Asymmetric synthesis of diverse glycolic acid scaffolds via dynamic kinetic resolution of α-keto esters

Article abstract of DOI:10.1021/ja3102709

The dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation has been developed as a technique for the highly stereoselective construction of structurally diverse β-substituted-α- hydroxy carboxylic acid derivatives. Through the development of a privileged m-terphenylsulfonamide for (arene)RuCl(monosulfonamide) complexes with a high affinity for selective α-keto ester reduction, excellent levels of chemo-, diastereo-, and enantiocontrol can be realized in the reduction of β-aryl- and β-chloro-α-keto esters.

Full text of DOI:10.1021/ja3102709

Article
pubs.acs.org/JACS
Asymmetric Synthesis of Diverse Glycolic Acid Scaffolds via Dynamic
Kinetic Resolution of α‑Keto Esters
Kimberly M. Steward,† Michael T. Corbett,† 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
ABSTRACT: The dynamic kinetic resolution of α-keto esters via
asymmetric transfer hydrogenation has been developed as a
technique for the highly stereoselective construction of structurally
diverse β-substituted-α-hydroxy carboxylic acid derivatives. Through
the development of a privileged m-terphenylsulfonamide for
(arene)RuCl(monosulfonamide) complexes with a high affinity for
selective α-keto ester reduction, excellent levels of chemo-, diastereo-,
and enantiocontrol can be realized in the reduction of β-aryl- and β-
chloro-α-keto esters.
Scheme 1. β-Stereogenic Glycolic Acid Derivatives via
Reduction
1. INTRODUCTION
The enantioselective construction of α-hydroxy carboxylic acids
remains an active area of research due to their prevalence in
biologically active molecules1 and use in asymmetric synthesis.2
Reliable methods to prepare these compounds include
enantioselective glycolate aldol and alkylation reactions,3,4
reduction or alkylation of α-keto esters,5 Passerini-type
reactions,6 asymmetric cyanohydrin synthesis,7 and ester enolate
oxygenations.8 Despite advances in these methodologies, the
preparation of β-stereogenic glycolic acid derivatives remains
much more challenging, highlighting the importance of a
generalizable strategy to access these substructures.
The reduction of α-keto esters to give β-stereogenic-α-
hydroxy esters has largely been limited to the diastereoselective
reduction of enantioenriched substrates.9 A more direct, efficient
reaction manifold might arise from the asymmetric catalyst-
controlled reduction of configurationally labile racemic β-
substituted-α-keto esters. Such a reaction could in principle
proceed with concomitant formation of two (or more)
stereogenic centers in a single step and provide access to a
number of functionalized glycolic acid derivatives (Scheme 1).10
This strategy presupposes the application of a dynamic kinetic
resolution (DKR), a powerful tool for the conversion of racemic
materials into enantiomerically enriched products.11 In light of
the prominence and utility of DKR reactions of α-stereogenic-β-
keto esters, the absence of complementary isomeric variants from
racemic α-keto esters was surprising. As part of our laboratory’s
continued interest in glycolic acid synthesis,12 we have recently
developed a highly stereoselective dynamic kinetic resolution of
β-stereogenic-α-keto esters via asymmetric transfer hydro-
genation (DKR-ATH), yielding trisubstituted γ-butyrolactones
(vide infra).13 It occurred to us that substantial product diversity
might arise from a common mechanistic platform simply by
varying the identities of the nonhydrogen substituents (X and Y)
at the β-carbon. The successful creation of an attractive synthetic
protocol would require: (1) simple routes to the needed racemic
α-keto ester substrates; (2) reaction conditions that achieve rapid
substrate racemization; and (3) the identification of a reduction
catalyst that is enantiomer-selective, provides strong facial bias
during the diastereoselective reduction, and can be applied to
functionally diverse substrates. The subject of this Article is the
evaluation of this strategy and the presentation of a new (arene)
Ru catalyst system for the asymmetric dynamic reduction of a
range of racemic β-stereogenic-α-keto esters. The chemistry to
be detailed was enabled by a seemingly trivial, yet ultimately
crucial deviation from established art in asymmetric Ru-catalyzed
transfer hydrogenation.
