Can Hetero-Polysubstituted Cyclodextrins be Considered as Inherently Chiral Concave Molecules?

Article abstract of DOI:10.1002/anie.200907156

(Figure Presented) Learning curve: Regioselective twofold deprotection of benzylated cyclodextrins with diisobutylaluminum hydride affords products that can behave as enantiomers. For example, they can act as ligands for enantioselective Pd°-catalyzed reactions and their complexes display opposite circular dichroism signals (see picture). They can thus be seen as being inherently chiral cycle surrogates.

Full text of DOI:10.1002/anie.200907156

Communications
DOI: 10.1002/anie.200907156
Inherent Chirality
Can Hetero-Polysubstituted Cyclodextrins be
Considered as Inherently Chiral Concave Molecules?**
Samuel Guieu, Elena Zaborova, Yves Blꢀriot, Giovanni Poli, Anny Jutand,
David Madec, Guillaume Prestat, and Matthieu Sollogoub*
Dedicated to Professor Pierre Sinaꢁ
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Chemie
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The introduction of asymmetry in cyclic concave molecules
constituted of achiral repeating units can be achieved in
various ways and leads to different types of chirality. This goal
was first achieved through attachment of a chiral moiety to
the cyclic scaffold; asymmetry is therefore due to the added
with DIBAL-H exclusively delivers the face-to-face diol 3 as a
single regioisomer, with no traces of the alternative regioiso-
mer CD 4 (Scheme 1).
[14,15]
[1]
stereogenic center located remotely from the cavity. In
contrast, hetero-polysubstitution of the repeating units
afforded molecules that are qualified as inherently chiral
species, as they are devoid of stereogenic atoms, and it is their
[2]
cavity as a whole that is asymmetric. More precisely,
inherent chirality is defined as the association of a two-
dimensional chiral pattern of functionalities with a curva-
[3]
ture. Consequently, racemization is operated by inside-out
inversion of the curvature of the inherently chiral cycle,
whereas opening of the cycle induces removal of the chirality.
To date, asymmetrically substituted cavitands have been
[
4]
synthesized 1) as racemic mixtures, which were resolved by
[
5]
HPLC on a chiral stationary phase, 2) by introduction of a
[6]
chiral auxiliary and resolution or separation of the diaste-
[
7,8]
reoisomers,
the inclusion complex between a racemic host and an
or more recently 3) through crystallization of
[
9]
enantiomerically pure guest. Only very few reports of
enantioselective syntheses of hetero-polysubstituted inher-
ently chiral concave cycles have been reported, all of which
[
10,11]
present modest selectivities and/or yields.
Within the general class of concave molecules, cyclo-
dextrins (CDs) are an exception because they are rendered
intrinsically chiral by their chiral sugar subunits. Conse-
quently, as native CDs are already chiral, the hetero-
functionalization of CDs does not induce chirality. Further-
more, the lack of efficient and regioselective methods to poly-
Scheme 1. Twofold DIBAL-H deprotection regiospecifically affords 3.
The other regioisomer 4 has a mirror-image substitution arrangement.
Bn=benzyl.
[
12]
heterofunctionalize CDs
ments in this direction. However, we have devised a unique
methodology to regioselectively functionalize the primary rim
has largely hampered develop-
[13]
[
14–17]
of CDs by using an iterative deprotection strategy.
An
initial diisobutylaluminum hydride (DIBAL-H) induced
deprotection of a perbenzylated a-CD affords diol 1, which
has diametrically opposed alcohol functions (face-to-face
diol). When the hydroxy groups of 1 are converted into
R groups, and provided R is judiciously chosen to induce local
steric decompression in CD 2, a second deprotection of CD 2
Both CDs 3 and 4 are chiral enantiopure molecules with
C symmetry. Compounds 3 and 4 do not share the same
2
connectivity and are therefore constitutional isomers, how-
ever, they exhibit mirror-image functionalization patterns at
their upper rims because of their opposing topologies (A and
B, Scheme 1). Therefore, such upper-rim functionalization
creates a new topological stereogenic unit, the layout of which
is solely controlled by the chirality of the CD scaffold that
undergoes the second DIBAL-H deprotection step. It should
be noted, however, that the existence of the topological
stereogenic unit is independent of the chirality of the starting
scaffold and would persist if incorporated in an achiral
scaffold (A and B, Scheme 1). As a consequence, we reasoned
that 3 and 4 can be regarded, and possibly exploited, as
topological equivalents of inherently chiral scaffolds, as the
CD component provides the curvature, and the array of
primary-rim substitution acts as a two-dimensional chiral
pattern. The virtual inside-out inversion of the CD cone of 4
would lead to the same molecule 4 with the mirror-image
orientation of the primary-rim substitution (Scheme 2).
