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Atroposelective Synthesis of Axially Chiral Biaryl Compounds.

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Reviews
G. Bringmann, M. Breuning et al.
DOI: 10.1002/anie.200462661
Biaryl Synthesis
Atroposelective Synthesis of Axially Chiral Biaryl
Compounds**
Gerhard Bringmann,* Anne J. Price Mortimer, Paul A. Keller, Mary J. Gresser,
James Garner, and Matthias Breuning*
Keywords:
asymmetric synthesis · atropisomerism ·
axial chirality · biaryl compounds ·
stereoselectivity
Angewandte
Chemie
5384
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Angewandte
Chemie
Biaryl Synthesis
A rotationally hindered and thus stereogenic biaryl axis is the
structurally and stereochemically decisive element of a steadily
growing number of natural products, chiral auxiliaries, and
catalysts. Thus, it is not surprising that significant advances have
been made in the asymmetric synthesis of axially chiral biaryl
compounds over the past decade. In addition to the classic
approach (direct stereoselective aryl–aryl coupling), innovative
concepts have been developed in which the asymmetric information is introduced into a preformed, but achiral—that is,
symmetric or configurationally labile—biaryl compound, or in
which an arylC single bond is stereoselectively transformed into
an axis. This Review classifies these strategies according to their
underlying concepts and critically evaluates their scope and
limitations with reference to selected model reactions and applications. Furthermore, the preconditions required for the existence
of axial chirality in biaryl compounds are discussed.
1. Introduction
Since the first resolution of tartaric acid by Louis Pasteur
in 1848,[1] the stereoselective synthesis of compounds containing one or more stereogenic centers has emerged as one of
the most important fields in chemistry. Numerous excellent
diastereo- and enantioselective procedures have been developed which belong nowadays to the standard repertoire of
synthetic chemistry.[2] Axial chirality, by contrast, as a stereogenic element in rotationally hindered biaryl compounds of
natural and synthetic origin, has often been overlooked or
treated as an “academic curiosity”.[3] This, however, has
changed with the recognition that the configuration at a biaryl
axis can be a decisive factor in governing the pharmacological
properties of a bioactive compound[4] and that axial chirality
is the fundamental basis for useful reagents and catalysts in
asymmetric synthesis.[5]
Natural products equipped with a rotationally hindered
biaryl axis are far more widespread and structurally diverse
than initially assumed.[4] Many representatives of this class of
axially chiral metabolites exhibit remarkable bioactivities,
like the famous antibiotic heptapeptide vancomycin (1,
Figure 1).[6, 7] This molecule contains three types of stereoelements—numerous stereogenic centers, two “chiral” planes,
and a stereogenic biaryl axis, which together impose the rigid
3D structure necessary for an efficient binding to peptides of
bacterial cell walls.[6] Knipholone[8] (2) possesses solely axial
chirality and occurs with varying degrees of enantiomeric
purity in nature;[9] compounds of this family of 1-phenylanthraquinones have recently been shown to exhibit good
antimalarial[10] and antitumor[11] activities, the latter particularly when M configured. Mastigophorene A (3), a C2symmetric bisphenol bearing additional stereogenic centers,
has been found to stimulate nerve growth.[12] The class of
axially chiral natural products is, however, not restricted to
CC-coupled biaryl compounds. (M)-Murrastifoline-F ((M)4), for example, is a biscarbazole with the two—otherwise
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
From the Contents
1. Introduction
5385
2. Preconditions for Axial Chirality and
Mechanisms of Atropisomerization
5387
3. Biaryls by Asymmetric CC Coupling 5391
4. Atroposelective Transformations of
Prostereogenic Biaryl Compounds
5407
5. Asymmetric Biaryl Synthesis by
Construction of an Aromatic Ring
5418
6. Summary and Outlook
5419
identical—“halves” connected by a heterobiaryl CN
bond.[13]
Axially chiral biarylic auxiliaries and catalysts exhibit
excellent chirality transfer properties.[5] A prime example is
the diphosphine binap (5, Figure 2),[14] which is the ligand of
choice in Ru-catalyzed asymmetric hydrogenations of C=C
and C=O bonds.[15] The more complex epoxidation catalyst 6
possesses two axially chiral binaphthyl subunits embedded in
a sterically demanding backbone.[16] More recently, attention
has been focussed on non-C2-symmetric biaryl compounds
such as the tertiary aminophenol 7, which catalyzes the
enantioselective addition of diethylzinc to aldehydes.[17] The
isoquinoline-containing phosphine quinap (8) is an example
of an axially chiral heteroaromatic biaryl; it has been used as a
ligand in Pd-catalyzed asymmetric allylic alkylation reactions.[18]
Owing to the importance of axially chiral biaryl compounds, a variety of excellent methods for their directed,
atroposelective construction have been developed. Herein,
we present an overview of the most efficient and practicable
methods presently known for the atroposelective synthesis of
axially chiral biaryl compounds.[19–24] Major consideration is
[*] G. Bringmann, A. J. Price Mortimer, M. Breuning
Institut f,r Organische Chemie
Universit/t W,rzburg
Am Hubland, 97074 W,rzburg (Germany)
Fax: (+ 49) 931-888-4755
E-mail: bringman@chemie.uni-wuerzburg.de
breuning@chemie.uni-wuerzburg.de
P. A. Keller, M. J. Gresser, J. Garner
Department of Chemistry
University of Wollongong
Wollongong 2522 (Australia)
[**] Novel Concepts in Directed Biaryl Synthesis, Part 110. Part 109: G.
Bringmann, R.-M. Pfeifer, P. Schreiber, K. Hartner, N. Kocher, R.
Brun, K. Peters, E.-M. Peters, M. Breuning, Tetrahedron 2004, 60,
6335–6355.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5385
Reviews
G. Bringmann, M. Breuning et al.
Figure 2. Selected examples of axially chiral ligands and catalysts.
Figure 1. Selected examples of naturally occurring axially chiral biaryl
compounds.
given to the different fundamental strategies elaborated: their
conceptual classification, the stereochemical principles that
govern the asymmetric induction at the axis, their applicability, and their limitations.
As the phenomenon of axial chirality relies on the
rotational stability of an aryl–aryl single bond, important
preconditions for this stability, as well as the different
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mechanisms of atropisomerization, are discussed in Section 2.
As outlined in Scheme 1, three fundamentally different
strategies have, to date, been realized for the atroposelective
synthesis of axially chiral biaryl compounds. The classic
concept, which is discussed in Section 3, involves biaryl
formation in a single step by CC coupling, with the two
aromatic portions being joined with simultaneous asymmetric
induction (9 + 10!11).[19, 22, 23] The second approach, by
contrast, relies on the atroposelective transformation of an
existing, but stereochemically not yet defined, biaryl system
(Section 4).[20, 21] Within this two-step approach, a nonstereoselective coupling step thus precedes the introduction of the
stereochemical information at the axis (12!11). Finally,
Section 5 summarizes the few known methods in which a CC
bond between an arene and a precursor substituent is
transformed into a chiral biaryl axis by construction of an
Gerhard Bringmann studied chemistry in
Giessen and Mnster (Germany) and
received his PhD with Prof. B. Franck in
1978. After postdoctoral studies with Prof.
Sir Derek H. R. Barton in Gif-sur-Yvette
(France), and his habilitation in 1984 at the
University of Mnster. He became a full professor of Organic Chemistry at the University
of Wrzburg in 1987. In 1998 he declined
an offer of the position of a director at the
Leibniz Institute of Plant Biochemistry in
Halle. His research interests lie in the field
of analytical, synthetic, and computational
natural products chemistry.
Paul Keller completed his BSc (Hons)
(1985) and PhD (1991) at the University of
New South Wales (Australia), before taking
up an Alexander von Humboldt funded postdoctoral fellowship in Germany. Since 1994,
he has worked at the University of Wollongong, Australia, and is currently Associate
Professor in Organic and Medicinal Chemistry. His interests lie in drug design and development, the development of synthetic fullerenyl chemistry, and the design and synthesis
of chiral catalysts.
Anne J. Price Mortimer was born in Stokeon-Trent (UK) in 1977. She studied chemistry at St. John’s College, University of
Oxford, before going on to complete a DPhil
under the supervision of Prof. S. G. Davies
in 2003, investigating the synthesis of bamino acid natural products. From 2003 to
2005 she was a postdoctoral researcher in
the group of Prof. G. Bringmann, developing
novel methodologies for the synthesis of
axially chiral biaryls, and held an Alexander
von Humboldt research fellowship from 2004.
Mary J. Gresser, born in 1981, completed
her BSc (Hons) at the University of Wollongong (Australia). She commenced her PhD
in 2003 under the supervision of Associate
Professor Paul A. Keller, investigating the
synthesis of chiral ligands for palladiumbased catalysis.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Biaryl Synthesis
introduced by Kuhn[26] in 1933 and originally referred solely
to biaryl compounds. In general, there are two necessary
preconditions for axial chirality in biaryl molecules
(Figure 3):[27, 28] a rotationally stable axis and the presence of
Scheme 1. Schematic overview of the existing strategies for atroposelective syntheses of axially chiral biaryl systems.
aromatic ring, usually with a central-to-axial chirality transfer
(13!11).
2. Preconditions for Axial Chirality and Mechanisms
of Atropisomerization
2.1. The Phenomenon of Axial Chirality
Optical activity due to axial chirality has been known
since the early 20th century and was first correctly described
by Christie and Kenner in 1922.[25] The term “atropisomerism” (from the Greek, a = not and tropos = turn) was
James Garner, born in 1976, studied chemistry at the University of Newcastle (Australia), before going on to complete a PhD
in 2003 under the supervision of Dr Adam
McCluskey, on the development of structurally unprecendented CRH1 antagonists. He
is currently a postdoctoral research fellow
under the direction of Associate Professor
Paul A. Keller, investigating the synthesis of
6,6’-bisindoles.
Matthias Breuning, studied chemistry at the
University of Wrzburg (Germany), where
he completed his PhD in 1999 under Prof.
G. Bringmann. After a postdoctoral stay
with Prof. E. J. Corey at Harvard University
(USA), he joined Bayer AG in 2001 as a
senior research scientist. Since 2002 he has
been working on his habilitation at the University of Wrzburg, supported by an EmmyNoether fellowship of the DFG. His main
research interests lie in the field of asymmetric synthesis, in particular in the development of novel catalysts and their application
in natural products synthesis.
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Figure 3. Selected substitution patterns that result in axial chirality.
different substituents on both sides of the axis as indicated in
14, that is, A ¼
6 B and A’ ¼
6 B’. If A = A’ and B = B’, the
molecule has C2 symmetry (but is still chiral) as in 15, 16, and
17. Surprisingly to the casual observer, even biaryl compounds with four constitutionally identical substituents may
be chiral if these are connected pairwise through two bridges
as in the D2-symmetric diether 18.[29] Axially chiral biaryl
compounds that bear different ortho substituents, such as the
dimeric orcinol (15),[30] are found ubiquitously (compare most
of the biaryl species discussed in this article). Although less
common, axial chirality may also result from an inequivalence
of meta substituents, as found in the bimesityls 16[31] and in the
naphthylisoquinoline alkaloid ancistrocladisine (19).[32] Furthermore, heteroaromatic systems provide the possibility to
introduce chirality merely from the position of the heteroatom, as found in the dipyridyl quateraryl 17.[33]
The absolute axial configuration can be denoted by
analysis of a Newman projection along the biaryl axis
(Figure 4). After assignment of priority to the ortho (or
meta) substituents according to the CIP rules,[34] the analysis is
done by following the shortest 908 path from the substituent
of highest priority at the proximal ring to the highest-ranking
one at the distal ring (i.e. here from A to A’). If this 908 turn is
counterclockwise as in 20, the absolute configuration is M (for
minus); if it is clockwise as in ent-20, then the descriptor is P
(for plus).[35, 36]
For the stereochemical assignment of pairwise enantiotopic substituents in prochiral biaryl compounds of type 21,
the arc between the substituent of interest and the substituent
of highest priority on the other aryl ring is considered, giving
rise to the descriptors pro-M and pro-P (see Figure 4,
bottom), after the system of Hanson and Helmchen.[37, 38]
The other crucial precondition for atropisomerism is the
rotational stability of the biaryl axis. The temperature has a
profound influence: On the one hand, even biaryl compounds
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Bringmann, M. Breuning et al.
state.[41, 43–45] In many cases, the barrier to rotation can be
rationalized in terms of substituent effects.
2.2.1. Effects of Nonbridging Substituents
ortho Substituents increase the atropisomerization barrier
in nonbridged biaryl compounds by their steric repulsion
(compare 22 and 25, Figure 5), corresponding largely to the
van der Waals radii of the substituents, that is, I > Br > Me >
Cl > NO2 > CO2H > OMe > F > H.[46]
Figure 4. Assignment of absolute configuration in chiral biaryl species
and descriptors for paired substituents in prochiral biaryl compounds
(note that the same descriptor results, regardless of the position of
the observer).[38]
with a low degree of steric hindrance will suffer impeded
rotation if sufficiently cooled down,[39] and split up into
atropoenantiomers or -diastereomers if unsymmetrically
substituted; on the other hand, biaryl species that are axially
chiral at room temperature may start to atropisomerize upon
heating, resulting in thermodynamically controlled equilibrium mixtures (i.e. in a full loss of chiral information in the case
of enantiomers).[40, 41] As an arbitrary, but useful definition,[42]
atropisomers are recognized as physically separable species
when, at a given temperature, they have a half-life t of at least
1000 s (16.7 min). Thus the minimum free energy barrier DG°
1
required varies with temperature (e.g. DG°
200 K = 61.6 kJ mol ,
°
1
°
1
DG300 K = 93.5 kJ mol , and DG350 K = 109 kJ mol ). The configurational stability of axially chiral biaryl compounds is
determined by three major factors:
1) the (combined) steric demand of the substituents in
proximity to the axis;
2) the existence, length, and rigidity of bridges; and
3) the involvement of atropisomerization mechanisms different from a merely physical rotation about the axis, for
example, by photochemically or chemically induced
processes.
2.2. Atropisomerization by Physical Rotation
Physical—that is, thermal—rotation about a biaryl axis
has, in selected cases, been shown by quantum-chemical
calculations to occur through twisted (i.e. nonplanar) transition states in which the bonds to the ortho substituents and
the aryl rings are distorted, thus permitting the substituents to
pass each other more easily than in a rigid planar transition
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Figure 5. Configurational stability of di- to tetra-ortho-substituted biaryl
compounds.
Open-chain (i.e. nonbridged), mono-ortho-substituted
biaryl compounds do not form stable atropisomers at room
temperature. With two substituents next to the axis, atropisomerism at room temperature is only observed if both
groups are bulky, as in 1,1’-binaphthyl (23)[47] and in 2,2’bis(trifluoromethyl)biphenyl (24 a),[48] so that in the transition
state 22 even the interactions of R and R’ with the small
hydrogen atoms provide sufficient steric repulsion for
restricted rotation.[49] As a rule, tri-ortho-substituted biaryl
compounds form stable atropisomers; in the transition state
25, two substituents now must pass one another for rotation to
occur, rather than a substituent passing a hydrogen atom. The
biphenyl 26[50, 51] is an example of such an axially chiral biaryl
system. Nevertheless, sterically less demanding substituents
may still permit slow axial rotation as observed with the
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Biaryl Synthesis
naphthylisoquinoline alkaloid dioncophylline E (27), whose
atropisomerization occurs within a few hours at room
temperature.[52] Conformational stability is virtually guaranteed for tetra-ortho-substituted biaryl compounds, even if the
substituents are all small, as in the tetrafluorobiphenyl 28
1 [53]
(DG°
The rotational barriers can be
358 K = 108 kJ mol ).
extremely high, as in the auxiliary binol (29, DG°
493 K =
158 kJ mol1),[41] making these compounds configurationally
stable even under forcing conditions; in many cases the
atropisomerization temperature is so high that it cannot be
reached without decomposition.[54] Ancistrocladine (30), as an
example, can be dehydrogenated at 200 8C without loss of
atropisomeric purity;[55] at higher temperatures, the molecule
disintegrates.