Received: October 22, 2012
Published: November 27, 2012
© 2012 American Chemical Society
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2. RESULTS AND DISCUSSION
Article
became clear that new chiral space would need to be explored to
achieve high levels of enantiocontrol. Utilizing the “mother
diamine”/diaza-Cope approach to the synthesis of C2-symmetric
1,2-diamines,19 screening of a number of chiral diamine
backbones was conducted. The α-naphthyl/triisopropylbenze-
nesulfonamide ligand L8 considerably increased the selectivity
(88:12 er, Table 2). To further optimize the ligand structure,
2.1. Ligand/Catalyst Design. Inspired by the efficacy of
Noyori’s (arene)RuCl(monosulfonamide-DPEN)14 in both the
asymmetric reduction of simple ketones15 and the dynamic
reduction of α-substituted β-keto esters and amides,16 we took
this complex as our point of departure in ligand/catalyst design.
Utilizing formic acid:triethylamine (5:2 mixture)17 as the organic
reductant and 1a as a test substrate, a screen of ligands and
precatalysts was undertaken (Table 1). Initial studies looked at
Table 2. Evaluation of Sulfonamides on α-Naphthyl
Backbone
a
a
Table 1. Evaluation of Chiral Diamine Ligands
a
Conditions: As described for Table 1.
perturbations of the sulfonamide were examined due to its
apparent ability to directly impact the chiral environment (Table
1, L1 vs L2). Because less sterically encumbering sulfonamides
(L9−L12) resulted in erosions in selectivity, we sought to
synthesize bulkier sulfonamides by exploring new chiral space at
the 2,6-positions of the arylsulfonamide.20 A number of diverse
sulfonyl chlorides were synthesized through a one-pot double
alkylation/sulfonylation of 1,3-dichlorobenzene.21 The simplest
m-terphenyl sulfonamide variant L14 distinguished itself as being
uniquely effective for providing high levels of enantioselectivity
for the title reaction (95:5 er). The use of electron-withdrawing
(L15) or -releasing substituents (L16) provided no improve-
ment in selectivity. The α-naphthyl backbone and m-
terphenylsulfonamide operate synergistically; no improvement
in enantiocontrol with the DPEN/m-terphenylsulfonamide
ligand L5 was observed (Table 1, entry 5). The α-naphthyl
ethylenediamine backbone has been used sporadically in
asymmetric synthesis, and the use of the m-terphenylsulfonamide
for enantioselective catalysis is rarer still.22
2.2. Synthesis of Trisubstituted γ-Butyrolactones. This
DKR-ATH was found to be applicable for a range of β-aryl α-keto
esters (Table 3).13 Electron-rich, electron-poor, and heteroaryl
substituents were tolerated at the β-position providing γ-
butyrolactone products in high yield and enantioselectivity.23
Additionally, the reduction of 1g was performed on a 10 g scale
employing reduced catalyst loading (1 mol % Ru) yielding
enantiopure lactone 2g in 72% yield following a single
a
Conditions: 1a (1.0 equiv), [RuCl2(arene)]2 (0.02 equiv), L (0.08
equiv), HCO2H:NEt3 (5.0 equiv), [1a]0 = 0.1 M in DMF, 75 °C, 16 h.
the steric effects of the sulfonamide in Ru(II)-complexes
possessing a (1S,2S)-diphenylethylenediamine (DPEN) back-
bone. Subjecting 1a to 2 mol % of the ruthenium dimer
[RuCl2(arene)]2 and Noyori’s ligand L1 (Ru atom:L mole ratio
1:2) in DMF at 75 °C18 provided the desired γ-butyrolactone in
high yield (90%) and diastereoselectivity (>20:1 dr), but with
low levels of enantiocontrol (57:43 er, entry 1). DPEN-based
ligands featuring bulkier sulfonamides (L2−L5) provided only
modestly higher levels of selectivity (entries 2−5). Employing
L2, a screen of (arene)Ru(II)-precatalysts was conducted to
determine the role of the arene in the stereoselectivity of the
reduction; however, no improvements were observed moving
away from [RuCl2(p-cymene)]2 (entries 6 and 7). In addition to
DPEN, 1,2-diaminocyclohexane and 1,2-aminoindanol were also
investigated as chiral backbones (L6 and L7), but yielded
comparable results (entries 8 and 9).
