Dynamic kinetic asymmetric transformations of β-stereogenic α-ketoesters by direct aldolization

Article abstract of DOI:10.1002/anie.201306873

Dynamic kinetic asymmetric transformations (DyKAT) of racemic β-bromo-α-keto esters by direct aldolization of nitromethane and acetone provide access to fully substituted α-glycolic acid derivatives bearing a β-stereocenter. The aldol adducts are obtained

Full text of DOI:10.1002/anie.201306873

Angewandte
Chemie
DOI: 10.1002/anie.201306873
Asymmetric Catalysis
Dynamic Kinetic Asymmetric Transformations of b-Stereogenic
a-Ketoesters by Direct Aldolization**
Michael T. Corbett and Jeffrey S. Johnson*
Abstract: Dynamic kinetic asymmetric transformations
(DyKAT) of racemic b-bromo-a-keto esters by direct aldoli-
zation of nitromethane and acetone provide access to fully
substituted a-glycolic acid derivatives bearing a b-stereocenter.
The aldol adducts are obtained in excellent yield with high
relative and absolute stereocontrol under mild reaction con-
ditions. Mechanistic studies determined that the reactions
proceed through a facile catalyst-mediated racemization of
the b-bromo-a-keto esters under a DyKAT Type I manifold.
D
eracemization is a valuable method for the generation of
chiral molecules from simple racemic starting materials.[1]
Although there are a plethora of reported dynamic kinetic
processes, most are arguably either complexity-neutral trans-
formations (hydrogenation, acylation, etc.) or generate
a single stereogenic center. Dynamic kinetic asymmetric
Scheme 1. Development of a DyKAT of b-stereogenic a-ketoesters.
a) Dynamic kinetic reduction by asymmetric transfer hydrogenation
(DKR-ATH).[5] b) Dynamic kinetic asymmetric transformation (DyKAT)
by direct aldolization.
À
transformations (DyKAT) that utilize a C C bond-forming
step in the construction of multiple stereocenters are highly
valuable synthetic strategies.[2] Herein, we describe dynamic
kinetic asymmetric transformations of racemic b-bromo-a-
ketoesters with both nitromethane and acetone through
direct aldolization.[3]
delivering it with high stereoselectivity to a hindered
ketone. We postulated that the identity of the b-substituent
of the a-ketoester would be important in promoting the
À
On the basis of the pioneering work of Noyori and co-
workers in the development of the dynamic kinetic resolution
(DKR) of b-ketoesters by ruthenium-catalyzed hydrogena-
tion,[4] our research group recently disclosed a protocol for
ruthenium(II)-catalyzed dynamic kinetic reduction by the
asymmetric transfer hydrogenation (DKR-ATH) of b-stereo-
genic a-ketoesters to afford secondary glycolic acid deriva-
tives (Scheme 1a).[5] Our groupꢀs longstanding interest in the
synthesis of complex fully substituted glycolates[6] prompted
us to investigate reaction manifolds for the dynamic addition
of carbon nucleophiles to b-stereogenic a-ketoesters to
provide access to products of this type (Scheme 1b). For
a DyKAT to be realized, a catalyst must be identified that can
effectively racemize the a-ketoester without promoting self-
condensation while also activating the nucleophile and
desired reactivity owing to its direct impact on both the b-C
H acidity and the steric environment about the ketone. To this
end, we selected b-halo-a-ketoesters to investigate this
potential reactivity profile owing to their successful previous
use as substrates in DKR reactions.[5b,7]
We commenced our investigation by exploring the Henry
addition of nitromethane to b-bromo-a-ketoesters
1 (Table 1). A number of methods have been reported for
the Henry addition to pyruvates;[8] however, there is limited
precedent for non-pyruvic alkyl a-ketoesters and b-branched
substrates.[9] Quinidine (I) was found to catalyze the nitro-
aldol addition of (Æ)-1a in quantitative yield with good
diastereoselectivity albeit poor enantioselectivity (Table 1,
entry 1). Although bifunctional catalysts II and III only
provided marginal improvements in enantioselectivity when
CH2Cl2 was used (Table 1, entries 2 and 3), a solvent screen
revealed that III in methyl tert-butyl ether (MTBE) provided
2a with d.r. > 20:1 and e.r. 92.5 :7.5 (Table 1, entry 6).
