Conformationally driven asymmetric induction of a catalytic dendrimer

Article abstract of DOI:10.1021/ja802308a

Nature-s catalysts promote the reactions necessary for life with extremely high specificity by folding into specific shapes capable of communicating remote structural information to an active site. Achieving this objective in synthetic systems has been ha

Full text of DOI:10.1021/ja802308a

Published on Web 05/29/2008
Conformationally Driven Asymmetric Induction of a Catalytic Dendrimer
Jianfeng Yu, T. V. RajanBabu,* and Jon R. Parquette*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
Received March 29, 2008; E-mail: parquette.1@osu.edu; rajanbabu.1@osu.edu
The exquisite selectivity realized by enzymes relies on the
dynamic conformational properties produced by molecular folding
to communicate structural information over large distances to the
active site. In contrast, synthetic catalysts generally depend on static,
proximal structural information for selectivity.1 The quest for truly
biomimetic molecules that exploit a chiral, folded secondary
structure in asymmetric catalysis2 remains as an unrealized objective
in the search for function in abiological systems.3 Achieving this
objective would minimally require the amplification and relay of
local stereochemistry to the reactive/catalytic site via an intervening
secondary structure. Although the branched, macromolecular
structure of a dendrimer offers unique potential to replicate the
microenviroment of an enzyme active site,4 reports of rate enhance-
ments or even modest increases in selectivity by dendrimers with
catalytic cores are rare.5 These enhancements have been attributed
to polarity changes or substrate preconcentration within the micro-
environment of the dendrimer.6 The design of dendritic catalysts
that function by noncovalently propagating chiral information to a
catalytic site represents a particularly challenging objective, which
has not yet been achieved.7 Here, we show how remote chirality
within a dendritic catalyst can be relayed over 14 bonds to control
the enantioselectivity of a prototypical reaction.
-
Figure 1. Structure of LRh+(COD) SbF6 precatalysts.
To explore the potential for a conformationally dynamic molecule
to transmit remote chirality to a catalytic process, we presented a
pair of first-generation dendrons at the 3 and 3′ positions of a 2,2′-
bis(diphenylphosphinoxy)biphenyl scaffold (Figure 1). These den-
drons exist in highly mobile helical conformations that are capable
of expressing local chirality at the termini as an M or P helical
bias.8 Likewise, the conformational lability of the biphenyl core,9
and that of the corresponding nine-membered rhodium chelate,10
permits a rapid interchange between the two forms of axial chirality.
Accordingly, dendritic precatalysts C2-C4 interconvert among a
minimum of six diastereomeric conformations. The efficacy of these
molecules as asymmetric catalysts requires a delicate balance
between flexibility, needed to communicate remote chirality to the
catalytic site via this conformational interchange, and structural
integrity during the entire catalytic process.
Table 1. Hydrogenation of (Z)-Methyl
2-acetamido-3-phenylacrylatea
catalyst
solvent
T (°C)
ee (%)b
catalyst
solvent
T (°C)
ee (%)b
C1
toluene
THF
toluene
THF
rt
rt
rt
rt
57(S)
68(S)
18(R)
14(R)
C4
toluene rt
toluene -20 91 (S)
87 (S)
C2
THF
R-C5 toluene rt
S-C5 toluene rt
rt
84 (S)
97 (R)
99 (S)
C3
toluene
THF
rt
rt
57(S)
46(S)
a Reaction conditions: 0.3 mol % of LRh+(COD)SbF6-, 50 psi.
b Enantiomeric excesses determined by GC (Chirasil-L Val).
selectivity, we turned our attention to catalysts derived from
oxazoline-terminated dendrons.13 The oxazoline nitrogens in these
systems form stronger hydrogen bonds with the pyridine-2,6-
dicarboxamide N-H’s than the corresponding ester carbonyl
groups. The rigidified helical structure experiences a higher helical
interconversion barrier (for dendrons in C3, ∆Gq ) 12.3 kcal/mol)
and a greater P helical bias, compared with the ester-terminated
dendrons in C2 (∆Gq e 8.0 kcal/mol, not measurable by NMR).
In accord with this notion, hydrogenation of 1 using precatalyst
C3 in toluene produced the S enantiomer of 2 in 57% ee. To further
enhance the helical bias in the dendrons, we explored the isopropyl-
substituted analogue C4. This catalyst provided product 2 in 87%
ee in toluene at rt and 91% ee at -20 °C. Dendritic catalysts
C2-C4 exhibited enantioselectivities in toluene higher than those
in THF, in contrast to C1.
[Dend]Rh+ precatalyst C2 was composed of dendrons displaying
(S)-(1-methoxypropan-2-yl)-2-acylaminobenzoate termini. Applica-
tion of this precatalyst to the hydrogenation of (Z)-methyl 2-acet-
amido-3-phenylacrylate, 1, in toluene produced (R)-2 in 18% ee
(Table 1).11 Although the selectivity of C2 was significantly lower
than that of the corresponding atropisomeric precatalyst derived
from (S)-1,1′-binaphthyl-2,2′-diol (C1),12 it revealed the potential
for the structure to relay the local terminal chirality to the catalytic
site.
One could envision a mechanism for communication of the
terminal stereochemistry to the catalytic center whereby the helical
secondary structure of the dendron directly influences the environ-
Reasoning that the low M-P helical interconversion barrier of
the ester-terminated dendron in C2 might be a source of low
9
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2008 American Chemical Society
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C O M M U N I C A T I O N S
Figure 2. Chiral information propagates from the dendron terminal groups
to the catalytic center via the biphenyl core, which serves to relay chirality
to the catalytic site via its axial chirality.
Figure 4. Atropisomeric nature of binaphthyl core locks axial chirality of
central core in (R)-C5, which precludes relay of dendron helicity to catalytic
center.
Figure 5. Top: 31P NMR spectra of C2-C5. Bottom: Temperature-
dependent spectra of C3.