Bulky substituents in the meta positions increase the
configurational stability of biaryl compounds by “buttressing”
the ortho substituents, thus preventing their bending out of
the way in the transition state.[46, 56, 57] For example, rotation in
the tetraiodobiphenyl 31 b (Figure 6) is considerably more
difficult than in its diiodo analogue 31 a (DG°
298 K =
1 [56]
126 kJ mol1 vs. DG°
298 K = 98 kJ mol ).
The presence of a six-membered bridge still considerably
facilitates rotation, but to a lesser extent. A comparative
study was done on the benzonaphthopyranones 32 and 33
(Figure 7), which exist as racemic mixtures of their helically
Figure 7. Atropisomerization barriers and structures of six-membered
lactone-bridged biaryl compounds 32 a–e and 33 a,c,f. Note that the
M/P descriptors given apply to 32 a,c–e and 33 a,c,f.[63]
Figure 6. The effect of meta (left) and para (right) substituents on the
configurational stability of biaryl compounds.
para Substituents influence the rotational barrier mainly
by electronic effects,[43, 57] as evidenced by the 4,4’-substituted
biphenyls 24.[57] Electron donation by resonance from the
substituent at C4 increases the sp3 character at C1, thus
facilitating the out-of-plane bending at these positions. This
decreases the strain in the transition state and, therefore,
lowers the barrier to rotation (24 b–e). By the same token,
electron-withdrawing groups, which restrict the out-of-plane
bending by decreasing the electron density at C1, raise the
barrier (24 f,g).[58]
2.2.2. Bridged Biaryl Systems
The effect of a bridging ring on the restricted rotation of a
biaryl system varies greatly with the ring size. In systems in
which two of the ortho substituents are replaced by a single
bridging atom (i.e. a five-membered ring is formed), rotation
is usually not hindered at room temperature.[59]
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
distorted atropoenantiomers (M)- and (P)-32 and -33 (torsion
angles from 268 for 33 a to 368 for 33 f).[45, 60, 61] DG°
298 K
increases with the steric demand of the ortho substituent R.[62]
Thus, 32 a–d (R = H, OMe, Me, Et) atropisomerize quickly at
room temperature with half-lives t298 K < 1 min, whereas the
lactone 32 e (R = iPr) is at the brink of atropisomerism
(t298 K = 28 min). The enantiomers of the largely distorted
derivative 33 f (R = tBu; see X-ray crystal-structure diagram,
Figure 7, bottom) are configurationally stable and can be
resolved by both physical and chemical methods.
Stereogenic centers in the bridge can strongly influence
the—now atropodiastereomeric—equilibrium as, due to the
exocyclic substituents (axial or equatorial), the bridge adopts
the thermodynamically favorable conformation. In the acetal
34 (Figure 8), which has a single stereogenic center, the
conformer with the methoxy group in an axial position is
preferred (ax-34/eq-34 = 91:9), apparently as a consequence
of an exo-anomeric effect.[64] The atropodiastereomerization
processes eq-34Qax-34, however, are still fast[62] and are
comparable to those for the related lactone 32 c (see
Figure 7). The biaryl compounds 35[65] and 36[66] are configurationally unstable at room temperature, and occur as 1:1
mixtures of atropodiastereomers, despite the presence of two
stereogenic centers in the bridge, whereas 37, with the
dioxolane system enforcing a di-equatorial conformation,
exists as a single diastereomer.[66]
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Bringmann, M. Breuning et al.
Figure 8. The configurational stability of six-membered bridged biaryl
compounds that bear stereogenic centers in the bridge.
Biaryl compounds containing seven-membered rings
exhibit rotational stabilities almost comparable to those of
their unbridged analogues.[67] Larger bridges, including those
formed by hydrogen bonding,[68] can induce atropisomerism
by geometrical constraints of the ring, even in biaryl systems
with relatively little axial hindrance. The synthetic biphenyls
38[40, 69] and 39[70] are examples of such compounds that have
just two substituents next to the axis, but are configurationally
stable at room temperature (Figure 9). Even the tripeptide
Figure 10. Photoracemization of 1,1’-binaphthyl (23) and bestriarene C
(42).
character of the triplet state, the bond order of the aryl–aryl
linkage increases, which causes a flattening of the structure
(smaller torsion angle aT); the electronic stabilization energy
thus gained greatly lowers the rotational barrier (Eact,triplet =
8 kJ mol1), despite the stronger steric interactions resulting
from the shorter biaryl bond. The naturally occurring 1,1’biphenanthrene, bestriarene C (42), undergoes remarkably
swift photoracemization:[74] Illumination with a fluorescent
lamp leads to a rapid loss of optical purity (t295 K = 30 min).
2.4. Chemically Induced Atropisomerization
Figure 9. Macrocyclic bridged biaryl compounds that are axially chiral
despite low steric hindrance in the proximity of the axis.
The chemical conditions may substantially lower the
rotational barrier of a biaryl compound if they lead to
intermediates that are more prone to atropisomerization. The
ubiquitously used chiral auxiliary binol (29) is configurationally stable even at elevated temperatures (see Figure 5); no
loss of optical purity is observed upon heating at 100 8C for
24 h under neutral conditions.[75] In acidic media (e.g. 1.2 n
HCl in dioxane/water), however, 29 racemizes within 24 h at
100 8C (Figure 11).[75] The de-aromatized cationic species 43,
antibiotic biphenomycin A (40), which does not have any
ortho substituents next to the axis, occurs as a single
atropodiastereomer.[71] It is, however, not clear whether 40
is conformationally stable (high barrier) or, rather, labile with
the atropodiastereomeric equilibrium completely shifted
towards that isomer (thermodynamic effect).
2.3. Photochemically Induced Atropisomerization
In a number of cases, photoracemization of enantiomerically enriched biaryl compounds has been observed; the
mechanisms suggested vary according to the particular
molecular structure.[72–74] For example, 1,1’-binaphthyl (23),
which is configurationally stable at room temperature (see
Figure 5), racemizes readily via the triplet excited state 41
(Figure 10).[73] It has been proposed that, due to the diradical
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Figure 11. Acid-catalyzed racemization of binol (29) via the protonated
intermediate 43; structures of michellamines A–C (44 a–c).
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Biaryl Synthesis
which has a C(sp3)C(sp2) bond instead of the original biaryl
axis, has been proposed as the intermediate that facilitates the
racemization. The acid-catalyzed atropodiastereomerization
of a binaphthyl-bridged bipyridyl in Scheme 55 is another
example.[76, 77] Binol (29) also racemizes upon heating in a
basic environment (e.g. 0.67 n KOH in butanol); its dianionic
bisphenolate has been suggested to promote the interconversion (for the electronic effects of donor groups on the
rotational barrier, see Figure 6).[75, 78] In a similar way, the
michellamines A–C (44 a–c), which possess a central axis that
is configurationally unstable and two outer, configurationally
stable ones, can be interconverted under basic conditions
(0.5 m aq KOH, MeOH, RT, 6 days).[79] This led to the
discovery that, in contrast to michellamines A and B (44 a,b),
michellamine C (44 c), which had initially also been isolated,
is not a natural product, but an artifact of the workup
conditions.[79, 80]
The seven-membered bridged biaryl lactam (P)-45
(Figure 12), although configurationally stable at 140 8C for
7 days, undergoes acid-catalyzed atropisomerization to the
Figure 12. Proton-catalyzed atropodiastereomerization of the sevenmembered bridged biaryl amide 45.
thermodynamically more stable diastereomer (M)-45
(46 % de) within 3 days upon addition of a catalytic amount
of p-toluenesulfonic acid.[81] The acyliminium species 46,
formed reversibly by protonation, facilitates the interconversion due to its more planar structure (all bridging atoms sp2
hybridized) and, in particular, due to the intermediate
destruction of the five-membered oxazolidine ring annellated
to the bridge, which rigidifies the biaryl system in 45 (compare
also the dioxolane-annellated 37 and 36, Figure 8).
In some cases, it is the reactivities of the ortho substituents
themselves that are the origin of unexpectedly low rotational
barriers. For example, the enantiomerically pure hydroxy
aldehyde (M)-47 (Figure 13), a fourfold ortho-substituted
biaryl compound and thus anticipated to be configurationally
fully stable, still racemizes slowly at room temperature even
1
under neutral conditions (DG°
t296 K =
296 K = 99 kJ mol ,
[62, 82]
[83]
6.5 h).
Quantum-chemical calculations and experimental work[64, 82] show that the formation of the lactol intermediate 48 is the reason for this type of chemically induced
atropisomerization. As a biaryl system bridged with a sixmembered ring, 48 has a low atropisomerization barrier. A
solely physical rotation about the axis can be excluded since
the O-protected analogue (M)-49 is configurationally
stable.[82] Such a chemically induced atropisomerization
process via a lactol-bridged species has been postulated[84]
to be the reason for the lack of optical activity in the natural
product cynandione A (50).[85]
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Figure 13. Atropisomerization of the biaryl hydroxyaldehyde 47 via its
lactol 48; structure of the natural product cynandione A (50).
In summary, the occurrence of atropisomerism strongly
depends on the temperature, the steric demand of the ortho
substituents, and the length and rigidity of bridges, be they
constitutive or transient. The effects of meta and para
substituents and the chemical mechanism of atropisomerization also have to be taken into account.
3. Biaryls by Asymmetric CC Coupling
The classic approach to the synthesis of axially chiral
biaryl compounds entails a direct, atroposelective aryl–aryl
coupling step, that is, the construction of the axis occurs
simultaneously with the asymmetric induction. There are
several options to introduce the stereochemical information,
roughly divisible into diastereo- and enantioselective
approaches (Scheme 2). Diastereoselective biaryl couplings
have been realized by three different strategies: The simplest
involves the incorporation of a chiral bridge (often sourced
from the chiral pool) to prelink the two aryl substrates,
subsequently permitting a favorable intramolecular reaction
(51!11), as discussed in Section 3.1. Diastereoselective
intermolecular coupling reactions can be effected by utilizing
arenes that are modified by a chiral auxiliary, normally in one
of the ortho positions next to the coupling site (as in 9 + 52!
11, see Section 3.2), or by using a (tracelessly) removable
chiral element, for example, in the form of planar-chiral h6chromium complexes or ansa compounds (as for 9 + 53!11,
see Section 3.3).
An overall enantioselective approach has been achieved
by employing a chiral leaving group, as in 55, which is
eliminated in the coupling step (54 + 55!11, see Section 3.4). An enantioselective biaryl coupling will also result
if the stereochemical information is induced through a chiral
additive. Both stoichiometric and catalytic oxidative dimerizations have been realized with metal-based reagents (e.g.
with Cu) by using chiral ligands, usually amines, to induce the
axial configuration (56 + 57!11, see Section 3.5). Furthermore, based on redox-neutral couplings (9 + 10!11, for
example, Suzuki reactions), enantioselective procedures have
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(Scheme 3); these are accessible from (M)-binol ((M)-29)
and the corresponding aromatic diacids by twofold (symmetric, R = R’) or sequential (unsymmetric, R ¼
6 R’) esterification.[86] Ullmann coupling of (M)-58 led to (M)-59 with
Scheme 3. Atroposelective preparation of the biaryl diacids 60 by
Ullmann coupling of the (M)-binol-bridged diesters (M)-58.
Scheme 2. Basic strategies for the direct, atroposelective construction
of biaryl axes.
recently been developed, typically employing catalytic quantities of chiral bidentate N,P-ligands (see Section 3.6).
It is important to keep in mind that the construction of a
configurationally stable biaryl compound is, by definition, a
sterically hindered reaction, which often requires “forcing”
conditions to provide the coupled products in reasonable
yields. This, on the other hand, can cause a concomitant
atropisomerization at the axis, hence leading to diminished
atroposelectivities. Thus, care has to be taken that the
reaction conditions employed are still mild enough not to
interfere with the stereochemical integrity of the biaryl axis.
3.1. Intramolecular Coupling with Chiral Tethers
The coupling of two aryls units, pre-fixed through a chiral
bridge, is a popular strategy in asymmetric biaryl synthesis
since it provides two clear advantages: good yields for the
intramolecular aryl–aryl bond formation, and the possibility
to produce both homo- and cross-coupled biaryl compounds.
The approaches of this type can be divided into two principal
categories: those in which the bridge, or the chiral parts
thereof, are part of the intended product, and those in which
the tether is an artificial auxiliary (i.e. not part of the final
target) that has to be eliminated in the end.
Miyano et al. pioneered this method in the early 1980s by
employing diester-bridged systems of type (M)-58
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excellent stereocontrol (up to “100 %” de), albeit in low
chemical yields if a sterically hindered axis was created.
Hydrolysis of (M)-59 afforded the biaryl diacids (M)-60 with
recovery of (M)-29. Further studies on other diester tethers
revealed that the rigidity of the binol bridge is crucial to attain
high asymmetric inductions.
Significant progress was made in this area by Lipshutz
et al.,[87] who introduced diether bridges combined with a
more efficient coupling method via higher-order cuprates.[88]
The best chirality transfers were obtained with C2-symmetric
bridges derived from tartaric acid which bear two stereogenic
centers (Scheme 4),[89] as in the reaction of (R,R)-61 to give
(P)-62 (“100 %” de). The biaryl 2,2’-diol thus obtained are
valuable both as ligands and as precursors to natural products.
Sargent and co-workers proposed that the cyanocuprate
intermediates preferentially adopt the gauche conformation
63 A rather than the diaxial conformation 63 B, thus leading to
the observed stereochemical outcome.[90] Sugimura et al.
successfully introduced 1,3-diol-derived tethers.[91] For example, the intramolecular coupling reactions of 64 gave (M)-65
in 54 % (R = Me) or 78 % (R = Ph) yield with
> 99 % de.
This strategy has found application in the (partial) synthesis of natural products (and derivatives)[92–96] and ligands
for catalytic asymmetric synthesis;[97–100] some examples are
shown in Scheme 5. Lipshutz et al. synthesized (P)-66,[92] a
model system for the AB system of vancomycin (1, Figure 1),
and O-permethyltellimagrandin II ((P)-67),[96] a member of
the ellagitannin family. The natural product kotanin ((P)-69)
was constructed by Lin and co-workers.[93, 94] The enantiomerically pure diphosphines (P)-70 and (M)-71, used as the chiral
ligands in catalytic asymmetric hydrogenations, were prepared by GenÞt, Marinetti, and co-workers[97, 98] and by Chan
and co-workers,[99] respectively.
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the additional steps required to introduce and remove the
tether, in combination with the harsh conditions (e.g. BBr3)
needed to cleave some of the ether bridges. In view of the fact
that these are intramolecular coupling reactions, the yields
are relatively modest in many cases (generally 50–80 %).
Lipshutz and co-workers extended this methodology to
7,7’-bridged 2-naphthols of type (R,R)-72 (Scheme 6),[101, 102]
Scheme 4. The use of diether tethers bearing two stereogenic centers
in the diastereoselective synthesis of biaryl compounds.
Scheme 6. Atroposelective synthesis of the binaphthols (M)-73 by
using a remote 7,7’-tether.
with the option to prepare unsymmetrical biaryl compounds
by sequential etherification. Oxidative biaryl coupling with
MnVI gave the macrocyclic binaphthols (M)-73 in good yields
and excellent diastereoselectivities of up to 97 %. Furthermore, the chiral bridge of (M)-73 can be used as a linker for
polymer attachment. The resulting solid-supported ligands
were used successfully in a range of catalytic asymmetric
reactions.[103] 2-Amino-2’-hydroxy binaphthyls (so-called
“nobin”-ligands) have also been assembled through this
route.[104]
Intramolecular coupling reactions of arenes employing an
all-carbon chiral bridge have also been undertaken.[66, 105] Our
group made use of an acetonide-protected diol tether,[66] as in
(R,R)-74 (Scheme 7); the extra rigidity due to an additional
ring annellated to the bridge creates a configurationally stable
biaryl axis after coupling, thus compensating for the labilizing
effect of the short bridge (compare Figure 8). Although biaryl
Scheme 5. Use of diethers of the type 68 in the atroposelective
synthesis of biaryl ligands and natural products.
The use of 2,2’-linked chiral tethers allows an efficient and
versatile preparation of axially chiral biaryl compounds. The
asymmetric inductions observed are good to excellent, and, if
atropodiastereomeric product mixtures are obtained, these
are normally easy to resolve. Both C2-symmetric and, by
sequential etherification, heterocoupled products are obtainable, and although substitution patterns are constrained by
the tethering site, a range of valuable products have been
synthesized by this method. Drawbacks to this approach are
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Scheme 7. Atroposelective intramolecular biaryl formation by using the
all-carbon-tethered precursor (R,R)-74.
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formation occurred with excellent stereocontrol to give (M)37 as a single diastereomer, the yield of the coupling reaction
was low. Another problem was the lack of stereochemical
integrity at the axis upon acetal cleavage in (M)-37, as the
intermediate diol is configurationally semistable owing to the
central six-membered ring, thus leading to a lower enantiopurity in the ring-opened product (M)-75.
If the target biaryl system itself bears stereogenic centers,
the artificial bridge between the two coupling partners does
not need to carry stereochemical information. As part of their
synthesis of derivatives of calphostine, Merlic et al. bridged
the naphthalenes (R)-76 with phthaloyl chloride to give, after
oxidation,
the
bis(ortho-naphthoquinone)
(R,R)-77
(Scheme 8).[106] Oxidative coupling delivered the perylene-
((P,P)-81),[112] a dimeric ellagitannin with antitumor activity,[113] was synthesized from 80 (74 % yield). The stereochemically decisive step was a twofold oxidative biaryl
formation, which afforded both axes in a P-configured form
(Scheme 9).[114]
Scheme 9. Total synthesis of the ellagitannin coriariin A ((P,P)-81)
through a twofold biomimetic oxidative biaryl coupling.
