Enantioselective β-Protonation by a Cooperative Catalysis Strategy

Article abstract of DOI:10.1021/jacs.5b02887

An enantioselective N-heterocyclic carbene (NHC)-catalyzed β-protonation through the orchestration of three distinct organocatalysts has been developed. This cooperative catalyst system enhances both yield and selectivity, compared to only the NHC-catalyz

Full text of DOI:10.1021/jacs.5b02887

Communication
pubs.acs.org/JACS
Enantioselective β‑Protonation by a Cooperative Catalysis Strategy
Michael H. Wang, Daniel T. Cohen, C. Benjamin Schwamb, Rama K. Mishra, and Karl A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, Silverman Hall, Evanston,
Illinois 60208, United States
S
* Supporting Information
ABSTRACT: An enantioselective N-heterocyclic carbene
(NHC)-catalyzed β-protonation through the orchestration
of three distinct organocatalysts has been developed. This
cooperative catalyst system enhances both yield and
selectivity, compared to only the NHC-catalyzed process.
This new method allows for the efficient conversion of a
large scope of aryl-oxobutenoates to highly enantioen-
riched succinate derivatives and demonstrates the benefits
of combining different activation modes in organocatalysis.
dvances in sustainable and selective reaction development
for applications in bioactive molecule construction,
A
chemical synthesis, and material science rely on translating
innovative concepts into new catalytic asymmetric approaches.1
The orchestration of independent catalysts to promote unique
transformations is a powerful strategy for reaction discovery.2
Within the field of N-heterocyclic carbene (NHC) catalysis,3
cooperative catalysis has been demonstrated as a viable strategy
for improving yield, selectivity, and expanding substrate
scope.2d,4 Of particular interest is the ability of NHCs to
generate homoenolates, or carbonyl β-anions.5 These unique
nucleophiles have been utilized in various CX π systems to
form C−C/C−N bonds, allowing access to a wide array of
heterocycles and bioactive compounds.4b,6 Yet, C−H bond
formation through the β-protonation of homoenolates has only
been achieved with low enantioselectivity.7 The proton is
effectively the simplest functional group in chemistry, and its
manipulation is the basis of many modern catalytic processes.1a,8
The development of catalytic asymmetric α-protonations of
enolates through malonates, silyl enol ethers, ketenes, and α,β-
unsaturated carbonyls has led to novel strategies for the synthesis
of compounds of interest possessing tertiary carbon stereo-
centers (Figure 1).1a,2b,9 By contrast, to the best of our
knowledge a highly enantioselective β-protonation has not
been achieved. In addition to general considerations of
enantioselective α-protonationracemization under protona-
tion conditions and selectively generating pure E- or Z-
enolatesβ-protonation encounters the additional challenges
of generating the necessary homoenolate under catalytic
conditions and imparting enantioinduction through interactions
with remote functional groups of the chiral catalyst.9b−d Hence, a
selective β-protonation would be an enabling and distinctive
addition to the broad class of asymmetric protonation trans-
formations.
Figure 1. Asymmetric protonation.
an organocatalytic alternative to chiral auxiliary and metal-
mediated transformations,11 as well as direct access to easily
differentiated succinate products. An unexplored route to chiral
succinic esters is asymmetric β-protonation of 2-substituted-
oxobutenoates. Compared to standard alkyl/aryl substituted
homoenolates, the ester/aryl substitution of oxobutenoates
carries two important functions: to provide an opportunity for
cooperative carbonyl activation and to promote rapid NHC-
homoenolate equivalent formation.4b We proposed that HBD
cocatalyst coordination would impart greater steric bulk near the
β-position and therefore enhance enantioselectivity. This new
approach would provide a conceptually distinct and comple-
mentary Umpolung strategy12 to known reductions of β,β-
disubstituted carbonyl substrates11a,13 and access chiral succinic
esters in the process.
Our investigation commenced by examining the enantiose-
lective β-protonation of β-ethyl ester cinnamaldehyde derivative
1. Combining 1 with ethanol in the presence of Hunig’s base and
̈
triazolium salt A produced saturated bis-ester 2 in 80% isolated
yield and 66:34 er (Table 1, entry 1). We then directed our efforts
toward optimizing the reaction through cooperative catalysis.
