An enantioselective claisen rearrangement catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja103631u

In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step. This catalytic system was applied to the synthesis of enantioenriched kojic acid derivatives, a reaction of demonstrated synthetic utility for which other methods for catalytic enantioselective Claisen rearrangements have not provided a satisfactory solution.

Full text of DOI:10.1021/ja103631u

Published on Web 06/15/2010
An Enantioselective Claisen Rearrangement Catalyzed by N-Heterocyclic
Carbenes
Juthanat Kaeobamrung, Jessada Mahatthananchai, Pinguan Zheng, and Jeffrey W. Bode*
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
Received October 16, 2009; E-mail: bode@org.chem.ethz.ch
Table 1. Catalytic, Enantioselective Couplings with Kojic Acidsa
Substoichiometric enantioinduction in the venerable Claisen rear-
rangement has remained a formidable challenge to the increasingly
diverse strategies for catalysis of organic reactions.1 Chiral Lewis
acids2,3 and Jacobsen’s ureas4 can induce excellent levels of enanti-
oselectivity in a variety of Claisen rearrangements but suffer from slow
catalyst turnover. In seeking to devise a catalytic Claisen reaction that
overcomes this limitation, we considered the possibility of an enan-
tioselective variant of the Coates-Claisen reaction5,6 of enols and
acetals of unsaturated aldehydes that would give lactone products as
a means of catalyst turnover. In this communication, we document
the use of chiral N-heterocyclic carbenes (NHCs) as catalysts for highly
enantioselective Claisen rearrangements via the intermediacy of
catalytically generated R,ꢀ-unsaturated acyl azoliums (Scheme 1).
Scheme 1
a Reaction conditions: 0.1 M PhCH3, 24 h. b Yield refers to isolated
yield after chromatography. c Absolute configuration determined by
conversion to (S)-phenylsuccinic acid.
Acyl azoliums are fascinating reactive intermediates with chemistry
quite distinct from that of other activated carboxylic acid derivates.7
Our recent work,8 and that of many other groups,9 has focused on
their catalytic generation by internal redox reactions of R-functionalized
aldehydes, but these species have long been studied for their unusual
reactivity and role in biochemical pathways.7,10 Unlike other acylating
agents, acyl azoliums display a high preference for ester formation or
hydrolysis rather than amide formation.11 This is attributed to the rapid
formation of kinetically important hydrates or hemiacetals that undergo
general base catalyzed C-C bond cleavage in the acid or ester forming
step.7 Therefore, trapping acyl azolium I with a suitable enol should
lead to metastable hemiacetal II poised for Claisen rearrangement
followed by lactonization to effect catalyst turnover (Scheme 1).
Importantly, Zeitler has invoked the intermediacy of acyl azolium I
in the NHC-catalyzed redox esterification of ynals to give (E)-R,ꢀ-
unsaturated esters.9b
We selected catalytic, enantioselective Claisen rearrangements of
kojic acid derivatives as a starting point for our studies. Wender and
others have established the synthetic utility of the Claisen rearrange-
ment in elaborating readily available kojic acid into platforms for
complex molecule synthesis12 but also noted the failure of chiral Lewis
acid approaches,13 such as those documented by Hiersemann,3 to
suitably control the absolute stereochemistry. Elegant work on chiral
transition-metal-catalyzed Claisen rearrangements, including that of
Kozlowski and Mikami,14 does not appear to be applicable to this
substrate class.
The combination of kojic acids, ynals, and chiral N-mesityl
substituted precatalyst 1 led to the formation of somewhat unstable
dihydropyranones. Upon completion of the reaction, simply stirring
these products in MeOH for 6 h led to ring-opening, a procedure we
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8810 J. AM. CHEM. SOC. 2010, 132, 8810–8812
10.1021/ja103631u  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Effect of Azolium Counterion on Conversiona
adopted for product isolation (Table 1). A standard course of
optimization identified the conditions shown in Table 1. The addition
of a catalytic base (NEt3, N-Me-morpholine) increased the reaction
rates but led to side products and a decrease in enantiopurity. In the
absence of a triazolium salt, no reaction occurred regardless of whether
or not base was present. Within our focus on reactions of kojic acid
derivatives, the reaction proceeded with a broad range of ynals
including both aromatic and aliphatic derivatives, all in good yield
and with exceptional enantioselectivity.
X )
% conv 1 h
% conv 2.5 h
% conv 12 h
Cl-
10
100
7
16
na
10
0
70
na
Scheme 2. Azolium-Catalyzed Annulations of Ynals via Claisen
Rearrangements
OAc-
CF3CO2
-
20
trace
0
-
ClO4
0
-
SbF6
0
0
-
SbF6 + NMM(30%)
30
35
86
a
1
Determined by H NMR analysis against an internal standard.
hemiacetal II; (3) the conjugate addition of kojic acid to III; (4) the
Claisen rearrangement of II to give III; (5) the lactonization of III to
give IV and effect catalyst turnover. These mechanistic possibilities
can be differentiated by analysis of the reaction kinetics. Kinetic studies
of azolium-catalyzed processes such as the benzoin and Stetter reactions
are often plagued by the presence of multiple rate-determining steps
and catalyst inhibition;21 however, this system proved somewhat more
tractable to analysis. We determined the empirical rate law for the
reaction of kojic acid 17 with 2,4-dichlorophenyl substituted ynal 18
to be
Although we have not exhaustively explored the scope of this
reaction, we have found that many enolic compounds couple with ynals
to give the expected products (Scheme 2). We were pleased to find
that pyruvic esters are excellent substrates, provided that a weak amine