Therefore, although chirality of CDs 3 and 4 is theoretically
provided by the CD component, these two CDs possess all the
properties that confer inherent chirality to a curved macro-
cycle.
[
18]
[*] Dr. S. Guieu, E. Zaborova, Prof. Y. Blꢀriot, Prof. G. Poli, Dr. D. Madec,
Dr. G. Prestat, Prof. M. Sollogoub
Institut Parisien de Chimie Molꢀculaire (UMR CNRS 7201)
UPMC Univ Paris 06
FR 2769 C. 181, 4 place Jussieu, 75005 Paris (France)
Fax: (+33)1-4427-5504
E-mail: matthieu.sollogoub@upmc.fr
Homepage: http://www.umr7611.upmc.fr/les_equipes/
glycochimie/equipe.htm
Dr. A. Jutand
Dꢀpartement de Chimie, UMR CNRS-ENS-UPMC 8640,
Ecole Normale Supꢀrieure, Paris (France)
[
**] We thank Cyclolab for generous supply of a-cyclodextrin and Dr.
Christophe Desmarets for help with circular dichroism. M.S. would
like to warmly thank Prof. Kurt Mislow and Prof. Henri Kagan for
very useful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907156.
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Scheme 2. Inside-out inversion of the curvature of 4 induces inversion
of the substituent arrangement, as expected for an inherently chiral
concave cycle.
Scheme 4. Synthesis of L1. a) 1. BnCl; 2. DIBAL-H; 3. MsCl, 4. LiAlH4,
2% (4 steps); b) DIBAL-H, 75%; c) 1. MsCl, pyridine, 73%; 2. Ph PH,
6
2
nBuLi, 93%. Ms=mesyl.
This fascinating apparent theoretical paradox prompted
us to experimentally confirm the anticipated topological
pseudoenantiomeric relationship between CDs 3 and 4.
RajanBabu et al. showed that enantioselectivity could
depend only on the local chirality of a six-membered ring of
reaction. Accordingly, the divinyl CD 7 was first synthesized
from a-CD (57% over four steps) and then deprotected with
[
15]
DIBAL-H (90% yield) to give the face-to-face diol 8. This
compound was then converted into the dideoxy CD 9 through
mesylation, subsequent hydride reduction (80% yield), and
reductive ozonolysis (93% yield). Diol 9 is the topological
regioisomer of the face-to-face diol 6 produced by the direct
DIBAL-H deprotection of 5. Diphosphine L2 was obtained
from 9 using the same methodology as for L1 (Scheme 5).
Finally, diphosphine L3 was obtained in 56% yield from diol
[
19]
two vicinal carbon atoms that bear chelating groups.
Furthermore, following the seminal work of Reetz and
[20]
Waldvogel on phosphine-modified CDs, Matt, Armspach,
and co-workers elegantly demonstrated that a transition
metal can be efficiently chelated above the cavity of a CD by
two phosphine groups installed on the primary rim, thereby
[21-25]
forming metallo-capped CDs.
We therefore designed
[
15,18]
three new CD-based diphosphines L1–L3 in order to evaluate
1.
[
26]
them as topological pseudoenantiomeric ligands, the chir-
ality of which stems from the regioisomery of their substitu-
tion patterns. Ligands L1 and L2 bear diametrically opposed
phosphine, methyl, and benzyloxymethyl groups in a mutual
mirror-image arrangement on the primary rim. The diphos-
phine L3 has a symmetrical substitution pattern and can be
[27]
used as pseudoachiral ligand (Scheme 3).