Addition of thiourea HBD1, which has demonstrated high
reactivity among achiral H-bond donors,10a,14 produced a
significant increase in enantioselectivity but also resulted in
diminished yield (entry 2). Conducting the reaction at a lower
We decided to pursue cooperative NHC/H-bond donor
(HBD)3e,10 activation for an enantioselective β-protonation of
α,β-unsaturated aldehydes. If successful, this process would offer
Received: March 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02887
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Journal of the American Chemical Society
Communication
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope
a
b
Isolated yields. Determined by HPLC (chiral stationary phase).
temperature provided an increase in enantioselectivity, though
the yield was further suppressed (entry 3). We hypothesized that
side reactions were occurring following the β-protonation event
(but prior to catalyst regeneration) thereby furnishing
unproductive byproducts. To test this hypothesis we introduced
an acyl transfer agent to increase the rate of catalyst
regeneration.15 Gratifyingly, addition of a DMAP cocatalyst
incorporated higher enantioselectivity and good yield (entry 4)
compared to the initial single catalyst system. After a survey of
triazolium precatalysts showed no improvement in either yield or
selectivity (entries 5−8), the HBD was evaluated. The urea
analog (HBD2) provided a significant increase in yield, with
minimal impact on enantioselectivity (entry 9). Further inquiries
into the core structure of the carbonyl-activation cocatalyst led to
the investigation of squaramides, which Rawal has demonstrated
to be excellent H-bond donor catalysts.16 Incorporation of
HBD3 provided high yields with a slight erosion of
enantioselectivity (entry 10). While the omission of DMAP
provided the highest levels of enantioselectivity (entry 11),
addition of only 5 mol % of DMAP provided moderately
improved yields and, more importantly, a significant decrease in
reaction time (entry 12, 24 h vs 36 h for 100% conversion).
With an optimized system that balances selectivity and
reactivity, the scope for the asymmetric β-protonation was
explored (Table 2).17 Both electron-rich and -poor substituents
about the aryl ring were well tolerated (6−12). Ortho-
substitution on the aryl group led to lower enantioselectivity
(10). Changing the steric size of the ester functionality had a
positive impact on enantioselectivity (15−17), with tert-butyl
ester (17) giving the highest level of enantioselectivity. Finally,
the catalytic system was tolerant of different nucleophiles
necessary for catalyst turnover (19−22).18,19
a
Yields are of isolated product after column chromatography; er was
determined by chiral HPLC analysis. Yield and er values given in
parentheses represent substrates run with 5 mol % DMAP cocatalyst.
succinate derivatives have various therapeutic applications.21 The
ability to independently synthesize the ester groups allows for
complete regioselectivity in the synthesis of butanoic acids, γ-
butyrolactones, and β-amino esters (Scheme 1). Starting with
a
Scheme 1. Succinate Differentiation
A practical advantage of this catalytic strategy is the ease of
chemoselectively elaborating these succinic esters. Succinic acids
are valuable chiral building blocks for the synthesis of bioactive
natural products, peptidomimics, and β-amino acids,20 and
a
Reagents: (a) BH3·THF; (b) BF3·OEt2; (c) DPPA, t-BuOH.
B
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benzyl ester 16 or 20, hydrogenolysis furnishes the α- or β-aryl-
butanoic acid (23 and 24, respectively) quantitatively. Selective
borane reduction of the acid followed by Lewis acid catalyzed
lactonization gave 2- and 3-aryl-γ-butyrolactone derivatives (25
and 26). Alternatively, a Curtius rearrangement in tert-butanol
affords Boc-protected β2- and β3-amino esters (27 and 28). From
simple starting materials, our NHC/HBD cooperative catalysis
system allows easy synthetic differentiation to access privileged
regioisomers rapidly, efficiently, and selectively.
thereby allowing for an si-face protonation. NMR spectroscopy
provided evidence that the HBD is involved in the protonation
event: the intermolecular interaction of substrate and HBD was
observed through 1D NOESY where the methylene protons of 1
exhibited an NOE with the ortho-aryl-hydrogens of HBD1
(Figure 3).23 Combining the DFT calculations, observed NOE,
In key control experiments to probe the complementary roles
of the base and proton source, we observed low deuterium
incorporation at the β-position (Scheme 2, eq 1). This suggests a
a
Scheme 2. Control Experiments
Figure 3. Stereoinduction model.
