The synthesis of optically active calix[4]arenes with one or three substituents on the methylene bridges

Article abstract of DOI:10.1039/c0cc02689a

A facile synthesis of optically active mono and trisubstituted calix[4]arenes is described wherein the chirality at the methylene bridges arises from centers of chirality present in the diyne and the bis-carbene complex from which they are constructed.

Full text of DOI:10.1039/c0cc02689a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The synthesis of optically active calix[4]arenes with one or three
substituents on the methylene bridgesw
Vijay Gopalsamuthiram, Rui Huang and William D. Wulff*
Received 20th July 2010, Accepted 16th September 2010
DOI: 10.1039/c0cc02689a
A facile synthesis of optically active mono and trisubstituted
calix[4]arenes is described wherein the chirality at the methylene
bridges arises from centers of chirality present in the diyne and
the bis-carbene complex from which they are constructed.
Calixarenes are among the small group of privileged scaffolds
for the construction of supramolecular hosts.1 Although a
plethora of synthetic methods have been developed for the
synthesis of calixarenes, very few methods exist for the pre-
paration of calixarenes with substituents in the methylene
bridges of the calix. At present, only a handful of methods
have been described in the literature that allow for the
preparation of mono-, 1,2 and 1,3-di-, and tetra-substituted
calix[4]arenes where all of the substituents are on the methylene
bridges.2 1,2,3-Tri-substituted calix[4]arenes with all substituents
Scheme 1
on the methylene bridges have not been reported. While some
of these methods afford the product as a single diastereomer,
none of these methods offer the potential to prepare optically
active variants. This is a consequence of the methods used
for linking the arene rings to the methylene spacers since
they involve intermediates with either radicals, cations or
carbanions at the methylene carbon or involve the intermediacy
of compounds that have sp2 carbons bridging the rings.
In this regard, we recently demonstrated the utility of the
reaction of diynes with bis-carbene complexes in the first
synthesis of optically active di- and tetra-substituted calix[4]-
arenes (Scheme 1).3 This process generates two of the benzene
rings of the calixarene as well as the macrocyclic ring in a
single step. With this triple annulation protocol we were able
to gain stereoselective access to enantiomerically pure 1,2-di-
methoxy calix[4]arenes and to different diastereomers of
tetra-methoxy calix[4]arenes also in optically pure form. We
would like to report herein the synthesis of the first examples
of optically active mono- and tri-substituted calix[4]arenes
with all substituents on the methylene bridges.
and 65% ee along with a 13% yield of the bis-addition
product.
Advantage was taken of this outcome to access the mono-
substituted diyne (S)-10 so that a greater diversity of methylene
substituted calix[4]arenes could be achieved. The optical purity
of 7 was only 65% ee but it is was found that this could be
increased to 93.4% ee with enzymatic kinetic resolution
with Novozyme 435 and vinyl acetate (Scheme 3).5 The key
carbon–carbon bond forming step in the synthesis of (S)-10 is
the alkynylation of benzyl bromide 9 which utilizes a
palladium catalyzed coupling of an alkynyl indium reagent.6
According to the observations of Pu,4 the absolute configuration
of 7 is expected to be (S) when using (S)-BINOL. This
configurational assignment was confirmed by the method of
Horeau (see ESIw). On this basis the assignment of the
During the optimization studies for the synthesis of bis-
alkynols by the addition of zinc acetylide4 to the dialdehyde 4,
we noted that the complete conversion of the dialdehyde 4
requires the addition of 4 equivalents of the zinc acetylide and
gives, after desilylation, the diol (S,S)-6 in 50% yield and
99.2% ee along with a 38% yield of the meso diol corresponding
to 6 (Scheme 2). The use of two equivalents of the zinc
acetylide gives the mono-addition product 7 in 75% yield
Department of Chemistry, Michigan State University, East Lansing,
MI 48824, USA. E-mail: wulff@chemistry.msu.edu;
Fax: +1 (517)3531793; Tel: +1 (517)3559715 ext. 373
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all new compounds including
X-ray data for (S)-12. CCDC 785086. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc02689a
Scheme 2
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8213–8215 | 8213