On the basis of these preliminary findings that asymmetric
transfer hydrogenation catalysts from this family present in the
literature were found to provide inadequate levels of selectivity, it
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a
Table 3. DKR-ATH Substrate Scope
Scheme 3. Approaches to δ-Oxygenated Glycolic Acid
Derivatives
b
c
entry
R2
2
yield (%)
er
1
2
3
4
5
4-Cl-C6H4
2b
2c
2d
2e
2f
94
84
90
88
82
72
91
91
88
96:4
95.5:4.5
95:5
4-Me-C6H4
4-MeO-C6H5
4-CN-C6H5
2-Me-C6H5
piperonyl
95:5
89:11
95:5
d
6
2g
2h
2i
7
8
9
2-furyl
95:5
N-Ts-indol-3-yl
N-Boc-indol-3-yl
96.5:3.5
96:4
2j
enantioselective Michael addition of a free glycolate enolate has
been reported.30
a
b
c
Conditions: As described for Table 1. Isolated yield. Enantiomeric
d
ratio determined by HPLC/SFC analysis. [RuCl2(p-cymene)]2 (0.5
Based on the success of the DKR-ATH of γ,γ-dicarboalkoxy-α-
keto esters (1, vide supra), we postulated that β-substituted-δ-
keto-α-hydroxy esters might be accessible via a chemoselective
dynamic reduction of α,δ-diketo esters directly delivering the
formal “free” glycolate Michael adducts. Implicit in this analysis is
the need for complete site selectivity in the reduction. Methods
for the selective reduction of an aldehyde in the presence of less
reactive carbonyls, that is, ketones and esters, are well-
established.31 While significant progress has been made in
achieving the inverse process, the selective reduction of a ketone
in the presence of an aldehyde,32 the discrimination between two
ketones remains a challenging task. Examples of the latter include
the chemoselective reduction of 2,4-diketo acid derivatives using
rhodium-aminophosphane-phosphinite catalysts33 or baker’s
yeast34 and aluminum-mediated selective reductions of diaryl
ketones.35 Our tactic takes advantage of the heightened reactivity
enjoyed by α-dicarbonyls and establishes a simple catalytic
method for achieving the formal asymmetric glycolate Michael
construction without recourse to auxiliary control or protection
of the hydroxyl group (Scheme 3c).
mol %), L14 (2 mol %), 10 g scale, >99.5:0.5 er recrystallized.
recrystallization. The absolute stereochemistry of the trisub-
stituted γ-butyrolactone products was determined by X-ray
crystallographic analysis of 2b.24
The obtained functionally rich γ-butyrolactones can be
deployed in secondary transformations (Scheme 2). Diaster-
Scheme 2. Reactions of Lactone Reduction Product 2a
2.3.2. Glyoxylate Stetter Addition with Enones. Indirect
methods for the preparation of the requisite α,δ-diketo esters 5
have been reported by us10b and others,36 but the most direct and
atom economical approach to these substrates would be a new
Stetter reaction between commercial ethyl glyoxylate and α,β-
enones.37 This reaction was previously reported to be
unsuccessful with thiazolium carbenes,36c but we have found
that effective catalysis can be realized by employing the Rovis
triazolium carbene derived from salt 4.38 As outlined in Table 4,
this glyoxylate Stetter addition is highly efficient, tolerant of a
number of ketonic substrates and substituents at the β-position,
and can be performed on a multigram scale (entry 1). Notably,
with the 1,4-dien-3-one dibenzylideneacetone, exclusive mono-
addition was observed (entry 5).
2.3.3. Chemoselective DKR-ATH of α,δ-Diketo Esters. Our
investigation into the chemoselective DKR-ATH began with an
examination of the reduction of α,δ-diketo ester 5a. As shown in
Table 5, our initial studies confirmed the feasibility of selectively
reducing the α-keto ester in the presence of an aryl ketone, as we
observed exclusive formation of δ-keto-α-hydroxy ester 6a as a
single diastereomer. Subjecting 5a to our previously optimized
reaction conditions, 2 mol % of [RuCl2(p-cymene)]2 and
diamine ligand L14 (Ru atom:L mole ratio 1:2) in DMF at 70
°C using HCO2H/Et3N as the reductant, provided 6a in 96%
yield and a 91:9 er (entry 1). Lower levels of selectivity were
eoselective alkylation of 2a employing allyl bromide and DBU
provided tetrasubstituted lactone 3a bearing an all-carbon
quaternary center in high yield. Krapcho decarboxylation25
gave access to α-unsubstituted lactone 3b (86% yield) that
formally arises from cinnamic acid. When decarboxylation was
preceded by alkylation with dibromomethane, dehalodecarbox-
ylation26 resulted and afforded α-alkylidene γ-butyrolactone 3c.