Scheme 8. Highly atropodiastereoselective intramolecular oxidative
coupling in (R,R)-77 to give the perylenequinone (M)-78.
quinone (M)-78 as a single diastereomer in 51 % yield. The
additional rigidity induced by the phthaloyl linkage is
responsible for the excellent stereocontrol, as evident from
the analogous intermolecular coupling of the benzoyl derivative (R)-79, which proceeded with only 33 % de.[107]
The second large field of application of atropodiastereomeric intramolecular coupling reactions targets biaryl compounds that contain a chiral bridge as a structural element.
Although very specialized, this (often biomimetic) approach
has been used successfully in the synthesis of several complex
natural products.
The ellagitannins are plant secondary metabolites characterized by one or more atropisomeric hexahydroxydiphenoyl moieties attached to a glucopyranose core,[108] which has
been postulated to control the axial configuration in the
biosynthetic oxidative coupling step.[109] Along these lines,
Feldman and co-workers developed a biomimetic synthetic
strategy, which, besides validating the theory, has led to the
successful preparation of several simplified model biaryl
compounds and a number of natural products under virtually
complete stereocontrol.[110, 111] For example, coriariin A
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The atroposelective construction of the biarylic AB fragment was one of the major challenges in the total synthesis of
vancomycin (1) and was successfully achieved by Evans
et al.[115, 116] In this biomimetic approach, the additional (nonnatural) ortho methoxy group at the A ring of the tripeptide
82 (Scheme 10), as required to permit an oxidative biaryl
coupling, had a strong impact on the asymmetric induction at
the biaryl axis formed, as a result of its interaction with
stereocenter Ca of the chiral backbone: The epimer (S)-82,
with the natural S configuration at Ca (R = H, R’ = NHAc)
delivered the non-natural atropodiastereomer (M,S)-83 with
94 % de, whereas the non-natural R epimer at Ca, (R)-82 (R =
NHAc, R’ = H), gave (P,R)-83 with 94 % de and the naturally
occurring P configuration at the biaryl axis. It was argued that
a syn-coplanar conformation of the artificial ArOMe bond
and the hydrogen atom at Ca is maintained throughout the
coupling step, thus avoiding the destabilizing 1,3-allylic
repulsion between the larger NHAc group at Ca and ArOMe that would occur during formation of the minor
atropisomers. For a subsequent “correction” of the wrong
axial configuration, see Scheme 57.
More recently, Nicolaou et al. reported the completion of
the first total synthesis of the complex, polycyclic secondary
metabolite diazonamide A[117, 118] (Scheme 11, for an alternative approach, see Scheme 53). Witkop-type[119] photocyclization of the chiral bridged aryl bromide 84 afforded the
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Scheme 12. Atropodiastereoselective synthesis of the lignan (M)-87.
Scheme 10. Joint influence of the non-natural ortho methoxy group at
the A-ring and the stereocenter at Ca on the configuration at the biaryl
axis in the synthesis of the AB fragment of vancomycin (1, Figure 1).
oriented atroposelective preparation of a large number of
axially chiral biaryl compounds (e.g. for the evaluation of
structure–activity relationships in high-throughput assays)
was published by Schreiber and co-workers.[123] A highly
diverse family of N,O-bridged biaryl compounds 89 was
prepared from (S)-88 with good to excellent diastereoselectivities by coupling via higher-order cuprates (a small
selection of substances of this library is shown in
Scheme 13). The kinetic product (P,S)-89 initially obtained
gave rise to the other atropodiastereomer (M,S)-89 upon
heating, often with good de values.
Scheme 11. The photocyclization of 84 to give (M)-85 in the synthesis
of diazonamide A.
macrocyclic biaryl (M)-85. Although the yield was modest,
(M)-85 was the only atropodiastereomer observed.
The stegane series of lignans is another family of axially
chiral bridged biaryl compounds that can be synthesized
atroposelectively through oxidative intramolecular coupling
by taking advantage of stereogenic centers present in the
bridge,[120] again following the biosynthetic pathway.[121] In a
recent example shown in Scheme 12, Waldvogel and coworkers synthesized the lignan (M,S,S)-87 in 50 % yield from
the precursor (S,S)-86 in the presence of molybdenum
pentachloride, with no evidence of formation of the diastereomeric product.[122]
Among the numerous biaryl coupling reactions mentioned in this Review, the only one directed at a diversityAngew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Scheme 13. Synthesis of a family of tethered biaryl compounds 89 with
either desired axial configuration.
The method was applied to the polymer-supported synthesis of a library of > 400 axially chiral biaryl compounds
(Scheme 14). The chiral b-amino alcohols 91 and the two aryl
subunits 92 and 93 were attached stepwise to the pregrafted
linker 90 to give the polymer-fixed dibromide 94. Biaryl
coupling, optional atropisomerization, and eventual release
afforded the compounds 95. Points of diversity for this library
were the substitutions at the biaryl compound (R, R’) and at
the tether (R*) and the axial configuration. Biological testing
of this archive in phenotype and protein-binding screens was
moderately successful.
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Scheme 15. Synthesis of axially chiral biphenyls 98 by SN2 Ar reaction
of oxazolinylbenzene (S)-97 and influence of the electron-donating
properties of the ortho substituent R of the aryl Grignard reagent on
the asymmetric induction.
3.2. Intermolecular Coupling with Chiral ortho Substituents
ortho substituents of the aryl Grignard reagent.[127, 130, 131] In
general, at least one ortho substituent with an accessible free
electron pair (most commonly, OMe) is required to ensure a
well-defined transition state (see mechanism, Scheme 16).
Thus, the biphenyls (P,S)-98 were obtained with > 80 % de if
In contrast to intramolecular diastereoselective biaryl
coupling reactions, intermolecular variants require only one
of the two aromatic moieties to be chemically modified (only
by a chiral auxiliary, not by a bridge!), thus allowing a
relatively free substitution pattern at the second arene ring.
To ensure efficient chirality transfer, the asymmetric information is normally located in one of the ortho substituents,
that is, close to the coupling site.
The coupling of aryl carboxylic esters that bear a chiral
alcohol function should be a convenient access to axially
chiral biaryl systems. All such attempts, however, have as yet
failed to give atroposelectivities > 50 % de.[124, 125] The major
breakthrough in this field came from Meyers and co-workers,
who developed an efficient method for the stereoselective
construction of axially chiral biaryl compounds by nucleophilic aromatic substitution (SN2 Ar) of chiral ortho-methoxy(oxazolinyl)arenes with aryl Grignard reagents. The oxazoline moiety carries the chiral information and, additionally,
facilitates the nucleophilic attack by stabilizing the developing negative charge.
l-Valinol-derived oxazolines such as (S)-97 (Scheme 15),
which are easily prepared from the corresponding benzoic
acid, are the chiral coupling partners of choice in most
cases.[126–129] Regioselective nucleophilic displacement of the
ortho-methoxy function in (S)-97 by aryl Grignard reagents
(prepared from 96 and magnesium) delivered the tetra-orthosubstituted biphenyls 98. The sense of the asymmetric
induction and the levels of atropodiastereoselectivity strongly
depend on the relative electron-donating abilities of the two
Scheme 16. The stereochemical course of the SN2 Ar reaction of aryl
Grignard reagents on chiral aryl oxazolines.
Scheme 14. Synthesis of a library of axially chiral biaryl compounds of
the type 95 on polystyrene-based macrobeads.
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the second ortho substituent R exhibited no (R = Me) or very
low (R = CH2OTBS) electron-donating abilities. The Mconfigured atropodiastereomer (M,S)-98, however, was preferentially formed (60 % de) if the electron-donor character of
R was superior to that of OMe (e.g. R = 1,3-dioxolan-2-yl). In
the case of comparable donating abilities, as for R = CH2OMe
or CH2OBn, the reactions proceeded with low stereocontrol
( 20 % de). Steric effects, such as the relative size of R and
OMe, are of minor importance, as highlighted by the fact that
with R = Me and R = CH2OTBS the same M-configured
diastereomers (M,S)-98 were obtained, with similar asymmetric inductions.
As a consequence of these experimental observations, the
reaction is believed to proceed through an addition–elimination mechanism, with the overall diastereoselectivity determined by both steps (Scheme 16).[127, 130] Initially, a chelate
complex is formed between the aryl Grignard reagent and the
ortho-methoxy(oxazolinyl)arene. Of the two possible diastereomeric arrangements, 99 B is strongly favored over 99 A, as
the former avoids the steric repulsion of the substituent R of
the oxazoline moiety with the ortho substituents of the
Grignard reagent. Nucleophilic addition in 99 B leads to the
aza-enolates 100 A and 100 B. If the substituent R’ does not
exhibit significant chelating abilities, complexation of the
methoxy group to the magnesium center strongly favors the
intermediate 100 B. After elimination of MeOMgBr, the
stereochemical alignment of the two aryl moieties thus fixed
is transferred into the axially chiral biaryl product 101 B.
However, if R’ is also able to act as a chelator to MgII, the azaenolates 100 A and 100 B are formed in ratios that reflect the
relative donating abilities of R’ and OMe, thus leading
preferentially to 101 A or 101 B or mixtures thereof.
This technique was used to produce several axially chiral
biaryl natural products and derivatives,[128, 132–135] some of
which are shown in Scheme 17: ( )-schizandrin ((P)-104)[128]
Scheme 17. Biaryl natural products prepared by nucleophilic aromatic
substitution of aryl Grignard reagents 102 on aryl oxazolines of type
103.
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and (+)-isodiospyrin ((P)-105)[132] (both the non-natural
enantiomers), O-methylancistrocline ((P)-106),[133] and ( )steganone ((M)-107).[134]
The main advantages of this method, which allows
convenient access to cross-coupled (i.e. non-C2-symmetric
biaryl systems), are its simplicity, reliability, and robustness.
The chiral oxazoline substituent is easily prepared from the
corresponding aromatic acid and the amino alcohol, and can
be transformed, after biaryl formation, into a variety of
functional groups. Some limitations arise from the use of an
aryl Grignard reagent and its structural requirements: To
attain high atropodiastereoselectivities, one of the substituents ortho to the coupling position (usually OMe) must
possess a free electron pair to chelate the magnesium, while
the other one must not. However, the substitution pattern of
the biaryl products formed, namely an ortho-methoxy group
and a C1 unit from the oxazoline in the ortho’ position, is
common to many natural products and so this route has a
wide field of application.
Chiral ortho-bromo(oxazolinyl)arenes are also suitable
starting materials for asymmetric Ullmann homocoupling
reactions to give C2-symmetric biaryl products with high
diastereomeric purities. This section deals only with those
cases that are known to proceed through a stereoselective
aryl–aryl bond-formation step; many homocouplings of sterically less congested phenyls are first-order transformations,[136] that is, the (more or less) racemic biaryl compound
initially produced is subsequently resolved by diastereoselective formation of a copper–chelate complex, and are, as such,
treated in Section 4.2.4.
The Ullmann homocoupling of the 1-bromo-2-oxazolinylnaphthalenes (S)-108 gave the binaphthyls (P)-109 with
diastereoselectivities that were strongly dependent on the
steric demand of the substituent R of the oxazoline
moiety;[126, 137, 138] only with the bulky tBu group was an
excellent 94 % de achieved (Scheme 18).[139] Meyers and
Nelson proposed the diaryl cuprates 111 as the stereochemically decisive species.[137, 138] Intermediate 111 A, which leads
to the observed product (P)-109 by reductive elimination of
CuI, avoids the steric repulsion between the two tBu groups of
the oxazoline portions and is, thus, energetically favored over
111 B. More recently, based on X-ray crystal structures of
related aryl–copper species, Andrus et al. suggested an
alternative intermediate.[140] It was argued that an eightmembered Cu4 aggregate of type 110 might be formed, with
the two naphthyl rings arranged in a more or less antiparallel
fashion. According to this model, the stereoselectivity would
be controlled by the steric interactions of the flanking tBu
groups with the bridged bromine atoms; intermediate 110, in
which these repulsions are avoided, is energetically favored
over the diastereomer with tBu and the bridging Br atom both
on the same side (not shown).
The method has found application in the atroposelective
synthesis of the cotton-seed-derived natural binaphthyl (P)gossypol ((P)-114, Scheme 19).[141, 142] Treatment of the naphthyl oxazoline (S)-112 with copper in refluxing DMF delivered the biaryl (P)-113 in 80 % yield and with a high
asymmetric induction of 89 % de. Further transformation of
(P)-113 into the target (P)-114 was straightforward.
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Scheme 20. The a-methoxy-b-sulfinyl side chain as an effective chiral
controller in the atroposelective Suzuki coupling reactions of (R,R)-115
with 116; the absolute configuration of the products (R,R)-117 at the
biaryl axis is unknown.
Scheme 18. Asymmetric Ullmann coupling of the 1-bromo-2-oxazolinylnaphthalenes (S)-108 to give (P)-109.
Scheme 19. Atroposelective synthesis of the natural product (P)-gossypol ((P)-114).
The Ullmann coupling of aryl oxazolines provides efficient access to C2-symmetric binaphthyls, but a drawback is
the high price of the tert-leucinol-derived oxazoline required
for high stereocontrol. It should be noted again that many
examples of Cu-mediated reductive coupling reactions are
not based on a stereoselective aryl–aryl bond-formation step,
but on a subsequent deracemization of a biaryl species
initially produced in a more or less racemic form (see
Section 4.2.4).
Apart from these well-investigated cases with oxazolines
as the chiral ortho substituents,[143] an a-methoxy-b-sulfinyl
side chain next to the coupling position was found to be an
effective asymmetric inductor in stereoselective Suzuki
reactions, as demonstrated by Colobert and co-workers in
2003 (Scheme 20).[144] Coupling of the iodides (R,R)-115,
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which are accessible in three steps from the corresponding
esters, with the boronic acids 116 delivered the biaryl products
(R,R)-117 (absolute axial configuration unknown) in high to
excellent yields (up to 99 %) with almost complete asymmetric induction (> 98 % de). Both stereogenic elements in the
side chain are required for the high chirality transfer:
Removal of the stereocenter at the sulfoxide by oxidation
to the sulfone led to diminished atropodiastereoselectivities
(70 % de), while inversion of the configuration of the
methoxy-substituted Ca atom failed to give any significant
asymmetric induction (10 % de, “mismatched case”). The
“opposite” couplings of phenyl boronic acids with 1-bromo-2(a-methoxy-b-sulfinyl)naphthalenes were less stereoselective
(only up to 70 % de). Further investigations into the development of efficient procedures for desulfurization and removal
of the chiral side chain are necessary to allow an extension of
this promising method to the atroposelective synthesis of a
wider range of biaryl systems.
Besides the element of axial chirality, many biaryl natural
products bear additional stereocenters, which can be used as
the chiral controlling units for the atroposelective construction of the biaryl axis. Two examples of such (rather special)
approaches with internal asymmetric induction are described
below.[145–147]
The perylenequinone calphostin A ((P)-120), a potent
protein kinase C inhibitor, contains two chiral b-benzoyloxypropane side chains; this stereochemical information was
used in the atroposelective total synthesis of (P)-120 by
Coleman et al. (Scheme 21).[145] Oxidative homocoupling of
the chiral naphthalene (S)-118 via a higher-order aryl cuprate
delivered the binaphthalene (P)-119 in 70 % yield. In view of
the remote position of the stereocenter, the 78 % de obtained
was remarkable. Transformation of (P)-119 into the target
(P)-120 was achieved in six steps.
Most members of the rapidly growing class of naphthylisoquinoline alkaloids (for examples, see Schemes 26, 64, and
67) bear a methyl group at the C3 stereogenic center of the
isoquinoline portion. Lipshutz et al. investigated whether an
appropriate substituent at this position can induce a good
central-to-axial chirality transfer (Scheme 22).[146] Suzuki
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naphthyl moiety is forced into a position above the face of the
Pd center, with the bulky OTIPS substituent directed away
from the dppf ligand. Reductive elimination of PdII in 124
should lead to the observed product (P)-123.
Even though the latter approaches have been developed
for the atroposelective synthesis of relatively special target
biaryl systems, they clearly demonstrate that remote stereogenic centers can also induce high levels of central-to-axial
chirality transfer.
3.3. Intermolecular Coupling with the Element of Planar Chirality
Scheme 21. Atropodiastereoselective synthesis of the perylenequinone
calphostin A ((P)-120).
The methods described in the preceding section require
the presence of a chiral auxiliary attached to an appropriately
modified ortho substituent. Thus, a worthwhile strategy would
be based on a fixed (but not covalently bound), tracelessly
removable stereogenic element. These conditions are fulfilled
by planar-chiral transition-metal–arene complexes in which
the metal fragment activates the arene by h6-coordination
and, at the same time, serves as a source of chiral information.
This concept was realized by Uemura and co-workers with
[(arene)Cr(CO)3] complexes such as 126 (Scheme 23).[22] For
Scheme 22. Efficient atropodiastereoselective synthesis of the
korupensamine A related naphthylisoquinolines (P)-123 b and c by
using the chelating properties of a linked PPh2 unit.
