Key words
atropisomeric axis - atropisomeric biaryls - C–H arylation
1 Introduction
Figure 1 Representative atropisomeric molecules
Atropisomerism[1a] is a fundamental feature of many molecular scaffolds with important application
in materials, pharmaceuticals, natural products and in organic synthesis as chiral
catalysts. This chiral element, resulting from the hindered rotation around an axis,
has been recognized as an important factor governing the biological activities of
many natural products.[1`]
[c]
[d] Representative examples are depicted in Figure [1], including not only the well-known vancomycin but also (hetero)biaryl motifs such
as rivularin D (Figure [1]). Moreover, atropisomerism is the fundamental feature of classes of ligands in asymmetric
catalysis. Indeed, BINOL, BIPHEMP or SEGPHOS are undeniably privileged chiral inductors.[2] More recently, atropisomeric pyridine-derived ligands[3] have also attracted increasing attention. Several modern materials,[4] including liquid crystals and molecular machines, may also contain atropisomeric
biaryl elements.
The key importance of atropisomerism is further illustrated by the expanding number
of applications of such molecules in pharmaceutical industry.[5] Indeed, an analysis of 1900 small drug molecules from the USD FDA Drug Bank (FDA:
Food and Drug Administration) reveals that approximately 15% of FDA-approved scaffolds
contain one or more atropisomeric axes and an additional 10% of molecules are ‘proatropisomeric’,
meaning that a simple modification of a molecule in proximity of an axis would render
it chiral.[5] Even more marked, the prevalence of atropisomeric compounds has been expanding dramatically
since 2011 and, in 2018, almost one out of three FDA-approved small molecules contained
an atropisomeric element and an additional 16% were proatropisomeric.[5]
Consequently the past decade has witnessed significant advances in the field of atropisomeric
synthesis of biaryls.[6] The most common strategies to access such compounds include (1) stereoselective
transformations of prochiral or racemic biaryls;[7]
[6b] (2) methods relying on a central-to-axial chirality transfer;[8] (3) de novo synthesis of an aromatic ring,[9] or (4) asymmetric transition-metal-catalyzed cross-coupling of functionalized moieties
(Figure [2]).[10]
Figure 2 Different approaches towards atropisomeric biaryls
In addition, atroposelective metal-catalyzed C–H functionalization has recently become
established as a powerful strategy for the atroposelective construction of chiral
biaryls.[6g] Applications of the C–H activation protocols for the synthesis of the enantiomerically
enriched atropisomeric compounds remain rare and are mainly concerned with the stereoselective
C–H functionalization of prochiral or racemic biaryls through the introduction of
an additional ortho-substituent on a biaryl substrate bearing a directing group (Figure [3], Pathway A).[11] Without doubt, the synthesis of atropisomeric biaryls through C–H functionalization
of an atropo-unstable precursor can be considered as one of the most general and efficient
strategies. Enantioselective or diastereoselective approaches, together with the elegant
use of a transient chiral directing group, have paved the way to a variety of high-value-added
biaryls of interest either in the field of natural biologically active products or
asymmetric catalysis.[11] In contrast, efficient control of atroposelectivity through direct C–H arylation
(Figure [3], Pathway B) of (hetero)arenes certainly appears much more challenging. In fact,
the atroposelective coupling of two bulky aryl moieties has been recognized as extremely
difficult, even by using standard cross-coupling protocols, such as Suzuki couplings.[10] Indeed the difficulty of these reactions arises from the antagonism between the
steric hindrance of both coupling partners (a prerequisite to ensure the configurational
stability of the biaryl) translating to the drastic reaction conditions necessary
to promote the Ar–Ar bond-forming event and the limited atropostability of the newly
generated compounds under the reaction conditions. This antagonism could explain the
current scarcity of enantioselective Suzuki–Miyaura biaryl coupling reactions for
which different classes of both mono- and bidentate ligands and Pd-catalysts have
been designed.[12] It is also important to note that the current substrate scope of atroposelective
Suzuki couplings is generally limited to specific substrates, such as trisubstituted
binaphthyl, phenyl-naphthyl and, more sporadically, biphenyl compounds and substrates
bearing coordinating substituents such as an aldehyde or phosphonate group. However,
the synthesis of tetrasubstituted cores or heterobiaryls via Suzuki coupling remains
an essentially unmet goal.