This substructure is prominent in natural product chemistry, and
bioactivities within this subclass are well documented.27
2.3. “Free” Glycolate Michael Adducts Using Chemo-
selective DKR-ATH of α,δ-Diketo Esters. 2.3.1. DKR-ATH
Approach to “Free” Glycolate Michael Adducts. Access to δ-
oxygenated glycolic acid derivatives via asymmetric glycolate
Michael reactions is limited. The most common approach to this
class of compounds is the addition of stoichiometric chiral
glycolate enolates to α,β-unsaturated ketones and esters,28 and in
each case the protected glycolate is obtained (Scheme 3a). Only
recently has a catalytic enantioselective variant been disclosed;
that method uses oxazolones as the α-hydroxy acid surrogate
(Scheme 3b).29 To the best of our knowledge, no catalytic
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a
Table 4. Scope of the Glyoxylate Stetter Addition with
Enones
Table 6. Chemoselective Dynamic Reduction Scope
a
b
c
entry
R1
R2
6
yield (%)
er
d
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
6a
6b
6c
6d
6e
6f
97
95
86
72
91
92
94
96
70
93
95
92
94
98:2
96:4
96:4
93:7
99:1
99:1
98:2
96:4
83:17
98:2
98:2
91:9
97:3
98:2
b
entry
R1
R2
5
yield (%)
2
3
4-I-C6H4
4-MeO-C6H5
Me
c
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
5a
5b
5c
5d
5e
5f
97
95
86
72
91
92
94
96
70
93
95
92
94
74
4
2
3
4-I-C6H4
4-MeO-C6H5
Me
5
(E)-CHCHPh
piperonyl
C6H5
6
4
7
4-Cl-C6H4
4-MeO-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
CO2Et
6g
6h
6i
5
(E)-CHCHPh
piperonyl
C6H5
8
C6H5
6
9
C6H5
7
4-Cl-C6H4
4-MeO-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me- C6H4
CO2Et
5g
5h
5i
10
11
12
13
14
C6H5
6j
8
C6H5
C6H5
6k
6l
9
C6H5
C6H5
10
11
12
13
14
C6H5
5j
piperonyl
C6H5
6m
6n
C6H5
5k
5l
N-Boc-indol-3-yl
C6H5
95
C6H5
a
b
c
Conditions: As described for Table 5. Isolated yield. Enantiomeric
piperonyl
C6H5
5m
5n
d
ratio determined by SFC analysis. Reaction performed using 0.05 mol
N-Boc-indol-3-yl
C6H5
% [RuCl2(p-cymene)]2.
a
Conditions: Unless otherwise noted, all reactions were performed on
b
a 2.0 mmol scale in PhCH3 (4 mL) at ambient temperature. Isolated
yield. Reaction performed on a 20 mmol scale.
c
reaction conditions further highlights the catalyst’s strong
preference for the α-keto ester (entry 5). Aryl halides were also
tolerated (entries 2,7). To evaluate the catalytic efficiency of this
system, the reduction of 5a was performed using 0.05 mol % of
[RuCl2(p-cymene)]2; no loss in reaction efficiency was observed
as 6a was obtained in 98:2 er (entry 1).
a
Table 5. Chemoselective DKR-ATH: Reaction Optimization
The absolute configuration and syn-stereochemical relation-
ship of the α-hydroxy ester products were determined by
converting 6c to lactone 3b via a Baeyer−Villiger oxidation
followed by in situ lactonization; spectral data and optical
rotation were in agreement with those previously obtained by us
for 3b (Scheme 4).13
b
c
entry
solvent
DMF
T (°C)
yield (%)
er
1
2
3
4
5
6
70
rt
94
93
90
91
96
98
91:9
DMF
87:13
65:35
78:22
97:3
2-MeTHF
DCE
70
70
70
rt
Scheme 4. Stereochemical Analysis of δ-Keto-α-hydroxy
Esters
DMSO
DMSO
97:3
a
Conditions: 5a (1.0 equiv), [RuCl2(p-cymene)]2 (0.02 equiv), L14
b
(0.08 equiv), HCO2H:NEt3 (5.0 equiv), [5a]0 = 0.1 M, 16 h. Isolated
yield. Enantiomeric ratio determined by SFC analysis.
