Palladium-Catalyzed, tert-Butyllithium-Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A

Article abstract of DOI:10.1002/anie.201510328

A palladium-catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium-halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst-induced remote point-to-axial chirality transfer. It takes two: A palladium-catalyzed direct homocoupling of aryl halides in the presence of tBuLi enabled the synthesis of even tetra-ortho-substituted symmetric biaryl compounds in high yield (see scheme). The method was applied to the asymmetric synthesis of mastigophorene A in just eight steps through straightforward enantioselective installation of the benzylic quaternary stereocenter and highly diastereoselective homocoupling.

Full text of DOI:10.1002/anie.201510328

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International Edition: DOI: 10.1002/anie.201510328
German Edition: DOI: 10.1002/ange.201510328
Biaryl Synthesis
Palladium-Catalyzed, tert-Butyllithium-Mediated Dimerization of Aryl
Halides and Its Application in the Atropselective Total Synthesis of
Mastigophorene A
Jeffrey Buter+, Dorus Heijnen+, Carlos Vila+, Valentín Hornillos, Edwin Otten,
Massimo Giannerini, Adriaan J. Minnaard,* and Ben L. Feringa*
In memory of Richard F. Heck (1931–2015)
Abstract: A palladium-catalyzed direct synthesis of symmetric
biaryl compounds from aryl halides in the presence of tBuLi is
described. In situ lithium–halogen exchange generates the
corresponding aryl lithium reagent, which undergoes a homo-
coupling reaction with a second molecule of the aryl halide in
the presence of the palladium catalyst (1 mol%). The reaction
takes place at room temperature, is fast (1 h), and affords the
corresponding biaryl compounds in good to excellent yields.
The application of the method is demonstrated in an efficient
asymmetric total synthesis of mastigophorene A. The chiral
biaryl axis is constructed with an atropselectivity of 9:1 owing
to catalyst-induced remote point-to-axial chirality transfer.
T
he synthesis of biaryl compounds has been studied for more
than a century[1] and is an important process in organic
chemistry, as the biaryl structure is present in numerous
natural products, bioactive compounds, agrochemicals, dyes,
and ligands. Symmetric biaryl compounds play a crucial role
in catalysis, as a range of ligands possess this structural motif
(Scheme 1). Furthermore, natural products with a symmetric
biaryl moiety, not necessarily enantiomerically pure, show
interesting biological activities.[2]
Symmetric biaryl compounds can be synthesized in a wide
variety of ways. A classic approach is the Ullmann cou-
pling,[3,4] but also nickel-, palladium-, and iron-catalyzed
coupling reactions between different organic halides and
organometallic reagents, such as Grignard, zinc, boron, and
tin reagents, are known.[5] These methods, however, are
generally not employed in the synthesis of symmetric tetra-
ortho-substituted biaryl compounds, with the exception of the
Suzuki–Miyaura coupling. Despite its efficiency, the Suzuki–
Miyaura coupling requires two independently synthesized
reagents to be coupled, namely, an aryl halide and an aryl
boron reagent. This feature makes the synthesis of symmetric
biaryl compounds inherently less efficient, especially for
Scheme 1. Representative ligands and natural products with a symmet-
ric biaryl structure.
natural product synthesis, for which step count is an important
issue. However, this disadvantage can be circumvented by the
homocoupling of aryl halides through the in situ generation of
aryl lithium reagents by lithium–halogen exchange.[6,7] Such
an approach might therefore provide a valuable alternative.
Despite important recent advances, the homocoupling of
organolithium reagents under Pd catalysis has received little
attention.[8–12] The methodologies reported so far were rather
limited in their scope and did not involve the construction of
sterically congested tetra-ortho-substituted biaryl com-
pounds, except for three examples of a copper-mediated
coupling reported by Spring and co-workers.[8] Furthermore,
the application of this type of coupling methodology in the
synthesis of biaryl-containing natural products has not been
reported.
[*] J. Buter,[+] D. Heijnen,[+] Dr. C. Vila,[+] Dr. V. Hornillos, Dr. E. Otten,
Dr. M. Giannerini, Prof. Dr. A. J. Minnaard, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: a.j.minnaard@rug.nl
b.l.feringa@rug.nl
[+] These authors contributed equally to this work.