Scheme 23. Highly atropodiastereoselective Suzuki cross-couplings of
the phenylboronic acids 125 with the planar-chiral [(arene)Cr(CO)3]
complexes 126 (all compounds racemic).
coupling of the naphthyl boronic ester 121 with the OTIPS
derivative (R,S)-122 a gave the biaryl product (P)-123 a with
low selectivity (11 % de), thus indicating that steric bulk alone
is not sufficient for good stereocontrol. The situation changed
dramatically when a diphenylphosphanyl group, which can act
as an additional binding site for the palladium catalyst, was
attached, as in (R,S)-122 b and c. In both cases, the Pconfigured biaryl compounds (P)-123 b and c were obtained
exclusively; the benzoic ester linked PPh2 derivative (R,S)122 c showed an increased redox stability and gave a better
yield than the diphenylphosphanyl alkoxide (R,S)-122 b. The
origin of the nearly complete chirality transfer in the reaction
of (R,S)-122 b with 121 was explained by formation of the
intermediate 124, in which the chelating PPh2 group efficiently blocks the bottom face of the palladium atom. The
exploratory model reactions these planar-chiral substrates
were used in a racemic form. Pd-catalyzed Suzuki coupling of
the phenyl boronic acids 125 with 126 delivered the biaryl
chromium complexes syn-127 or anti-127 with excellent
atropodiastereoselectivities (up to “100 % de”),[148–151] generally leading to the sterically more congested atropodiastereomer syn-127, in which the substituent R is directed towards
the Cr(CO)3 fragment (Scheme 23, entries 1–3). If an ortho
carbonyl group is present, the thermodynamically more
favored atropodiastereomer anti-127 may also be obtained
as the sole product (Scheme 23, entries 4 and 5), probably due
to subsequent isomerization at the biaryl axis under the
reaction conditions, as the consequence of the lower rotational barrier (see below). There is, however, no clear trend as
the analogous reactions of [(ortho-formyl arene)Cr(CO)3]
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complexes gave stereochemically inconsistent results
(Scheme 23, entries 6 and 7). In general, the electron-withdrawing Cr(CO)3 fragment must be located on the aryl halide
portion as it accelerates the oxidative addition to Pd0.[22, 152]
The alternative coupling of an aryl halide with a {Cr(CO)3}complexed aryl boronic acid resulted in poor coupling yields.
Extension of the method to di-ortho-substituted aryl boronic
acids and 2-substituted 1-naphthyl boronic acids led, in many
cases, to diminished yields and stereoselectivities.[22, 149, 153]
It has been proposed that the initial formation of the
thermodynamically less stable syn product is caused by steric
repulsions in the two relevant diastereomeric cis-diorganopalladium intermediates 128 A and 128 B (Scheme 24).[22, 149]
Scheme 25. Atropodiastereomerization of syn-130 to give anti-130
under thermal conditions and axial rotation upon oxidation of syn-131
to give anti-132 (all compounds racemic).
decreases, for example, in the oxidation of the CH2OH
substituent of syn-131 to the respective formyl group of anti132 (Scheme 25, bottom).
Planar-chiral [(arene)Cr(CO)3] complexes have been used
in the atropoenantioselective synthesis of the AB fragment of
vancomycin (1, for the structure, see Figure 1),[157, 158] of the
naturally occurring biaryl compounds ( )-steganone ((M)107; Scheme 17),[159] and of korupensamines A ((P)-137) and
B ((M)-137).[160, 161] The latter two were prepared in an
atropodivergent approach (Scheme 26) from the enantiomerically pure planar-chiral [(arene)Cr(CO)3] complex (PS)133.[160, 162, 163] Its Suzuki coupling with the naphthyl 1-boronic
acid 134 delivered the planar and axially chiral biaryl (P,PR)-
Scheme 24. Stereochemical origin of the observed formation of the
thermodynamically less stable [(biaryl)Cr(CO)3] complexes syn-129. The
blue arrow indicates the rotation that occurs upon biaryl-bond formation.
In both species, the {Cr(CO)3} fragment is directed towards
the other arene moiety thus avoiding severe steric interactions with the bulky PPh3 ligands, but 128 A is thermodynamically favored due to the weaker steric repulsions between H
and RL relative to those between R and RL in 128 B. The ratedetermining reductive elimination in 128 A leads, under
kinetic control, to the chromium biaryl complex syn-129 as
the simultaneous rotation around the forming biaryl axis
proceeds in a way that minimizes the steric interactions: The
H atom is turned “outside” towards the bulky PPh3 ligand and
the substituent R moves “inside” towards the {Cr(CO)3}
moiety.
By heating in aromatic solvents, the trisubstituted biaryl
compounds syn-130 can be isomerized to give the thermodynamically more stable atropodiastereomers anti-130
(Scheme 25, top).[149, 154, 155] Similar attempts with naphthalene
biaryl chromium complexes resulted in lower conversion rates
owing to increased steric bulk restricting rotation around the
biaryl axis. Functionalization of one of the ortho substituents
may also lead to a thermodynamically driven axial rotation,
even at room temperature.[149, 154, 156] This occurs preferentially
(but not necessarily)[154] if the steric demand of the substituent
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Scheme 26. Atropodivergent synthesis of korupensamines A ((P)-137)
and B ((M)-137) starting from the enantiomerically pure
[(arene)Cr(CO)3] complex (PS)-133.
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135 in 74 % yield. After oxidation of the CH2OH group to the
aldehyde, the axial configuration can be inverted by thermal
diastereomerization to give the M-configured biaryl (M,PR)136 in 65 % yield. Both biaryl compounds (P,PR)-135 and
(M,PR)-136 were demetalated and used as intermediates in a
total synthesis of (P)- and (M)-137.[164, 165]
The major advantages of the “[(arene)Cr(CO)3] method”
are the high yields and the excellent, in many cases almost
complete, stereoselectivities achieved in the aryl–aryl coupling step, and that both atropisomers are, in principle,
accessible from a single planar-chiral precursor by thermal
axial isomerization. The {Cr(CO)3} fragment can be removed
by photooxidative demetalation (hn, O2) with yields between
50 and 90 %, depending on the substrate. Besides the toxicity
of the chromium compounds, the most problematic limitation
is the restricted and laborious access to the enantiomerically
pure [(aryl halide)Cr(CO)3] complexes that are crucial for the
preparation of stereochemically homogeneous biaryl systems.[166] Furthermore, the otherwise excellent coupling yields
and diastereoselectivities decrease with increasing steric
hindrance at the coupling sites, thus hampering the atroposelective synthesis of, for example, tetra-ortho-substituted
biaryl compounds. The range of tolerated substituents is
limited; there seems to be no general rule and extensive trials
are required to find the respective optimum system. To date,
Suzuki couplings of more-sophisticated (and, thus, harder-toaccess) [(aryl halide)Cr(CO)3] complexes have not been
reported.
An elegant approach without any transition-metal complex was reported by Miyano and co-workers (Scheme 27).[167]
Nucleophilic attack of enantiomerically pure dioxocyclophane (PR)-139 by the naphthyl Grignard reagents 140 and
141 with concomitant cleavage of the ansa chain delivered
(P)-138 and (P)-142, respectively, in high yields and ee values.
The opposite stereoarrays at the biaryl axes of (P)-138 and
(P)-142 appear to be a result of the coordination abilities of
the ortho-methoxy group versus the steric demand of the
naphthalene ring.[63]
provides the advantage of an easy introduction of the chiral
auxiliary into the molecule; it is then automatically replaced
in the aryl–aryl bond formation, without the necessity of an
additional removal step. Furthermore, with the asymmetric
information located so close to the reaction center, high levels
of chirality transfer should be achievable. This promising
and—overall—enantioselective approach has been realized in
the coupling of aryl Grignard compounds with chirally
modified alkoxy arenes and aryl sulfoxides. As with the
related Meyers methodology (see Schemes 15–17),[126, 137] an
ester (or oxazoline) function ortho to the leaving group is
necessary to stabilize the intermediate negative charge and to
ensure formation of a rigid and stereochemically well-defined
transition state.
As early as 1982 Wilson and Cram screened several chiral
alcohols for their suitability as chiral leaving groups, but only
(R)-menthol was found to give satisfactory optical purity and
chemical yields in the coupling step.[168] Later, Miyano and coworkers investigated coupling reactions of the alkyl 1-(R)menthoxynaphthalene-2-carboxylates (R)-143 with the naphthyl Grignard reagents 140 and 141.[169] The binaphthyls (P)144 and (P)-145 were obtained in high yields with up to
98 % ee (Scheme 28). The influence of additional stereochemical information in the ester group on the enantioselectivity is
inconsistent and negligible (see also beginning of Section 3.2).
Scheme 28. Atropoenantio- or atropodiastereoselective biaryl synthesis
by SN2Ar on the chirally modified 1-(R)-menthoxy naphthalenes (R)143.[63]
Scheme 27. Atroposelective synthesis of (P)-138 and (P)-142 by
Grignard coupling of 140 and 141 with the planar-chiral dioxocyclophane (PR)-139.[63]
3.4. Intermolecular Coupling with Chiral Leaving Groups
Biaryl synthesis by nucleophilic aromatic substitution
(SN2Ar) offers the chance to use a chiral leaving group as the
source of the asymmetric information. This concept usually
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The two products, (P)-144 and (P)-145, have opposite
axial configurations (despite their identical stereodescriptors),[63] which was explained by chelate versus nonchelate
control (Scheme 29):[169, 170] Of the two possible chelate
complexes 146 formed between the two reactants in the
initial step, the diastereomer 146 B is thermodynamically
favored over 146 A owing to the asymmetry of the menthol
leaving group. Aryl migration in 146 B preferentially leads to
the conformer 147 A if a coordinating group, in this case OMe,
is present. Its strong intramolecular ligation to the magnesium
center overrides the steric repulsion between the two
naphthyl moieties. In the absence of a coordinating substitu-
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Scheme 31. Atropoenantioselective binaphthyl syntheses by using the
chiral sulfoxides (R)-151 as starting materials.
Scheme 29. Chelation versus nonchelation control in atropoenantioselective biaryl formation through SN2Ar reaction with chiral leaving
groups.
ent (R = H), conformer 147 B is favored, in which the
destabilizing steric interactions are minimized. The respective
axial twists are conserved into the products (P)-145 and (P)144.
In contrast to the formation of binaphthyls, the analogous
preparation of biphenyls proved to be more difficult, with triortho-substituted examples giving mainly modest atropoenantioselectivities.[171] The reaction of 148 with (R)-149 to
afford the tetra-ortho-substituted biphenyl (M)-150 did,
however, proceed in high chemical yield and optical purity
(Scheme 30).
Scheme 30. Highly atropoenantioselective coupling of 148 with the aryl
(R)-menthylether (R)-149 to give (M)-150.
Chiral sulfoxides as non-ether-based leaving groups were
evaluated by the groups of Baker and Sargent
(Scheme 31).[172] Grignard coupling of 140 with the naphthyl
1-sulfoxides (R)-151 delivered the binaphthyls (M)-152 in
good to high yields and with excellent stereocontrol (95 % ee).
Nevertheless, this approach is hampered by several disadvantages: No coupling reaction was observed with the sterically
more demanding 2-methoxy derivative of 140, and the
preparation of (R)-151 in enantiopure form is rather labor-
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intensive. The more easily accessible tolyl analogue of (R)151, in which tBu is replaced by pTol, is less suited for this type
of biaryl coupling since it racemizes under the reaction
conditions, thus leading to diminished atropoenantioselectivities (60–82 % ee).
Even though the initial investigations were done more
than 20 years ago, this approach is still in its infancy. Chiral
leaving groups that are more widely applicable and easier to
attach chiral leaving groups need to be developed to make
this method, which relies on a stoichiometric use of the chiral
auxiliary, more flexible and therefore competitive to other
Grignard-based biaryl coupling reactions.
3.5. Oxidative Homocoupling in the Presence of Chiral Additives
The oxidative coupling of phenols is by far the most
widespread pathway in the biosynthesis of biaryl natural
products; it is also a common laboratory method for the
formation of binol (1,1’-dinaphthalene-2,2’-diol) derivatives
from the respective 2-naphthols.[173] Owing to the good
availability of the “monomeric” substrates, the convenient
reaction protocols, and the importance of the products as
chiral auxiliaries in asymmetric synthesis, many attempts have
been undertaken to translate this chemistry into atroposelective syntheses.
The most widely investigated catalysts to fulfill this goal
have been chiral amine–copper salts, mainly due to the ease of
ligand screening. It should be noted that the first preparation
of highly enantiomerically pure binaphthyls reported by
Brussee et al., by the homocoupling of 2-naphthol in the
presence of CuCl2 and amphetamine, was shown to be a
dynamic kinetic resolution of binol and not the consequence
of an atropoenantioselective biaryl coupling step, and will
thus be covered in Section 4.2.4.[174]
Highly successful and truly enantioselective oxidative
biaryl couplings[175] catalyzed by CuI in the presence of a chiral
amine were published by Kozlowski and co-workers in
2001,[176–179] with the C2-symmetric (S,S)-1,5-diazadecalin
(S,S)-155 as the ligand and O2 as the stoichiometric oxidant
(Scheme 32). In the presence of CuI and (S,S)-155 (10 mol %
each), the homocoupling of the 2-naphthol derivatives 154 to
give (M)-156 proceeded in good yields with up to 92 % ee. A
coordinating substituent at C3 (carboxylic or phosphonate
ester, benzoyl) is crucial to attain high atroposelectivities, as is
clear from the low stereocontrol achieved in the preparations
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Scheme 33. Atropoenantioselective preparation of the perylenequinone
(M)-161 by using a CuI/(S,S)-155-catalyzed oxidative homocoupling as
the stereochemical key step.
Scheme 32. CuI-catalyzed oxidative homocoupling of 2-naphthols of
type 154 in the presence of the chiral diamine (S,S)-155 and O2.
of binol itself (29, 16 % ee). Thus, the stereochemical outcome
was rationalized by bidentate coordination of the substrate to
the chiral amine–copper complex.[176, 180] As exemplified for
the homocoupling of 154 a, electron transfer should lead to
the formation of the tetrahedral [CuI] complex 157, which
carries a C-centered radical.[176] The second substrate should
approach from the less-hindered top face to give 158 stereoselectively. Tautomerization along with clockwise rotation
around the forming biaryl axis should then establish the
observed axial configuration.
Although the requirement for a suitable substituent at C3
to aid bidentate coordination is an obvious limitation to its
scope, this method does provide efficient catalytic enantioselective access to chiral binol derivatives. The synthetic
potential of this approach was demonstrated by the enantioselective preparation of the perylenequinone (M)-161 catalyzed by CuI/(S,S)-155 (Scheme 33).[181, 182]
The oxidative homocoupling of 2-naphthols in the presence of ruthenium(ii)–salen catalysts (Scheme 34) developed
by Katsuki and co-workers involves a single-electron transfer
upon irradiation with visible light.[183] (M)-Binol ((M)-29) and
its derivatives (M)-164 a and b were obtained in reasonable
chemical yield and optical purity (65–68 % ee), whereas a low
ee value of 33 % was found for the methoxy-substituted biaryl
(M)-164 c. The ester 162 d failed to give a coupling product.
With regard to the structural requirements in the salen
catalyst (P,P)-163, changes in the chiral bridge did not
significantly affect the stereoselectivity. Substitution of the
two axially chiral binaphthyl moieties by simple aryl groups,
however, decreased the enantioselectivity considerably, indicating the crucial role of the two binaphthyl units around the
metal center for the chirality transfer.
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Scheme 34. Oxidative homocoupling of 2-naphthols catalyzed by the
[RuII(salen)Cl(NO)] complex (P,P)-163.
A variety of VIV-based catalysts have also been studied for
their application in asymmetric oxidative biaryl couplings.[184, 185] Most successful so far have been “dimeric”
oxovanadium(iv) complexes of chiral Schiff bases with a
biaryl backbone (Scheme 35). With 5 or 10 mol % of (M,S,S)167 or (S,S)-168 as the chiral catalyst and O2 as the
stoichiometric oxidant, the homocoupling of 2-naphthol
(153) and its derivatives 162 and 165, which bear substituents
at C6 or C7, proceeded in high yields with excellent stereocontrol (up to 97 % ee).[184] Intriguingly, the complex (S,S)168, which contains a configurationally labile biphenyl axis
and, thus, may exist as a mixture of (possibly interconverting)
diastereomers, is as selective as (M,S,S)-167 with its configurationally stable M-binaphthyl scaffold.
In general, all the oxidative couplings described so far[186]
were performed on 2-naphthol-derived substrates to give
homodimeric 2,2’-dihydroxy-1,1’-binaphthalenes. The recent
development of more-effective catalytic systems resulted, in
many cases, in high chemical yields and optical purities with
model substrates, but the potential of these methods for
application to more-sophisticated substrates remains to be
proven, also in terms of a wider tolerance towards functional
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3.6. Redox-Neutral Cross-Coupling Catalyzed by Chiral Metal
Complexes
Scheme 35. Oxidative homocoupling of 2-naphthols catalyzed by the
chiral oxovanadium(iv) complexes (M,S,S)-167 and (S,S)-168.
groups. Despite the limited range, the synthetic importance of
the products thus easily accessible may lead to prominent
applications of the method to the large-scale production of
enantiopure C2-symmetric binaphthols in the future.