c
observed when the reduction was conducted at room temper-
ature (87:13 er, entry 2). Further optimization revealed that high
levels of enantioselectivity (97:3 er) could be obtained by
performing the reaction in DMSO at room temperature (entry
6). The chemoselectivity observed is remarkable in light of the
extensive use of (arene)RuCl(sulfonamide) complexes for
asymmetric transfer hydrogenation of aryl ketones.14,15,17
To determine if the [RuCl2(p-cymene)]2/L14 catalyst system
was uniquely effective for the reduction of α-keto esters, the
chemoselectivity of transfer hydrogenation catalysts known to
reduce simple ketones was evaluated with 5a (Scheme 5). The
Scheme 5. Investigations into the Observed Chemoselectivity
With optimal reaction conditions in hand, we next explored
other substrates in the chemoselective dynamic reduction (Table
6). For all substrates examined, exclusive reduction of the α-keto
ester was observed, irrespective of the electronic characteristics
of the δ-ketone. High yields and enantioselectivities were
obtained for substrates incorporating electron-rich, electron-
poor, and heteroaryl substituents at the β-position. The level of
selectivity for 6l (entry 12, 91:9 er) is noteworthy as this
demonstrates that the scope is not limited to β-aryl substrates
(vide infra).39 Additionally, other reducible functional groups
remained intact: the retention of the α,β-enone in 6e under the
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1
Figure 1. In situ monitoring of the reduction of ( )-5a by H NMR spectroscopy in DMSO-d6. Blue panel, α,δ-diketo ester 5a; red panel, in situ
monitoring of reduction of α,δ-diketo ester 5a to 6a (∼50% conversion); green panel, α-hydroxy-δ-keto ester 6a (with added HCO2H/Et3N).
use of ligand L2 in the reduction, which is known to reduce
acetophenone,40 also afforded 6a as the sole product, albeit with
lower levels of enantioselectivity (69:31 er). This result caused us
to wonder if the δ-ketone was possibly undergoing in situ
“protection” as the lactol 7 following reduction of the α-keto
ester and that this intermediate masked the δ-ketone from further
reduction. To test this hypothesis, the reduction was monitored
by 1H NMR spectroscopy in DMSO-d6, but 7 was not detected:
only the diketo ester 5a and hydroxy ester 6a were observed
(Figure 1).
chemistry, and these functional arrays can be converted to
their derived enantioenriched epoxides or engage in nucleophilic
substitution to provide a variety of functionalized product classes.
The emergence of halohydrin dehalogenase (HheC), an enzyme
produced by Agrobacterium radiobacter AD1, as a biocatalyst for
the kinetic resolution of racemic haloalcohols highlights the
importance of methods for the preparation of optically pure
terminal halohydrins.41 The catalytic asymmetric preparation of
halohydrins has been limited principally to desymmetrization
reactions of epoxides42 and alkenes43 or kinetic resolution of
terminal epoxides.42d,g,l,m,44 Methodology designed to directly
access internal halohydrins from unsymmetrical precursors is
largely underdeveloped (vide infra). We sought to develop a
stereoselective Ru-catalyzed dynamic kinetic resolution of β-
chloro-α-keto esters that would provide an efficient route to β-
chloro-α-hydroxy esters.
We then examined the transfer hydrogenation of several other
ketone substrates using the standard reaction conditions used in
Table 6 (Scheme 6). Interestingly, acetophenone and ethyl 2-
Scheme 6. Other Keto Ester Reductions
Access to chiral β-chloro glycolic acid derivatives is currently
limited to enzymatic processes or stereospecific opening of
glycidic esters with strong acids. While enzymatic reductions45
and kinetic resolutions46 have been shown to impart good levels
of diastereo- and enantioselectivity, these processes are substrate
limited and lack generality. Chloride addition to optically pure
glycidic esters often necessitates harsh reaction conditions,
suffers from nonideal regio- and stereoselectivity, and lacks
significant precedent for aliphatic substrates.47 The dynamic
kinetic resolution of α-chloro-β-keto esters has been developed
for some time,48 but the dynamic kinetic resolution of β-chloro-
α-keto esters that would provide isomeric products is heretofore
unknown. Thus, we sought to develop a simple, flexible synthesis
of β-chloro glycolic acid derivatives employing a dynamic kinetic
resolution asymmetric transfer hydrogenation (DKR-ATH) of β-
chloro-α-keto esters (Figure 2).
