Tetrahedron Letters
Asymmetric synthesis of diarylmethane derivatives by dynamic
kinetic resolution
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Lewis M. Gooch, Steven B. Rossington, James A. Wilkinson
Biomedical Research Centre, University of Salford, Salford M5 4WT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric allylation of ortho-methoxydiphenylmethane has been carried out with high yields and ee of
up to 94% using the chiral ligand (À)-sparteine as an additive. Results of reactions performed under var-
ious conditions suggest that a dynamic kinetic resolution of two rapidly interconverting diastereomeric
complexes is occurring.
Received 19 March 2015
Revised 27 April 2015
Accepted 2 May 2015
Available online 8 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Organolithium chemistry
Asymmetric synthesis
Dynamic kinetic resolution
Introduction
two complexes with the electrophile to give 3. However, if the
equilibration of complexes (R)-2 and (S)-2 is slow under the reac-
The substituted diarylmethane motif is found in numerous nat-
ural products and pharmacologically-relevant structures and a
variety of efficient enantioselective methods have been developed
for its synthesis.1 We have previously reported an approach involv-
ing lateral lithiation of various diarylmethanes in the presence of a
chiral ligand.2 These substrates included 2-benzylanisole 1 which
we were able to allylate in high yield with 60% ee (Scheme 1).
Our tentative assumption of a dynamic kinetic resolution was
based on the high sensitivity of the reaction to changes in elec-
trophile and the failure of warm–cool cycles to produce high
enantioselectivity.2a
Our original response to the moderate enantioselectivity
obtained for the lateral lithiations of diarylmethane 1 was to use
other stabilising groups, which gave much better results.3
Recently, we have revisited the original substrate as part of a total
synthesis and made a more thorough study of its lateral lithiation.
We now report a significant improvement in the enantioselectivity
of the allylation of 1 based on the use of a dynamic kinetic
resolution.
tion conditions, a dynamic thermodynamic resolution is possible.5
Results
Our previous studies had shown that the organo-
lithium/sparteine complex derived from 1 possessed a small
degree of configurational instability at À78 °C.6 This led us to
assume that if higher temperatures were employed, along with
slow addition of a solution of the electrophile, equilibration of
the diastereomeric complexes would occur more quickly than
quenching. Allyl bromide was chosen for the initial studies as the
major product (R)-3 had a known specific rotation for the 60% ee
sample that had been confirmed by work with NMR chiral shift
reagents and conversion to compounds of known absolute config-
uration.7 The results of experiments at different temperatures are
shown in Table 1.
Increasing the temperature up to À20 °C we observed a steady
increase in the enantioselectivity with a maximum 92% ee being
obtained using allyl bromide with an addition time of 150 min
(achieved by the slow addition of allyl bromide (0.8 mmol) dis-
solved in ether (50 mL)). This result was confirmed by conversion
of the product to carboxylic acid 4 and methyl ester 5 which were
both known from a previous work (Scheme 3). A ytterbium shift
reagent was also used with the ester, and gave results in agree-
ment with the specific rotation measurements.8
Dynamic resolutions of diastereomeric complexes between an
organolithium and a chiral ligand have been used by a number of
groups to achieve high enantioselectivities in a variety of transfor-
mations.4 Dynamic resolution takes place under kinetic control if
the interconversion of the diastereomeric complexes (R)-2 and
(S)-2 (Scheme 2) occurs more quickly than the reactions of the
At higher temperatures much lower conversion to the product
was observed leading us to assume that the organolithium can
be slowly quenched by solvent under these conditions since the
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