Catalyst modifications to the secondary alcohol led to the
identification of o-toluoyl-substituted IV as the optimized
catalyst structure (Table 1, entry 7). Attempts to further
enhance the selectivity through the addition of tetrabutylam-
monium bromide (TBABr)[7a] or lowering the reaction
temperature to 08C provided no improvement (Table 1,
entries 8 and 9). Gratifyingly, the iPr ester (Æ)-1b was
converted into 2b with e.r. 96:4 as a single diastereomer
when IV was employed in 2-methyltetrahydrofuran (2Me-
THF; Table 1, entry 11). Under these optimized reaction
[*] M. T. Corbett, Prof. Dr. J. S. Johnson
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
E-mail: jsj@unc.edu
Homepage: http://www.unc.edu/jsjgroup/Home.html
[**] The project described was supported by Award No. R01 GM084927
from the National Institute of General Medical Sciences. M.T.C.
acknowledges the University of North Carolina at Chapel Hill
Department of Chemistry for an Ernest L. Eliel Graduate Fellowship.
X-ray crystallography was performed by Dr. Peter S. White.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306873.
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Communications
Table 1: Optimization of the Henry DyKAT.[a]
Table 2: Optimization of the acetone aldol DyKAT.[a]
Entry
Catalyst
Solvent
d.r.[b]
2:1
14:1
8:1
5:1
9:1
>20:1
>20:1
>20:1
>20:1
e.r.[c]
4:96
12:88
19.5:80.5
16:84
9.5:90.5
4.5:95.5
10.5:89.5
14.5:85.5
96:4
1[d]
2
3
4
5
6
7
8
A
B
B
B
B
B
C
D
E
acetone
Entry
1
Catalyst
Solvent
d.r.[b]
13:1
12:1
11:1
e.r.[c]
62:38
72:28
80:20
80.5:19.5
88:12
92.5:7.5
93:7
93:7
93:7
92:8
96:4
acetone/dioxane (1:9)
acetone/EtOAc (1:9)
acetone/MeCN (1:9)
acetone/DMF (1:9)
acetone
acetone
acetone
acetone
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
I
II
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeCN
MTBE
MTBE
MTBE
MTBE
MTBE
III
III
III
III
IV
IV
IV
IV
IV
V
16:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
6
7
9
8[d]
9[e]
10
11
12
[a] Reactions were performed on a 0.20 mmol scale and proceeded to full
conversion as adjudged by TLC. [b] The diastereomeric ratio was
1
determined by H NMR spectroscopic analysis of the crude product.
2Me-THF
2Me-THF
[c] The enantiomeric ratio was determined by HPLC analysis on a chiral
stationary phase. [d] The reaction was performed with A (20 mol%) in
the absence of PNBA for 3 h. DMF=N,N-dimethylformamide.
13:87
[a] Reactions were performed on a 0.20 mmol scale and proceeded to full
conversion as adjudged by TLC. [b] The diastereomeric ratio was
determined by H NMR spectroscopic analysis of the crude product.
1
[c] The enantiomeric ratio was determined by HPLC analysis on a chiral
stationary phase. [d] The reaction was carried out with TBABr (10 mol%)
as an additive. [e] The reaction was performed at 08C for 30 h.
a slight improvement and delivered 3b quantitatively with e.r.
96:4 as a single diastereomer (entry 9).
Having optimized the reaction conditions, we probed the
scope of both the direct Henry and acetone-aldolization
DyKAT of b-bromo-a-ketoesters (Scheme 2). In addition to
a phenyl group (products 2b and 3b), the reactions were
tolerant of both ortho- and para-substituted aryl groups at the
g-position and provided aldol adducts 2b–e and 3b–e in high
yield and selectivity. Heteroaryl (Æ)-1 f also reacted effi-
ciently under the reaction conditions to cleanly provide 2 f
and 3 f. A range of linear alkyl substrates underwent
aldolization with no loss in selectivity to provide 2g–i and
3g–i with similarly high efficiency, thus indicating that
aromatic interactions between the substrate and the catalyst
are not required for high levels of selectivity. The increased
steric requirements of g-branching resulted in low diastereo-
selectivity and moderate enantioselectivity in the formation
of 2j and 3j. The absolute configuration of (2R,3R)-2b and
(2R,3R)-3e was in each case determined by X-ray crystallog-
raphy, and the other products were assigned by analogy.[13]
Given that catalysts IV and E are derived from cinchona
alkaloids, their pseudoenantiomeric catalysts V and B are
readily available and provide access to both enantiomeric
series of Henry and acetone-aldolization adducts. Although V
provided ent-2b with only e.r. 87:13, a single recrystallization
provided enantiomeric enrichment to e.r. 99:1 (Scheme 3).