ethyl-3-oxobutanoate, which are prototypical test substrates for
new transfer hydrogenation catalysts, are not reduced with this
catalyst system. This lack of reactivity further highlights the
unique preference for α-keto esters conferred by the newly
developed terphenylsulfonamide/di-α-napthylethylenediamine
ligand. Reducing tert-butyl 2-oxo-4-phenylbutanoate under the
standard conditions proceeded efficiently, imparting good levels
of enantioselection and highlighting the potential applicability of
this catalyst for simple α-keto esters.
2.4. Chlorohydrin Synthesis. 2.4.1. DKR-ATH Approach to
Optically Active Chlorohydrins. The investigations described
above provide simple access to useful enantiomerically enriched
glycolate building blocks, but Scheme 1 implies a goal of
diversification in product structures that had not yet been
realized. In considering new substrates that might be useful for
DKR-ATH reactions, the potential integration of β-halo
substituents was appealing on several levels. Optically active
halohydrins are fundamental building blocks in organic
Figure 2. Dynamic kinetic resolution of β-chloro-α-keto esters.
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2.4.2. Direct Catalytic β-Chlorination of α-Keto Esters. The
relative dearth of direct, catalytic β-functionalizations of α-keto
esters presented an obstacle to the implementation of this
synthetic plan; in particular, methods for the direct β-
halogenation of α-keto esters are scarce.9k,45b,c,49 Only two
examples of the direct β-chlorination of singly activated α-keto
esters have been reported, and those require either long reaction
times or harsh reaction conditions.45b,49a To synthesize the
requisite β-chloro substrates for the anticipated DKR-ATH, the
development of a mild chlorination reaction of α-keto esters was
pursued. A screen of various Cu(II)-diamine and Ni(II)-diamine
complexes led to the identification of Sodeoka’s Ni(OAc)2-
diamine complex 89i as an effective catalyst for the β-chlorination
of α-keto esters 9 using N-chlorosuccinimide (NCS) under mild
reaction conditions.50 As outlined in Table 7, the chlorination
proceeds with good selectivity for the singly halogenated
product, is tolerant of a variety of functionalized aliphatic
substrates, and can be performed on a multigram scale (entry 1).
The elevated acidity of β-aryl substrates favored dichlorination
(entry 9); therefore, the requisite β-aryl substrates were prepared
via Darzens reaction.51
2.4.3. DKR-ATH of β-Chloro-α-keto Esters. The reduction of
β-chloro-α-keto esters with NaBH4 proceeds with high levels of
diastereoselectivity to afford the syn-diastereomer via Felkin−
Ahn control.46a Initial investigations into the DKR-ATH of 10a
revealed that ethylenediamine-derived 11a also afforded
excellent levels of syn-selectivity (Figure 3); however, the
diastereochemical outcome was powerfully influenced by ligand
selection. Upon switching to Noyori’s parent Ru(II)-complex
possessing a (1S,2S)-diphenylethylenediamine (DPEN) back-
bone (11b),14 a significant erosion in syn-diastereoselection was
observed, albeit with promising levels of enantioselectivity. The
bulkier triisopropyl-DPEN ligand (11c) gave modest anti-
diastereoselection with improved enantiocontrol. Exploiting
the unique properties associated with the terphenylsulfonamide
(vide supra), the DPEN-derivative 11d led to appreciable ligand-
controlled diastereoselection providing anti-12a with excellent
levels of enantioselectivity. The α-naphthyl backbone (11e)
employed in the reduction of β-aryl-α-keto esters was found to
provide slightly higher levels of diastereoselection albeit with a
small loss in enantioselectivity. The diastereoselectivity and
enantioselectivity were further improved in DMF at 0 °C
employing only 1 mol % of the Ru catalyst (in this case, the
conveniently prepared and stored dehydrohalogenated variant of
11d). Considering diastereoselectivity only, the continuum
expressed by Figure 3 (>20:1 syn:anti → 1:9 syn:anti at 298
K) represents approximately 2.5 kcal/mol modulation of
diastereomeric transition states through simple substituent
modifications on a common ligand framework.