As part of our research program on the use of organo-
lithium compounds in palladium-catalyzed cross-coupling
reactions,[13,14] we are interested in the synthesis of symmetric
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201510328.
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biaryl compounds with these
highly reactive reagents. We
present herein a highly efficient
and selective homocoupling of
aryl halides. We also applied
this methodology in the con-
struction of the naturally occur-
ring symmetric, tetra-ortho-
substituted biaryl compound
mastigophorene A (Scheme 1).
As
a starting point for
developing the homocoupling
reaction, we initially chose 2-
bromoanisole (1a) as a model
substrate. In search for the
optimal reaction conditions
(see the Supporting Informa-
tion) we eventually arrived at
Pd-PEPPSI-IPent[15]
(C1;
1 mol%) and tBuLi (0.7 equiv)
as the catalyst and lithiating
reagent, respectively. Full con-
version was observed, and the
desired product 2a was isolated
in 86% yield. Pd-PEPPSI-IPr[16]
(C2) proved to be an equally
efficient catalyst. The use of
0.7 equivalents of tBuLi in the
reaction is intriguing. Generally
in Li–X exchange reactions
with tBuLi, 2 equivalents of
the reagent are used to com-
pensate for the elimination of
tBuBr, which is formed in
situ.[17] We postulate that the
Scheme 2. Scope of the palladium-catalyzed homocoupling of aryl bromides in the presence of tBuLi (see
product 2a for coupling with an aryl iodide and an aryl chloride). [a] C1 (1 mol%) was used. [b] C2
(1 mol%) was used. [c] The reaction was carried out on a 6 mmol scale with C2 (0.5 mol%) for 2 h.
[d] The reaction was performed at 508C.
solvent (toluene), the slow addition of tBuLi, and the reaction
rate contributed to the suppression of the elimination of
tBuBr. In toluene, tBuLi forms a tetrameric aggregate[18] and
thus exhibits lower reactivity than that of monomeric tBuLi in
THF, a solvent generally used in Li–X exchange reactions.[6b]
We studied the scope and limitations of our new method-
ology under the optimized conditions (Scheme 2). With 2-
chloroanisole, full conversion was not observed, and 2a was
obtained in 69% yield by the use of C1, whereas with 2-
iodoanisole, 2a was obtained in 95% yield. Next, various
aromatic bromides with a methoxy group at the ortho position
were studied. Biaryl compounds 2b, 2c, and 2d, with different
electron-donating substituents on the aromatic rings, were
obtained in excellent yield. Even 2e, a tetra-ortho-substituted
biaryl compound, was successfully synthesized in 75% yield
in 1 h at room temperature. To construct 2 f, the reaction had
to be performed at 508C. These conditions provided 2 f in
85% yield, without affecting the selectivity. Binaphthyl
derivatives 2g and 2h were obtained in 90 and 92% yield,
respectively.
dimethylamino group at the ortho position also provided
the corresponding biaryls 2k and 2l. Subsequently, we
performed the reaction with aryl bromides bearing electron-
withdrawing groups: ortho- and meta-bromotrifluoromethyl-
benzene were converted into the corresponding fluorinated
biaryl compounds 2m and 2n in good yields. Lower selectivity
was observed in the synthesis of compounds 2o–q, which were
consequently obtained in only moderate yields. However, 4-
bromodibenzofuran reacted efficiently to afford biaryl 2r in
88% yield. To demonstrate the synthetic utility of the
presented methodology, 2a was prepared on a gram scale
(1.12 g, 6 mmol) with Pd-PEPPSI-IPr (0.5 mol%) in 98%
yield in 2 h.
Although the recently developed palladium-catalyzed
cross-coupling reactions with lithium reagents display
a broad scope,[14] no application has been reported so far
within the realms of natural product synthesis. The efficiency
of the homocoupling procedure described herein prompted us
to explore the method in a total synthesis leading to the
dimeric sesquiterpene mastigophorene A (Scheme 1).
