J. Am. Chem. Soc. 2001, 123, 5213-5220
5213
Chiral Softballs: Synthesis and Molecular Recognition Properties
Jose´ M. Rivera, Toma´s Mart´ın, and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and the Department of Chemistry, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and the
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
ReceiVed NoVember 27, 2000
Abstract: Studies on the different congeners of the softball were undertaken to explore structural variants for
enantioselective encapsulation. Two different spacer elements in the monomeric subunit render the dimeric
softball chiral although the monomer itself is achiral. The dimers represent capsules with dissymmetric cavities
with volumes ranging from 190 to 390 Å3. The cavities are distorted spheres, and asymmetric guests, such as
naturally occurring terpenes, generally prefer one enantiomer of the capsule to its mirror image. The selectivities
are moderate (up to 4:1). The complexation studies show that the host capsules are flexible enough to arrange
themselves comfortably around a guest but still maintain enough rigidity to be influenced by the occupancy
of a chiral guest. The enantiomeric capsules can interconvert (racemize) by dissociation and recombination of
their subunits.
Introduction
create a receptor that completely surrounds its target. This
defines, of course, a molecule within a molecule, one of the
emerging tools of modern physical organic chemistry. They
provide chambers that stabilize reactive intermediates,9 reveal
new forms of stereoisomerism,10 accelerate reactions,11 and
probe the intrinsic characteristic of the liquid state.12 This
research was undertaken to invent and evaluate molecule-within-
molecule complexes that feature dissymmetric cavities.
Rigid structures are typically associated with selective
recognition, so that carcerands and cryptophanes, held together
by covalent bonds, would seem to have an advantage for
enantioselectivity. These molecular hosts show high energetic
barriers to guest exchange and often require forcing conditions
to equilibrate; only modest selectivities have been seen. The
use of weak intermolecular forces instead of covalent bonds
for assembly of the receptor imparts reversibility to the guest-
exchange process, a process that we call encapsulation.13,14 We
found that dissymmetric spaces were also accessible through
assemblies held together by weak intermolecular forces. Guest
enantioselectivity was possible even with the flexibility inherent
in such systems. Moreover, stereochemical information was
shown to flow from the host to the guest and vice versa.
Enantioselection has always been a motive of molecular
recognition. So many different chiral receptors have been
examined that another version might be hard to justify:
Cyclodextrins,1 crown ethers,2 cryptophanes,3 cyclophanes,4
carcerands,5 baskets,6 and even some structures that are not
macrocyclic7 have all been worked over. These structures often
have high symmetries, and the cavities, when they do have
cavities, are not particularly asymmetric. The enantioselectivity,
particularly with neutral targets, leaves something to be desired,8
and we have kept an inner eye on the problem. As our early
work with cleft-like structures became more sophisticated and
the concave receptors made contact with an ever-increasing
fraction of the convex targets’ surfaces, it appeared feasible to
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10.1021/ja004080i CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001