Figure 3 Atroposelective formation of biaryls via C–H activation
Taking account the recent advances achieved in the field of C–H activation, it was
evident that chemists would try to synthesize atropisomeric biaryl moieties by direct
C–H arylation of (hetero)arenes (Figure [3], Pathway B). To atteint this goal, the issue of the antagonism beween hindrance
necessary to reach atropostability and elevated temperatures required not only to
activate the C–H bond, but also to couple two hindered moieties, needs to be tackled.
The few elaborated strategies that have been used to achieve this challenge are discussed
in detail in this short review.
2 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Thiophene
Derivatives
2 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Thiophene
Derivatives
The first efforts in this challenging field, unambiguously illustrating the inherent
difficulty of atroposelective C–H arylation, were undertaken by Yamaguchi and Itami.
In 2012 they reported the Pd-catalyzed coupling reaction between naphthylboronic acids
and thiophene derivatives using the chiral ligand, 2,2′-bis(oxazoline) BOX in presence
of TEMPO (Scheme [1]).[13] To ascertain the configurational stability of the substituted aryl thiophenes, the
rotational barrier was evaluated by DFT calculation and was high enough (33 kcal/mole
for 3-methyl-4-(2-methylnaphthalene-1-yl)thiophene) to exist as a stable isomer at
room temperature. After optimization of the reaction conditions the authors succeeded
in affording the enantioenriched heterobiaryl products. The results showed unambiguously
a clear antagonism between efficiency and stereoselectivity of this transformation.
To achieve a satisfactory enantiomeric excess, a bulky naphthyl boronic acid with
an isopropyl group in the ortho-position was required, but the product was isolated in a significantly decreased
yield. One year later a second-generation catalytic system was proposed by Itami and
Yamaguchi.[14] A novel sulfoxide-oxazoline SOX ligand and a catalytic amount of iron-phthalocyanine
(FePc) as cooxidant were employed. By using these aerobic conditions the atropoisomeric
arylated product was obtained in better yield but with a slightly lower chiral induction.
Scheme 1 Synthesis of atropisomeric heterobiaryls via asymmetric C–H arylation of thiophene
derivatives
Following these seminal works, which clearly showed the extremely challenging nature
of atroposelective C–H arylation, this field remained uncharted for several years
and, only very recently, have major breakthroughs been achieved, using first diastereoselective,
and later on, enantioselective protocols.
3 Atropodiastereoselective Intermolecular Pd-Catalyzed C–H Arylation towards Terphenyl
Scaffolds Bearing Two Atropisomeric Axes
3 Atropodiastereoselective Intermolecular Pd-Catalyzed C–H Arylation towards Terphenyl
Scaffolds Bearing Two Atropisomeric Axes
Targeting elaboration of unprecedented chiral scaffolds, Colobert and Wencel-Delord
in 2018 were interested in the conception of optically pure molecules containing two
contiguous atropisomeric axes.[15] They envisaged that such molecules might be obtained by combining diastereoselective
C–H functionalization[16] of biaryls and stereoselective C–H arylation. Such triaryl scaffolds should exhibit
a unique tridimensional structure, thus becoming an appealing platform to construct
unprecedented chiral ligands.
The authors had already reported the Pd-catalyzed atropodiastereoselective C–H acetoxylation
and halogenation of biarylsulfoxide substrates[11b]
[h]
[i] On the basis of this work, they hypothesized that the C–H arylation should be possible.
