Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C?H Arylation

Article abstract of DOI:10.1002/anie.201806527

Atropo-enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo-enantioselective palladium(0)-catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio-determining CMD to yield configurationally stable eight-membered palladacycles.

Full text of DOI:10.1002/anie.201806527

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Accepted Article
Title: Axially Chiral Dibenzazepinones via a Pd(0)-Catalyzed Atropo-
enantioselective C-H Arylation
Authors: Nicolai Cramer, Christopher G. Newton, Elena Braconi,
Jennifer Kuziola, and Matthew D. Wodrich
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806527
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Axially Chiral Dibenzazepinones via a Pd(0)–Catalyzed Atropo-
enantioselective C–H Arylation
Christopher G. Newton,[a] Elena Braconi,[a],‡ Jennifer Kuziola,[a],‡ Matthew D. Wodrich[b] and Nicolai
Cramer[a]*
Abstract: Atropo-enantioselective C–H functionalization reactions
are largely limited to the dynamic kinetic resolution of biaryl
substrates through the introduction of steric bulk proximal to the axis
of chirality. Herein we report
a highly atropo-enantioselective
palladium(0)-catalyzed methodology that forges the axis of chirality
during the C–H functionalization process, enabling the synthesis of
axially chiral dibenzazepinones. Computational investigations
support experimentally determined racemization barriers, while also
indicating C–H functionalization proceeds via an enantio-determining
CMD to yield configurationally stable 8-membered palladacycles.
Scheme 1. Palladium-catalyzed atropo-enantioselective C–H functionalization
strategies towards axially chiral biaryls.
A wide range of natural products[1] and pharmaceuticals[2] exhibit
Our laboratory has
a long-standing interest in the
restricted rotation about
a biaryl axis, often resulting in
development and application of chiral ligand families, particularly
for enantioselective C–H functionalization.[11] Recent reports
have demonstrated that under Pd(0)/Pd(II) catalysis, TADDOL-
differences in biological activity between each stereoisomer.
This stereogenic element is also immensely important in the field
of asymmetric catalysis, where it commonly serves as the sole
source of enantiocontrol.[3] Surprisingly, relatively few atropo-
enantioselective approaches towards axially chiral biaryls from
achiral precursors have been reported. The most common
strategies include biaryl desymmetrization, de novo synthesis of
an aromatic ring, in-situ point-to-axial chirality transfer, or
transition-metal catalyzed cross-coupling of functionalized
organometallics.[4] Enantioselective C–H functionalization
reactions have emerged as a powerful tool for the rapid
generation of structural complexity.[5] Within this field, high levels
of enantiocontrol have been demonstrated for the synthesis of
both point, and planar chiral molecules, across several
mechanistically disparate processes.[5e] However, atropo-
enantioselective approaches towards axially chiral molecules
remain rare, likely as a result of competitive racemization under
the typically elevated reaction temperatures. Nevertheless, a
small number of examples have been reported, mainly
derived
phosphorus(III)
ligands
can
facilitate
C–H
functionalization under very mild conditions.[6b,12,13] Given these
advancements, coupled with the importance of biaryl
atropisomers, we became interested in the development of
atropo-enantioselective C–H arylation strategies for the
synthesis of configurationally sensitive targets. In particular,
axially chiral dibenzazepinones represent an underexplored
pharmacophore, especially when considering the prevalence of
related benzazepinone and dibenzodiazepine containing
drugs.[14]
Although
both
achiral
and
point
chiral
dibenzazepinones with potent biological activity are known
(Figure 1),[15] enantioselective routes towards derivatives bearing
exclusively an axis of chirality have yet to be disclosed.[16] Herein
we report the realization of such a strategy via a palladium(0)-
catalyzed intramolecular C–H arylation of achiral amides.
proceeding via directed C–H functionalization ortho to
a
preformed biaryl axis (Scheme 1a).[6,7] In contrast, effective
control of atropo-enantioselectivity, whilst simultaneously forging
the axis of chirality, appears inherently more challenging
(Scheme 1b).[8–10] To date, only two substrates have been
prepared under Pd catalysis via this approach (72 % ee and
27 % yield).[8]
Figure 1. Biologically active dibenzazepinones.
[a]
Dr. C. G. Newton, E. Braconi, J. Kuziola, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
Dr. M. D. Wodrich
Laboratory for Computational Molecular Design
EPFL SB ISIC LCMD, BCH 5121
1015 Lausanne (Switzerland)
Early scouting experiments in the laboratory were guided by
computational prediction of product racemization kinetics.
Ultimately, amide 1a bearing a methyl substituent ortho to the
aryl-bromide functionality was identified as a promising lead for
intramolecular cyclization (Table 1). Despite the sterically
crowded nature of the reaction center, dibenzazepinone 2a
[b]
[‡]
These authors contributed equally to this work.