C5 produced (R)-2 in 97% ee demonstrates both the dominance of
the binaphthyl core and the critical role that the dynamic axial
chirality of the biphenyl core plays in communicating the dendron
helicity to the rhodium center in C4. The ability of biphenyl-based
ligands to mediate asymmetric induction upon coordination of a
proximal chiral ligand to render the axial antipodes diastereomeric
supports this relay mechanism.14 Although the P helical bias of
(R)-C5 and (S)-C5 is identical to that of C4 by CD, locking the
axial chirality of the binaphthyl core in (R)-C5 effectively blocks
the chiral influence of the dendron on the catalytic center. The
“matched” diastereomer, (S)-C5, constructed from (S)-1,1′-binaph-
thyl-2,2′-diol, affords (S)-2 in 99% ee, which is also consistent with
the minor impact of the dendrons on selectivity when the core is
conformationally locked. The remarkable improvement in selectivity
of C4 and C5 compared with that of C1 likely reflects a synergistic
steric effect associated with ortho-substitution of biphenyl or
binapthyl cores.15
Figure 3. Top: Dynamic interconversion of M and P helical conformations
in oxazoline-terminated dendrons. Bottom: Circular dichroism and UV
-
spectra of LRh+(COD)SbF6 precatalysts in acetonitrile at rt.
ment around the rhodium center (Figure 2). Alternatively, the
dendron helicity might be relayed via the axial stereochemistry of
the biphenyl core, which then directs the stereoselectivity. It is
noteworthy that the sense of chirality of the product 2 depends on
the helical configuration of the dendron. For example, circular
dichroism (CD) spectra of C2 displayed a negative excitonic couplet
centered at ca. 316 nm, which indicated a preference for an M
helical conformation of the dendrons (Figure 3).8d Conversely, the
positive couplet centered at ca. 309 nm for C3/C4 reveals a P helical
bias.13b Accordingly, the M bias in C2 produces (R)-2, whereas
the P bias in C3 and C4 produces (S)-2. The amplitude of the
excitonic couplet similarly correlates with enantioselectivity in the
order C2 < C3 < C4.
To understand how this helical bias is relayed to the catalytic
center, an atropisomeric analogue of C4 was constructed from (R)-
1,1′-binaphthyl-2,2′-diol [(R)-C5] (Figure 4). By analogy to C1,
the R configuration of the binapthyl core in (R)-C5 would favor
the formation (R)-2, whereas the P helical bias of the dendron would
afford (S)-2, resulting in a potential mismatch. The fact that (R)-
The complexity of the CD spectra precluded direct determination
of the sense of axial chirality of biphenyl core in C2-C4. However,
the 31P NMR spectra provided additional support for the role of
the biphenyl core as a chiral relay. Each of the complexes exhibited
a doublet in their 31P NMR spectra due to the occurrence of
1
phosphorus/rhodium J(P,Rh) coupling (Figure 5). These spectra
also displayed a second smaller doublet, which decreased in
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C O M M U N I C A T I O N S
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proportion going from C3 to C4, and was not present in atropiso-
meric (R)-C5. The doublet for C2 appeared as a broadened doublet
at ambient temperature that partially resolved into two sets of
doublets at 45 °C. The enantioselectivity of 2 inversely correlates
with the proportion of the minor doublet. Consequently, these
additional peaks likely reflect the coexistence of a minor diaster-
eomeric complex arising from the axial stereoisomers of the
biphenyl core. The ratio of the diastereomers improves upon cooling
to -40 °C, providing further support for the dynamic nature of
these conformational isomers. It is also noteworthy that rhodium
coordination significantly improves the ratio of axial stereoiso-
mers.16 Equal proportions of the diastereomeric conformations are
indicated by the 31P NMR spectra of the uncomplexed forms of
C2-C4, each of which displays two peaks of equal intensity
(Supporting Information). This contrasts with the spectra of
uncomplexed ligand of (R)-C5, which exhibits a single 31P
resonance, as would be expected for a C2-symmetric atropisomeric
system.
In conclusion, we have demonstrated the first example of a
dendritic catalyst that directs the stereoselectivity of a catalytic
process by dynamically transferring the conformational chirality
of a dendritic structure to the catalytic center. Experimental evidence
supports a chiral relay mechanism that propagates the local terminal
chirality of the dendron to the axial chirality of the biphenyl core
via the helical secondary structure of the dendron. The exact details
of the kinetic origin of asymmetric induction remains under
investigation;17 however, the empirical relation between confor-
mational preferences of ground-state precatalysts and the sense of
asymmetric induction in Rh-catalyzed hydrogenation is well-
established.18 The results reported here illustrate the potential for
synthetic supramolecular systems to derive selective function from
dynamic structural properties.
Acknowledgment. This paper is dedicated to Professor David
J. Hart on the occasion of his 60th birthday and more than 30 years
of service to chemistry at The Ohio State University. This work
was supported by the National Science Foundation Collaborative
Research in Chemistry program (CRC-CHE-526864). We thank
Hui Shao for assistance in preparation of Figure 2.
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Supporting Information Available: Experimental procedures,
compound characterization, and 31P NMR spectra for C1-C5, and 1H
and 13C NMR spectra for synthetic intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 4952–4953.
(16) Although the oxazoline-terminated dendrons coordinate efficiently to Ni(II),
Cu(II), and Zn(II) metals (ref 13a), we did not observe any evidence in the
31P NMR spectra consistent with such coordination in the dendritic
phosphinites.
(17) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746–1754.
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