Besides such chemically induced oxidative biaryl couplings of 2-naphthols, there is a single report on an electrochemical variant, utilizing a TEMPO-modified graphite-felt
electrode in the presence of a stoichiometric amount of ( )sparteine (( )-173, Scheme 36), by Osa et al.[187] (P)-Binol
((P)-29) and its derivatives (P)-171 and (P)-172 were
obtained in high yields (> 90 %) and with excellent atropoenantioselectivities (99, 94, and 98 % ee, respectively). This
electro-oxidative method, however, has three disadvantages:
1) It is not catalytic with respect to the chiral auxiliary ( )173; 2) the (+) enantiomer of ( )-173, which is necessary to
produce the M atropoenantiomers, is not commercially
available; and 3) the equipment needed is not found in
standard synthetic laboratories.
Scheme 36. Electrochemical oxidative homocoupling of 2-naphthols in
the presence of ( )-sparteine (( )-173).
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Redox-neutral biaryl couplings, widely used in nonstereoselective biaryl synthesis,[19] provide several benefits: They
proceed under relatively mild conditions, they are not
restricted to a specific substitution pattern, and they allow
regioselective cross-coupling of two different aromatic moieties—in contrast to the homocouplings described in the
preceding section. The catalytic enantioselective version
offers two additional advantages, making such an approach
a nearly ideal method: First, the target biaryls are often
accessible with all the substituents required already in place,
thus avoiding any subsequent modification, for example, as in
the case of diastereoselective coupling procedures with an
attached chiral auxiliary. Second, with a chirally modified
transition metal as the carrier of asymmetric information, it is
one of the few methods that allows the catalytic and, thus,
highly economical use of the chiral information. Despite all
these favorable premises, there has been, as yet, only limited
research activity in the field.
Based on initial investigations by the Kumada group,[188]
Hayashi, Ito, and co-workers achieved the first successful
atropoenantioselective cross-coupling of aryl halides with aryl
Grignard reagents (Kumada cross-coupling).[24, 189] The axially
chiral binaphthalenes (M)-178 and (M)-179 were obtained in
excellent yields and enantiopurities (up to 95 % ee)
from 174 or 175 and 176 in the presence of
5 mol % of NiBr2, chirally modified with the ferrocenylphosphine (PS,S)-177 (Scheme 37).[162, 190, 191] This principle was
extended to the atroposelective preparation of ternaphthalenes.[192] Cross-coupling of 2 equivalents of 176 with 1,5dibromonaphthalene (180) catalyzed by Ni–(PS,S)-177 b delivered the desired ternaphthalene (M,M)-181 and meso-181 in a
84:16 ratio. The nearly complete stereocontrol (99 % ee) in
the formation of (M,M)-181 was interpreted as a result of the
twofold asymmetric induction over both cross-coupling
steps.[193] The methoxy group in the ligand (PS,S)-177 b is
crucial for a good chirality transfer ((PS)-177 a: 1 % ee vs.
(PS,S)-177 b: 83 % ee). It was postulated that this group
functions as a coordination site for the magnesium cation of
the incoming Grignard reagent in the transmetalation step,
thus creating the required defined stereochemical array (see
the Meyers mechanism, Scheme 16).[189]
Due to the very few examples to date of the atropoenantioselective Kumada cross-coupling,[191] an evaluation of the
scope and limitation of this method is not yet possible. The
use of aryl Grignard reagents, however, makes this approach
incompatible with several usual functional groups.
The Suzuki cross-coupling[194] is a most convenient
method for the preparation of biaryl compounds as it utilizes
aryl boronic acids or esters as the nucleophilic arene species;
these are easy to handle (air-stable and storable) and are
tolerant of a wide range of other functional groups. On the
other hand, the Suzuki coupling normally requires relatively
high temperatures and is susceptible to steric hindrance,
which hampered its application in asymmetric biaryl synthesis
for a long time. Recent solutions to these problems,[195]
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(3 mol %) modified by the ferrocene-derived bidentate
ligands (PS,S)-177 (6 mol %) as the catalytic systems.[196, 197]
With (PS,S)-177 b, which bears a methoxy substituent, the
binaphthyl (M)-178 was obtained in a good yield but with a
disappointingly low 14 % ee; the P,N-derivative (PS,S)-177 c
allowed a reasonably good enantioselectivity (63 % ee), albeit
compromised by a mediocre chemical yield (44 %). This result
is in contrast to the Kumada coupling (see preceding
Scheme), in which (PS,S)-177 b was used successfully and
(PS,S)-177 c failed to promote the coupling.[197] It was proposed that the stronger donor character of the NMe2 group is
necessary to precoordinate the less basic boronic acid in the
same way that the methoxy substituent does with the
magnesium cation of the aryl Grignard reagent in the
Kumada coupling.[197] Suzuki cross coupling of the sterically
more demanding aryl iodide 184 with the cyclic boronic ester
185 delivered the bis-ortho-substituted binaphthyl derivative
(M)-179 in 60 % yield with a good 85 % ee.[196, 197]
In the group of Johannsen, the air-stable ferrocenylderived monophosphines (PR)-186 have been utilized as the
chiral ligands for the [Pd2(dba)3]-catalyzed preparation of
(M)-179[198] from 175 and 183 (Scheme 39).[199] Depending on
the aryl substituent of (PR)-186, selectivities of 43–54 % ee
were attained.
Scheme 37. Nickel-catalyzed atropoenantioselective Kumada cross-coupling of 1-bromonaphthalenes with the 2-methyl-1-naphthyl Grignard
reagent 176 in the presence of the chiral ferrocenylphosphine (PS,S)177 b.
however, triggered exploratory research in asymmetric
Suzuki cross-couplings.
First investigations by Cammidge et al. in 2000 used 1iodonaphthalene (182) and 2-methylnaphthalene-1-boronic
acid (183) as model substrates (Scheme 38) with PdCl2
Scheme 39. Asymmetric synthesis of the dinaphthalene (M)-179 in the
presence of the planar chiral ferrocenyl monophosphine (PR)-186.[198]
Scheme 38. Atropoenantioselective Suzuki couplings with the
bidentate ferrocenylphosphines (PS,S)-177 as the chiral ligands.
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The most successful[200] asymmetric Suzuki couplings have
so far been published by Buchwald and co-workers.[201] Initial
screening showed that [Pd2(dba)3] and the electron-rich biaryl
aminophosphine (P)-188 were the catalytic system of choice.
As shown by the examples given in Scheme 40, cross-coupling
of the naphthyl phosphonate 187 with several phenyl boronic
acids 125 delivered the axially chiral biaryls (+)-189 (absolute
configuration not determined) in excellent yields (as high as
98 %) with up to 92 % ee. These are the only asymmetric
Suzuki couplings reported so far in which a phenyl (instead of
a naphthyl) boronic acid was used. The amount of Pd/(P)-188
(ratio 1.2:1) can be lowered to as little as 0.2 mol % without
any decrease in the optical purity (Scheme 40, entries 5 and
6). As shown in separate experiments, the phosphonate group
is not necessary to achieve the high stereocontrol; it can,
however, be converted into a PPh2 substituent, thus permitting easy access to axially chiral monodentate phosphines.
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Scheme 40. Selected examples of the asymmetric Suzuki cross-coupling of 187 with different phenyl boronic acids 125 in the presence of
the biaryl aminophosphine (P)-188.
There are very few applications of the asymmetric Suzuki
cross-coupling in the directed synthesis of biaryl natural
products; one notable example was reported by Nicolaou
et al. (Scheme 41).[202, 203] In model studies towards the atro-
Scheme 41. Model studies towards the atroposelective synthesis of the
biaryl fragment of vancomycin (1, Figure 1).
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poselective synthesis of the biaryl fragment of vancomycin
(1), the Pd-catalyzed cross-coupling of the iodophenyl 191
and the cyclic boronic acid 190 to give 192 was investigated.
Even though 191 is chiral, the two stereogenic centers do not
influence the configuration at the biaryl axis in 192, as is
evident from the coupling in the presence of PPh3 (0 % de).
However, (M)-192 and (P)-192 were obtained with high
atroposelectivities (> 90 % de) in the presence of (M)-binap
((M)-5) and (P)-binap ((P)-5), respectively, as the chiral
ligands.[204] Although the stereocontrol was excellent, the low
chemical yields and the high amount of the chiral ligands used
were not satisfactory.
The easy handling of the aryl precursors, the lack of
dependence on particular substitution patterns, the relatively
mild reaction conditions, and the catalytic nature of the
reaction with regard to the chiral ligands all add up to make
the asymmetric Suzuki coupling an attractive reaction strategy. However, only recent improvements have allowed its
application in stereoselective biaryl synthesis, and there are,
as yet, no standard procedures available; each new catalyst
and substrate still requires time-consuming optimization of
the particular reaction conditions (compare the different
reaction conditions used in Schemes 38–41). Furthermore, the
applicability of the method is often hampered by very long
reaction times (up to 1 week) and the occurrence of hydrodeboronation, which requires excess aryl halide. New, moreeffective ligands that deliver good and reliable chemical
yields and optical purities under standardized conditions for a
broad variety of substrates (including more-sophisticated
systems) will have to be designed. The Suzuki cross-coupling
could then become one of the most important methods for
atroposelective biaryl coupling.
No asymmetric biaryl couplings with other aryl metal
species such as aryl zinc (Negishi coupling) or aryl stannanes
(Stille coupling) have so far been reported, but there is a
single example of the use of a CareneC(sp3) cleavage with ipso
substitution (Scheme 42).[205] Treatment of 193 with 2-(1naphthyl)-2-propanol (194) in the presence of Pd(OAc)2 and
(M)-binap ((M)-5) delivered 2-methoxy-1,1’-binaphthalene
(195) in 83 % yield with a moderate 63 % ee under extrusion
of acetone. As this procedure avoids the use of any aryl metal
species, it may offer new perspectives for atroposelective
biaryl cross-couplings.
A different, Pd-free approach for the atropoenantioselective preparation of axially chiral biaryl compounds, with
aryl lead compounds as the synthetic equivalents of aryl
Scheme 42. Asymmetric biaryl coupling of 193 with the 2-(1-naphthyl)2-propanol 194 in the presence of Pd(OAc)2 and (M)-binap ((M)-5).
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cations and lithiated phenols as the nucleophiles, was
presented by Yamamoto and co-workers (Scheme 43).[206] In
the presence of excess brucine (201) as the chiral auxiliary of
choice, cross-coupling of lithiated 2-naphthol (Li-153) with
Scheme 44. Asymmetric biaryl synthesis by nucleophilic aromatic substitution with the chiral chelating agent (R,R)-205.
4. Atroposelective Transformations of Prostereogenic
Biaryl Compounds
Scheme 43. Asymmetric coupling of aryl lead complexes with lithiated
phenols in the presence of brucine (201).
the aryl lead 196 furnished the biaryl (M)-197 in 83 % yield
with 89 % ee, whereas the analogous reaction with aryl amines
as the substrates occurred less stereoselectively, probably due
to concomitant autocatalysis of the generated amine. The
method was also applied successfully to the synthesis of
teraryls. For example, treatment of 198 with 199 (2.5 equiv) in
the presence of 201 delivered (M,M)-200 in 99 % yield with
> 98 % de and 61 % ee.[207] The use of brucine in catalytic
amounts gave similar ee values but lower chemical yields. The
observed selectivity was rationalized by coordination of
brucine (201) and the phenolate to the lead atom to give,
after reductive elimination of Pb(OAc)2, either (R)-202 or
(S)-202 as the intermediates, both of which have the correct
stereochemical pre-M orientation at the future biaryl axis.
Fast tautomerization conserves the axial configuration in the
product (M)-197.
Tomioka and co-workers reported an efficient transitionmetal-free asymmetric synthesis of biaryl compounds by
nucleophilic aromatic substitution; the chiral information is
provided by a catalytic amount of the chelating agent (R,R)205 (Scheme 44).[208] 1-Naphthyl lithium (203) forms a complex with (R,R)-205 that adds stereoselectively to the 1-aryl
fluoride 204 bearing an aldimine side chain, to give the
postulated intermediate 206. Elimination of LiF and centralto-axial chirality transfer affords (M)-207, with concomitant
regeneration of the diether (R,R)-205. The reaction was,
however, sensitive to small changes in the reaction conditions,
and there has been little exploration of the substitution
patterns tolerated.
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Besides the conventional approach of direct, atroposelective biaryl coupling described in the preceding section, highly
efficient alternative strategies have been found in which the
construction of the target biaryl species is carried out over two
separate steps: a nonstereoselective CC coupling reaction
and a second step that finally establishes the absolute
configuration at the biaryl axis. This concept permits an
optimization of each of the two steps independently.
For such an introduction of the stereochemical information at a preformed axis, the biaryl substrate has to be either
rotationally hindered but achiral or chiral but configurationally unstable. The first criterion is met if (at least) one of the
two aromatic portions is constitutionally symmetric, as in 208
(Scheme 45). An enantiotopos-differentiating transformation
of one substituent (here Y!Z) will reduce the symmetry and,
thus, lead to axially chiral biaryl products of type 209.
Concrete realizations of this approach are discussed in
Section 4.1. Nonsymmetric biaryl compounds such as 12 and
212 that are macroscopically achiral owing to rapid atropisomeric interconversion can be used as substrates for dynamic
kinetic resolution. One option, though rarely used, is the
atropoenantiomer-differentiating introduction of another
ortho substituent, which establishes and simultaneously
“locks” the axial conformation as in 210 (see Section 4.2.1).
Alternatively, atropoenantiomer-differentiating bridging of
the two aromatic “halves” of 12 delivers axially chiral biaryl
species of the type 211 if this process is associated with an
increase in the rotational barrier sufficient to reach configurational stability (see Section 4.2.2). Vice versa, the cleavage
of a short bridge that causes configurational instability, as in
212 AQ212 B, allows an elegant access to axially chiral biaryl
products (see Section 4.2.3). Moreover, biaryl compounds
that are configurationally stable under normal conditions can
undergo atropodiastereomerization if transiently bridged by a
transition metal; this protocol can be used for the dynamic
kinetic resolution of biaryl species that are stereochemically
stable under ordinary conditions, for example, rac-11!
(213 AQ213 B)!11 (see Section 4.2.4).
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(214) by atropodiastereoselective formation of an eightmembered diether bridge (Scheme 46).[209, 210] Upon etherification of 214 with the chiral dimesylate (S)-215, the biaryl
(P)-216 was obtained in a diastereomerically pure form.[211]
Scheme 46. Desymmetrization of 214 by atropodiastereoselective formation of a diether bridge.
Scheme 45. Concepts for the atroposelective synthesis of biaryl compounds with preformed, but stereochemically not yet undefined biaryl
precursors.
The excellent stereocontrol was rationalized to result during
the formation of the second ether linkage: Of the two
diastereomeric SN2-type transition states, (M)-217 is disfavored owing to the steric interactions of the methyl substituent with one of the aromatic rings. The method is limited to
symmetrically substituted 2,2’,6,6’-tetrahydroxy biaryl compounds, but further modification of the two remaining
hydroxy functions in the resulting biaryl diethers is possible[210, 211] (e.g. by conversion into the corresponding ditriflates
followed by Pd-catalyzed cross-coupling), thus broadening
the scope of the method.
As part of the enantioselective synthesis of the antiinflammatory drug candidate A-240610.0 (221, Scheme 47), Ku
and co-workers discovered an elegant central-to-axial chirality transfer. Upon O-deprotonation to 219, the axially
Before going into details, it should be noted that these
methods, which rely on a separation of the coupling step and
the introduction of the stereogenic information, are not
necessarily more labor-intensive than the direct asymmetric
coupling procedures described in the preceding section. The
diastereoselective aryl–aryl bond-formation reactions, for
example, necessitate the introduction and removal of a
chiral auxiliary, and therefore require at least three steps for
the atroposelective construction of a biaryl axis.
4.1. Desymmetrization of Configurationally Stable but Achiral
Biaryl Compounds
The transformation of rotationally fixed, but symmetric
(and hence achiral) biaryl species into axially chiral products
requires a desymmetrization of the arene moiety which can be
realized by an atropoenantiotopos or atropodiastereotopos
modification of one of its substituents.
Harada and co-workers even succeeded in breaking the
symmetry of the D2d-symmetric tetra-ortho-hydroxybiphenyl
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Scheme 47. Desymmetrization of 218 using an internal central-to-axial
chirality transfer.
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prostereogenic, but centrochiral biaryl 218 underwent an
atropodiastereotopos-differentiating migration of the sterically more accessible OTBSP, energetically driven by the
formation of a phenolate from an alkoxide, with an excellent
98 % de.[212] This remarkable reaction was, however, not taken
advantage of stereochemically, as the targeted drug candidate
221 does not actually have a configurationally stable biaryl
axis owing to the labilizing effect of the ether bridge.
