Dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation

Article abstract of DOI:10.1021/ja3027136

The dynamic kinetic resolution of β-aryl α-keto esters has been accomplished using a newly designed (arene)RuCl(monosulfonamide) transfer hydrogenation catalyst. This dynamic process generates three contiguous stereocenters with remarkable diastereoselect

Full text of DOI:10.1021/ja3027136

Communication
pubs.acs.org/JACS
Dynamic Kinetic Resolution of α-Keto Esters via Asymmetric Transfer
Hydrogenation
Kimberly M. Steward, Emily C. Gentry, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 2799-3290, United States
S
* Supporting Information
ABSTRACT: The dynamic kinetic resolution of β-aryl α-
keto esters has been accomplished using a newly designed
(arene)RuCl(monosulfonamide) transfer hydrogenation
catalyst. This dynamic process generates three contiguous
stereocenters with remarkable diastereoselectivity through
a reduction/lactonization sequence. The resulting enan-
tioenriched, densely functionalized γ-butyrolactones are of
high synthetic utility, as highlighted by several secondary
derivatizations.
he conversion of racemic compounds into enantiomeri-
cally enriched products via a dynamic kinetic trans-
T
formation is a powerful approach to asymmetric synthesis.1 The
advantages of this technique are fully realized when the racemic
starting materials are trivial to access and a racemization
pathway is simple to implement. As such, the asymmetric
hydrogenation of configurationally labile α-substituted β-keto
esters (Figure 1a) remains the archetypal dynamic kinetic
resolution (DKR);2 this process is used to create >100 tons of
enantioenriched material each year.3 The success of the
reaction relies upon the acidity of the carbon acid that
facilitates interconversion of the two enantiomers through the
achiral enol. In contrast, the analogous resolution of less acidic
α-keto esters has remained essentially undeveloped,4 despite its
enormous potential synthetic utility and complementary nature
of the products (Figure 1b). Herein we describe the first highly
enantioselective dynamic kinetic asymmetric transfer hydro-
genation (DKR-ATH) of β-aryl α-keto esters, a transformation
that (1) allows direct access to trisubstituted γ-butyrolactones,
(2) establishes three contiguous stereocenters with complete
diastereocontrol, (3) employs a newly designed ruthenium
catalyst, (4) exhibits high catalyst efficiency, and (5) utilizes
readily available starting materials.
Figure 1. Dynamic kinetic resolution of keto esters.
At the reaction design stage, we applied the self-imposed
constraint to not only establish a convenient and scalable route
to the α-keto ester precursors but also strategically incorporate
structural elements that would allow us to productively merge a
dynamic process with downstream complexity-building events.
Specifically, we envisioned a diastereoselective dynamic
reduction of α-keto ester 1 to create the α- and β-stereocenters;
the incorporation of a diester at the γ-position was projected to
facilitate substrate synthesis and also allow a third stereocenter
to be established by concomitant lactonization of the nascent
hydroxyl group (Figure 1c). The functionality presented in α-
keto ester 1 collectively constitutes a retron for a carbene-
catalyzed Stetter addition between ethyl glyoxylate and readily
available benzylidene malonate derivatives.5 The implementa-
tion of the strategy outlined in Figure 1c would provide direct
access to synthetically useful enantioenriched γ-butyrolactones,
which notably would arise from four commercial reagents
(aldehyde, dimethyl malonate, ethyl glyoxylate, and formic
acid) and three catalytic steps (Knoevenagel reaction, Stetter
reaction, DKR/lactonization). As revealed by Table 1, the new
glyoxylate Stetter reaction catalyzed by the Rovis triazolium
Received: March 20, 2012
Published: April 17, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
a
Table 1. Glyoxylate Stetter Reaction Substrate Scope
Table 2. Evaluation of Chiral Diamine Ligands
entry
ligand
% yield
er
b
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
90
87
84
84
73
88
82
92
57:43
70:30
70:30
72:28
73:27
60:40
88:12
94:6
entry
R
product
% yield
1
2
3
4
5
6
C6H5
1a
1b
1c
1d
1e
1f
96
95
92
93
90
78
91
87
89
84
93
4Cl-C6H5
4Me-C6H5
4MeO-C6H5
4NC-C6H5
2Me-C6H5
piperonyl
c
7
1g
1h
1i
8
2-furyl
9
3-N-TsIndole
3-N-BocIndole
CH2CHPh
10
11
1j
1k
a
Conditions: Unless otherwise noted, all reactions were performed on
a 2.0 mmol scale in PhCH3 (4 mL) at ambient temperature for 16 h.
Isolated yield. Reaction performed on a 10 mmol scale.
b
c
carbene5c is efficient for a number of substrates and can be
performed on a multigram scale. A major challenge associated
with stereoselective carbonyl umpolung catalysis, viz., the
configurational vulnerability of the stereocenter next to the
ketone, is rendered moot here since the racemate is the desired
product.
a
Conditions: 2a (1.0 equiv), [RuCl2(p-cymene)]2 (0.02 equiv), L
(0.08 equiv), [2a]0 = 0.1 M in DMF, 70 °C, 16 h.
m-terphenyl sulfonamide variant, L8, distinguished itself as
being uniquely effective for providing high levels of
enantioselectivity for the title reaction (94:6 er, entry 8). The
α-naphthyl backbone and m-terphenylsulfonamide operate
synergistically; no improvement in enantiocontrol with the
DPEN/m-terphenylsulfonamide ligand L4 was observed. The
α-naphthylethylenediamine backbone has been used sporadi-
cally in asymmetric synthesis, and the use of the m-
terphenylsulfonamide for enantioselective catalysis is rarer