Scheme 5. Synthesis of L2. a) 1. BnCl; 2. DIBAL-H; 3. (COCl) , DMSO
2
then Et N; 4. Ph PCH Br, nBuLi, 57% (4 steps); b) DIBAL-H;
3
3
3
c) 1. MsCl, pyridine, 99%; 2. LiAlH , 80%, c) 1. MsCl, pyridine, 99%;
4
2
. LiAlH , 80%, O /NaBH , 93%; d) 1. MsCl, pyridine, 84%; 2. Ph PH,
4
3
4
2
nBuLi, 60%.
Scheme 3. Structures of ligands L1–L3.
To validate our concept and probe the anticipated
topological pseudoenantiomeric relationship between L1
0
and L2, the popular Tsuji–Trost Pd -catalyzed substitution
Based on our knowledge of regioselective deprotection of
CDs, we synthesized the dideoxy CD 5 using the DIBAL-H
deprotection method starting from a-CD (62% yield over
four steps). Regioselective deprotection of 5 was driven by
of 1,3-diphenylallyl acetate with the dimethylmalonate
[28]
anion
was selected as a benchmark reaction. Classical
conditions were used to test ligands L1–L3 (10 mol%), using
0
dimeric allyl palladium chloride as the Pd precursor
[
15]
steric orienting effects to afford face-to-face diol 6 in 75%
yield. Diol 6 was then conveniently converted into the
diphosphine CD L1 in 68% yield, by using the methodology
(10 mol%) and the couple BSA (3 equiv)/AcOK (3 mol%)
as the enolizing system. While use of L3 afforded the desired
allylated product in modest yield of 19%, the use of L1 and
L2 led to satisfactory yields of 77% and 87%, respectively.
Quantification of the enantiomeric excesses by HPLC
[24]
developed by Matt, Armspach, and co-workers, in which
mesylation followed by nucleophilic substitution by lithium
diphenylphosphide was employed (Scheme 4).
[
29]
1
analysis
and H NMR spectroscopy in the presence of
[
30]
Access to L2 is not as straightforward as L1, owing to the
unidirectionality of the DIBAL-H-induced debenzylation
chiral europium salts, showed clear opposite enantioselec-
tivities (30%) arising from the use of regioisomeric pseudo-
2
316
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enantiomeric ligands L1 and L2. Moreover, the pseudoachiral
ligand L3 did not induce any enantioselectivity, thus ruling
out the role of the sugar chirality in this asymmetric induction
(
Figure 1).
Figure 1. CDs L1 and L2 induce opposite enantioselectivities in a
Tsuji–Trost reaction, whereas L3 gives a racemic mixture, as shown by
the H NMR spectra of the products (methyl ester hydrogen atom
1
Figure 2. Synthesis of complexes 11 and 12, and circular dichroism
spectra of L1, L2, 11, and 12. a) [{Pd(h -PhC H Ph)(m-Cl)} ]; b) NaBF .
3 3 2 4
3
signals in the presence of the chiral resolution reagent [Eu(hfc) ]).
3
3
a) [{Pd(h -C H )Pd(m-Cl)} ], ligand L1–L3, CH (CO Me) , BSA, AcOK,
3
5
2
2
2
2
CH Cl , RT. BSA=N,O-bis(trimethylsilyl)acetamide.
2
2
vast range of possible applications where an easily accessible
pure chiral concave structure is required.
The opposite enantioselectivities observed for L1 and L2
imply that the environments around the metal in the
Received: December 18, 2009
Published online: February 28, 2010
3
corresponding h -allyl complexes are enantiomeric. We there-
fore recorded the circular dichroism spectra of the two ligands
3
Keywords: cavitands · chirality · cyclodextrins ·
homogeneous catalysis · selectivity
L1 and L2 as well as the two corresponding [Pd(h -
.
+
PhC H Ph)(L)] complexes 11 and 12, which were synthe-
3
3
[
31]
sized by following a reported procedure. As expected, both
uncomplexed ligands displayed a negative Cotton effect in the
low-wavelength region (250–300 nm); this feature is charac-
teristic of the chirality of the sugar units, which is the same in
both species. For the complexes 11 and 12, the situation is
strikingly different. In the region above 350 nm, which is the
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