Enantioselective synthesis of biphenols from 1,4-diketones by traceless central-to-axial chirality exchange

Article abstract of DOI:10.1021/ja108717r

A method for the enantioselective synthesis of biphenols from readily prepared 1,4-diketones is reported. Key to the success of this method is the highly selective transfer of central to axial chirality during a double aromatization event triggered by BF<

Full text of DOI:10.1021/ja108717r

Published on Web 12/09/2010
Enantioselective Synthesis of Biphenols from 1,4-Diketones by Traceless
Central-to-Axial Chirality Exchange
Fenghai Guo, Leah C. Konkol, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208, United States
Received September 27, 2010; E-mail: r-thomson@northwestern.edu
Abstract: A method for the enantioselective synthesis of biphe-
nols from readily prepared 1,4-diketones is reported. Key to the
success of this method is the highly selective transfer of central
to axial chirality during a double aromatization event triggered
by BF3 ·OEt2. On the basis of X-ray crystallographic data, a
stereochemical model for this chirality exchange process is put
forth.
Axially chiral biaryls are an important class of molecules because
of their widespread use in asymmetric catalysis and the fact that
many biologically active natural products contain biaryl linkages.1
Typical methods for enantioselective biaryl synthesis involve direct
asymmetric coupling2 or atropselective transformation of preformed
Figure 1. Chirality-exchange-based synthesis of biphenols.
aromatic rings (Figure 1A).3 As a consequence of our investigations
into the synthesis of 1,4-diketones,4 we speculated that linked
Scheme 1. Initial Development of the Biaryl Synthesis
bicyclic compounds such as dione 2 (Figure 1B) might aromatize
with efficient central-to-axial chirality exchange as a result of the
restricted rotation about their central carbon-carbon bond.5,6
Because the sp3 stereogenic centers that impart chirality in the dione
precursor are simultaneously destroyed during the creation of the
biaryl axis, we consider such transformations to involve “traceless”
stereochemical exchange.7 Such reactions may thus be considered
With the validity of this concept established, we wished to expand
distinct from related methods for atroposelective synthesis that rely
the range of potential substrates to include enones that possessed
upon external control elements that are removed or destroyed in a
ꢀ-aryl groups. To achieve this goal, we developed a modified variant
separate synthetic manipulation after formation of the stereogenic
of the system reported by Hayashi and co-workers for the rhodium-
axis.8,9
catalyzed 1,4-addition of arylzinc species to 2,3-dihydro-4-pyri-
dones.12 We found that in the presence of TMSCl, [RhCl((R)-
In this communication, we report the successful implementation
of traceless stereochemical exchange for the synthesis of biphenols,
arguably the most important class of axially chiral compounds. Our
BINAP)]2 catalyzed the conjugate addition of a range of arylzinc
reagents to enone 4 to provide the corresponding enol silanes, which
study began with enones 1a and 1b, which were accessed by the
after workup and purification afforded the desired enones (i.e., 5)
enantioselective conjugate addition of dimethyl- or diethylzinc to
in high yield and with good levels of enantioselectivity (Table 1).
Oxidative dimerization of the ꢀ-aryl-substituted enones proceeded
readily under the copper(II) chloride-promoted conditions we had
the corresponding achiral dimethylketal quinone using the method
reported by Feringa and co-workers.10 After investigating a number
of reported conditions for oxidative dimerization of ketones, we
found that the conditions reported by Saegusa and co-workers in
1975 provided the greatest yield of the desired dimeric 1,4-diketones
(Scheme 1).11 Thus, treatment of ketone 1a with LDA followed
by the addition of copper(II) chloride afforded 2a in 66% yield
(99:1 e.r.). In contrast to the monomer 1a, which readily aromatized
in the presence of Lewis acids, dione 2a proved to be remarkably
stable under a variety of conditions, most likely because of the
high degree of steric congestion imparted by the four contiguous
stereocenters. Ultimately, we found that exposure of 2a to excess
BF3 ·OEt2 in toluene at reflux gave the desired biaryl 3a smoothly
and in good chemical yield. More importantly, complete transfer