still.12
As outlined in Table 3, we have found this DKR-ATH to be
broad in scope for a number of β-aryl α-keto esters.13 High
yields and enantioselectivities (up to 94% yield and 96.5:3.5 er)
were obtained for substrates incorporating electron-rich,
electron-poor, and heteroaryl substituents at the β-position.
The product lactones exhibit high incidence of crystallinity. The
syn,anti-relationship of the trisubstituted γ-butyrolactone
products was determined by NOESY experiments, and the
absolute configuration was established by X-ray crystallographic
analysis of 2b.14
To demonstrate the synthetic utility and catalytic efficiency
of this method, the reaction was performed on multigram scale
(Scheme 1). Additional experimentation revealed that the
catalyst loading could be lowered to 1 mol % with no loss in
reaction efficiency. The reduction was trivially performed on a
10 g scale with 1g, yielding lactone 2g (er 95:5);
recrystallization yielded enantiomerically pure lactone in 72%
yield.
The reduction products present functionality immediately
amenable to further manipulation (Scheme 2). Lactone 2a
undergoes facile diastereoselective alkylation upon treatment
with allyl bromide and DBU, yielding tetrasubstituted lactone
3a bearing an all-carbon quaternary carbon center (94% yield).
Krapcho decarboxylation15 afforded α-unsubstituted lactone 3b
(86% yield), which is primed to undergo further enolate-based
Our point of departure for this study with respect to catalyst
development was Noyori’s (arene)RuCl(monosulfonamide-
DPEN),6 a catalyst that has tremendous efficacy in both the
asymmetric reduction of simple ketones7 and the dynamic
reduction of α-substituted β-keto esters and amides.8 We
elected to employ formic acid as the organic reductant and
triethylamine as the base using 1a as the test substrate. Initial
studies identified [RuCl2(p-cymene)]2 as the optimal precata-
lyst,9 and a number of chiral 1,2-diaminoethane monosulfona-
mide ligands were screened for selectivity (Table 2). Subjecting
1a to 2 mol % of the ruthenium dimer and Noyori’s ligand L1
(Ru atom:L mole ratio 1:2) in DMF at 70 °C provided the
desired γ-butyrolactone in high yield (90%) and diastereose-
lectivity (>20:1 dr), but with low levels of enantiocontrol
(57:43 er, entry 1). A significant increase in the enantiose-
lectivity was observed by modification of the sulfonamide (L2−
L4), but desirable levels of selectivity were not obtained
(entries 2−4). Employing 1,2-diaminocyclohexane and 1,2-
aminoindanol to serve as the chiral backbone (L5 and L6)
yielded comparable results (entries 5 and 6).
Based on these observations, it was clear that a new chiral
ligand would need to be identified to achieve high levels of
enantiocontrol. The development of the “mother diamine”/
diaza-Cope approach to the synthesis of C2-symmetric 1,2-
diamines10 allowed facile screening of a number of chiral
diamine backbones. We found that the α-naphthyl/triisopro-
pylbenzenesulfonamide ligand L7 considerably increased the
selectivity (Table 2, 88:12 er, entry 7). To further optimize the
ligand structure, perturbations of the sulfonamide were
examined due to its apparent ability to directly impact the
chiral environment (entry 1 vs entry 2). A number of diverse
sulfonyl chlorides were accessed through a one-pot double
alkylation/sulfonylation of 1,3-dichlorobenzene.11 The simplest
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Journal of the American Chemical Society
Communication
a
versatility of the product classes obtainable, we expect this
method to be of significant value in the areas of both natural
product and medicinal agent synthesis.
Table 3. DKR-ATH Substrate Scope
In summary, we have designed a new asymmetric transfer
hydrogenation catalyst that has led to the successful develop-
ment of the first dynamic kinetic resolution of β-aryl α-keto
esters. Under the reaction conditions, spontaneous lactoniza-
tion of the α-hydroxyl group onto the pendant ester occurs to
provide trisubstituted γ-butyrolactones with complete diaster-
eocontrol. With respect to the rubric of green chemistry, it is
instructive to inventory the three steps that lead to the lactones
2: (i) the Knoevenagel condensation is amine-catalyzed and
generates water as the byproduct; (ii) the glyoxylate Stetter
addition is carbene-catalyzed and is 100% atom economical,
generating no stoichiometric byproducts; (iii) the DKR-ATH
reaction uses a chiral ruthenium catalyst and formic acid as the
reductant and generates only CO2 and CH3OH as byproducts.
Further studies to understand the origin of selectivity, extend
this method to other β-stereogenic α-keto esters, and identify
other green, dynamic transformations with α-keto esters are
ongoing in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral, HPLC, and crystallo-
graphic (CIF) data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
a
Conditions: as described for Table 2.
Corresponding Author
jsj@unc.edu
Scheme 1. Catalyst Efficiency and Scalability
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences, Novartis, and Amgen. K.M.S. acknowledges an NIH
NRSA Fellowship to Promote Diversity in Health-Related
Research.
bond constructions. Of particular importance, alkylation with
dibromomethane followed by dehalodecarboxylation16 afforded
α-alkylidene γ-butryolactone 3c. This substructure is featured in
3% of all known natural products, and members of this subclass
exhibit a wide range of biological activity.17 Due to the
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