a
Reagents: (cond A) 10 mol % A, 30 mol % HBD3, 40 mol % i-
Pr2Net, 72 h; (cond B) 10 mol % A, 30 mol % HBD3, 10 equiv EtOH;
(cond C) 10 mol % A, 30 mol % HBD3, 40 mol % i-Pr2NEt, 5 mol %
DMAP.
knowledge of NHC catalysis, and the known activation modes of
HBDs, intermediate I (Figure 3) emerges as the working
stereochemical model for activation and enantioinduction. The
coordination of the HBD presumably increases the steric
interaction proximal to the β-position of the homoenolate and
allows for more selective protonation. This hypothesis is further
supported by our substrate scope, which demonstrated increased
enantioselectivity as the β-ester increased in steric size (Table 2,
15−17) and decreased enantioselectivity when there were
competing sites for hydrogen bonding (12).24
Given the data above, we propose the following reaction
pathway (Scheme 3): initial deprotonation of A gives the active
catalyst species, the free carbene (NHC). Following addition of
the NHC to 1, a formal [1,2] proton shift gives extended Breslow
intermediate I. HBD3 coordinates to the ester, providing
additional steric interactions near the β-position, and enhances
facial selectivity. β-protonation and subsequent tautomerization
strong kinetic isotope effect as a result of proton exchange
between the azolium salt, base, and Breslow intermediate.22
Additionally, while the base presumably acts as a proton shuttle
to facilitate the overall transformation, the chirality of the base
does not affect the stereoselectivity of the protonation step (eqs 2
and 3). Finally, this catalytic system is amenable to larger scale
reactions (5 mmol), with a negligible difference in yield or
enantioselectivity. Furthermore, on a larger scale, the HBD
cocatalyst can be efficiently recovered by precipitation from the
unpurified reaction mixture by dilution with CH2Cl2 (eq 4).
To gain insight into the roles of each catalyst, we combined our
DFT calculations and experimental evidence to propose a model
for facial selectivity of the NHC homoenolate (Figure 2). This
observed stereochemical assignment was corroborated by DFT
modeling of ground state structures, which proposed homo-
enolate intermediate NHC_HE2 as more energetically favorable.
The benzyl group of the NHC framework blocks the re-face
Scheme 3. Proposed Reaction Pathway
Figure 2. DFT calculations of homoenolate, computed with
Schrodinger interface using Jaguar DFT with B3LYP/6-31G**.
̈
C
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Journal of the American Chemical Society
Communication
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affords acyl azolium II. Catalyst turnover can be enhanced by acyl
transfer catalyst DMAP, which forms pyridinium III and
regenerates the NHC catalyst. Finally, acylation of the alcohol
regenerates DMAP and furnishes chiral succinate 2.
This novel cooperative process is a new, metal-free route to
succinic esters and the strategy of deploying multiple catalysts in
unison expands the concepts and utility of organocatalysis.
Ultimately, this catalytic system delivers the first highly
enantioselective, high yielding β-protonation of β,β-disubstituted
enals, due in part to unique contributions of all three catalysts: the
NHC, HBD, and acyl transfer species. This system leverages
distinct reactivity modes modeled from different organocatalysis
strategies (nucleophilic catalysis + hydrogen bond donor
activation) in a synergistic manner to efficiently promote a
challenging bond-forming reaction. The efficient and operational
simplicity of utilizing distinct, compatible catalysts versus
complex, elaborated single structures with multiple activation
sites could lend itself to many catalytic systems in the future.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectral data, and crystallographic
data. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/jacs.5b02887.
(b) Bernasconi, M.; Muller, M.-A.; Pfaltz, A. Angew. Chem., Int. Ed.
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2014, 53, 5385. For a selected example of a chiral auxiliary, see:
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AUTHOR INFORMATION
■
Corresponding Author
*scheidt@northwestern.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH NIGMS
(GM073072).
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Chem. − Eur. J. 2005, 11, 4751. (b) Muller, C. E.; Schreiner, P. R. Angew.
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(17) All substrates were evaluated with the NHC-HBD cooperative
catalyst conditions. If the isolated yields were deemed lower than a
practical level of ∼60%, then 5 mol % DMAP was employed (yield and
er given in parentheses).
(18) The absolute configuration of 22 was established by X-ray
diffraction. The remainder products were assigned by analogy.
(19) The use of the Z-alkene isomer of 1 undergoes an intramolecular
cyclization to provide a substituted furanone (not shown; see
Supporting Information for details).
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DOI: 10.1021/jacs.5b02887
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