Nevertheless, the route via the axially chiral biaryl (M)-220
was necessary to obtain good yields in the final etherification
step.[213] Despite its limitation to compounds that bear an achiral alcohol substituent in the ortho position, the approach
allows access to axially chiral biaryl compounds otherwise
difficult to prepare.[212]
An enantioselective dilithiation of the “axially proprostereogenic” tetra-ortho-methylated biphenyl 222 in the
presence of the chiral auxiliary ()-sparteine (()-173),
followed by an electrophilic quench with carbon dioxide,
was reported by Raston and co-workers (Scheme 48).[214] The
biaryl diacid (+)-223 was obtained with moderate stereocontrol (40 % ee).
A remarkable enantiotopos-differentiating cross-coupling
reaction was developed by Hayashi and co-workers.[216]
Treatment of the achiral 2,6-ditriflates 226 (Scheme 50) with
Grignard reagents in the presence of the chiral palladium
Scheme 50. Atropoenantiotopos-differentiating desymmetrization of
226 by cross-coupling in the presence of catalytic [PdCl2{(S)-alaphos}]
(227).
Scheme 48. Desymmetrization of 222 via enantioselective di-lithiation;
the absolute configuration of (+)-223 is unknown.
In an approach by Matsumoto et al. in which enzymes are
used for the desymmetrization of prochiral biaryl compounds,[215] 2,6-diacetoxy-2’-alkyl biaryls 224 (Scheme 49)
were enantioselectively monohydrolyzed at the OAcP group
with Candida antarctica lipase (CAL) and Pseudomonas
cepacia lipase (PCL). The axially chiral 2-acetoxy-6-hydroxybiaryls (M)-225 were obtained in moderate to high yields (51–
94 %) and excellent enantioselectivities ( 96 % ee), even for
derivatives bearing small substituents R (e.g. R = Me). In all
cases, the M atropisomer predominated, for which, however,
no stereochemical rationalization was given.
complex 227 delivered the axially chiral biaryl compounds
(P)-228 in good yields and high to excellent enantioselectivities (up to 99 % ee). The stereochemical origin of the
asymmetric inductions observed was not discussed. Even
though most cross-couplings were performed with the naphthyl derivative of 226 (R, R’ = benzo), biphenyls with smaller
substituents such as R = Me also allowed good stereocontrol.
Because bulky Grignard reagents R’’MgBr were used exclusively, no statement is possible about the steric size of R’’
necessary for attaining high enantioselectivities. The remaining OTf group in the products (P)-228 can be subjected to a
second cross-coupling reaction, thus providing access to a
wider range of biaryl compounds. The method is of appreciable synthetic potential; it has, for example, been used in the
synthesis of the biaryl monophosphine ligand 229, a catalyst
for asymmetric hydrosilylation reactions.
The pioneering work on the desymmetrization of configurationally stable, but achiral biaryl species has led to
intriguing novel asymmetric approaches to axially chiral
biaryl products. The enantioselectivities have been good to
excellent. Still, all these methods lack a broader applicability
due to the substitution patterns required in the starting
materials and the not yet fully explored tolerance of functional groups and more-sophisticated substrates.
4.2. Atroposelective Conversion of Axially Chiral but
Configurationally Unstable Biaryl Compounds
4.2.1. Atropoenantioselective Introduction of Another ortho
Substituent
Scheme 49. Desymmetrization of 224 by atropoenantiotopos-differentiating enzymatic O-deacetylation using CAL (Candida antarctica lipase)
or PCL (Pseudomonas capacia lipase).
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The conceptually simplest way to produce chiral biaryl
compounds from configurationally labile biaryl species is to
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introduce, in an enantiomer-differentiating manner, a further
ortho substituent, thereby locking the axial configuration.
Murai and co-workers reported the atropoenantioselective
alkylation of 2-(1-naphthyl)-3-methylpyridine (230) through
rhodium-catalyzed aryl CH/olefin coupling (Scheme 51).[217]
The yields and enantioselectivities were mediocre with all
chiral catalysts screened; the best result (37 % yield, 49 % ee)
was achieved with the planar- and centro-chiral catalyst
(pR,R)-177 b.
et al. discovered a noteworthy atropodiastereoselective macrolactonization reaction.[219] Ring closure of the configurationally flexible model bisindole 235 afforded (M)-236 as a
single isomer (Scheme 53). The bulk of the NBoc2 group was
found to be pivotal for the excellent atropodiastereomeric
differentiation; with the sterically less demanding NHBoc
substituent, no preferred axial configuration was obtained.
Scheme 53. Atropodiastereoselective synthesis of the diazonamide A
model (M)-236 by macrolactonization.
Scheme 51. Atroposelective ortho ethylation of 230.
Owing to the aforementioned problems of enantioselectivity and the poor reactivity and regioselectivity, this direct
approach has, as yet, been little used.
4.2.2. Atropodiastereoselective Bridge Formation
The bridging of ortho substituents to give medium to large
rings can provide considerable rotational stability relative to
the corresponding open-chain system (see 38 and 39,
Figure 9). Therefore, asymmetric syntheses have been envisaged in which the chiral information is introduced by a
diastereoselective formation of a bridge, whereby an initially
rotationally labile and hence macroscopically achiral biaryl
system is “locked” into one of the two possible atropodiastereomeric forms.
In their studies towards ellagitannin derivatives, Nativi
and co-workers found that treatment of racemic, configurationally unstable 2,2’-dibenzoyl dichloride (232) with the
glycopyranose derivative 233 resulted in the formation of the
sugar-bridged biaryl product (P)-234 as a single atropodiastereomer, albeit in low yield (40 %, Scheme 52).[218] The rigid
scaffold of 233 was pivotal to ensure efficient resolution, as
analogous esterifications of 232 with more flexible rhamnose
derivatives led to low de values.
As part of their investigations towards the synthesis of the
cytotoxic marine natural product diazonamide A, Feldman
Scheme 52. Dynamic kinetic resolution of 2,2’-dibenzoyl dichloride
(232) by a glucopyranose-based scaffold.
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Levacher and co-workers discovered an intriguing
dynamic kinetic resolution through the formation of a
lactam bridge.[220, 221] Thus, configurationally unstable iso- or
heterocyclic biaryl compounds 237, equipped with ester and
keto functions in the ortho positions, react with (R)-phenylglycinol ((R)-238) to afford the bicyclic lactams (M)-240 with
excellent diastereoselectivities (> 95 % de; Scheme 54). The
axial configuration is dictated by the newly generated N,Oacetal stereocenter in the oxazolidine moiety of the intermediate 239.[222]
Scheme 54. Atropodiastereoselective synthesis of the biaryl lactams
(M)-240.
An efficient reaction sequence in which the chiral bridge
is used temporarily was developed by Hayashi and coworkers.[76] Upon esterification with the dichloride (M)-241
of (M)-1,1’-binaphthyl-2,2’-dicarboxylic acid, the configurationally unstable bipyridine diols 242 gave the respective
dilactones (M,P)-243 with 67–92 % de (Scheme 55). These
diastereomers constitute the kinetic products, since the axial
configuration in the bipyridyl moieties can be completely
inverted by thermal equilibration (accelerated considerably
by addition of acid)[77] to give the pure atropodiastereomers
(M,M)-243, without any decrease in stereochemical purity at
the binaphthyl axis. Subsequent N-oxidation of (M,P)-243
and (M,M)-243 enhanced the rotational barrier at the
bipyridine axis so that upon cleavage of the chiral auxiliary,
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An alternative approach is the dynamic kinetic resolution
of configurationally labile biaryl compounds by locking one of
the two possible atropodiastereomeric conformations by
chelation with a transition metal. This can be achieved if
either the metal is chirally modified by another ligand[223] or if
the biaryl substrate itself bears stereogenic centers.
A CuI-mediated deracemization of biaryl compounds was
described by Ikeda and co-workers.[224, 225] Upon addition of
CuOTf, the 2,2’-bis(2-oxazolinyl)biphenyl derivatives 246,
which are configurationally labile at the axis (e.g., for R =
tBu: t283 K = 0.07 s), gave the complexes (P)-247 as single
diastereomers (Scheme 57). These complexes can be used as
catalysts in asymmetric cyclopropanation reactions. The
formation of the respective M atropisomers (M)-247 is
energetically disfavored owing to severe steric interactions
between the substituents R (Scheme 69).
Scheme 55. Synthesis of the 2,2’-bipyridine N,N’-dioxides (P)-244 or,
optionally, (M)-244.
the 2,2’-bipyridine N,N’-dioxides (P)-244 and (M)-244,
respectively, were obtained as configurationally stable products. Therefore, this is one of the very few overall enantiodivergent methods that permit access to either of the two
biaryl atropoenantiomers in high purity by using the same
chiral auxiliary. The obtained N,N’-dioxides (M)-244 have
been successfully applied as catalysts in enantioselective
allylations of aldehydes.
Such a secondary, thermodynamically driven inversion of
an initially installed axial configuration was used in the
synthesis of the aglycone of vancomycin (1, Figure 1) by
Evans et al.,[116] as the biaryl axis formed at an earlier stage
was of the undesired, non-natural M orientation (see
Scheme 10). After construction of the planar-chiral CD ring
system, the “wrong” axial configuration was elegantly “corrected” through complete axial inversion (Scheme 56): Thermal equilibration of (M)-245 at 55 8C gave the desired natural
axial isomer (P)-245 with high diastereoselectivity.
Scheme 57. Atropodiastereoselective bridging of the bisoxazoline-substituted biphenyls 246 by CuOTf.
More widely investigated is the dynamic kinetic resolution
of configurationally labile biaryl–metal complexes by coordination of a second chiral ligand. This topic was recently
reviewed[223] and thus will be dealt with only briefly here.
A classic example of such complexes, as given by Mikami,
Noyori, and co-workers in 1999,[226, 227] is the ruthenium
complex 250 (Scheme 58), which was obtained by treatment
Scheme 58. Control of the axial configuration in the Ru-complex
(P)-250.
Scheme 56. “Correcting” a “wrong” initial axial configuration by thermodynamic control: inversion of the axial configuration of (M)-245 by
thermal equilibration to give the naturally configured diastereomer (P)245, a precursor to the vancomycin aglycone.
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of racemic, configurationally labile [RuCl2(biphep)] (rac-248)
with the enantiopure diamine (S,S)-249. Although initially
there was no preference for one diastereomer, atropodiastereomerization occurred upon heating to give the thermodynamically more stable complex (P)-250 in a diastereomerically pure form. Compounds of this type have been used as
enantioselective hydrogenation catalysts.
In summary, the bridging of conformationally flexible
biaryl compounds can also provide stability in di-orthosubstituted biaryl systems at room temperature. An obvious
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synthetic limitation of this approach is that the auxiliary
bridge must remain part of the ultimate product, as its
cleavage will lead back to a configurationally unstable biaryl
compound, unless further transformations are undertaken.
Therefore, this strategy has found its main field of application
in the synthesis of biaryl natural products (or analogues) that
bear appropriate functionality (i.e. a bridge and a controlling
stereoelement), but has so far found limited use in general
asymmetric biaryl synthesis. The kinetic resolution of biaryl
compounds by chelation to a chirally modified metal center
allows the application of otherwise achiral ligands in asymmetric catalysis. The approach is normally restricted to the
formation and thus use of only one of the two possible
atropodiastereomeric complexes—thus excluding the possibility to differentiate between a matched and a mismatched
situation for application in asymmetric synthesis. Still, the
strategy takes advantage of the well-known benefits of a
chiral biaryl backbone in such catalytic systems, whilst
avoiding the costly asymmetric synthesis or resolution of
rotationally stable biaryl ligands.
The first crucial step of this approach, the synthesis of the
biaryl lactones, is straightforward, as demonstrated for a
whole series of model compounds 33 with a variety of steric
bulk at the axis (Scheme 60). The easily accessible esters 256
4.2.3. Stereoselective Cleavage of a Bridge
Scheme 60. Preparation of the biaryl lactones 33.
Stereochemically labile lactone-bridged biaryls are the
key intermediates of a very efficient—and practicable—
strategy developed by our group for the asymmetric synthesis
of even highly hindered biaryl compounds.[20] As is the case
with the other concepts described in this section, this
approach separates the aryl–aryl bond formation from the
introduction of the stereochemical information at the biaryl
axis, thus avoiding a direct asymmetric biaryl-coupling step.
The principle of this strategy is depicted in Scheme 59. Initial
pre-fixation of ortho-bromobenzoic acids 251 and phenols 252
delivers bromoesters 254, which give the configurationally
unstable biaryl lactones 255 by PdII-catalyzed aryl–aryl
coupling. Atropoenantio- or atropodiastereoselective cleavage of the bridge by using a variety of possible chiral
nucleophiles establishes the axial configuration at the resulting, now configurationally stable (as it is open-chained) biaryl
products 253.
Scheme 59. The principle of the lactone strategy.
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undergo smooth aryl–aryl cross-coupling in the presence of
catalytic amounts of Pd(OAc)2 or the more reactive palladacycle 257.[61, 228] Owing to the favorable pre-fixation of the two
aromatic units, the formation of the biaryl bond to form the
six-membered ring occurs regioselectively and in high yields
(up to 91 %), even in cases of severe steric hindrance (for the
structures and dynamics of such lactone-bridged biaryl
species 33, see Figure 7). As an example, the sterically
severely distorted tBu-substituted lactone 33 f is obtained in
excellent yield (81 %) with 257 as the catalyst.
The second crucial step requires the atroposelective
transformation of the axially prostereogenic lactones 33 into
configurationally stable biaryl compounds, which can be
achieved simply by cleavage of the bridge with chiral O, N, or
H nucleophiles (Scheme 61).[20, 229, 230] Potassium (S)-1-phenylethylamide ((S)-259) and sodium (R)-menthoxide ((R)-261)
were the N and O nucleophiles of choice for the atropodiastereoselective ring opening of 33 b and 33 c, leading to the
respective biaryl amides 258 and esters 260 in good yields (70–
97 %) and diastereoselectivity (74–90 % de).[231–233] Almost
complete control of the configuration at the biaryl axis was
attained in the atropodiastereoselective cleavage of 33 c with
the sterically more demanding sodium (R)-8-phenylmenthoxide ((R)-262), delivering exclusively the ester (M,R)-263 c
in 95 % yield.[232]
The atropoenantioselective reduction of 33 was successfully accomplished either with (P)-binal-H ((P)-266) or, even
better, with borane in the presence of the (S)-CBS reagent
((S)-267).[228, 234] The biaryl diols (P)-268 b and (M)-268 c were
obtained in high yields (> 90 %) and with up to 97 % ee. Even
if only catalytic amounts of (S)-267 were used, the stereocontrol was preserved to a large degree (88 % ee with
0.1 equiv vs. 97 % ee with 3.0 equiv).[228, 234] The size of the
ortho substituent next to the axis (and the structure of the
lactone 33 in general) usually has no influence on the
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Scheme 61. Atroposelective ring opening of the lactones 33 b, c with chiral N, O, and H nucleophiles.[63]
direction of chirality transfer, making the ring-opening
reactions not only efficient with respect to the chemical
yields and optical purities, but also reliable with respect to the
expected configuration.
No predominant axial configuration was found upon ring
cleavage with chiral C nucleophiles.[235] The b-ketosulfoxide
(R)-265 c, for example, was obtained as a 1:1 mixture of its
atropodiastereomers after treatment of 33 c with (R)-264. This
is apparently not due to a nonstereoselective attack, but the
consequence of the low configurational stability of (R)-265 c
at the axis. As is the case with most of the known biaryl
compounds that bear an ortho-hydroxy and an ortho’-keto
function,[62, 64, 82, 84] (R)-265 c is configurationally semistable at
the axis (t298 K = 1.5 h; see also Figure 13), and thus rapidly
loses any stereochemical information possibly attained in the
ring-opening reaction. It can, however, be obtained diastereomerically pure by a single crystallization step.[236]
From a stereochemical point of view, the transformation
of the lactones 33 into axially chiral biaryl compounds[20] can
be considered as a dynamic kinetic resolution[237]
(Scheme 62). The chiral nucleophile selectively attacks only
one of the two atropoenantiomers of 33, say (M)-33, which is
steadily resupplied from the remaining enantiomer (P)-33
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Scheme 62. The assumed mechanistic course of the lactone cleavage
with chiral nucleophiles; the stereodescriptors have been arbitrarily
given for R = H, alkyl.[63]
through the rapid (M)-33Q(P)-33 equilibrium (see
Figure 7),[238] thus allowing conversion of the entire racemic
material of 33 into a stereochemically homogeneous product
of either configuration. For the approach vector of the
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nucleophile, an axial attack is strongly favored over an
equatorial one, as predicted by quantum-chemical calculations.[239, 240] Consequently, the initial attack of 33 with an ideal
chiral N or O nucleophile Nu* leads to just a single
tetrahedral (orthoester-like) intermediate, for example, only
to (M,R)-269, which will—more or less irreversibly—burst
open to give (M)-270 and, after protonation, lead to the
axially chiral biaryl ester or amide. The same pathway,
followed by a rapid second hydride transfer to (M)-270 to give
(M)-271, probably also accounts for the atroposelective
reduction of the lactones 33 with chiral H nucleophiles.[241]
In addition to the versatility and the smooth conditions
under which the atroposelective ring opening of 33 can be
accomplished, the lactone approach offers another important
advantage: the possibility to prepare either of the two
atropisomers from the same precursor (“atropodivergence”).
