Dynamic kinetic asymmetric cross-benzoin additions of β-stereogenic α-keto esters

Article abstract of DOI:10.1021/ja508521a

The dynamic kinetic resolution of β-halo α-keto esters via an asymmetric cross-benzoin reaction is described. A chiral N-heterocyclic carbene catalyzes the umpolung addition of aldehydes to racemic α-keto esters. The resulting fully substituted β-halo glycolic ester products are obtained with high levels of enantio- and diastereocontrol. The high chemoselectivity observed is a result of greater electrophilicity of the α-keto ester toward the Breslow intermediate. The reaction products are shown to undergo highly diastereoselective substrate-controlled reduction to give highly functionalized stereotriads.

Full text of DOI:10.1021/ja508521a

Communication
pubs.acs.org/JACS
Dynamic Kinetic Asymmetric Cross-Benzoin Additions of
β‑Stereogenic α‑Keto Esters
C. Guy Goodman and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
Scheme 1. DKRs with β-Halo α-Keto Esters
ABSTRACT: The dynamic kinetic resolution of β-halo α-
keto esters via an asymmetric cross-benzoin reaction is
described. A chiral N-heterocyclic carbene catalyzes the
umpolung addition of aldehydes to racemic α-keto esters.
The resulting fully substituted β-halo glycolic ester
products are obtained with high levels of enantio- and
diastereocontrol. The high chemoselectivity observed is a
result of greater electrophilicity of the α-keto ester toward
the Breslow intermediate. The reaction products are
shown to undergo highly diastereoselective substrate-
controlled reduction to give highly functionalized stereo-
triads.
but can offer some unique advantages.8 DKRs utilizing
configurationally labile α-keto esters offer the opportunity to
generate highly functionalized glycolates. Reactions developed
he benzoin condensation is a carbene- or cyanide-
Tcatalyzed reaction that couples two carbonyl compounds
to give α-hydroxy ketones via carbon−carbon bond formation.
The reaction proceeds with concurrent generation of a
include enantioconvergent transfer hydrogenation (Scheme
stereogenic center and is the archetype of a catalytic umpolung
1A) and direct aldolization with acetone and nitromethane
(polarity inversion) reaction.1 Its significance and widespread
use largely flow from two defining characteristics: (1) its
capacity to generate useful and ubiquitous α-hydroxy ketones,
and (2) the 100% atom efficiency inherent to the reaction. As a
consequence, significant research effort has been devoted to
various aspects of the transformation. Methods now exist for
the asymmetric homobenzoin reaction (the coupling of two
identical aldehydes).2 The union of two different carbonyls
(cross-benzoin addition) provides the possibility of accessing a
more diverse set of α-hydroxy ketones;3 however, controlling
the chemoselectivity of these reactions (i.e., constitutional
isomer distribution) is difficult, particularly in the intermo-
lecular manifold. Asymmetric cross-benzoin additions have
been achieved through the deployment of miscellaneous
strategies and reagents using enzymatic,4 metallophosphite,5
and carbene6 catalysis. Despite the aforementioned positive
attributes, a limitation present in all of these methods is that
they generate only a single stereocenter during the C−C bond
forming event. To the best of our knowledge, a cross-benzoin
coupling that generates more than one stereocenter, and thus a
higher level of complexity, has yet to be reported.7 In this
communication we describe a chemoselective, cross-benzoin
dynamic kinetic resolution (DKR) which couples aldehydes
and racemic α-keto esters. The reactions generate vicinal
stereocenters during the C−C bond construction with excellent
levels of diastereo- and enantiocontrol.
(Scheme 1B).9 Seeking to expand this work we envisioned that
N-heterocyclic carbene (NHC) catalyzed cross-benzoin of
aldehydes and α-keto esters would give access to previously
inaccessible products (Scheme 1C).
To date, NHC-catalyzed DKR transformations have been
described for the formation of β-lactones from β-keto esters10
and simple kinetic resolutions are known for [3 + 4]
cycloadditions of azomethine imines and enals.11 While cross-
benzoin procedures using α-keto esters have been disclosed, all
previous asymmetric examples have used ketones bearing
aromatic substituents and as such are nonenolizable.6c,d For a
NHC-catalyzed DKR to be achieved, the heretofore unknown
use of enolizable α-keto esters was compulsory. That structural
change brings with it the possibility of undesired homo- and
cross-aldolization in addition to the known benzoin dimeriza-
tion (Scheme 2). We were cognizant that our projected
reaction conditions were mechanistically viable for promoting
all of these processes.12 Accordingly, we sought to identify
conditions that would chemoselectively deliver the cross-
benzoin product while fulfilling the required parameters for a
DKR.