Isolated from the liverwort Mastigophora diclados,[19a]
mastigophorene A and B (Scheme 1) showed neurotrophic
(nerve-growth-stimulating) activity,[19b] and have therefore
been regarded as potential therapeutic agents for neuro-
Heterocycles are also efficient coupling partners, as shown
by the smooth dimerization of 3-bromo-2-methoxypyridine to
afford the corresponding bipyridine 2i in 85% yield. Aryl
bromides with an electron-donating thiomethyl or N,N-
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degenerative diseases.[20] Additionally, it was found that
mastigophorene A and B exhibit neuroprotective properties
at concentrations as low as 0.1–1 mm.[19c] But foremost it is
their molecular architecture, a highly sterically congested
benzylic quaternary stereocenter together with a chiral biaryl
axis, which sparked our interest.
Geminal dimethylation and subsequent removal of the
enone functionality (thioenone formation and reduction
with Raney Ni)[21] gave rise to dimethylherbertenediol (10)
in 56% over the three steps. Subsequently, 10 was brominated
to furnish 11, thus setting the stage for the pivotal homocou-
pling.
To date, two atropselective total syntheses of mastigo-
phorene A and B have been reported, both of which consisted
of more than 20 steps.[21,22] Recently, some of us reported an
asymmetric palladium-catalyzed conjugate addition of ortho-
substituted aryl boronic acids to cyclic enones, with applica-
tion in the asymmetric total synthesis of (À)-herbertenediol
(the mastigophorene A and B monomer), in just six steps.[23]
This synthetic sequence in combination with the palladium-
catalyzed homocoupling described herein was envisioned to
give straightforward access to enantiomerically pure masti-
gophorenes A and B. The hindered biaryl axis in the
mastigophorenes presented us with the formidable challenge
of constructing this stereochemical element in a diastereose-
lective manner.
Our synthetic approach thus relied on the construction of
enantiomerically pure 11 (Scheme 3) by following our pre-
viously reported route to herbertenediol.[23] This compound
was synthesized by starting with the palladium-catalyzed
asymmetric conjugate addition of aryl boronic acid 6 to
pentenone 5 to give compound 7 (46% yield, 92% ee).[23]
Dehydrogenation of 7 provided enone 8 in 72% yield.[24]
Initial attempts under the optimized conditions for
homocoupling barely afforded the desired homocoupling
product (< 5% yield), since significant dehalogenation of 11
occurred, and incomplete conversion. We reasoned that the
crowded cyclopentyl scaffold in 11, although apparently
remote from the coupling site, impeded successful homocou-
pling. This hypothesis led us to investigate the influence of
steric bulk of the para substituent in the homocoupling
reaction. As model substrates, analogues of 11 with a methyl
or a tBu substituent were prepared (see the Supporting
Information for their synthesis). Homocoupling of methyl
substrate 12a under slightly modified conditions, with
5 mol% of C1 and 1.2 equivalents of tBuLi, gave the
corresponding biaryl product in 68% yield (Table 1,
entry 1). However, upon the application of these conditions
Table 1: Optimization of the homocoupling for sterically congested
substrates.
Entry[a] Substrate Conditions Dehalogenation Homocoupling [%][b]
[%][b]
(Yield [%][c])
1
2
3
4
12a
12b
12a
12a
RT
RT
08C
25
80
15
15
75 (68)
20 (15)
85 (79)
85
RT, slow
addition[d]
5
12b
08C, slow 20
80 (75)
addition[d]
[a] Reactions were carried out with 5 mol% of the catalyst. [b] Conversion
and selectivity were determined by GC/MS analysis. [c] Yield of the
isolated product after column chromatography. [d] tBuLi was added at
a rate of 2 drops every 5 min.
with tBu-substituted 12b, poor selectivity for homocoupling
over debromination was observed, and consequently the
product yield dropped significantly. This result indicates that
there is indeed an influence of the para substituent on the
homocoupling, thus suggesting either an interaction between
the catalyst/ligand system and the para substituent or simply
an electronic effect. Although steric interactions are poten-
tially detrimental for the formation of the homocoupled
product, stereochemical information in the para substituent
might be transferred in this way.
During further optimization (see the Supporting Infor-
mation), for methyl substrate 12a, it was found that a lower
reaction temperature (08C) and the aliquoted addition of the
Scheme 3. Asymmetric synthesis of bromodimethylherbertenediol (11).
DCE=dichloroethane, DMF=N,N-dimethylformamide, DMSO=dime-
thylsulfoxide, TFA=trifluoroacetate.