View Online
Scheme 3
Fig. 1 Crystal structure of (S)-12 visualized by the Mercury program.
absolute configuration of all calixarenes was made assuming
that the configuration of diyne (S)-10 does not change during
the triple annulation.
more stable than an axial methoxy. The 1H NMR assignment
of (S)-12 as having the cone conformation was confirmed by
an X-ray diffraction analysis (Fig. 1). The X-ray structure
reveals that (S)-12 adopts the cone former that has the
methoxyl in an equatorial position. Interestingly, the analysis
reveals that there are two molecules in the unit cell that are
interlocked by the mutual projection of a methyl group on the
para-position of the outer rim into the bowl of the other
calixarene.
The first chiral calix[4]arene that we attempted to prepare
with diyne (S)-10 was the mono-methoxy derivative 12. The
reaction of the unsubstituted carbene complex 117 and 1
equivalent of the mono-methoxy substituted diyne (S)-10
(93.4% ee) was carried out at 2.5 mM in 1,2-dichloroethane
at 100 1C to give a single product as indicated by TLC and 1H
NMR which was isolated in 31% yield and identified as the
calix[4]arene (S)-12. The 1H NMR spectrum indicated that
this compound exists exclusively as the cone conformer and
the singlet at d = 5.98 ppm indicates that the methoxy group is
in an equatorial position.2j,8
The first example of a 1,2,3-trisubstituted calix[4]arene was
prepared from the reaction of the diyne (S)-10 and the bis-
carbene complex (S,S)-13 which has both of its methylenes
substituted with methoxy groups. This reaction gave the
(S,S,S)-tri-methoxycalix[4]arene 13 in 32% yield which by its
1H NMR spectrum exists as the cone conformer as shown in
Scheme 5, which has two equatorial and one axial methoxy
groups. As with the formation of (S)-12, a diastereomer of 13
is possbile. This diastereomer has one equatorial and two
axial methoxy groups and a ring flip would be expected to
preferentially favor (S)-13.
The calixarene (S)-12 as drawn in Scheme 4 would result
from the approach of the carbene complex 11 from the back-
side of (S)-10. Approach from the frontside of (S)-10 would
give a diastereomeric calixarene that is a diastereomer of
(S)-12 where the cone conformer would have an axial methoxy
group. However, the flip of all the phenyl rings through the
anulus would be expected to be rapid for this compound and
would produce a compound that would be in identity with
(S)-12. Since only a single diastereomer of (S)-12 is seen, it
must be the case that an equatorial methoxy is significantly
Two diastereomers are possible from the reaction of diyne
(S)-10 with the meso-biscarbene complex 14. Indeed, this
reaction gave a 1.0 : 1.4 mixture of diastereomers (S,R,S)-15
Scheme 4
Scheme 5
ꢀc
This journal is The Royal Society of Chemistry 2010
8214 | Chem. Commun., 2010, 46, 8213–8215