The utility of these reactions is highlighted not only by the
mild, operationally simple reaction conditions, but by the
near-quantitative yield of products following a simple filtra-
conditions, ent-2b was obtained with d.r. > 20:1 and e.r. 87:13
with the pseudoenantiomeric catalyst V (Table 1, entry 12).
During the course of our optimization of the Henry
reaction conditions, we observed that l-proline (A) catalyzed
the addition of acetone to (Æ)-1b to provide ent-3b in
quantitative yield with e.r. 96:4, albeit with low diastereose-
lectivity (Table 2, entry 1). Although related to the l-proline-
catalyzed DKRs reported by Zhang and co-workers for highly
activated 2-oxo-3-arylsuccinates and a,g-diketoesters,[10] we
sought to develop a DyKAT of the less-activated b-bromo-a-
ketoester (Æ)-1b. A number of direct acetone aldolization
reactions of a-ketoesters with a range of catalysts have been
reported.[11,12] We chose to examine catalysts derived from the
cinchona alkaloids on the basis of their efficiency in the Henry
reaction (Table 1). The cinchonidine-derived primary-amine
catalyst B with p-nitrobenzoic acid (PNBA) as a cocatalyst in
acetone/dioxane (1:9) delivered ent-3b with good diastereo-
and enantioselectivity (Table 2, entry 2). An examination of
other polar solvents did not provide satisfactory improvement
(Table 2, entries 3–5); however, a reaction run neat in acetone
with B provided ent-3b with e.r. 95.5 :4.5 as a single diaste-
reomer (entry 6). Attempts to further increase the enantio-
selectivity by the use of either C or D proved ineffective
(Table 2, entries 7 and 8), but pseudoenantiomeric E provided
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tion of the crude reaction mixtures through a plug of
silica gel; no aqueous workup is required.
To better understand the mechanistic nuances of
the DyKAT, we sought to elucidate the racemization
pathway of this reaction. During the development of
an “interrupted” Feist–Bꢁnary reaction, Calter and
co-workers proposed that the reaction of 1,3-dike-
tones with b-bromo-a-ketoesters proceeds by DKR,
in which the SN2 halide displacement is promoted by
TBABr or TBAI (Scheme 4a).[7] Since our reactions
do not generate stoichiometric bromide and the
addition of TBABr provided no improvement
(Scheme 4b), we examined the nature of our
dynamic system by studying the Henry reaction as
a representative system.
We began our studies by monitoring the enan-
tiomeric compositions of both starting material and
product during the course of the reaction of (R)-
1b.[14] Although substrate racemization is obligatory
for successful dynamic kinetic resolutions and cer-
tain DyKAT subtypes, this assay is seldom perform-
ed.[2e,15] This experiment confirmed that the product,
(2R,3R)-2b, is obtained with uniform selectivity and
that starting material remains racemic throughout
the entire course of the reaction. Notably, (R)-1b
was racemized in less than 30 min to (Æ)-1b in the
presence of IV, thus highlighting the configurational
lability of b-bromo-a-ketoesters under general base
catalysis (Scheme 5a). When the catalyzed Henry
addition was conducted with CD3NO2, a primary
kinetic isotope effect (kH/kD = 2.8) and only 36% D
incorporation at the b-position were observed
(Scheme 5b).[16] These data suggest that racemiza-
tion is at least partially an intimate ion process with
protonation from the ammonium salt (protonated
catalyst) rather than nitromethane, and generation
of the reactive nitronate species contributes to the
overall reaction rate. In situ monitoring of the
Scheme 2. Scope of the DyKATs. Reactions were performed on a 0.20 mmol scale.
The yield of the isolated product is reported in each case. The diastereomeric ratio
(d.r.) was determined by 1H NMR spectroscopic analysis of the crude product.
The enantiomeric ratio (e.r.) was determined by HPLC analysis on a chiral
stationary phase. [a] The reaction was performed for 42 h.
Scheme 4. Dynamic kinetic resolution through SN2 halide displace-
Scheme 3. Access to both enantiomeric series.
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Scheme 5. Racemization and deuterium-labeling studies.
reaction by No-D 1H NMR spectroscopy[17] in 2-MeTHF
revealed no intermediates, thus confirming that the catalyst
resting state is the neutral amine and corroborating the
hypothesis that nitronate formation is an uphill process.