This feature is highly attractive in the synthesis of chiral
auxiliaries and catalysts, which for a broad applicability of the
method should be accessible in both enantiomeric forms. Such
a demand is easily met with the lactone method as all the
nucleophiles used to cleave the bridge (see Scheme 61) are
commercially available in both enantiomeric forms. An
example is the atroposelective synthesis of the biaryl amino
alcohols (P)-7 and (M)-7 (Scheme 63), which have been
demonstrated to be efficient catalysts for the enantioselective
addition of diethylzinc to aldehydes (up to 98 % ee).[17] In the
key step, ring opening of 33 c with sodium (S)-menthoxide
((S)-261) delivered the ester (P,S)-260 c in 87 % yield, while
the analogous reaction with the enantiomeric reagent (R)-261
gave (M,R)-260 c.[232] Furthermore, the minor product diastereomers, (M,S)-260 c and (P,R)-260 c, also obtained in the
alcoholysis of 33 c, are not wasted, but can be easily recycled
by acid-catalyzed recyclization back to the lactone.[242]
Though not always required, this is a worthwhile option
allowing economical use of precious material, for example, in
multistep natural product syntheses.
The concept presented here is not restricted to sixmembered biaryl lactones, but can be extended to other
configurationally labile biaryl by the permanent or transient
existence of short bridges, such as ortho-hydroxy-ortho’aldehydes. An example is the naphthylisoquinoline 275
(Scheme 64). As discussed in Section 2 (Figure 13), these
Scheme 64. The atroposelective reduction of biaryl hydroxyaldehydes
as a complement to the lactone cleavage, in this case applied to the
synthesis of the natural product dioncopeltine A ((M)-274).
Scheme 63. Two further advantages of the lactone method: atropodivergence and “chiral economy”, illustrated in the directed synthesis of
(P)-7 or (M)-7.
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compounds do not form stable atropisomers, despite their
formally ring-opened structure, because they are in equilibrium with their cyclic—and thus configurationally labile—
lactol isomers. If the substituents next to the axis are
small,[243, 64] the stereoselective reduction of such hydroxyaldehydes (275!(M)-273, > 90 % de) provides a useful alternative to the lactone reduction (272!(M)-273, > 90 % de),
as illustrated in the atroposelective synthesis of the antimalarial naphthylisoquinoline alkaloid dioncopeltine A ((M)274).[244]
The seven-membered lactones 276 (Scheme 65) have
significantly higher atropisomerization barriers than their
six-membered analogues 33 (Figure 7). The interconversion
rate of 276 is too slow (t298 K 10 days) to be used in a dynamic
kinetic deracemization, but a normal (i.e. nondynamic)
kinetic resolution with subsequent thermal recycling of the
unconverted starting material is possible.[245, 246] Thus, reduc-
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Scheme 66. Atropodiastereoselective biaryl lactone formation by using
planar chirality as the chiral inductor, with subsequent ring cleavage
and conversion into the metal-free biaryl products 281.[63, 162]
Scheme 65. Atropoenantioselective synthesis of (P)-4,4’-bisorcinol
((P)-15) and (+)-isokotanin A ((M)-278) by kinetic resolution of the
configurationally stable biaryl lactone 276.
tion of racemic 276 with borane in the presence of the (S)CBS reagent ((S)-267) delivered the diol (M)-277 in 46 %
yield with 75 % ee (95 % ee after crystallization) and the
lactone (P)-276 in 43 % yield with 96 % ee, when the reaction
was quenched at 56 % conversion. The relative rate constant
krel was calculated to be 27.[247] The lactone (P)-276 can be
recycled by thermal racemization at 100 8C (t298 K = 6.6 min)
and resubmitted to a renewed ring cleavage with kinetic
resolution; alternatively it can used as an enantiopure
precursor for further synthesis. In the application presented
here, (P)-276 was converted into (P)-4,4’-bisorcinol ((P)-15),
while the diol (M)-277 was transformed into (+)-isokotanin A
((M)-278), both with high enantiomeric purities.
Within the lactone concept, a joint collaboration between
Uemura and co-workers and our group showed that the
element of planar chirality is excellently suited for transferring chiral information to the axis.[248] Treatment of the
configurationally unstable lactones 279 a and 279 b
(Scheme 66), which bear an R-configured 1-hydroxyethyl
substituent ortho to the biaryl axis, with [CpRu(CH3CN)3]PF6
delivered the centro-, axial-, and planar-chiral complexes
(M,R,PR)-280 a and (P,R,PR)-280 b[163] regio- and diastereoselectively, owing to the directing effect of the OH function.
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Cleavage of the lactone bridge with sodium methoxide and
subsequent decomplexation gave the axially chiral biaryl
compounds (M,R)-281 a and (P,R)-281 b as single diastereomers.
The potential and practicability of the lactone method has
been demonstrated by its application in the atroposelective
synthesis of more than 30 natural products and several useful
catalysts,[20] some examples of which are presented in
Scheme 67.[249–252] The lactone method is compatible with a
variety of functional groups, works under mild conditions, and
permits flexible and reliable access to a broad spectrum of
structurally diverse biaryl species with any desired configuration at the axis. The carboxy- and phenol-derived ortho
functions resulting from the ring-opening do not necessarily
have to be part of the product, as they can easily be
transformed or removed (see 282 and 285). The lactone
approach has also been used, among others, by Molander
et al. in the total synthesis of (+)-isoschizandrin (283)[250] and
by Abe, Harayama, and co-workers in a formal total synthesis
of ()-steganone ((M)-107).[251] Severe limitations of the
method are not yet known.[253] The key six-membered biaryl
lactone intermediates are C1-symmetric and thus require the
availability of two different building blocks (the phenolic
moiety and the acid component). Hence the advantages of the
method over other procedures are of particular significance
for constitutionally unsymmetrical target molecules, whereas
for simple C2-symmetric products other procedures (e.g.
homocoupling with subsequent racemate resolution if
required) may be competing alternatives.
One other example in which an even shorter bridge—this
time in a five-membered ring—is cleaved atropoenantioselectively, was reported by Hayashi and co-workers.[254] The
asymmetric nickel-catalyzed cross coupling of the dibenzothiophenes 287 with Grignard reagents in the presence of
chiral phosphines, including 289 and 290, delivered the biaryl
thiophenols 288 (Scheme 68). In some cases, both the
chemical (up to 97 %) and optical yields (up to 95 % ee)
were excellent, but this was not always true and the success of
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G. Bringmann, M. Breuning et al.
Scheme 67. A selection of C1-, C2-, and C3-symmetric axially chiral biaryl natural products and catalysts that have been prepared by the lactone
method;[249–252] further examples in this Review: N,O-ligands (P)-7 and (M)-7 (Scheme 63), dioncopeltine A ((M)-274, Scheme 64), (+)-isokotanin A
((M)-278), and (P)-4,4’-bisorcinol ((P)-15, Scheme 65).
this intriguing reaction varied both with the size of the
Grignard reagent employed and the nature of the original
ortho substituents. It is believed that the nickel catalyst first
inserts into the CS bond, with the stereochemically deciding
step being the transmetalation of the Grignard reagent or the
following reaction.
4.2.4. Transient Formation of a Short Metal Bridge
Scheme 68. Atropoenantioselective ring-cleaving biaryl synthesis by
Ni-catalyzed C-alkylation or -arylation in the presence of chiral phosphines.
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As a rule, biaryl compounds with four ortho substituents
are configurationally stable, even under forcing conditions
(compare Figure 5). If equipped with two chelating groups
next to the axis (e.g. binol (29)), however, an (albeit rather
slow) atropisomerization can occur in the presence of an
appropriate transition metal such as CuI/II, permitted by the
resulting metallacycle with its (slightly) lower rotational
barrier (see Section 2.2.2). If the metal or the substrate
itself is chirally modified, this opens the possibility for the
conversion of a racemic biaryl substrate into atropisomerically pure material by dynamic kinetic resolution, often
already in situ, in the course of its formation.
Many Ullmann couplings of chiral ortho-halogenated
oxazolinylbenzene derivatives, as developed by Meyers and
co-workers,[126, 137] are examples of the latter situation (for
purely kinetically controlled atroposelective Ullmann cou-
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plings,[255] see Section 3.2). For example, the copper-mediated
homocoupling of the l-valinol derived oxazoline (S)-291 in
DMF gave, after extended heating for 40 h, the atropodiastereomer (P)-292 in 58 % yield with 86 % de
(Scheme 69).[256, 257] However, if the reaction was stopped
Scheme 70. Total synthesis of mastigophorene A (3, Figure 1) by diastereoselective Ullmann coupling of the l-alaninol-derived aryl oxazoline (S)-294.
Scheme 69. Ullmann coupling of (S)-291 with subsequent dynamic
kinetic resolution by isomerization to the thermodynamically favored
CuI complex (P)-293.
after 1 h, after which time all the starting material had already
been consumed, (P)-292 was isolated with much lower
selectivity (24 % de). As shown by the graph in Scheme 69,
the de value of (P)-292 increases with prolonged heating until
a plateau is reached after 40 h. This proved that the high
degree of stereoselectivity was not caused by an asymmetric
coupling step, but was the consequence of a thermodynamically controlled deracemization (first-order asymmetric transformation).[136, 258] It was postulated that the copper complexes
formed initially, (P)-293 and (M)-293, slowly interconvert at
the elevated reaction temperature, thus leading to the
preferred formation of the diastereomer (P)-293 and alleviating the steric repulsion between the two isopropyl groups of
the oxazoline moieties. The product (P)-292 was further used
in a short synthesis of an ellagitannin.[114, 259]
This strategy was further applied to the total synthesis of
the axially chiral natural product mastigophorene A (3).[260] A
key step of this approach was the asymmetric Ullmann
homocoupling of the l-alaninol-derived aryl oxazoline (S)294,[261] which gave the biaryl compound (P)-295 in 75 % yield
with 76 % de (Scheme 70).
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
The Ullmann coupling of ortho-bromo(oxazolinyl)arenes
with in situ dynamic kinetic resolution allows efficient access
to axially chiral biaryl products with good to high stereocontrol. The prolonged heating required may, however, not be
suitable for biaryl compounds with more-sensitive functional
groups. Advantageously, the direct kinetically controlled
Ullmann couplings of ortho-bromo(oxazolinyl)arenes (see
Section 3.2) and the thermodynamic isomerizations described
here always lead to the same stereochemical array at the
biaryl axis, thus making the resulting axial configuration
predictable and independent of the actual mechanism
involved.
A spectacular early example of an atropoenantioselective
biaryl synthesis by dynamic kinetic resolution was reported by
Brussee et al.[174, 262] (P)-Binol ((P)-29) was prepared in 98 %
yield with 96 % ee by CuCl2-induced oxidative homocoupling
of 2-naphthol (153) in the presence of a large excess of
amphetamine ((S)-296) (Scheme 71). The high enantiomeric
purity, however, was not the result of an asymmetric coupling
step, as initially assumed, but the consequence of stereoselective crystallization. Of the two intermediately formed
diastereomeric complexes composed of CuII, (S)-296, and
(M)- or (P)-29 (no more details were given), only that
containing the P-configured enantiomer of 29 crystallized,
Scheme 71. Atropoenantioselective preparation of (P)-binol ((P)-29) by
oxidative coupling of 2-naphthol (153) with concomitant stereoselective crystallization in the presence of amphetamine ((S)-296).
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G. Bringmann, M. Breuning et al.
steadily resupplied by concomitant atropisomerization of the
remaining complex in solution (second-order asymmetric
transformation).[136] The applicability of this reaction seems to
be restricted to binol, and even in this important case,
stereoselective crystallization only occurs within a narrow
temperature range.
Recently, Wulff and co-workers published a highly
enantioselective deracemization that is independent of any
particular coupling step (Scheme 72).[263] Sonication of the
Scheme 73. The concept of atroposelective biaryl synthesis by construction of an aromatic ring.
have been used to realize this exciting—though less general—idea.
Thus, the groups of Gutnov and of Heller synthesized
axially chiral 2-aryl pyridines by a catalytic asymmetric [2 +
2 + 2] cycloaddition.[265] The reaction of the 1-naphthyl diyne
299 with alkyl or aryl nitriles in the presence of the cobalt
catalyst 301 (Scheme 74) gave the pyridines (M)-300 in good
Scheme 72. Deracemization of rac-297 and rac-298 by using a complex
of Cu2+ and ()-sparteine (()-173).
racemic, ortho-dihydroxylated biaryl ligands vanol (297) and
vapol (298)[264] in the presence of a chiral CuII complex,
prepared in situ from CuCl and ()-sparteine (()-173) by air
oxidation, delivered the respective P-configured compounds
nearly enantiopurely and in good yields. This deracemization,
which occurred in homogeneous solution, is again a firstorder asymmetric transformation that relies on the lowered
rotational barrier and the relative thermodynamic stabilities
of the intermediate CuII complexes formed. The mechanism is
also supported by calculations that indicate that the complex
[(P)-297/CuII/()-173] is more stable than its M diastereomer
by as much as 16.4 kJ mol1. The deracemization also worked
for binol (up to 94 % ee). Such ()-sparteine-mediated transformations are more generally applicable than that described
above, which relies on a diastereoselective crystallization;
nevertheless, despite the good ee values attained, definite
drawbacks are the large excess of auxiliary required together
with its availability in only one enantiomeric form.
5. Asymmetric Biaryl Synthesis by Construction of
an Aromatic Ring
Besides the more classical direct asymmetric coupling
reactions (as described in Section 3) and the atroposelective
transformations on already prepared biaryl systems (see
Section 4), a fundamentally new strategy for the construction
of chiral biaryl compounds has emerged recently. In this
concept, a preformed arylC single bond is transformed
atroposelectively into the biaryl axis upon construction of the
second arene ring from an aryl C substituent (Scheme 73).
The chirality transfer to the axis results from a stereogenic
center or by enantioselective catalysis. Only a few methods,
which often involve asymmetric organometallic catalysis,
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Scheme 74. Atropoenantioselective synthesis of the 1-aryl-5,6,7,8-tetrahydroisoquinolines (M)-300 by asymmetric [2+2+2] cycloaddition.
chemical yields and optical purities (up to 89 % ee). The
analogous reaction of a naphthyl nitrile with an alkyl diyne,
however, led only to poor yields and moderate ee values.
Independently, Shibata et al. reported related, but iridium-catalyzed [2+2+2] cycloadditions of diynes of type 302
with the alkyne 303 to construct the twofold axially chiral
teraryls 304. (S,S)-Me-duphos ((S,S)-305) was used as the
chiral ligand (Scheme 75).[266] Excellent diastereoselectivities
(the meso form was not observed) and enantioselectivities (>
99 % ee) were achieved. Furthermore, the catalyst loading
could be lowered to 0.5 mol % with no significant loss of
selectivity. Besides such teraryls, a biaryl compound was also
synthesized by this method, albeit with only up to 81 % ee.
Nishii, Tanabe, and co-workers published a central-toaxial chirality transfer in the formation of (M)-1-arylnaphthalenes (M)-307 from the enantiomerically pure dichlorocyclopropane precursors (S,S)-306 (Scheme 76).[267] The
Lewis acid promoted benzannellation produced chiral biaryl
products with almost complete enantiomeric purity. The high
degree of stereocontrol was rationalized by the conformational constraints upon formation of the intermediate carbocation (306!pre-(M)-308!pre-(M)-309), with the ortho
substituent R being orientated away from the eliminating,
Lewis acid bound hydroxy group. Conjugation between the
cyclopropyl methyl cation and the benzene ring ensures that
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Scheme 75. Atropoenantio- and atropodiastereoselective construction
of teraryls by iridium-catalyzed [2+2+2] cycloaddition.
Scheme 77. Enantioselective synthesis of (M)-314 from the a-substituted ketone (R)-311 with an intermediate central-to-axial chiraliy transfer.
A reaction that has received much attention in this area is
the DFtz benzannellation of Fischer carbenes with alkynes.
The stereochemical array at the new biaryl axis was controlled
by chiral bridges[270] and stereogenic centers in the ortho
position.[271, 272] In a pioneering study, Wulff and co-workers[270]
treated two chromium carbenes connected by a chiral tether
(i.e. (R,R)-315) with the 1,3-butadiyne 316 (Scheme 78). Both
Scheme 76. Central-to-axial chirality transfer in benzannellation of the
enantiomerically pure diaryl-2,2-dichlorocyclopropylmethanols 306.
Scheme 78. Double benzannellation of a bis(chromium carbene) species (R,R)-315 to give (P)-317.
free rotation about the single bonds in pre-M carbocation 309
is sufficiently hampered such that this conformation is fully
conserved in the axial configuration of the dihydronaphthalene (M)-310 and, thus, in the biaryl product (M)-307.