of chirality from 2a was observed, as biaryl 3a was formed in a
99:1 ratio of enantiomers. The same outcome was observed when
enone 1b was subjected to the identical sequence (Scheme 1).
used previously for the aliphatic substrates (Table 1). Reasonable
yields were obtained in the syntheses of these highly congested
1,4-diketones (i.e., 6), which were isolated as single diastereomers
with enantiomeric ratios of at least 99:1 in all cases, despite the
lower enantiopurity of the individual monomers. Such enhancement
of enantiopurity was an expected outcome of this process on the
basis of Horeau’s amplification of chirality principle.13 That is to
say, the minor monomeric enantiomer is removed through formation
of a diastereomeric dione that can be separated by conventional
chromatography. Aromatization of the diones proceeded smoothly
and with complete stereochemical transfer upon exposure to
BF3 ·OEt2, providing the biphenol compounds (i.e., 7) in high yield.
The absolute and relative configurations of dione 6c (A in Figure
2) were confirmed through X-ray crystal structure analysis using
anomalous dispersion from a copper-source X-ray diffractometer.14,15
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18 J. AM. CHEM. SOC. 2011, 133, 18–20
10.1021/ja108717r  2011 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective Synthesis of Biphenols: Rh-Catalyzed 1,4-Addition/Oxidative Coupling/Aromatization Sequence
5
6
7
entry
Ar
yield (%)a
erb
yield (%)a
erb
yield (%)a
erb
1
2
3
4
5
6
7
8
Ph (5a)
2-naphthyl (5b)
4-OMe-Ph (5c)
4-Me-Ph (5d)
89
87
92
90
88
90
89
80
94:6
94:6
94:6
94:6
96:4
92:8
95:5
95:5
56 (80)
51 (78)
50 (70)
63 (74)
66 (74)
73 (81)
48 (69)
52 (74)
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
77
82
86
89
88
85
75
78
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
4-F-Ph (5e)
3,5-di-Me-Ph (5f)
3,5-di-OMe-Ph (5g)
3,4-methylenedioxy-Ph (5h)
a Isolated yields after chromatography. Numbers reported in parentheses refer to yields based on recovered starting material. b Determined by HPLC.
In conclusion, we have devised an effective method for the
enantioselective construction of biaryl compounds through traceless
central-to-axial chirality exchange that has provided a range of chiral
biphenols with high levels of enantiopurity. Furthermore, in order
to expand the diversity of substrates available for this method, we
developed an enantioselective rhodium-catalyzed addition of arylz-
Figure 2. Stereochemical model (Ar ) 4-MeO-Ph).
inc reagents to achiral dimethylketal quinones, which should find
application beyond the chemistry described herein. Current research
efforts are focused on applying this concept of traceless chirality
exchange to the synthesis of biologically active natural products
and novel ligands for asymmetric catalysis.
As anticipated, oxidative dimerization proceeded with formation
of the newly forged carbon-carbon bond anti to the ꢀ-substituent.
Dione 6c adopts a conformation wherein each substituent is
equatorially disposed and where the dihedral angle (ω) between
Acknowledgment. Support for this work was provided by
the carbonyl carbon atoms is ∼49°. A Newman projection drawn
NorthwesternUniversity(NU)andtheNIH/NIGMS(1R01GM085322).
along the central carbon-carbon bond between the two rings may
therefore be approximated by structure B in Figure 2, wherein the
carbonyl groups are in a gauche relationship. If aromatization occurs
We thank Kiel Lazarski (NU) and Dr. Amy Sargeant (NU) for
assistance with X-ray structure analysis.
from this conformation without rotation about the central carbon-
carbon bond, then the product thus obtained should possess the
dures, spectral data for all compounds, and crystallographic data (CIF).
Supporting Information Available: Detailed experimental proce-
S absolute configuration. X-ray structural analysis of biphenol
7c confirmed this assignment. Similarly, biphenol 3a (Scheme
1) was shown to possess the R configuration, which is consistent
with the proposed model (Figure 2) in view of the fact that the
absolute configuration of the monomeric enone 1a precursor was
R.15 Therefore, it appears that given an enone of known
configuration, one should be able to reliably predict the
configuration of a chiral axis formed through this traceless
stereochemical exchange process.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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