Enantioselective Claisen rearrangements with a hydrogen-bond donor catalyst

Article abstract of DOI:10.1021/ja803370x

N,N-Diphenylguanidinium ion associated with the noncoordinating BArF counterion is shown to be an effective catalyst for the [3,3]-sigmatropic rearrangement of a variety of substituted allyl vinyl ethers. Highly enantioselective catalytic Claisen rearrangements of ester-substituted allyl vinyl ethers are then documented using a new C₂-symmetric guanidinium ion derivative. Copyright

Full text of DOI:10.1021/ja803370x

Published on Web 06/25/2008
Enantioselective Claisen Rearrangements with a Hydrogen-Bond Donor Catalyst
Christopher Uyeda and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street, Cambridge, Massachusetts 02138
Received May 6, 2008; E-mail: jacobsen@chemistry.harvard.edu
Chorismate mutases catalyze the [3,3]-sigmatropic rearrangement
of chorismate to prephenate. Structural, site-directed mutagenesis, and
computational studies have established the importance of several key
hydrogen-bond donating residues in the active site of the enzyme.
Through a combination of transition-state stabilization and restriction
of the substrate in a reactive conformation, chorismate mutase is
capable of achieving rate accelerations on the order of 106 relative to
the thermal reaction.1 Acceleration of the Claisen rearrangement has
also been observed in hydrogen-bonding solvents;2,3 using quantum
mechanical computational methods, Jorgensen has advanced a model
for the aqueous acceleration of the Claisen rearrangement involving
H-bond interactions between two water molecules and the core
heteroatom of the allyl vinyl ether in the optimized transition state
structure.4 Consistent with this hypothesis, compounds capable of dual
hydrogen-bonding such as ureas and thioureas have been studied in
the context of Claisen rearrangement reactions and have been
demonstrated to induce modest rate accelerations when used in
stoichiometric or superstoichiometric amounts.5 However, negligible
rate accelerations have been realized under catalytic conditions. We
report here catalysis of the Claisen rearrangement by simple guani-
dinium ions, and the development of chiral variants for highly
enantioselective rearrangements of ester-substituted allyl vinyl ethers.
Figure 1. Guanidinium BArF catalysts.
Table 1. Claisen Rearrangements Catalyzed by 1a
Approaches to the asymmetric catalysis of the Claisen rearrangement
have focused on the use of Lewis acidic metal complexes based on
aluminum,6a–c boron,6d–f magnesium,6g and copper;6h,i however, in
almost all cases, these systems suffer from strong product inhibition
or competing background pathways. To date, only one example of an
asymmetric Claisen rearrangement utilizing catalytic quantities of a
Lewis acid has been realized: Hiersemann’s highly enantioselective
rearrangement of ester-substituted allyl vinyl ethers using copper(II)
bisoxazoline complexes.6h,i
a Reactions carried out on a 0.1 mmol scale in 0.5 mL of C6D6.
b Conversions measured by 1HNMR integration relative to p-xylene as
an internal standard. c Extensive decomposition observed.
Although urea and thiourea derivatives effectively promote a broad
range of important transformations via H-bonding,7 our evaluation of
representative chiral and achiral catalysts of this class revealed that
none provided significant rate acceleration in model Claisen rearrange-
ment reactions. This result was predictable on the basis of earlier
experimental and computational studies.5 In contrast, the simple N,N′-
diphenylguanidinium salt 1 was found to induce rate enhancements
in the rearrangement of a variety of substituted allyl vinyl ethers (Table
1).8 Substrates bearing electron-donating substituents at the 4- (e.g.,
4) or 6-positions (e.g., 5,6), or electron-withdrawing groups at the
2-position (e.g., 8) all underwent rearrangement with significant rate
acceleration in the presence of catalytic levels of 1. These observations
are aligned with the proposal that transition structures with a high
degree of charge separation are most susceptible to stabilization by
hydrogen-bond donors.9 Claisen rearrangement of aryl ether 7 was
also catalyzed by 1 to provide the corresponding ortho-prenylated
phenol in high yield.
catalyst development, we observed that C2-symmetric guanidinium ions
derived from trans-1-pyrrolo-2-aminocyclohexane were particularly
effective, and fine-tuning of the pyrrole substituents led to the
identification of 2 as the optimal catalyst (see Supporting Information).
High enantioselectivities were obtained in the rearrangement of a
range of substrates in reactions carried out between 22 and 40 °C over
the period of several days (Table 2). Optimal rates and enantioselec-
tivities were observed in hexanes, despite the fact that catalyst 2 is
virtually insoluble in this solvent; use of dichloromethane or benzene
resulted in slightly suppressed ee values, and no catalysis was observed
in ethereal solvents such as diethyl ether or TBME.
Substrates bearing methyl- or ethyl-substituents at the 1-position
afforded products in high enantioselectivities (Table 2, entries 1 and
2); however, more sterically hindered isopropyl or isobutyl derivatives
were less reactive and underwent rearrangement with diminished ee
values (73% and 69% ee, respectively).11 Disubstituted compounds
(Table 2, entries 3 and 4) rearranged to form adjacent tertiary
stereogenic centers in high enantio- and diastereoselectivity with the
Efforts to induce asymmetric rearrangement of substrates 4-6 using
chiral guanidinium ion catalysts proved unsuccessful, with product
formation in low-to-negligible enantioselectivities. In contrast, ester-
substituted allyl vinyl ether 8 underwent reaction in moderate enan-
tioselectivity with a variety of guanidinium catalysts.10 After extensive
9
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10.1021/ja803370x CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Claisen Rearrangements Catalyzed by
2a
Figure 2. (a) ORTEP plot (50% probability ellipsoids for non-hydrogen
atoms) of the guanidinium ion 2 (counterion omitted for clarity) as a complex
with two isopropanol molecules. (b) Fully optimized, lowest-energy
transition structure for the N,N′-dimethylguanidinium-promoted Claisen
rearrangement of 9 at the B3LYP/6-31G(d) level of theory.
chiral guanidinium ions as hydrogen-bond donor catalysts in other
reactions is the focus of ongoing studies.
Acknowledgment. This work was supported by the NIGMS
(Grant GM-43214). We thank Dr. Eric Ashley for helpful discussions
and Dr. Douglas Ho for carrying out the X-ray structural analysis.
Supporting Information Available: Complete ref 12; complete
experimental procedures, summary of catalyst optimization studies, and
characterization data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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to two isopropanol molecules (Figure 1, 2a). DFT studies were
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state of the Claisen rearrangement of representative substrate 9.12
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dinium ion catalyst, and the lowest energy transition structure identified
is depicted in Figure 2b. Transition state stabilization via hydrogen-
bonding interactions between catalyst and both the ether- and ester
carbonyl-derived oxygens are evident. As expected, the computed
transition structure of the catalyzed reaction bears greater charge
separation between the allyl and oxallyl fragments relative to the
transition structure of the uncatalyzed thermal rearrangement.
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Although guanidinium BArF species have approximately the same
equilibrium acidity as N,N′-diarylthioureas,13 they possess superior
catalytic activity in all of the Claisen rearrangements we have studied
to date. The basis for this unexpected difference and application of
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