Since the racemization of 1b is catalyst-mediated via
a chiral onium enolate, the Henry addition proceeds through
a DyKAT.[1c] The moderate deuterium incorporation excludes
a DyKAT type II mechanism wherein the chiral onium
enolate would directly participate in an ene-type reaction
with aci-nitromethane.[18] Calter and co-workers employed
a pyrimidinyl-bridged bisquinidine catalyst in their “inter-
rupted” Feist–Bꢁnary reaction to overcome poor selectivities
observed with quinidine itself, thus suggesting that both chiral
amines may be involved in the enantiodetermining step.
Nonlinear effects have been studied only sparingly with
cinchona-derived catalysts.[19] To elucidate whether a non-
Figure 1. Evaluation of nonlinear effects in catalyzed Henry reactions.
À
through the formation of vicinal stereocenters in a single C C
bond-forming event. Mechanistic studies provided evidence
for a DyKAT type I manifold in the Henry addition of
nitromethane to b-bromo-a-ketoesters. Extensions of these
transformations and the discovery of new dynamic reaction
manifolds for a-labile carbonyl substrates are of ongoing
interest in our research group.
linear effect was observed in our Henry reaction, we Experimental Section
Henry aldol reaction: A 1 dram vial (1 dram = 3.697 mL) equipped
employed a mixture of the pseudoenantiomeric catalysts IV
and V. The Henry reaction was found to exhibit a linear
relationship between the diastereomeric composition of the
catalyst and the reaction enantioselectivity (R2 = 0.997), thus
eliminating the possibility that a dimeric catalyst species
operated by concomitant activation of electrophile and
nucleophile (Figure 1). On the basis of these collective data,
we propose that the reaction proceeds through a DyKAT
type I manifold (Scheme 6).[20]
with a magnetic stir bar was charged with b-bromo-a-ketoester 1b
(59.8 mg, 0.20 mmol, 1.0 equiv) and MeNO2 (110 mL, 2.00 mmol,
10.0 equiv) in 2Me-THF (1.0 mL, 0.2m). Catalyst IV (8.6 mg,
0.02 mmol, 0.1 equiv) was added, the vial was capped, and the
reaction mixture was stirred for 18 h at room temperature. The
reaction mixture was then filtered through a 2 cm pad of SiO2, washed
through with Et2O (5 ꢂ 2 mL), and concentrated in vacuo to afford
analytically pure 2b (69.9 mg, 97% yield, d.r. > 20:1) as a white solid
(m.p.: 113–1168C).
Acetone aldol reaction: A 1 dram vial (1 dram = 3.697 mL)
equipped with a magnetic stir bar was charged with b-bromo-a-
ketoester 1b (59.8 mg, 0.20 mmol, 1.0 equiv) in acetone (1.0 mL,
0.2m). Catalyst E (5.9 mg, 0.02 mmol, 0.1 equiv) and PNBA (6.7 mg,
0.04 mmol, 0.2 equiv) were added, the vial was capped, and the
reaction mixture was stirred for 12 h at room temperature. The
reaction mixture was then filtered through a 2 cm pad of SiO2, washed
through with Et2O (5 ꢂ 2 mL), and concentrated in vacuo to afford
analytically pure 3b (67.9 mg, 95% yield, d.r. > 20:1) as a white solid
(m.p.: 103–1058C).
In conclusion, dynamic kinetic asymmetric transforma-
tions of b-bromo-a-ketoesters have been developed on the
basis of the direct aldolization of nitromethane and acetone.
The fully substituted b-bromo-a-glycolic acid derivatives
were obtained with high levels of diastereo- and enantiose-
lectivity in near-quantitative yield. The operationally simple
protocols offer rapid generation of molecular complexity
Received: August 6, 2013
Published online: November 12, 2013
Keywords: acetone aldol reaction · DyKAT · Henry reaction ·
.
a-ketoesters · organocatalysis
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[20] A reviewer pointed out that it might be simpler to classify these
reactions as dynamic kinetic resolutions. Admittedly, the differ-
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interconverting diastereomeric complexes; thus, rate differences
might reasonably be expected (or possible) for conversion of the
enantiomeric starting materials into the “locally achiral” inter-
mediate. This requirement is often taken to mean that the chiral
catalyst that mediates the productive asymmetric transformation
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