Another efficient conversion of C centrochirality into
axial chirality was utilized by the research groups of Hattori
and Miyano to synthesize the 1,1’-binaphthalene (M)-314
(Scheme 77).[268, 269] In this case, the a-substituted chiral
cyclohexanone (R)-311 served as a precursor to the new
aryl ring. Diastereoselective addition of the naphthyl
Grignard 141 in the presence of Yb(OTf)3 delivered (R,R)312, which was dehydrated to give the axially chiral arene–
olefin intermediate (M)-313 with 95 % ee. Oxidation with
DDQ afforded the desired chiral biaryl species (M)-314 in
74 % overall yield. Although this method is somewhat
indirect, it does have the advantage that chiral a-substituted
ketones are accessible by standard procedures.
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
aromatic rings of (P)-317 were assembled in a single step with
essentially complete control of the configuration of the biaryl
axis, albeit in low yield and with concomitant formation of
other products.
The synthetic strategy for the construction of chiral biaryl
compounds by the assembly of one (or both) of the aromatic
rings is highly innovative. This work is still in its infancy and
the generality of the concept is, as yet, largely limited in terms
of functional-group compatibility and substitution patterns
accessible.
6. Summary and Outlook
With the continuously increasing importance of axially
chiral biaryl compounds as chiral auxiliaries and ligands for
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G. Bringmann, M. Breuning et al.
asymmetric synthesis and as the structurally decisive element
in bioactive natural products, formidable efforts have been
undertaken recently to develop efficient methods for their
atroposelective synthesis. The approaches shown in this
Review are characterized by their conceptual diversity and
can be divided into three major classes:
1) the “classic” atroposelective aryl–aryl coupling reactions
(Section 3), which allow the preparation of axially chiral
biaryl compounds directly from their (suitably modified)
aromatic halves;
2) approaches that rely on the atroposelective conversion of
preformed, but stereochemically not yet differentiated
(i.e. achiral or configurationally labile) biaryl species to
give axially chiral products (Section 4); and
3) specialized methods in which a non-aryl substituent on an
aromatic ring is atroposelectively converted into the
second aromatic ring (Section 5).
Despite the originality and efficiency of some of these
approaches and regardless of whether the aryl–aryl coupling
and the asymmetric induction are achieved simultaneously or
stepwise, the stereoselective preparation of (complex) biaryl
compounds remains a challenging goal. Most currently
available methods meet only some, but not all of the following
demands:
1) excellent chemical yields and optical purities, even for
biaryl compounds with high steric hindrance (e.g. tetraortho-substituted derivatives) and biaryl species in which
the steric differentiation between the ortho substituents is
small—or even in cases in which the ortho substituents are
identical and axial chirality results only from groups in the
meta position;
2) access to virtually any substitution pattern, and compatibility with common functional and protecting groups;
3) use of cheap and easily accessible starting materials, chiral
catalysts, or auxiliaries (which should be available in both
enantiomeric forms); the latter have to be easy to attach
and remove;
4) mild and convenient reaction conditions that prevent
undesired atropisomerization at the biaryl axis formed;
5) possibility to synthesize either atropisomer from the same
precursor (“atropodivergence”) and to recycle any
unwanted minor atropisomer (“chiral economy”); and
6) the applicability to the atroposelective construction of
concrete functionalized target molecules such as complex
natural products.
Taking all this into account, it is understandable why,
despite the intense efforts and enormous progress of the past
decades, a reliable and generally applicable procedure that
fulfills all these demands satisfactorily is still lacking. Many of
the intriguing concepts described reflect the chemical creativity of the researchers and provide excellent approaches to a
specific class of target biaryl compounds, but are restricted to
a distinct substitution pattern (e.g. a particular functional
group in the ortho position), or fail if the steric hindrance
increases (e.g. tetra-ortho-substituted biaryl targets).
The methods that are currently most widely applied in the
asymmetric synthesis of complex axially chiral biaryl com-
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pounds are the “lactone concept” (Section 4.2.3) among the
stepwise (atropoenantio- or atropodiastereoselective) techniques, and the Meyers oxazoline method (Section 3.2) among
the direct (atropodiastereoselective) coupling procedures.
Catalytic enantioselective aryl–aryl couplings such as the
Suzuki coupling (Section 3.6), although still hampered by
several restrictions, are gradually improving and might, owing
to the economical use of the chiral catalysts, become further
methods of choice in the future.
Abbreviations
acac
BHT
binap
binol
Bn
Boc
BOM
Bz
Cbz
Cp
cod
dba
DCC
DDQ
DIAD
DMA
DMAP
DME
DMF
DMSO
dppf
KHDMS
MCPBA
MOM
Ms
M.S.
NMP
PCC
TBAF
TBS
Teoc
TEMPO
tfa
TFA
TFAA
Tf
TIPS
TMS
TMEDA
Tol
Ts
acetylacetonate
2,6-di-tert-butyl-4-methylphenol
2,2’-bis(diphenylphosphanyl)-1,1’binaphthyl
1,1’-binaphthyl-2,2’-diol
benzyl
tert-butyloxycarbonyl
benzyloxymethyl
benzoyl
benzyloxycarbonyl
cyclopentadienyl
1,5-cyclooctadiene
dibenzylideneacetone
1,3-dicyclohexylcarbodiimide
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
diisopropylazodicarboxylate
N,N-dimethylacetamide
4-(dimethylamino)pyridine
ethylene glycol dimethyl ether
N,N-dimethylformamide
dimethyl sulfoxide
1,1’-bis(diphenylphosphanyl)ferrocene
potassium hexamethyldisilazide
meta-chloroperbenzoic acid
methoxymethyl
methanesulfonyl
molecular sieves
1-methyl-2-pyrrolidinone
pyridinium chlorochromate
tetra-n-butylammonium fluoride
tert-butyldimethylsilyl
2-(trimethylsilyl)ethoxycarbonyl
2,2,6,6-tetramethyl-1-piperidinyloxy
trifluoroacetyl
trifluoroacetic acid
trifluoroacetic acid anhydride
trifluoromethanesulfonyl
triisopropylsilyl
trimethylsilyl
N,N,N’,N’-tetramethylethylenediamine
tolyl
4-toluenesulfonyl
For generous financial support of their own work in the field,
the authors would like to thank the Deutsche Forschungsgemeinschaft (mainly SFB 347 “Selective Reactions of Metal-
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Activated Molecules” and an “Emmy-Noether” fellowship for
M.B.), the Alexander von Humboldt Foundation (fellowship
for A.J.P.M.), and the Fonds der Chemischen Industrie. G.B.
thanks his scientific cooperation partners and, in particular, the
numerous enthusiastic students and co-workers who have
developed the “lactone concept” with great commitment and
skill—their names can be seen in the literature citations.
Received: November 18, 2004
Revised: March 1, 2005
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[219] K. S. Feldman, K. J. Eastman, G. Lessene, Org. Lett. 2002, 4,
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[222] For a related conformational locking, see compound 37
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[226] For the dynamic kinetic resolution of a configurationally
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[229] Only some selected procedures will be reported here; for more
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[230] For an example of an atroposelective ring cleavage with an
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acid with subsequent reduction with a chiral hydride-transfer
reagent, see: G. Bringmann, A. Wuzik, J. KMmmel, W. A.
Schenk, Organometallics 2001, 20, 1692 – 1694.
[231] G. Bringmann, M. Breuning, S. Tasler, H. Endress, C. L. J.
Ewers, L. GFbel, K. Peters, E.-M. Peters, Chem. Eur. J. 1999, 5,
3029 – 3038.
[232] G. Bringmann, M. Breuning, R. Walter, A. Wuzik, K. Peters, E.M. Peters, Eur. J. Org. Chem. 1999, 3047 – 3055.
[233] For an atropoenantioselective ring-opening of 33 c with Onucleophiles in the presence of a chiral catalyst, see: D.
Seebach, G. Jaeschke, K. Gottwald, K. Matsuda, R. Formisano,
D. A. Chaplin, M. Breuning, G. Bringmann, Tetrahedron 1997,
53, 7539 – 7556.
[234] a) G. Bringmann, T. Hartung, Angew. Chem. 1992, 104, 782 –
783; Angew. Chem. Int. Ed. Engl. 1992, 31, 761 – 762; b) G.
Bringmann, M. Breuning, Tetrahedron: Asymmetry 1999, 10,
385 – 390; c) G. Bringmann, T. Hartung, Synthesis 1992, 433 –
435; d) G. Bringmann, T. Hartung, Tetrahedron 1993, 49, 7891 –
7902.
[235] See references [20a,d].
[236] The axial configuration of atropisomerically pure (P,R)-265 c
obtained by crystallization can be preserved by quick transformation into a configurationally stable biaryl; see reference [62].
[237] H. Pellissier, Tetrahedron 2003, 59, 8291 – 8327.
[238] This does not apply to the tBu-substituted lactone 33 f, which is
configurationally stable (t298 K = 2.2 days, see Figure 7); however, 33 f can be reduced with high stereocontrol (krel > 200!)
by a “normal” (nondynamic) kinetic resolution, with subsequent recycling of the nonreacting enantiomer by thermal
racemization: G. Bringmann, J. Hinrichs, J. Kraus, A. Wuzik, T.
Schulz, J. Org. Chem. 2000, 65, 2517 – 2527.
[239] G. Bringmann, S. GMssregen, D. Vitt, R. Stowasser, J. Mol.
Model. 1998, 4, 165 – 175.
[240] G. Bringmann, D. Vitt, J. Org. Chem. 1995, 60, 7674 – 7681.
[241] For a more detailed discussion about the mechanism of the
lactone reduction, including the existence of a “stereochemical
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
Angewandte
Chemie
Biaryl Synthesis
[242]
[243]
[244]
[245]
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
leakage” at the level of the intermediates 269 and 270, see
references [20a,d,e], [240].
Such a recycling is also possible for biaryl amides (e.g. 258[231])
and biaryl diols (e.g. 268[20a]).
For more detailed investigations on the atropoenantioselective
reduction of model biaryl hydroxyaldehydes, see: a) G. Bringmann, M. Breuning, Synlett 1998, 634 – 636; b) reference [83].
G. Bringmann, W. Saeb, M. RMbenacker, Tetrahedron 1999, 55,
423 – 432.
G. Bringmann, J. Hinrichs, P. Henschel, J. Kraus, K. Peters, E.M. Peters, Eur. J. Org. Chem. 2002, 1096 – 1106.
For further kinetic resolutions of configurationally stable biaryl
lactones, see: a) G. Bringmann, J. Hinrichs, Tetrahedron:
Asymmetry 1997, 8, 4121 – 4126; b) reference [238].
On an analytical scale, even a krel value of 43 was attained.
a) K. Kamikawa, K. Norimura, M. Furusyo, T. Uno, Y. Sato, A.
Konoo, G. Bringmann, M. Uemura, Organometallics 2003, 22,
1038 – 1046; b) K. Kamikawa, M. Furusyo, T. Uno, Y. Sato, A.
Konoo, G. Bringmann, M. Uemura, Org. Lett. 2001, 3, 3667 –
3670.
a) Mastigophorene A (3): G. Bringmann, J. Hinrichs, T. Pabst,
P. Henschel, K. Peters, E.-M. Peters, Synthesis 2001, 155 – 167
and G. Bringmann, T. Pabst, P. Henschel, J. Kraus, K. Peters, E.M. Peters, D. S. Rycroft, J. Connolly, J. Am. Chem. Soc. 2000,
122, 9127 – 9133; b) knipholone (2): reference [10b] and G.
Bringmann, D. Menche, Angew. Chem. 2001, 113, 1733 – 1736;
Angew. Chem. Int. Ed. 2001, 40, 1687 – 1690; c) korupensamine A ((P)-137): reference [165] and G. Bringmann, M. Ochse,
Synlett 1998, 1294 – 1296; d) dioncophylline C (282): G. Bringmann, J. Holenz, R. Weirich, M. RMbenacker, C. Funke, M. R.
Boyd, R. J. Gulakowski, G. Fran\ois, Tetrahedron 1998, 54,
497 – 512; e) AB system 284 of vancomycin (1): G. Bringmann,
D. Menche, J. MMhlbacher, M. Reichert, N. Saito, S. S. Pfeiffer,
B. H. Lipshutz, Org. Lett. 2002, 4, 2833 – 2836.
(+)-Isoschizandrin (283): G. A. Molander, K. M. George, L. G.
Monovich, J. Org. Chem. 2003, 68, 9533 – 9540.
()-Steganone ((M)-107): H. Abe, S. Takeda, T. Fujita, K.
Nishioka, Y. Takeuchi, T. Harayama, Tetrahedron Lett. 2004,
45, 2327 – 2329.
a) MOP ligand 285: G. Bringmann, A. Wuzik, M. Breuning, P.
Henschel, K. Peters, E.-M. Peters, Tetrahedron: Asymmetry
1999, 10, 3025 – 3031; b) tripodal ligand 286: G. Bringmann, R.M. Pfeifer, C. Rummey, K. Hartner, M. Breuning, J. Org. Chem.
2003, 68, 6859 – 6863; see also: G. Bringmann, M. Breuning, R.M. Pfeifer, P. Schreiber, Tetrahedron: Asymmetry 2003, 14,
2225 – 2228.
There has been a single report in which the lactone method,
whilst working in principle, failed to give good atroposelectivities.[212]
a) T. Shimada, Y.-H. Cho, T. Hayashi, J. Am. Chem. Soc. 2002,
124, 13 396 – 13 397; b) Y.-H. Cho, A. Kina, T. Shimada, T.
Hayashi, J. Org. Chem. 2004, 69, 3811 – 3823.
Angew. Chem. Int. Ed. 2005, 44, 5384 – 5427
[255] For the asymmetric Ullmann coupling to either atropisomer of
8,8’-bis(oxazolinyl)-1,1’-binaphthalene from the same oxazolidine just by applying different conditions, see: a) A. I. Meyers,
A. Price, J. Org. Chem. 1998, 63, 412 – 413; b) A. I. Meyers,
M. J. McKennon, Tetrahedron Lett. 1995, 36, 5869 – 5872.
[256] T. D. Nelson, A. I. Meyers, Tetrahedron Lett. 1993, 34, 3061 –
3062.
[257] T. D. Nelson, A. I. Meyers, Tetrahedron Lett. 1994, 35, 3259 –
3262.
[258] The pivotal role of CuI/CuII in the atropodiastereomerization of
di(oxazolinyl)-substituted biphenyls was also demonstrated.[126], [257]
[259] T. D. Nelson, A. I. Meyers, J. Org. Chem. 1994, 59, 2577 – 2580.
[260] A. P. Degnan, A. I. Meyers, J. Am. Chem. Soc. 1999, 121, 2762 –
2769; the atropodiastereomer mastigophorene B ((M)-3) was
prepared accordingly.
[261] In this particular case, the normally used l-valinol-derived
analogue of (S)-294 gave a slightly lower selectivity (74 % de).
[262] For a similar reaction, see: K. Yamamoto, H. Fukushima, H.
Yumioka, M. Nakazaki, Bull. Chem. Soc. Jpn. 1985, 58, 3633 –
3634.
[263] a) Y. Zhang, S.-M. Yeung, H. Wu, D. P. Heller, C. Wu, W. D.
Wulff, Org. Lett. 2003, 5, 1813 – 1816; b) S. Yu, C. Rabalakos,
W. D. Mitchell, W. D. Wulff, Org. Lett. 2005, 7, 367 – 369; the
7,7’-dimethyl derivative of (S)-vapol was synthesized accordingly in 78 % yield with 99 % ee.
[264] Vanol (297) and vapol (298) were used as ligands in catalysts for
asymmetric Baeyer–Villiger reactions: C. Bolm, J.-C. Frison, Y.
Zhang, W. D. Wulff, Synlett 2004, 1619 – 1621.
[265] A. Gutnov, B. Heller, C. Fischer, H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, Angew. Chem. 2004, 116,
3883 – 3886; Angew. Chem. Int. Ed. 2004, 43, 3795 – 3797.
[266] T. Shibata, T. Fujimoto, K. Yokota, K. Takagi, J. Am. Chem.
Soc. 2004, 126, 8382 – 8383.
[267] Y. Nishii, K. Wakasugi, K. Koga, Y. Tanabe, J. Am. Chem. Soc.
2004, 126, 5358 – 5359.
[268] T. Hattori, M. Date, K. Sakurai, N. Morohashi, H. Kosugi, S.
Miyano, Tetrahedron Lett. 2001, 42, 8035 – 8038.
[269] For a central-to-axial chirality transfer in the field of naturally
occurring biaryl compounds, see: J. M. Wanjohi, A. Yenesew,
J. O. Midiwo, M. Heydenreich, M. G. Peter, M. Dreyer, M.
Reichert, G. Bringmann, Tetrahedron 2005, 61, 2667 – 2674.
[270] J. Bao, W. D. Wulff, M. J. Fumo, Eugene B. Grant, D. P. Heller,
M. C. Whitcomb, S.-M. Yeung, J. Am. Chem. Soc. 1996, 118,
2166 – 2181.
[271] A. V. Vorogushin, W. D. Wulff, H.-J. Hansen, J. Am. Chem. Soc.
2002, 124, 6512 – 6513.
[272] J. C. Anderson, J. W. Cran, N. P. King, Tetrahedron Lett. 2003,
44, 7771 – 7774.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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