J. Am. Chem. Soc. 1999, 121, 6751-6752
6751
have been resolved with chiral chromatographic procedures.4
Lipase-catalyzed transesterification has been used recently to
generate chiral calix[4]arenes with high enantiomeric excesses.5
Diastereoselective functionalization has also been used to prepare
chiral calixarene derivatives.6 Included in this area has been the
highly diastereoselective functionalization of calix[4]resorcinarene
derivatives involving the formation of tetrakis(3,4-dihydro-2-H-
1,3-benzoxazines) by the use of chiral nonracemic primary amines.
The presence of substituents attached to the inter-ring methine
carbon atoms precludes thermal racemization processes in calix-
[4]resorcinarene derivatives. The earlier publications suggest that
the control of diastereoselection is capricious with classical
Mannich protocols.7 In our hands the best results are obtained
using a bis(methoxymethyl ether), for example 2, as a bis(iminium
ion) precursor. Our experience shows that although the crystalline
tetrakis(3,4-dihydro-2-H-1,3-benzoxazines) remain diastereoiso-
merically stable over long periods of time, they undergo rapid
diastereoisomerization in solution in the presence of traces of
acids.7a We had previously determined the handedness of the
dihydro-2-H-1,3-benzoxazine rings in the dissymmetric structures
in one of a pair of enantiomers by a single-crystal X-ray structure
determination. In addition we established that the products were
diastereoisomerized to an unequal mixture of diastereoisomers
in acid-catalyzed reactions, via ring-opened iminium ions.7a
The First Enantioselective Syntheses of Axially
Chiral Enantiomerically Pure Calix[4]resorcinarene
Derivatives
Philip C. Bulman Page,*,† Harry Heaney,*,‡ and
Edward P. Sampler
Department of Chemistry, Loughborough UniVersity
Leicestershire LE11 3TU, U.K.
ReceiVed March 15, 1999
We report here our preliminary work that is designed to address
the enantioselective synthesis of axially chiral, enantiomerically
pure, calix[4]resorcinarene derivatives by the enantioselective
generation of diastereoisomerically pure tetrakis(benzoxazines)
followed by the removal of the chiral auxiliary. The key to our
strategy involves the alkylation of the four residual phenolic
groups that are present in diastereoisomerically and enantiomeri-
cally pure tetrakis(benzoxazines) 1 before removal of a chiral
auxiliary, thus ensuring that diastereoisomerization is precluded
as well as providing the necessary dissymmetry.
The chemistry of calixarenes1 continues to be widely studied,
and in particular the preparation in high yields of a range of calix-
[4]resorcinarene derivatives has provided interesting possibilities.
The structures of the thermodynamic products place the eight
phenolic hydroxyl groups on the upper rim of the C4V symmetric
products and these compounds have been utilized in a wide range
of syntheses.2 Important recent work has also concentrated on
stereochemical aspects of the chemistry of calixarenes. The
dissymmetry generated by unsymmetrical substitution of calix-
arenes was recognized as being related to the nonplanar structures
of the parent compounds,3a although a number of chiral calixarene
conformers are racemized thermally by processes involving
“through-the-annulus rotation”.3b The first example of the optical
resolution of such a compound was achieved with chiral liquid
chromatography.3c A large number of axially chiral calixarene
derivatives continues to be prepared as racemates, some of which
Recent studies of the O-benzylation of cyclophanes highlight
the problems of control of regioselectivity and in the determination
of the number of O-benzylation reactions that occur.8 Our early
attempts to achieve tetrakis(O-methylation) using a variety of
conventional protocols failed. However, we were able to depro-
tonate all four phenolic hydroxy groups in a THF solution of the
calix[4]resorcinarene 17a using 4 equiv of n-butyllithium at -78
°C. Methylation at low temperature with dimethyl sulfate then
gave the tetramethyl ether 3 in 45% yield, while the use of methyl
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10.1021/ja990819g CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999