Catalytic asymmetric α-aldol reaction of vinylogous N-heterocyclic carbene enolates: Formation of quaternary and labile tertiary stereocenters

Article abstract of DOI:10.1021/ol500830a

Simple N-heterocyclic carbene (NHC)-enolates are widely studied versatile species. However, their vinylogous siblings (i.e., vinylogous NHC-enolates) have been much less studied. Here we disclose the first catalytic asymmetric α-aldol reaction of vinylogous NHC-enolates. With trifluoropyruvate as the carbon electrophile, the efficient C-C bond formation process displays not only complete α-regioselectivity but also excellent stereocontrol over the two newly established challenging stereocenters (one quaternary and the other labile tertiary), furnishing a range of highly enantioenriched β,γ-unsaturated α-fluoroalkylated esters.

Full text of DOI:10.1021/ol500830a

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric α‑Aldol Reaction of Vinylogous N‑Heterocyclic
Carbene Enolates: Formation of Quaternary and Labile Tertiary
Stereocenters
Xiuqin Dong and Jianwei Sun*
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
S
* Supporting Information
ABSTRACT: Simple N-heterocyclic carbene (NHC)-enolates are
widely studied versatile species. However, their vinylogous siblings
(i.e., vinylogous NHC-enolates) have been much less studied. Here we
disclose the first catalytic asymmetric α-aldol reaction of vinylogous
NHC-enolates. With trifluoropyruvate as the carbon electrophile, the
efficient C−C bond formation process displays not only complete α-
regioselectivity but also excellent stereocontrol over the two newly established challenging stereocenters (one quaternary and the
other labile tertiary), furnishing a range of highly enantioenriched β,γ-unsaturated α-fluoroalkylated esters.
Scheme 1. C−C Bond Formation of Vinylogous NHC-
symmetric C−C bond formation is fundamentally
important in organic chemistry.1 In the past decade,
Enolates
A
organocatalytic C−C bond formation has seen exponential
development, providing an attractive complement to the
previously dominant metal- and biocatalytic approaches.2 In
particular, N-heterocyclic carbene (NHC) catalysis has
emerged as a versatile platform for the discovery of new C−
C bond-forming reactions.3 Notably, these processes are
typically highly enantioselective because of the excellent chiral
transfer ability of the NHC-bound “umpolung” reagents, such
as acyl anion equivalents, enolates, homoenolates, etc. Among
them, NHC-enolates have received tremendous attention due
to their versatility in reacting with various electrophiles to form
α-chiral carboxylic acid derivatives, thus representing an
attractive substitute to the traditional metal- and chiral
auxiliary-based enolates.4−9 However, in terms of C−C bond
formation, the majority of these reactions are cycloaddition
reactions (e.g., [4 + 2], [2 + 2], [2 + 2 + 2]).10 Intermolecular
asymmetric α-aldol-type reactions of NHC-enolates that do not
involve ring formation are scarce.11
Furthermore, in contrast to the intensive studies of simple
NHC-enolates, the reactivity of their vinylogous siblings (i.e.,
vinylogous NHC-enolates) have been much less studied,12,13
despite the widely accepted importance of vinylogous enolates
in remote C−C bond formation.14 Ye and Chi pioneered the
catalytic asymmetric C−C bond formation reactions of
vinylogous NHC-enolates, but these reactions are again limited
to cycloaddition at the γ position (Scheme 1).12 To the best of
our knowledge, C−C bond formation at the α position of
vinylogous NHC-enolates is unknown. In continuation of our
effort in NHC catalysis,13a,15 here we report an efficient C−C
bond formation that takes place not only selectively at the α
position but also without cycloaddition. Specifically, consider-
ing the importance of fluoro- and trifluoromethyl-substituted
molecules in medicinal chemistry and materials science,16 we
employed trifluoropyruvate as the carbon electrophile. Thus,
the new C−C bond is formed between quaternary and labile
tertiary (both allylic and α-carbonyl) stereocenters,17 which is a
challenge in terms of stereocontrol, particularly for acyclic
products (Scheme 1).
We started the study with racemic γ-reducible enal 1a as the
model substrate to generate the vinylogous NHC enolate and
methyl trifluoropyruvate 2a as the carbon electrophile (Table
1). Due to the presence of a labile (racemizable) tertiary
stereocenter in the desired product, the weak base K2HPO4 was
employed. Initial evaluation of various NHC precatalysts with
DCM as the solvent and MeOH as the nucleophile indicated
that the desired product 3a could be formed in low to moderate
yield, but with good diastereoselectivity and excellent
enantioselectivity (entries 1−6). Among them, triazolium salt
Received: March 19, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Reaction Condition Optimization
Table 2. Scope Study
a
a
The reaction was run with 1 (0.35 mmol), 2 (0.70 mmol), B (0.07
The reaction was run with 1a (0.05 mmol), 2a (0.06 mmol), precat.
mmol), K2HPO4 (0.7 mmol), R3OH (1.75 mmol), and solvent