View Online
Notes and references
1 (a) Calixarenes 2001, ed. Z. Asfari, V. Bohmer, J. Harrowfield and
¨
J. Vicens, Kluwer, Dordrecht, 2001; (b) W. Silwa and C. Kozlowski,
Calixarenes and Resorcinarenes, Wiley-VCH, 2009.
2 (a) M. Tabatabai, W. Vogt and V. Bohmer, Tetrahedron Lett., 1990,
31, 3295; (b) G. Sartori, R. Maggi, F. Bigi, A. Arduini, A. Pastorio
and C. Porta, J. Chem. Soc., Perkin Trans. 1, 1994, 1657;
(c) C. Gruttner, V. Bohmer, W. Vogt, I. Thondorf, S. E. Biali and
¨
¨
F. Grynazpan, Tetrahedron Lett., 1994, 35, 6267; (d) G. Sartori,
F. Bigi, C. Porta, R. Maggi and F. Peri, Tetrahedron Lett., 1995, 36,
8323; (e) S. E. Biali, V. Bohmer, S. Cohen, G. Ferguson,
¨
W. Vogt, J. Am. Chem. Soc., 1996, 118, 12938; (f) V. Bohmer,
¨
C. Gruttner, F. Grynszpan, E. F. Paulus, I. Thondorf and
¨
Liebigs Ann./Recl., 1997, 2019; (g) M. Bergamaschi, F. Bigi,
M. Lanfranchi, R. Maggi, A. Pastorio, M. A. Pelinghelli, F. Peri,
C. Porta and G. Sartori, Tetrahedron, 1997, 53, 13037;
(h) B. Klenke, C. Nather and W. Friedrichsen, Tetrahedron Lett.,
¨
1998, 39, 8967; (i) O. Middel, Z. Greff, N. J. Taylor, W. Verboom,
D. N. Reinhoudt and V. Snieckus, J. Org. Chem., 2000, 65, 667;
(j) K. Agbaria and S. E. Biali, J. Am. Chem. Soc., 2001, 123, 12495;
(k) P. A. Scully, T. M. Hamilton and J. L. Bennett, Org. Lett., 2001,
3, 2741; (l) S. Simaan, K. Agbaria and S. E. Biali, J. Org. Chem.,
2002, 67, 6136; (m) S. E. Biali, Synlett, 2003, 1; (n) S. Simaan and
S. E. Biali, J. Org. Chem., 2003, 68, 3634; (o) S. Simann and
S. E. Biali, J. Org. Chem., 2003, 68, 7685; (p) S. Simaan
and S. E. Biali, J. Phys. Org. Chem., 2004, 17, 752; (q) S. Simaan
and S. E. Biali, Org. Lett., 2005, 7, 1817; (r) L. Kuno, N. Seri and
S. E. Biali, Org. Lett., 2007, 9, 1577; (s) I. Columbus and S. E. Biali,
Org. Lett., 2007, 9, 2927; (t) I. Columbus and S. E. Biali, J. Org.
Chem., 2008, 73, 2598; (u) L. Kuno and S. E. Biali, J. Org. Chem.,
2009, 74, 48.
3 V. Gopalsamuthiram, A. Predeus, R. Huang and W. D. Wulff,
J. Am. Chem. Soc., 2009, 131(50), 18018–18019.
4 D. Moore and L. Pu, Org. Lett., 2002, 4, 1855.
5 C. Raminelli, J. V. Commaseto, L. H. Andrade and A. L. M. Porto,
Tetrahedron: Asymmetry, 2004, 15, 3117.
6 R. Riveiros, D. Rodriquez, P. Sestelo and L. Sarandeses, Org. Lett.,
2006, 8, 1403.
7 V. Gopalsamuthiram and W. D. Wulff, J. Am. Chem. Soc., 2004,
126, 13936.
Scheme 6
and (S,S,R)-16 in a combined 29% yield (Scheme 6). Although
they could not be completely separated, careful gradient
elution from silica gel did give a pure fraction of the
diastereomer (S,R,S)-15 with the remainder as an enriched
fraction of the (S,S,R)-16 (4.1 : 1.0). The structures of these
diastereomers are indicated in Scheme 6 with 15 having all
equatorial methoxyl groups and 16 having two equatorial and
one axial methoxy groups. These conformers would be
expected to be more stable than the ring-flipped diastereomers
with three axial methoxyl groups in the case of 15 and two
axial and one equatorial methoxy groups in the case of 16.
In summary, the first synthesis of optically active mono and tri-
substituted calix[4]arenes substituted on the methylene carbons
has been achieved by transfer of chirality from the unsymmetrical
mono-methylene substituted diyne (S)-10 that has been obtained
selectively by controlled addition to dialdehyde 4.
This work was financially supported by a grant from the
National Science Foundation (CHE-0750319).
8 For a review of the conformations of methylene substituted calix-
arenes, see ref. 2p.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8213–8215 | 8215