as a parameter to propose a substrate-ligand lone pair-π
interaction in a Pd-catalyzed redox relay Heck reaction14; therefore,
we interpret this variable similarly. Overall, the results from this
multidimensional correlation are consistent with our hypothesis
that noncovalent interactions are occurring between the benzyl
acrylate and the anthracenyl group on the phosphate, such as a π-
aIsolated yields after purification. bEnantiomeric ratios were deter-
mined by SFC.
Finally, the scope of the reaction was evaluated using the optimal
chiral anion, 2l, and 3,5‐dichlorobenzyl acrylate, 1q.16 Overall, ex-
cellent enantiomeric ratios are observed in moderate yields. Lower
yields are observed due to the competitive formation of the tradi-
tional Heck product. Nonetheless, both electron‐rich and -poor ar-
yldiazonium salts are well‐tolerated under the optimized reaction
conditions with electron‐withdrawing substituents (3u and 3v)
leading to slightly lower enantioselectivities. As boronic acids are
known to interact directly with phosphates,6 it was hypothesized
that compatibility between these two components may be an issue
for the boronic acid scope. This was not foreseen as a detriment
since the boronic acid could easily be exchanged with the corre-
sponding diazonium salt. In general, we observed that electron‐rich
arylboronic acids performed best in this chemistry, leading to
higher yields likely due to the increased rate of transmetallation
compared to electron-poor arenes. Of note, 2-naphthyl (3ad) and 5-
indole (3ae) groups were incorporated in 95:5 and 94:6 er, respec-
tively, albeit in low yields. Additionally, 3af was synthesized in
high enantioselectivity (98:2 er), which is a relevant building block
en route to the drug target CDP840 (Scheme 1a).2b Although a lim-
itation of this methodology lies in the reaction yields, the modular-
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Leonard, J.; Morphy, R.; Wales, M.; Perry, M.; Allen, R. A.; Gozzard,
ity of the coupling partners and step economy in this three-compo-
nent coupling reaction can compensate for these limitations. Addi-
tional studies aim to overcome the competitive Heck reaction via
exploration of different combinations of benzyl acrylates and chiral
phosphoric acids as this pathway is also sensitive to the identity of
these two species (Table S1).
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In conclusion, we have developed an enantioselective three-
component coupling reaction of benzyl acrylates, aryldiazonium
salts and arylboronic acids, providing a modular approach to the
synthesis of 1,1-diarylated products in high enantioselectivity. The
key to a highly selective process was realized by utilizing a chiral
anion phase-transfer strategy, wherein enantioselectivity was
closely tied to the identity of the CAPT catalyst. Additionally, er
values were surprisingly sensitive to the electronic and steric nature
as well as the position of substituents on the benzyl acrylate sub-
strate. We applied a multidimensional modeling technique to reveal
specific properties of the CAPT catalyst and the acrylate that may
be responsible for the observed range in enantioselectivity. These
results suggest that attractive noncovalent interactions, such as a π-
stacking interaction, between the two components are controlling
elements in the enantiodetermining step. Future studies include fur-
ther exploration of these putative interactions in order to understand
the origin of enantioselectivity and facilitate the improvement and
expansion of this and other reactions in development.
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Chem. Int. Ed. 2010, 49, 2750; (h) Xue, F.; Wang, D.; Li, X.; Wan, B.
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ASSOCIATED CONTENT
Experimental procedures and modeling and characterization data
can be found in the supporting information. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(8) Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. Acc. Chem. Res.
2016, 49, 1292.
(9) For structure-function analysis of BINOL-derived phosphoric acids,
see: (a) Reid, J. P.; Goodman, J. M. J. Am. Chem. Soc. 2016, 138, 7910.
(b) Reid, J. P.; Simón, L; Goodman, J. M. Acc. Chem. Res. 2016, 49,
1029.
(10)(a) Verloop, A. In Drug Design; Ariens, E. J., Ed.; Academic Press:
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macochem. Libr. 1977, 2, 63. (c) Verloop, A.; Tipker, J. Pharmaco-
chem. Libr. 1987, 10, 97. (d) Harper, K. C.; Bess, E. N.; Sigman, M. S.
Nature Chem. 2012, 4, 366.
(11)For substrates 1d, 1k, and 1l the NBO charge of the 2-hydrogen only
was considered. For 1e, the average NBO charge of the methyl hydro-
gens were included since these are most accessible compared to the
carbons. Thus, these hydrogens would likely represent a potential site
for a noncovalent interaction to occur.
(12)Hydrogen-bonding interactions of highly polar ortho-C-H bonds in 3,5-
bis(CF3)phenyl group in thiourea catalysts are known to be involved in
a variety of organocatalytic reactions. For selected examples, see: (a)
Okino, T., Yasutaka, H., Furukawa, T., Xu, X. Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119; (b) Berkessel, A.; Cleemann, F.; Mukher-
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K.; Gerbig, D.; Ley, D.; Hausmann, H.; Guenther, S.; Schreiner, P. R.
Eur. J. Org. Chem. 2012, 30, 5919.
(13)Milo, A.; Bess, E. N.; Sigman, M. S. Nature 2014, 507, 210.
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(15)(a) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979. (b)
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*sigman@chem.utah.edu
⁑E.Y. and M.J.H. contributed equally.
‡Department of Chemistry, Graduate School of Science, Kyushu
University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
‖Novartis Institute for Biomedical Research, Cambridge, Massa-
chusetts 02139, United States
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
The synthetic aspects were supported by National Institute of
Health (R01GM063540), and the modeling was supported by NSF
(CHE-1361296). E.Y. was supported by a Grant-in-Aid for JSPS
Fellows (JSPS KAKENHI, grant number: 26·2447). M.O. thanks
the Ermenegildo Zegna Group for a post-doctoral fellowship. We
gratefully acknowledge the Center for High Performance Compu-
ting (CHPC) at the University of Utah. We would like to thank Anat
Milo and Andrew J. Neel for insightful discussions and sharing
CAPT catalysts with us.
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J. A.; Reuberson, J. T.; Hutchinson, B.; Turner, P.; Boyce, B.; Barnes,
D.; Mason, B.; Cannell, A.; Taylor, R. J.; Zomaya, A.; Millican, A.;
(16)As these substrates demonstrated the same selectivity with the model
system, 1q was chosen over 1r due to lower cost.
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