(0.01 mmol), K2HPO4 (0.1 mmol), MeOH (0.25 mmol), and solvent
b
b
(DCM/MeCN = 1:2, v/v, 7.0 mL). Isolated combined yield of the
(0.5 mL). Combined yield of the diastereomers determined by
c
diastereomers. The dr value was determined by 1H NMR of the crude
1HNMR analysis of the crude reaction mixture with CH2Br2 as an
d
e
c
mixture. The ee value was determined by HPLC. Run at 0 °C.
internal standard. The ratio (dr and 3a/4) was determined by
d
1HNMR analysis of the crude reaction mixture. The ee value of the
that in all these examples the C(sp3)−C(sp3) bonds between
quaternary and labile tertiary stereocenters were all formed
under mild conditions with excellent stereocontrol, which is
particularly noteworthy for the formation of acyclic products.
In order to rationalize the absolute and relative stereo-
chemistry of the two new stereocenters in the products, we
have proposed conformation I for the vinylogous NHC-enolate
and transition state II for the C−C formation step (Figure 1).
e
major diastereomer determined by HPLC analysis. DCM/MeCN =
1:2 (v/v), 1.0 mL. 2.0 equiv of 2a.
f
B gave the most promising results (entry 2).18 Byproduct 4 was
also observed, as a result of α-protonation instead of C−C
bond formation of the corresponding vinylogous enolate. Next,
various bases were screened. Other weak bases K3PO4 and
NaOAc did not improve the product yield and diastereose-
lectivity. Relatively strong bases, such as Cs2CO3 and Et3N,
resulted in decreased stereoselectivity, presumably due to the
base-labile α tertiary stereocenter. Subsequent solvent screening
did not improve the results either (entries 11−15), but
interestingly we found that the formation of byproduct 4 was
suppressed with MeCN as solvent (entry 13). Inspired by this
observation, we next resorted to mixed solvent using DCM and
MeCN (v/v = 1:2), which slightly improved the product yield
(entry 16). Finally, increasing the loading of 2a resulted in the
further enhanced yield of 4a (75%) together with good
diastereoselectivity and excellent enantioselectivity (entry 17).
With the optimized standard reaction conditions, next we
carried out a scope study. As shown in Table 2, a wide range of
γ aryl- and alkyl-substituted enals 1 could participate smoothly
in the C−C bond formation process, and desired β,γ-
unsaturated α-alkylated esters 3 were formed with good to
excellent stereoselectivity. Ethyl trifluoropyruvate also provided
similar levels of efficiency and selectivity (entries 14−19).
Different alcohols, such as BnOH, allyl alcohol, and propargyl
alcohol, could also serve as effective nucleophiles to form the
corresponding ester products (entries 21−24). It is noteworthy
Figure 1. Plausible vinylogous NHC-enolate conformation and C−C
bond formation transition state.
In conformation I, the chiral NHC backbone of the Z-enolate
blocks the Si face and the electrophile approaches from the Re
face (bottom face) for new bond formation, thus determining
the absolute stereochemistry. In the C−C formation step, the
orientation of the trifluoropyruvate determines the relative
stereochemistry. We have proposed a six-membered chairlike
transition state (II), in which a molecule of MeOH activates the
electrophile carbonyl group through hydrogen bonding and
simultaneously approaches the developing acyl carbon. In this
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Letter
transition state, the large CF3 group adopts the equatorial
position (A-value of CF3 2.4−2.5 > A-value of CO2Me 1.2−
1.3).19 Thus, the enolate nucleophilic carbon attacks the Re face
of the carbonyl, thereby setting the quaternary stereocenter.
These rationalizations are in complete agreement with the
observed product stereochemistry.
The highly enantioenriched products obtained via our
catalytic intermolecular C−C bond-forming process can be
transformed into other useful molecules. For example, the C
C bond in product 3a can be efficiently hydrogenated to form
saturated diester 5 without erosion in stereoselectivity (eq 1).
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In summary, we have disclosed an unprecedented
intermolecular asymmetric α-aldol reaction of vinylogous
NHC-enolates, a type of versatile but less explored species
relative to simple NHC-enolates. In contrast to the known C−
C bond formation at the γ position of vinylogous NHC-
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quaternary and the other labile tertiary (both allylic and α-
carbonyl), are also established in an acyclic product with
excellent absolute and relative stereocontrol. A range of highly
enantioenriched β,γ-unsaturated α-fluoroalkylated esters have
been synthesized with high efficiency under mild conditions.
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molecules, such as densely functionalized tetrahydrofurans.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full spectroscopic data, and NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sunjw@ust.hk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by HKUST and Hong Kong
RGC (ECS605812 and M-HKUST607/12).
■
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