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For 15 h. [d] 0.10 mmol scale, with K2CO3 for 10 h. [e] Isolated yield.
could be accessed in good yield and enantioenriched form after
heating in the presence of a palladium(0) source, and TADDOL-
derived phosphoramidite L1 (er 74:26, entry 1). Given the
potential for erosion of enantiopurity over the course of reaction
(half-life of 2a determined to be 46 hours at 80 °C), optimization
studies were conducted with incomplete conversion to compare
reaction rates. Initial ligand screening focused on phosphorus
substitution, confirming the superiority of the NMe2-group over
larger phosphoramidite (entries 2–3), and phosphonite (entry 4)
derivatives. With respect to aryl-substitution, a similar trend was
observed, and phenyl-substituted L5 outperformed bulkier aryl
analogues, providing the target in an improved er of 86:14
(entries 5–7). A brief acid screen highlighted the importance of
this cocatalyst for both reactivity and enantioselectivity (entry 8),
and a notable improvement in enantiocontrol could be observed
with the introduction of aromatics on the acid backbone (entries
9-10). Some chiral carboxylic acids, eg (R)- and (S)-2-
phenylpropanoic acid and protected phenylalanines, were
screened but gave inferior results. Reducing the reaction
temperature to 60 °C provided a modest increase in er (entry 11),
and finally, exchanging Cs2CO3 for K2CO3 increased the rate of
reaction, allowing isolation of 2a in 91% yield and 94:6 er after
10 hours (entry 12).
We next explored the scope of the transformation (Scheme 2).
Interestingly, the introduction of electron donating substituents
on the aniline-derived moiety, such as in methoxy derivative 2b
and silyl-protected analogue 2c, greatly enhanced product
configurational stability without impacting enantioselectivity. In
the latter case, an increased palladium loading was necessary
for complete conversion, presumably as a consequence of
increased steric bulk near the site of functionalization. This trend
also held true for isopropyl-derivative 2d, however in this case a
reduction in enantioselectivity was also observed. Electron poor
substrate 2e, bearing an aryl-trifluoromethyl substituent, reacted
smoothly to provide the target in 84% yield and 95.5:4.5 er. As
anticipated, the importance of steric bulk adjacent to the biaryl
linker was confirmed through preparation of configurationally
labile 2f.
Table 1. Ligand screening and reaction optimization[a]
Entry
L#
Acid
T [°C]
Yield (Conversion) [%][b]
er
1
2
L1
L2
L3
L4
L5
L6
L7
L5
L5
L5
L5
L5
PivOH
PivOH
80
80
80
80
80
80
80
80
80
80
60
60
70 (85)
71 (80)
60 (68)
7 (29)
74:26
70:30
51:49
–
3
PivOH
4
PivOH
5
PivOH
71 (87)
46 (95)
90 (92)
24 (52)
48 (72)
74 (89)
77 (88)
91[e] (100)
86:14
75:25
77:23
57:43
87:13
91:9
6
PivOH
Scheme 2. Scope of atropo-enantioselective C–H arylation: 0.1 mmol 1, 10
mol% Pd(dba)2, 20 mol % L5, 30 mol% Ph2MeCCO2H, 150 mol% K2CO3, 0.25
M in mesitylene, 60 °C, 10 h; isolated yields. [a] With 20 mol% Pd(dba)2. [b]
Determined by 1H NMR. [c] 2.38 mmol 1l, 5 mol% Pd(dba)2, 10 mol % L5, 20
mol% Ph2MeCCO2H, 150 mol% K2CO3, 0.5 M in mesitylene, 60 °C, 14 h. [d]
At 90 °C.
7
PivOH
8
–
9
(Ph)3CCO2H
(Ph)2MeCCO2H
(Ph)2MeCCO2H
(Ph)2MeCCO2H
10
11[c]
12[d]
93:7
Introduction of a smaller N–Me substituent was detrimental for
reactivity (2g), however enantiocontrol remained markedly high
(98:2 er). The functional group tolerance of the reaction was
further demonstrated through screening a range of para-
substituted benzyl derivatives derived from 2-naphthylamine
94:6
[a] 0.05 mmol of 1a, 10 mol% Pd(dba)2, 20 mol% L#, 30 mol% acid, 150 mol%
Cs2CO3, 0.25 M in mesitylene at 80 °C for 4 h. [b] Determined by 1H NMR. [c]
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(2h–2l). Both electron-rich and electron-poor substrates
furnished the corresponding cyclic products in good yields, with
little impact on enantioselectivity or product stability. Notably,
aryl-chloride 2l proved to be a competent substrate, and no
evidence for competitive oxidative-addition was observed. In this
case, the reaction could be conducted on gram-scale, allowing
for a reduction in palladium, ligand, and acid loading, while still
maintaining a high yield and enantioselectivity (88%, 97:3 er,
1.21 g isolated). Moreover, the absolute configuration of the
biaryl axis present in 2l was confirmed through single crystal X-
ray analysis, and found to be S.[18] In the interest of accessing
more structurally diverse dibenzazepinones, we explored the
effect of reducing the number of equivalent phenyl substituents
in our cyclization precursors. Dibenzazepinone 2m, derived from
the corresponding diphenyl derivative, was accessed as a single
diastereoisomer in 96% yield and 98:2 er. In comparison, the
synthesis of dimethyl-derivative 2n required 90 °C for cyclization,
resulting in significant racemization. Ketal derivatives 2p–2r
reacted with excellent levels of enantioselectivity (up to 98:2 er),
while also demonstrating that altering the electronic nature of the
activated phenyl group is well tolerated.