a
Table 7. Ni(II)-Catalyzed β-Chlorination of α-Keto Esters
b
c
entry
R
10
mono:di
yield (%)
d
1
−CH2Ph
10a
10b
10c
10d
10e
10f
9:1
10:1
12:1
8:1
81
83
2
3
4
5
6
7
8
9
−CH2p-ClPh
−CH2p-MeOPh
−CH2CH2Ph
−CH2CHCH2
−CH2CCTMS
−(CH2)2CH3
−(CH2)3OBn
−Ph
84
78
13:1
10:1
13:1
13:1
1:>20
86
79
10g
10h
10i
87
86
trace
With optimized reaction conditions in hand, the relationship
between α-keto ester structure and reaction stereoselectivity was
assayed (Table 8). A variety of aliphatic substrates were found to
be amenable to the reaction conditions providing β-chloro α-
hydroxy esters with excellent levels of diastereo- and
a
Unless otherwise noted, all reactions were performed on a 1.0 mmol
b
scale. Determined by 1H NMR analysis of the crude reaction mixture.
c
d
Isolated yield. Performed on 8.0 mmol scale.
Figure 3. Ligand-controlled switch in diastereoselectivity. (a) Reactions were performed on 0.155 mmol scale employing 5 equiv of HCO2H:NEt3 (5:2).
(b) Determined by 1H NMR analysis of the crude reaction mixture. (c) Determined by chiral SFC analysis. (d) Performed with 1 mol % catalyst in DMF
(0.1 M) at 0 °C for 10 h. Complex 11da is the dehydrohalogenated variant of 11d; the structure is illustrated in Table 8.
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Article
a
whereas electron-withdrawing groups provided somewhat lower
diastereoselection (entries 4, 7, and 8).
Table 8. β-Aliphatic Substrates in the DKR-ATH
The absolute stereochemistry of the products was determined
by comparison to the known epoxide (2R,3S)-14,53 which was
synthesized from chlorohydrin (2S,3R)-13a upon exposure to
KOtBu (Scheme 7). To highlight the synthetic utility of the
Scheme 7. Secondary Transformations of Chlorohydrin
Products
b
c
d
entry
R
12
yield (%)
dr
er
e
1
−CH2Ph
−CH2p-ClPh
12a
12b
12c
12d
12e
12f
89
90
93
93
95
91
94
91
12:1
16:1
99:1
2
3
4
5
99.5:0.5
98.5:1.5
98.5:1.5
−CH2p-MeOPh
−CH2CH2Ph
−CH2CHCH2
−CH2CCTMS
−(CH2)2CH3
−(CH2)3OBn
20:1
16:1
f
>20:1
>20:1
>20:1
18:1
98:2
g
f
f
6
96.5:3.5
98.5:1.5
98:2
7
8
12g
12h
a
Unless otherwise noted, all reactions were performed on 0.155 mmol
b
scale employing 5 equiv of HCO2H:NEt3 (5:2). Isolated yield of anti-
c
diastereomer. Determined by 1H NMR analysis of the crude reaction
d
e
mixture. Determined by chiral SFC/HPLC analysis. Performed on
6.5 mmol scale. Determined following conversion to the benzoate
(see the Supporting Information). Performed at 23 °C for 10 h.
f
g
enantioselection. Alkene, alkyne, and benzyloxy functionality was
tolerated under the reaction conditions offering value-added
functional handles. The method was also scalable (entry 1). The
efficiency of these aliphatic substrates under the DKR-ATH
reaction conditions is a marked structural departure from the β-
aryl and β-ester requirements in antecedent work from our group
and the paradigm that aryl groups are necessary for high levels of
enantiocontrol due to ligand/substrate π/C−H interactions.52
Compatibility with β-aryl substrates was also demonstrated
under the optimized reaction conditions, providing adducts with
excellent levels of enantioselectivity (Table 9). The electronic
character of the aromatic ring was found to significantly impact
the diastereoselectivity of the reaction. Electron-releasing groups
engendered excellent diastereocontrol (entries 2, 3, and 10),
enantioenriched chlorohydrins as synthetic building blocks,
illustrative secondary transformations were pursued. Treatment
of chlorohydrin 13a with NaN3 afforded the azido alcohol 15
representing a formal synthesis of the paclitaxel C13 side-
chain.47b Notably, the syn-product 15 is stereocomplementary to
the anti diastereomer obtained from the glycidic esters that one
might derive from Darzens or Weitz−Scheffer reactions.