We began by examining the coupling of benzaldehyde and β-
chloro-α-keto ester 1a. Using catalyst A,13 glycolate 2a was
delivered with 96:4 enantiomeric ratio (er), and 4.5:1
diastereomeric ratio (dr), but only 25% conversion of 1a
The DKR subset of enantioselective transformations is less
Received: August 19, 2014
common than asymmetric reactions of achiral starting materials,
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
to the higher sense of diastereoselection, we elected to examine
the scope of the reaction using β-bromo-α-keto esters.
Next we began modifying the structure of 1 in order to probe
the allowable steric and electronic parameters of this cross-
benzoin process (Table 2). Varying the arene on the α-keto
Scheme 2. Chemoselectivity Challenges for the Coupling of
Aldehydes (blue) and Enolizable α-Keto Esters (Red) in the
Presence of Base and Carbene
Table 2. Cross Benzoin Additions of Aldehydes to β-Bromo
a)
α-Keto Esters
(Table 1, entry 1). Using more electron-rich catalyst B14 gave a
marked increase in both reactivity and dr without a notable
change in er (Table 1, entry 2).15 The importance of using an
electron rich catalyst was observed throughout the screening of
conditions, as electron-poor catalysts C6d and E6b routinely
gave low conversion of starting material (Table 1, entries 3, 5,
7, and 9). Using catalyst B with bromo ketone 1b increased the
observed dr with little effect on conversion or er (Table 1, entry
6). Screening the solvent and base16 revealed that TBME and
K2CO3 were optimal, providing tertiary alcohol 2b with >20:1
diastereoselection and 96:4 er (Table 1, entry 10). Efforts to
further increase stereoselectivity by introduction of steric bulk
at the ester position only resulted in reduced reactivity and
stereoselectivity (Table 1, entry 11). Under identical conditions
chloro variant 1a delivered ketone 2a with identical
enantioselectivity, but a dr of 14:1 (Table 1, entry 12). Due
a
Table 1. Catalyst and Substrate Optimization
b
c
entry
X
catalyst
solvent
conv. (%)
dr
er
1
2
3
4
5
6
7
8
9
10
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Cl
A
B
C
D
A
B
C
D
E
THF
THF
THF
THF
THF
THF
THF
THF
THF
TBME
TBME
TBME
25
4.5:1
14:1
1.5:1
>20:1
-
96:4
95:5
98:2
90:10
-
100
40
100
<5
a)
All reactions were run on a 0.20 mmol scale at room temperature for
>95
<5
>20:1
-
94:6
-
16 h. Diastereomeric ratios were determined by 1H NMR,
enantiomeric ratios by chiral HPLC or SFC. Yields unless otherwise
noted are of isolated products; some contain the minor diastereomer.
30
-
-
b)
Yield is reported as a 1H NMR yield utilizing ferrocene as an internal
<5
-
-
c)
B
B
B
100
54
>20:1
17:1
14:1
96:4
81:19
96:4
standard. The product was reduced with NaBH4 and the e.r. of the
diol was analyzed. Yield in parentheses represents a H NMR yield
utilizing mesitylene as an internal standard. The mass balance is
unreacted α-keto ester. Reaction was run using 20 mol % of catalyst
B. Isolated yield is reported for the diol formed via reduction of 2p
with NaBH4. The enantiomeric ratio was determined via Mosher ester
analysis of the isolated diol.
d
d)
1
11
e)
12
100
f)
a
b
g)
1
All reactions were run on a 0.10 mmol scale. Determined by H
NMR analysis of the crude reaction mixture. Determined by chiral
SFC analysis. Run with Pr as the ester.
c
d
i
B
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Journal of the American Chemical Society
Communication
ester delivered 2c and 2e without loss of reaction fidelity.
Removing the arene as well as changing the carbon chain length
provided 2d, 2f, and 2g cleanly with high stereoselectivity.
Inclusion of a β-branch point gave product 2h with >20:1 dr
and 94:6 er albeit in only 60% conversion of starting material.17
Variation of the aldehyde also provided data regarding
reaction generality. While both para- and meta-tolualdehyde
were well tolerated (2i and 2j), ortho-tolualdehyde proved to be
too sterically encumbered, giving no reaction. Electron-rich and
-poor aldehydes were slow to react providing 2l and 2m with
good stereoselectivity but incomplete conversion after 18 h.
While longer reaction time did not increase the yield, a slight
increase in catalyst loading provided full conversion of the β-
bromo α-keto ester.18 Heteroaromatic 2n was isolated in >20:1
dr, and 75:25 er, while indole-derived 2p was obtained with
10:1 dr and 98:2 er. One limitation of this method at the
current level of development is the requirement of aromatic
aldehydes in order to achieve high enantioselectivity, high-
lighted by the use of isobutyraldehyde which provided 2o with
14:1 diastereoselectivity but only 54:46 er.