for the latter proposal.[20] DFT computations further support this
scenario. Both isomers 5 and 5’ are roughly isoenergetic and
both have
a
low barrier for the reductive elimination
(TSelim(S)=5.2 kcal/mol, TSelim(R)=5.9 kcal/mol). In contrast, the
isomerization between the two species 5 and 5’ is largely
disfavored, having a substantially higher barrier for TSiso (21.4
kcal/mol). Consequently, the bound chiral ligand discriminates
between enantiotopic faces of the activated phenyl group in 4,
corresponding to an enantiodetermining CMD-step.
Experimental and computational studies provided further
insight into which structural features are responsible for product
configurational stability (Scheme 3a). PMB cleavage of 2i
proceeded smoothly, providing secondary lactam 3 in 88 % yield.
Although this derivative has a considerably smaller half-life than
its substituted precursor, its facile preparation creates
opportunity for introduction of functionality not tolerated during
C–H
functionalization.
DFT
computations
regarding
dibenzazepinone enantiomerization were conducted at the
PBE0-dDsC/TZ2P//M06/def2-SVP theoretical level, and are
summarized in Scheme 3b. For rotation about the biaryl axis to
occur, significant puckering of the nitrogen substituted aryl-
moiety is necessary, as illustrated by representative example
TS-2a (cf. X-ray of 2l). A concomitant decrease in conjugation
between the carbonyl and nitrogen atom of the amide
functionality is also observed, ultimately resulting in a significant
barrier to enantiomerization.[19] Notably, benchmarking of our
measured versus calculated configurational stabilities shows
good agreement (see SI for detailed data), highlighting the value
of this method as a predictive tool for future synthetic studies
towards axially chiral dibenzazepinones.
Mechanistically, the selective formation of a chiral axis
poses an intriguing problem with broader implications. Which
stage of the catalytic cycle is the enantiodetermining step? In
contrast to the clear identification of this crucial step in the
formation of point- and planar chiral molecules, two scenarios
can be envisioned (Scheme 4). Scenario I: The interconversion
barrier of the two relevant palladacycles 5→5’ (TSiso) is lower
than the activation energy for the reductive elimination (TSelim(S)
and TSelim(R)). As consequence, the C–H activation step would
not be connected to enantioselectivity. Rather, selectivity would
be linked to the differences in stability of 5 and 5’ (or TSelim(S)
and TSelim(R)). Scenario II: The barrier of interconversion TSiso is
significantly higher than reductive elimination. In this case, the
initial conformation of the palladacycle after the CMD-step would
directly translate to the final observed axial chirality. Since the
Scheme 3. Experimental and computational insight into dibenzazepinone
configurational stability.
In summary, we report a palladium-catalyzed atropo-
enantioselective C-H functionalization method for the synthesis
of axially chiral dibenzazepinones. A simple TADDOL-derived
phosphoramidite ligand provides high levels of enantiocontrol.
Accompanying computational investigations allow reliable
prediction of racemization barriers about the chiral axis.
Moreover, calculations suggest an enantiodetermining CMD-
step that proceeds via discrimination between enantiotopic faces
of a phenyl group to set the chiral axis, followed by a fast
reductive elimination.
nature of carboxylic acid additive has
a
bearing on
enantioselectivity (Table 1), this provides experimental evidence
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Acknowledgements
This work is supported by the Swiss National Science
Foundation (No. 175507). C. G. N. acknowledges support from
the “EPFL Fellows” co-funded by Marie Skłodowska-Curie,
Horizon 2020 program (No. 665667). M. D. W. thanks Prof. C.
Corminboeuf for financial support and access to computational
resources. We thank Dr. R. Scopelliti and Dr. F. Fadaei Tirani for
X-ray analysis of compounds 2c, 2e and 2l.
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Keywords: Asymmetric Catalysis • C–H Activation • Biaryl
Atropisomer • Palladium • Axial Chirality
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1843124 at: www.ccdc.cam.ac.uk/data_request/cif.
[19] Corresponding amine of 2l has a calculated ∆G‡rac of 22.4 kcal/mol.
[20] Computations at the PBE0-dDsC/TZ2P//M06/def2-SVP theoretical level
(see SI for full computational details). The very large ligand L5 has
been simplified by PMe3 for the calculations.
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Entry for the Table of Contents
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C. G. Newton, E. Braconi,‡ J. Kuziola,‡
M. D. Wodrich, N. Cramer*
Page No. – Page No.
Axially Chiral Dibenzazepinones via a
Pd(0)–Catalyzed Atropo-
enantioselective C–H Arylation
A palladium-catalyzed atropo-enantioselective route towards axially chiral
dibenzazepinones has been developed. A TADDOL-derived phosphoramidite
ligand provides high levels of enantiocontrol. Computational investigations provide
information on racemization barriers and suggest an enantiodetermining C–H
functionalization event.
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