Following triflate formation of chloroalcohol 12a, chemo-
selective displacement with NaN3 affords α-azido-β-chloro
ester 16 providing access to β-chloro-α-amino acid derivatives.
The DKR-ATH is also amenable to the reduction of β-fluoro-
α-keto esters. Preliminary investigations have revealed that
ketone 17 can be reduced under the optimized reaction
conditions to afford the derived fluorohydrin 18 in excellent
yield as a mixture of diastereomers (Scheme 8). Despite the lack
a
Table 9. Scope of β-Aryl Substrates in the DKR-ATH
Scheme 8. DKR-ATH of β-Fluoro-α-keto Ester 17
b
c
d
entry
Ar
13
yield (%)
dr
er
1
2
Ph
13a
13b
13c
13d
13e
13f
13g
13h
13i
93
95
94
74
85
80
82
73
91
93
14:1
>20:1
19:1
5:1
99.5:0.5
99:1
o-MeOPh
m-MeOPh
m-NO2Ph
p-ClPh
3
99.5:0.5
97.5:2.5
98.5:1.5
98.5:1.5
98:2
4
of diastereocontrol in the reaction,54 excellent levels of
enantioinduction were observed for both diastereomers. This
initial finding is quite encouraging in light of the responsiveness
of diastereocontrol to ligand structure in this reaction family
(vide supra).
5
10:1
8:1
6
p-CF3Ph
p-CNPh
p-NO2Ph
p-MePh
7
6:1
8
4:1
99:1
9
14:1
>20:1
99.5:0.5
99:1
10
p-MeOPh
13j
3. CONCLUSIONS
a
In summary, we have designed new (arene)Ru-
(monosulfonamide) asymmetric transfer hydrogenation cata-
lysts that have led to the successful development of a highly
modular dynamic kinetic resolution of β-substituted-α-keto
Reactions were performed on 0.155 mmol scale employing 5 equiv of
b
c
HCO2H:NEt3 (5:2). Isolated yield of anti-diastereomer. Determined
by H NMR analysis of the crude reaction mixture. Determined by
chiral SFC/HPLC analysis.
d
1
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esters. The productive merger of a common mechanistic
framework and a new m-terphenylsulfonamide-based catalyst
system allows for rapid, atom-economical construction of highly
functionalized glycolic acid derivatives with excellent levels of
chemo-, diastereo-, and enantioselectivity.
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences. K.M.S. acknowledges an NIH NRSA Fellowship to
Promote Diversity in Health-Related Research.
A formal asymmetric glycolate Michael reaction has been
established via a catalytic asymmetric chemoselective dynamic
reduction of α,δ-diketo esters. The latter are prepared via a new
atom economical carbene-catalyzed Stetter reaction between
commercial ethyl glyoxylate and α,β-enones. The enantioselec-
tive reduction proceeds with high enantio- and diastereoselec-
tivity for a number of substrates. Initial investigations into the
origin of the observed selectivity suggest that the [RuCl2(p-
cymene)]2/L14 catalyst system is uniquely effective for the
reduction of α-keto esters, as other ketone substrates (even
acetophenone) are unreactive under the standard reaction
conditions.
Additionally, a highly stereoselective synthesis of β-chloro
glycolic acid derivatives via asymmetric transfer hydrogenation
was developed. A Ni(II)-catalyzed chlorination of aliphatic α-
keto esters was developed to provide the requisite β-chloro-α-
keto esters. In the reduction of these ketones, careful catalyst
tuning allows for a remarkable ligand-controlled inversion of the
preference for syn-selectivity to provide access to anti-
chlorohydrins. The DKR-ATH proceeds with high levels of
diastereo- and enantioselectivity for a number of aliphatic and
aromatic substrates. The obtained chlorohydrins are versatile
chemical building blocks for valuable secondary transformations.
These studies collectively provide diverse glycolate-based
building blocks for synthesis. This study has highlighted some of
the preparative and practical aspects of these reactions, but open
questions with respect to mechanism clearly remain (Scheme 9).
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectral and HPLC/SFC data, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
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AUTHOR INFORMATION
Corresponding Author
jsj@unc.edu
■
Author Contributions
†These authors contributed equally.
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Notes
The authors declare no competing financial interest.
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