Moreover, two contiguous atropisomeric axes might be expected in the coupling between
biarylsulfoxides bearing an additional substituent in the meta-position and an ortho-substituted aryl iodide (Scheme [2]). Regarding the high steric hindrance of both coupling partners, a significant optimization
study was necessary; rewardingly, by using Pd(TFA)2 with an N-heterocyclic carbene ligand, Ag2CO3 and AgTFA, the expected ortho-orientated terphenyls were obtained in good yields and with excellent control of
both atropisomeric axes in a single transformation (Scheme [2]).[17] Use of 1,1,1,3,3,3-hexafluoroisopropanol as solvent and addition of molecular sieves
were crucial in this reaction. This catalytic system is compatible with a variety
of aryl-iodine coupling partners, including not only Cl- and Br-substituents, but
also coordinating motifs such as NPhth or OMe. Moreover, with a Cl- or MeO- group
in the ortho-position of the aryl iodide, the corresponding terphenyls were afforded in good yields
and with excellent stereoselectivities.
Scheme 2 Synthesis of terphenyls with two atropisomeric axes
From a mechanistic viewpoint, the stereoselectivity of the Ar1–Ar2 axis is induced during the C–H activation step, which favors palladacycle C over B. In intermediate C the steric interactions between the para-Tol group and the NHC ligand (L) are minimized (Scheme [3]). A rapid racemization of the substrate indicates dynamic kinetic resolution. Regarding
the chirality of the Ar1–Ar3 linkage, the oxidative addition of the aryliodide coupling partner would occur to
minimize the steric interaction between the SOp-Tol moiety and the ortho-substituent of the aryl iodide, thus controlling the chirality of the second atropisomeric
axis. Finally, reductive elimination from less congested PdIV intermediate D delivers the atropo-enantioenriched product. An epimerization half-life of ca. 73
days at 85 °C, consistent with the computed ΔG
‡ of 33 kcal mol–1 was observed for compound A (Scheme [2]) supporting of the configurational stability of the product during the reaction.
Scheme 3 Mechanistic proposal of the C–H arylation of biarylsulfoxides
This original tridimensional skeleton with two atropisomeric axes can be viewed as
a perfect structure for the synthesis of new chiral ligands. Indeed an X-ray crystal
structure showed a spatial proximity of Ar1 and Ar3 and an unusual ‘open clam shell’ architecture (Scheme [2]), that seems highly appealing for stereogenic ligand design. Therefore, some functional
group modifications were investigated and the diphosphine BiaxPhos was prepared through
double lithium exchange of the sulfinyl group and bromine atom followed by quenching
with chlorodiphenylphosphine. BiaxPhos was found to exhibit excellent reactivity and
enantioselectivity in Rh-catalyzed hydrogenation of the trisubstituted methyl (Z)-α-acetamidocinnamate. An S/N-Biax ligand bearing the sulfinyl and N-tosyl groups was also synthesized. Its efficiency in 1,2-addition of Et2Zn to benzaldehyde was tested and the corresponding stereogenic carbinol was obtained
in high yield and with excellent e.r. of 93:7 (Scheme [4]).
Scheme 4 Synthesis of atropopure BiaxPhos and S/N-Biax and their use in asymmetric catalysis
This work was the first example of a highly atroposelective Ar–Ar bond formation through
a C–H activation process and it also illustrates the potential of such methods to
access complex molecules with applications in asymmetric catalysis.
4 Atropo-enantioselective Intramolecular Pd-Catalyzed C–H Arylation towards Atropisomeric
Dibenzazepinones
4 Atropo-enantioselective Intramolecular Pd-Catalyzed C–H Arylation towards Atropisomeric
Dibenzazepinones
A few months later, an efficient protocol for intramolecular enantioselective C–H
arylation was reported by Cramer and co-workers,[18] targeting the synthesis of original atropisomeric benzazepinones (Scheme [5]). Benzazepinones are an interesting class of natural products.[19] Notably, point chiral and achiral dibenzazepinones or dibenzodiazepines are present
in some drugs, but atropisomeric dibenzazepinones have never been reported. The authors
thus surmised that such original atropisomeric products could be readily obtained
from bromo-aromatic amides, via Pd-catalyzed intramolecular C–H arylation, with a
concomitant introduction of chiral information. The key to success was based on the
use of Taddol-derived phosphorus(III) ligands. Such phosphoramidite ligands are known
to facilitate Pd0/PdII-catalyzed C–H functionalization under mild reaction conditions; the essential prerequist
for the atropostability of the newly generated axially chiral product. A careful optimization
of the reaction conditions allowed preparation of differently substituted dibenzazepinones
starting from achiral amides with different electron-donating (A, B, C) and electron-withdrawing (D) substituents on the aniline moiety, as well as a range of para-substituted benzyl groups on the 2-naphthylamine moiety (E, F, G). Notably, a gram-scale synthesis of dibenzazepinones bearing a para-chlorobenzyl on nitrogen atom E was achieved in excellent yield and enantioselectivity, even under reduced catalyst,
ligand, and acid additive loadings. The potential of this methodology was further
highlighted by its application to the synthesis of product F, bearing a stereocenter close to the biphenyl moiety in high diastereo- and enantioselectivities,
and a ketal derivative G.