The cross-benzoin product presents four functional groups
that are in principle uniquely addressable. As a first pass to
probe the reactivity, ketone 2m was reduced with NaBH4 to
provide diol 4m with >20:1 diastereoselection (Scheme 5).20
Scheme 5. Reduction of the Cross-Benzoin Product and
Determination of Relative and Absolute Stereochemistries
Coupling of 1b with benzaldehyde on a 1 g scale resulted in
91% yield of 2b without loss of stereoselectivity and with 74%
catalyst recovery. Benzoin (3) was also isolated in 9% yield
(Scheme 3).
Several additional cross benzoin products were also reduced
with high diastereoselectivity to their corresponding diols.21 An
X-ray diffraction study of 4m was carried out to assign the
relative and absolute stereochemistries as (1R,2S,3S).22 By
analogy, the cross-benzoin adducts were assigned as (2S,3S).
This configuration implicates the illustrated transition structure
5 as a plausible one to account for the stereochemical outcome
of the benzoin addition. In this model the α-keto ester exhibits
a strong polar Felkin-Ahn diastereofacial bias.23 The chiral
Breslow intermediate then selects for the reactive α-keto ester
enantiomer in part through strong facial bias imparted by the
indane subunit, but also through the orienting/activating effect
of the hydroxyl group.24 The precise disposition of the two
reactants with respect to the axis of the forming bond
(illustrated in red) is not known, but the gross features
described above are likely to be relevant.
In conclusion, we have developed the first stereoconvergent
cross benzoin reaction that utilizes racemic electrophiles. The
addition generates two stereocenters during the C−C bond
construction via the dynamic kinetic resolution of β-halo α-keto
esters. This NHC-catalyzed process generates a variety of fully
substituted β-halo α-glycolic acid derivatives in high diastereo-
and enantioselectivity utilizing a variety of aromatic aldehydes
and α-keto esters. Subsequent diastereoselective reduction
provides access to a number of highly functionalized and
stereochemically rich diols. Work is ongoing to define the pKa
limits in the electrophile for stereoconvergent reactions of
racemic α-keto esters and to examine other substitution
patterns that would broaden the scope of accessible product
types.
Scheme 3. Gram Scale Reaction of 1b and Benzaldehyde
The obtention of benzoin on larger scale led us to consider
the broader question of cross-benzoin chemoselectivity. We
considered the possibility that homobenzoin formation was the
faster process, but reversible under the reaction conditions. In
this scenario, the cross-benzoin reaction would serve as an
irreversible trap for the reversibly liberated benzaldehyde,
analogous to the observations of Enders et al. in their study of
cross-benzoin reactions with 1,1,1-trifluoromethylketones.6a To
evaluate the mechanism, we subjected 1b and 3 to the normal
reaction conditions (Scheme 4). Neither 2b nor benzaldehyde
Scheme 4. Determining the Source of the Observed Cross-
Benzoin Chemoselectivity
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral and HPLC data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
was observed during the course of the reaction, indicating that
benzoin formation is irreversible under these conditions. The
product distribution observed in Scheme 3 can thus be
considered as a reflection of the relative rate constants for
capture of the Breslow intermediate by the sterically hindered
but electronically activated α-keto ester versus a simple
aldehyde. Our results are congruent with those of Murry and
Frantz, who observed that benzoin was not a competent donor
in carbene-catalyzed additions to N-acyl imines.19
AUTHOR INFORMATION
Corresponding Author
* jsj@unc.edu
Notes
■
The authors declare no competing financial interest.
C
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Journal of the American Chemical Society
Communication
(c) Corbett, M. T.; Johnson, J. S. J. Am. Chem. Soc. 2013, 135, 594−
597. (d) Goodman, C. G.; Do, D. T.; Johnson, J. S. Org. Lett. 2013, 15,
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2014, 53, 255−259.
(10) (a) Cohen, D. T.; Eichman, C. C.; Phillips, E. M.; Zarefsky, E.
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(12) For homo-benzoin examples see ref 2c−f, in addition to:
O’Toole, S. E.; Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584−3593.
Homo-aldol reactivity of β-halo α-keto esters has been noted; for
details, please consult the Supporting Information for ref 9b.
(13) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876−8877.
(14) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
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(15) For discussion of the electronic effects of triazole carbene
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47, 696−707.
(16) See Supporting Information for base and catalyst screen.
(17) As measured by 1H NMR using an internal mesitylene standard.
(18) Only the reaction which provides 2m was subjected to a higher
catalyst loading (20 mol %).
(19) For a similar result see: Murry, J. A.; Frantz, D. E.; Soheili, A.;
Tillyer, R.; Grabowski, E. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123,
9696−9697.
ACKNOWLEDGMENTS
■
The project described was supported by Award R01
GM103855 from the National Institute of General Medical
Sciences. C.G.G acknowledges a Burroughs Wellcome Fellow-
ship in Organic Chemistry from the University of North
Carolina. X-ray crystallography performed by Dr. Peter S.
White.
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