Studies into diastereoselective D?tz benzannulations for the synthesis of axially chiral biaryls

Article abstract of DOI:10.1016/j.tetlet.2003.08.096

A series of racemic chiral ortho substituents on 1-phenylhex-1-yne have been found to control the atroposelective formation of a biaryl from D?tz benzannulation with pentacarbonyl(methoxyphenylmethylene)chromium(0). The results show there is a subtle balance between the chiral ortho substituent controlling atroposelectivity with a dr 3-5:1 and allowing benzannulation to proceed in yields of 44-67%.

Full text of DOI:10.1016/j.tetlet.2003.08.096

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7771–7774
Studies into diastereoselective Do¨tz benzannulations for the
synthesis of axially chiral biaryls
James C. Anderson,a,* John W. Crana and N. Paul Kingb
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 14 July 2003; revised 15 August 2003; accepted 21 August 2003
Abstract—A series of racemic chiral ortho substituents on 1-phenylhex-1-yne have been found to control the atroposelective
formation of a biaryl from Do¨tz benzannulation with pentacarbonyl(methoxyphenylmethylene)chromium(0). The results show
there is a subtle balance between the chiral ortho substituent controlling atroposelectivity with a dr 3–5:1 and allowing
benzannulation to proceed in yields of 44–67%.
© 2003 Elsevier Ltd. All rights reserved.
that methyl, methoxy, chloro and N-amide substituents
gave moderate to good yields of product, whereas
carbonyl derivatives and the nitro group were deleterious.
Axially chiral biaryls are important structural motifs in
many biologically active molecules1 and chiral ligands.2
The two most effective strategies for preparing these
systems are the atroposelective ring cleavage of configu-
rationally unstable lactone-bridged biaryls developed by
Bringmann3 and the direct atroposelective coupling of
two aromatic systems by stoichiometric4 and catalytic
methods.5 The latter approach, although the more flexible
of the two, still suffers from inherent difficulties associated
with steric hindrance.6 We have been pursuing a different
strategy which relies upon the construction of the biaryl
bond before the construction of the final aryl group (Eq.
(1)).7,8
In order to render this process atroposelective we con-
ceived of a number of stoichiometric strategies to control
the stereochemistry of the benzannulation reaction. Dis-
closure by Wulff of the simultaneous and stereoselective
construction of planar and axial centres of chirality by
an identical reaction8c convinced us that the most promis-
ing strategy would be the incorporation of a chiral
substituent ortho to the alkyne function. We had already
determined that bulky ortho amide or anilide groups
1
which exhibited evidence of atropisomerism in their H
NMR spectra gave no benzannulation products with
complex 2, probably because these systems were too
hindered.7,8c We had found that ortho achiral acetals gave
moderate yields of benzannulated products.7 Use of the
chiral acetal9 1; however, gave no evidence of diastereose-
lection in the crude 1H NMR spectrum and only a
moderate 39% yield of the isolated quinone (Scheme 1).10
Attempts to use chiral cyclic aminals, which are superior
to chiral acetals due to stereochemical relay of the
backbone chirality to the nitrogen,11 were investigated,
but benzannulation was thwarted again, presumably due
to steric hindrance. It seemed that there was a subtle
balance between the size of the chiral ortho substituent
which would allow benzannulation to proceed, but which
could also control atroposelectivity.
(1)
We have established the parameters for the racemic
synthesis of axially chiral biaryl compounds from the
Do¨tz benzannulation of a series of substituted aryl
acetylenes (Eq. (2)).7 In the ortho position it was found
(2)
The inhibition of the Do¨tz benzannulation where axially
chiral substituents and C2 symmetric auxiliaries were used
* Corresponding author. E-mail: j.anderson@nottingham.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.096