Scheme 5 Scope of the intramolecular atropoenantioselective C–H arylation
The rotational barrier of the newly accessed compounds was measured experimentally
and predicted based on DFT calculations. The half life of A was determined to be 46 hours at 80 °C and 15 years at 25 °C; a guarantee of the
configurational stability of the product during the reaction. In addition, DFT computational
analysis suggests that the C–H insertion step, which occurs via a CMD mechanism, is
enantiodetermining. Indeed, the two enantiomeric palladacycles H and H′ are isoenergetic and both have a low barrier for reductive elimination (5.2 and 5.9
kcal mol–1; Scheme [6]). Moreover, a calculated isomerization barrier of 21 kcal mol–1 appears to disfavor the equilibrium between H and H′. Accordingly, it can be surmised that the chiral Pd-complex discriminates between
the two enantotopic faces of the activated phenyl group, thus setting the atropisomeric
axis.
Scheme 6 Proposed stereomodel for the intramolecular atropoenantioselective arylation
This Pd-catalyzed C–H arylation process illustrates the power of the Taddol-derived
ligand in an enantioselective transformation leading to a high level of enantiocontrol
as well as excellent yields.
5 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Heteroarenes
5 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Heteroarenes
Following the intramolecular C–H arylation described above, Cramer and Baudoin reported
in 2020 the more challenging intermolecular atropoenantioselective C–H arylation of
electron-deficient heteroarenes.[20] In their initial study, they focused on the synthesis of Ar-HetAr scaffolds via
C–H arylation of 1,2,3 triazole derivatives, which are biologically relevant units
recognized as bioisosteres and pharmacophores. To achieve a configurational stability
of the heterobiaryl axis at 80–100 °C over prolonged reaction times, the coupling
between 1-methyl-4-phenyl-1H-1,2,3-triazole and 1-bromo-2-methoxy naphthalene, furnishing a product with four
ortho-substituents around the heterobiaryl axis, was selected (Scheme [7]). The racemization barrier of such compounds of approximately 32.4 kcal mol–1 and a half-life of 1076 years at 25 °C exclude the racemization risk under the reaction
conditions. The optimization study revealed that a larger dihedral angle of the ligand
induces a higher enantioselectivity and that the use of H8-BINAPO with Pd(dba)2 in the presence of PivOH and Cs2CO3 in acetonitrile was crucial to afford the highly sterically hindered heterobiaryl
derivative in excellent yield and atroposelectivity (93% yield, 95:5 e.r.) in 40 hours.
Such an optimized catalytic system features excellent reactivity and enantioselectivity
with respect to several different bromonaphthalenes with variation of the alkoxy group
ortho- to the stereogenic axis and various substituents at C6 of the naphthalene. Regarding
the modification of the aryl substituent of the 1,2,3-triazole, thienyl and 2-naphthyl
groups are well tolerated, giving excellent yields and stereoselectivities. However,
substrates such as sterically hindered ortho-tolyl and 1-naphthyl motifs result in lower enantioselectivities. Moreover, aliphatic-
and N-benzyl substituted triazoles are compatible substrates. Similar results were obtained
when changing the triazole ring to related azoles such as pyrazoles bearing an electron-withdrawing
group at C3. In contrast, C–H arylation of imidazopyrimidines performed poorly in
this catalytic system even at 100 °C in dioxane, indicating that further ligand optimization
will be necessary for this reaction.