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tBuLi (2 drops every 5 min; Table 1, entry 3 and 4, respec-
exerted by the crowded cyclopentyl moiety alone.[17a,b] It is
tively) did lead to significant improvement of the selectivity
for product 13a. When applying a combination of these
conditions to the homocoupling of the sterically demanding
tBu substrate 12b, we were pleased to see that this reaction
smoothly provided the homocoupled product, which was
isolated in in excellent yield (75%; Table 1, entry 5).
Following this optimization study, we carried out the
anticipated homocoupling of the enantiomerically pure
mastigophorene building block 11 (Scheme 4). Gratifyingly,
we obtained 14, although inseparable at this stage (see below)
from the debrominated product, dimethylherbertenediol (10;
therefore even more noticeable that the catalyst-induced
point-to-axial chirality transfer[26] in the homocoupling to give
(P)-14 overcame this intrinsic stereochemical bias towards
M helicity.
The high diastereoselectivity also indicates that the
reaction proceeds through an ionic (polar) mechanism
rather than a radical (oxidative-coupling) mechanism. This
hypothesis is further supported by the fact that we did not
observe side products arising from HC abstraction from the
solvent toluene at all.
Compound 14 was thus obtained together with the
dehalogenated compound 10. Since we were not able to
separate these products by flash column chromatography, we
treated the mixture with BBr3 to cleave the methoxy groups
(90% yield). The side products from the previous step were
removed by flash column chromatography, thus providing us
with pure mastigophorene A (observed rotation: À67.9 (c =
0.4, CHCl3); literature value:[19b] À65.3 (c = 0.4, CHCl3)) in
27% yield over two steps. Conclusive evidence for the axial
configuration was obtained by X-ray crystallography, which
clearly showed P helicity (Figure 1).
Scheme 4. Endgame of the mastigophorene A synthesis.
Figure 1. X-ray crystal structure of mastigophorene A.
Scheme 3). Investigation of the homocoupling product mix-
ture by 1H NMR and GC/MS analysis indicated that the
homocoupling reaction afforded a surprising diastereomeric
ratio of 9:1 in favor of P helicity of the biaryl axis. This result
is close to the 98:2 and comparable to the 88:12 diastereo-
selectivity observed in the atropselective total syntheses
reported by Bringmann et al.[22] and Degnan and Meyers,[21]
respectively. The exact mechanism for stereoinduction is
unknown, but it is most likely a consequence of the steric
clash between the apparently remote benzylic quaternary
stereocenter in 11 and the aromatic residues of the C1
catalyst.
The observed diastereoselectivity strongly suggests a cata-
lyst-induced point-to-axial chirality transfer involving a steric
interaction between the catalyst and the benzylic quaternary
stereocenter at the para position. This hypothesis is substan-
tiated by the fact that an oxidative coupling of the herberte-
nediol monomethyl ether (no imposed steric hindrance of the
added reagent) with di-tert-butyl peroxide provided ana-
logues of mastigophorenes A and B with very low asymmetric
induction (d.r. 40:60) in favor of the mastigophorene B
analogue.[25] The same ratio was observed for the natural
isolate, thus clearly indicating a chiral bias towards M helicity
In summary, we have developed a new catalytic system for
the synthesis of symmetric biaryl compounds from aryl
halides in the presence of tBuLi (0.7 equiv) and only
1 mol% of C1. The reaction takes place at ambient temper-
atures. Moreover, this methodology enables the synthesis of
tetra-ortho-substituted symmetric biaryl compounds in high
yields. We successfully implemented the newly developed
methodology in the shortest atropselective total synthesis of
mastigophorene A (eight steps). The major improvement
over previous stereoselective syntheses (> 20 steps) is a con-
sequence of the straightforward enantioselective installation
of the benzylic quaternary stereocenter and the highly
diastereoselective homocoupling reaction.
Acknowledgements
A.J.M. acknowledges The Netherlands Organization for
Scientific Research (NWO-CW) for a VICI grant. B.L.F.
acknowledges financial support from NWO-CW, National
Research School Catalysis (NRSC-Catalysis), the European
Research Council (ERC Advanced Grant 227897), the Royal
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Keywords: aryl lithium compounds · homocoupling ·
palladium · symmetric biaryls · total synthesis
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Received: November 11, 2015
Revised: January 11, 2016
Published online: February 15, 2016
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