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J. C. Anderson et al. / Tetrahedron Letters 44 (2003) 7771–7774
reaction conditions of which a selection are reported in
Scheme 2.13
The aryl acetylenes 6a, c, d gave reasonable yields of
benzannulation products, but 6b R1=Ph gave a com-
plex mixture of products. As expected as the ortho
substituent became progressively larger the yield of the
benzannulation product decreased slightly. The steri-
cally most hindered ether 6d R%=t-Bu gave
a
1
diastereomeric ratio of 14:5 by H NMR at an opti-
mum temperature of 75°C which ensured a reasonable
yield of 60%. Heating product 7d (dr 16:5) which had
been adsorbed on silica, to mimic the reaction condi-
tions, to 100°C led to an erosion in diastereomeric ratio
to 2:1 over 2 h. This suggested that the diastereomeric
ratio observed in this reaction was due to the formation
of a kinetic final product.
Scheme 1.
In order to investigate a removable chiral directing
group a series of benzylic silyl ethers were synthesised
in which the bulky silyl substituent could be hydrolysed
off after the benzannulation step. Treatment of 5a14
with a range of silyl protecting groups led to 8a–c in
good yield (Scheme 3). Subsequent benzannulation with
2 revealed that the TMS group was not stable to the
reaction conditions, but the more bulky TBDPS and
TIPS silyl ethers 8b and 8c led to benzannulated prod-
ucts. Due to their steric bulk a reaction temperature
below 100°C gave very low yields. However at 100°C
good yields and atroposelectivites were obtained. The
results again demonstrate a balance between steric bulk
in the ortho position which will allow benzannulation,
but also control atropisomer selectivity. The TBDPS
silyl ether 8b gave a 67% yield of 9b with an atropiso-
mer selectivity of 3:1. Heating product 9b to 140°C on
silica for 2 h resulted in equilibration to a 2:1 mixture
of diastereoisomers, while further heating led to degra-
dation of material.
Chiral sulfoxides are well known to be powerful auxil-
iaries for asymmetric synthesis and they have recently
been shown to be useful for the atropisomer selective
synthesis of axially chiral amides.15 Synthesis of a benz-
annulation precursor with an ortho sulfoxide 11 began
with diazotisation16 of aniline 10,17 treatment with
sodium thiophenolate18 and finally oxidation of the
sulfide with mCPBA (Scheme 4). Benzannulation with 2
under identical reaction conditions as before gave a
44% yield of biaryl 12 with a diastereomeric ratio of
5:1.19 A small portion was adsorbed on silica and
heated to 140°C for 2 h. Epimerisation to a 3:2 mixture
of diastereoisomers was observed.
Scheme 2.
prompted an examination of more basic systems. The
simplest class of compatible chiral sub-stituent it was
thought possible to introduce was a chiral ether (R=
CR1R2OR3, Eq. (1)). Although such substituents would
be able to rotate, it was thought there should be some
conformational preference and plenty of opportunity
for tuning through replacement of groups R1, R2 and
R3 (R=CR1R2OR3, Eq. (1)). A short series of chiral
benzylic ethers 6a–d were synthesised from aldehyde 4
(Scheme 2).12 Addition of an alkyl group to give ben-
zylic alcohols 5a–d proceeded in moderate yields due to
complications from reduction by the Grignard or alkyl
lithium reagent. Investigation of other organometallic
alkylating reagents would no doubt circumvent this
problem, but was not the immediate concern of this
research. Standard methylation was high yielding and
the ethers 6a–d were subjected to solid state Do¨tz
Scheme 3.

J. C. Anderson et al. / Tetrahedron Letters 44 (2003) 7771–7774
7773
is complex as it can arise through kinetic formation of
an intermediate tricarbonyl-h6-arene chromium(0) com-
plex or thermodynamic epimerisation of this com-
plex.8c,21 Due to our epimerisation studies of the
diastereomerically enriched final compounds we can
conclude that either route leads to kinetic biaryl prod-
ucts after decomplexation of chromium(0).
These results show that a chiral ortho substituent on an
aryl acetylene can dictate the formation of an axially
chiral biaryl system possessing three ortho substituents
that exhibits atropisomerism. This is an example of
central-to-axial chirality transfer in the benzannulation
of an aryl acetylene with a carbene complex.22 This
strategy requires a subtle steric balance between the
chiral ortho substituent being able to dictate atropose-
lectivity, but not hinder biaryl formation.
Scheme 4.
Acknowledgements
In order to begin to unravel how stereoselection was
being achieved we verified that the regiochemistry of
the Do¨tz benzannulation, in the chiral benzylic ether
series, was occurring with the aryl group of the acetyl-
ene being positioned adjacent to the phenolic hydroxyl
group before CAN oxidation. The mixture of
We would like to thank the EPSRC and GlaxoSmithK-
line for financial support, Mr. T. Hollingworth and Mr.
D. Hooper for providing mass spectra and Mr. T. J.
Spencer for micro analytical data.
1
diastereoisomers 13 was too complicated by H NMR
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