Scheme 7 Scope of the intermolecular atropoenantioselective C–H arylation of heteroarenes
Recently, compounds with contiguous chiral elements have been recognized as important
scaffolds with various topologies and application as chiral ligand, catalysts and
optical resolution agents.[15] Following this goal, a double intermolecular C–H arylation of 1,5-dibromo-2,6-dimethoxynaphthalene
with 1-methyl-4-phenyl-1H-1,2,3-triazole was achieved, affording the triaryl product bearing two stereogenic
axes (Scheme [8]). Interestingly no meso-isomer was observed.
Scheme 8 Double intermolecular atropoenantioselective C–H arylation of heteroarenes
To obtain insight into this novel C–H arylation transformation, mechanistic studies
have been performed. First, an intermolecular kinetic isotope effect of 1.8 was measured,
and the results suggested that the C–H bond cleavage is the rate-limiting step. The
metallation is believed to proceed through a concerted metalation-deprotonation (CMD)
mechanism, as supported by the crucial importance of the carboxylic acid co-catalyst
on the rate of the reaction but not on the enantioselectivity. Moreover, the reductive
elimination is expected to be the enantiodetermining event because of the strong influence
of the dihedral angle of the ligand on the obtained enantioselectivity.
This Pd-catalyzed C–H arylation shows unambiguously the potential of the straightforward
approach to obtaining medicinally relevant aryl-heteroarenes in excellent yields with
excellent control of the chiral axis formed in the presence of H8-BINAPO.
6 Rh-Catalyzed Atropo-enantioselective C–H Arylation of Diazonaphthoquinones
6 Rh-Catalyzed Atropo-enantioselective C–H Arylation of Diazonaphthoquinones
An alternative approach towards biaryl synthesis via stereoselective coupling was
reported in 2017 by Antonchick and Waldmann.[21] In this specific case a new chiral JasCp-Rh complex allowed direct coupling between
meta-substituted benzamides and highly reactive diazonaphthoquinones. After the rearomatization
step, the biaryl scaffold features two ortho-substituents adjacent to the newly generated aryl–aryl linkage, ensuring the configurational
stability of the atropisomeric structure (Scheme [9]). Such rare tetrasubstituted biaryl scaffolds can be obtained in high yields and
enantiomeric ratios, rendering this strategy truly useful. Moreover, further postfunctionalizations
can be envisaged because halide substituents are well tolerated.
More recently, a closely related RhIII-catalyzed coupling between N-phenyl nitrone and quinone diazide was disclosed by Li.[22] In this case, however, the atropisomeric biaryls are metastable and undergo intramolecular
dearomative trapping under oxidative conditions, delivering spirocyclic products in
high yields and optical purities.
Scheme 9 Atropisomeric tetrasubstituted biaryls by C–H functionalization with diazonaphthoquinones
7 Conclusion
Over the past decade, the scientific community has witnessed extraordinary advances
in asymmetric C–H activation that has enabled the development of efficient strategies
to control point chirality, while significantly less attention has been paid to the
synthesis of atropisomeric scaffolds. However, over recent years, significant advances
have also been achieved in this field, focusing first on the synthesis of atropisomeric
molecules via C–H functionalization of biaryls. This short review highlights the breakthroughs
in alternative and synthetically more challenging atroposelective C–H arylations.
The paucity of reports of this methodology shows unambiguously the difficulties encountered
in the stereoselective formation of the atropisomeric axis of chirality during the
C–H activation process combining two bulky moieties. Regarding enantioselective methodologies,
catalytic systems based on Taddol or H8-BINAPO ligands combined with Pd established
themselves as efficient methodologies for such C–H arylation. Nevertheless, atroposelective
C–H arylation methodology is still in its infancy and consequently the design of truly
versatile, atroposelective syntheses are still required; we hope that this short review
article will inspire further progress in this field.