base is added to promote enol formation. Phenolic compounds, such
as naphthols, give Claisen products but with diminished levels of
selectivity. The key R,ꢀ-unsaturated acyl triazolium I could be
generated from other substrates, including R,ꢀ-unsaturated aldehdyes
via in situ oxidation.15
d[P]
) kobs[1]1[RCHO]1/2[kojic acid]-1/2
(1)
dt
From this experimental rate law, we also determined the activation
parameters from the rate constant via an Eyring plot, which revealed
an activation enthalpy of 15.3 kcal/mol and activation entropy of -25.5
cal/K ·mol. The lactonization is excluded as the rate-limiting step by
the activation parameters. The redox reaction-protonation step is
excluded by isotopic labeling experiments, which show no kinetic
isotope effect for the protonation.22 The 1,2-addition of kojic acid to
I, as well as the 1,4-addition pathway, is excluded by the observed
negative order of the reaction in kojic acid. These experimental results
are consistent with a derived rate law (eq 2) for the Claisen
rearrangement that takes into consideration generation of the NHC
from the azolium, a steady-state approximation of the initial
aldehyde-NHC adduct, and rapid formation of hemiacetal II.23
In all prior reports on the use of azolium salts as catalysts or
precatalysts, including our own work, the addition of a base was
required, presumably to generate the N-heterocyclic carbene, which
is thought to be the active nucleophilic catalyst. This annulation
proceeds smoothly in the absence of added base but is slower and
counterion dependent; in contrast, NHC-catalyzed reactions in the
presence of base show no counterion effects.16 In the absence of base,
1H NMR investigations reveal no detectable loss of the azolium C-2
proton during the course of the reaction.17 While we cannot rule out
alternative mechanisms at this time,18 our current understanding is that
the chloride ion plays the role of base in generating a trace amount of
the nucleophilic carbene, which quickly attacks the aldehyde to initiate
the catalytic cycle. This is supported by comparing the reactivity of
precatalysts bearing different counterions (Table 2). The acetate
precatalyst is much more reactive than the chloride but led to product
epimerization. Precatalysts with less basic counterions, such as SbF6-
or ClO4-, are unreactive. The addition of a catalytic amount of a weak
amine base restores the activity to levels similar to that observed with
the chloride counterion.
During the preparation of this manuscript, Lupton reported a racemic
dihydropyranone-forming annulation from enolates via R,ꢀ-unsaturated
acyl azolium species, promoted by imidazolium-derived NHCs under
basic conditions.19 Although the starting materials and reaction
conditions are different from those for our process, the postulated
intermediates are identical and the reactions are likely to be mechanisti-
cally related. Lupton proposes a direct Michael addition of an enolate
to I, but our observations (vide supra) to date are more consistent with
the Claisen mechanism shown in Figure 1.20
d[P]
dt
[1]1[RCHO]1
k2 + k-1
) k2
(2)
[HX]
[RCHO] +
1 +
-
k1
(
)
Kg[X ]
This rate law rationalizes the partial positive order of the reaction in
aldehyde and the negative order of kojic acid, which inhibits generation
of the N-heterocyclic carbene by acting as a general acid (HX in eq
2). It explains the observation that the reaction rate increases in the
presence of added base by generating more of the NHC and provides
a role for the counterion of the azolium salt as a genral base to generate
the active catalyst (X- in eq 2).
Other observations are also most consistent with the Claisen
pathway. All attempts to effect conjugate additions with nucleophiles
that cannot undergo Claisen rearrangement, such as indoles or
hydroxamic acids,24 have failed; in most cases 1,2-adducts are obtained
instead. The well-studied chemistry of acyl azoliums documents the
rapid formation of hydrates and hemiacetals in their acylation
We considered five possible rate-determining steps for the overall
catalytic reaction, listed in red in Figure 1: (1) the initial redox reaction/
protonation to form I; (2) the 1,2 addition of kojic acid to give
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C O M M U N I C A T I O N S
Kozlowski (UPenn), Franziska Scho¨nebeck (ETH-Zu¨rich), and John
A. Kowalski (GlaxoSmithKline) for helpful discussions.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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isomer, which would not be expected in the conjugate addition pathway
(see Supporting Information).26 Finally, the excellent enantioselectivity
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1,2-addition adjacent to the chiral triazolium to give the Claisen
precursor. In contrast, a C-C bond forming conjugate addition would
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Although we cannot completely rule out a short-lived enolate-acyl
azolium ion pair, our results, including the activation entropy, are
consistent with the detailed studies of Coates and Curran on the related
Claisen rearrangement of 2-alkoxy-substituted vinyl ethers. More
importantly, these studies provide a new mode of substrate activation
unique to chiral N-heterocyclic carbenes and, via their ability to access
multiple catalytically generated reactive species in a tandem fashion,27
a pathway to induce high levels of enantioselectivity and provide
solution to catalyst turnover in a catalytic Claisen manifold.
Acknowledgment. We are grateful to NIGMS (National Institutes
of Health, GM-079339), the National Science Foundation (CHE-
0449587), and Bristol Myers Squibb for support of this research. J.K.
is a graduate fellow of the Royal Thai Government. We thank Marisa
JA103631U
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