Enantioselective synthesis of α-stereogenic γ-keto esters via formal umpolung

Article abstract of DOI:10.1021/ol301112m

A feasible method has been developed for the enantioselective synthesis of α-stereogenic γ-keto esters. By employing nitro(phenylsulfonyl) methane as an acyl anion equivalent, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various γ-keto esters with high optical purities.

Full text of DOI:10.1021/ol301112m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Enantioselective Synthesis of
r-Stereogenic γ-Keto Esters via
Formal Umpolung
G. K. Surya Prakash,* Fang Wang, Zhe Zhang, Chuanfa Ni, Ralf Haiges, and
George A. Olah
Loker Hydrocarbon Research Institute, Department of Chemistry, University of
Southern California, Los Angeles, California 90089-1661, United States
gprakash@usc.edu
Received April 25, 2012
ABSTRACT
A feasible method has been developed for the enantioselective synthesis of r-stereogenic γ-keto esters. By employing nitro(phenylsulfonyl)-
methane as an acyl anion equivalent, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various γ-
keto esters with high optical purities.
γ-Keto esters are among the most important synthetic
feedstocks for constructing complex molecules. Although
various methods have been developed for the preparation
of racemic γ-keto esters,1 the majority of them use arduous
synthetic procedures and/or utilize scarce reagents. Feasi-
ble protocols toward these compounds are thus ardently
sought. Enantioselective synthesis of R-stereogenic γ-keto
esters is mainly achieved through the conjugate addition of
various nucleophiles to 4-oxo-4-butenoates (eq 1, Scheme 1).2
Although metal-catalyzed asymmetric cyanation of R,β-
unsaturated carbonyl compounds paves an alternative route
to γ-keto esters,3 the method is disadvantageous in that it
employs hazardous cyanides that can react via a possible
undesirable 1,2-addition pathway (eq 2, Scheme 1).4
The above-mentioned challenges are essentially due to
the incompatible donating/accepting natures of the β- and
the γ-carbon atoms in γ-keto ester backbones. Therefore
implementation of an organocatalyzed conjugate addition
merged with an umpolung strategy5 could provide a robust
solution tothese issues (eq 3, Scheme 1).6,7 Inprinciple, this
proposal could be achieved by integrating an enantioselective
(1) (a) Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem. 1969, 34,
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r
10.1021/ol301112m
XXXX American Chemical Society

malononitrileꢀenone conjugate addition8 with an oxidative
degradation of the adducts (eq 4, Scheme 1).9 Nonetheless,
the applicability of this approach is significantly diminished
by the acute toxicity of malononitrile (via its metabolism to
CNꢀ in the body).10
been found to participate in various asymmetric conjugate
addition reactions, which further validates the analogous
NSM as a viable pronucleophile.16 To the best of our knowl-
edge, NSM is also user-benign, therefore prevailing over other
highly toxic acyl anion equivalents, such as malononitrile and
HCN. In spite of its vast potential as an acyl precursor, NSM
is disadvantaged by its high cost and limited synthetic
accessibility.12b,16e,17 To overcome this obstacle, our initial
efforts focused on developing a facile preparative approach
toward NSM. By modifying a known procedure,18 NSM can
be obtained on a 40 g scale without advanced purification
techniques (Scheme 2).
Scheme 1. Enantioselective Synthesis of γ-Keto Esters
Scheme 2. Improved Preparation of NSM
With readily accessible NSM in hand, we performed its
thiourea-catalyzed Michael reaction19 under the conditions
employed for that of FNSM (entries 1ꢀ7, Table 1; see
Supporting Information (SI) for details).16a However, the
reaction with NSM was found to be very sluggish (entries 1
and 2, Table 1). This is similar to the observation that
dinitromethane is less reactive than fluorodinitromethane
in the Michael reaction20 owing to R-fluorine effects.21
We thus increased the reaction concentration to 2 M, which
led to remarkable enhancements in reaction yields (entries
Addressing such an inherent synthetic challenge, we
envisaged nitro(phenylsulfonyl)methane (NSM, 1) to be
a versatile acyl anion precursor due to its superior proper-
ties over other active methylene pronucleophiles. First,
among strong carbon acids, NSM (pKa ≈ 7 in DMSO)11
and its R-substituted derivatives can undergo ready depro-
tonation to form the corresponding anions that can serve
as nucleophiles in many transformations.12 Second, the
oxidative degradation of primary nitroalkanes (NO2CH2R)13
and primary sulfones (RSO2CH2R0)14 usually requires harsh
reaction conditions, such as utilization of strong bases and/or
oxidants. In comparison, the oxidative methanolysis of the
nitro(phenylsulfonyl)methyl moiety (NO2CHSO2Ph) can be
achieved under considerably milder conditions.15 In particu-
lar, R-fluoro-R-nitro(phenylsulfonyl)methane (FNSM) has
(16) For enantioselective conjugate addition of FNSM, see: (a) Prakash,
G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad.
Sci. U.S.A. 2009, 106, 4090–4094. (b) Ullah, F.; Zhao, G.-L.; Deiana, L.;
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Zhu, M.; Dziedzic, P.; Ibrahem, I.; Hammar, P.; Sun, J.; Cordova, A.
Chem.;Eur. J. 2009, 15, 10013–10017. (c) Kamlar, M.; Bravo, N.; Alba,
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A.-N. R.; Hybelbauerova, S.; Cısarova, I.; Vesely, J.; Moyano, A.; Rios,
R. Eur. J. Org. Chem. 2010, 5464–5470. For other utilities of FNSM, see:
(d) Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.;
Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936. (e) Prakash,
G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A.
Beilstein J. Org. Chem. 2008, 4, 17. (f) Pan, Y.; Zhao, Y.; Ma, T.; Yang,
Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem.;Eur. J. 2010, 16, 779–782.
(17) NSM can be obtained via the oxidation of PhSCH2NO2, which
can be prepared using PhSCl and NaCH2NO2; see: (a) Barrett,
A. G. M.; Dhanak, D.; Graboski, G. G.; Taylor, S. J. Org. Synth.
1990, 68, 8–13. Using PhSCH2N3 and F2/H2O/CH3CN system, see:
(b) Carmeli, M.; Rozen, S. J. Org. Chem. 2006, 71, 4585–4589.
(8) For selected examples of nontransition metal catalyzed asymmetric
conjugate addition of malononitrile, see: (a) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313–1317.
(b) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am.
Chem. Soc. 2006, 128, 12652–12653. (c) Li, X.; Cun, L.; Lian, C.; Zhong, L.;
Chen, Y.; Liao, J.; Zhu, J.; Deng, J. Org. Biomol. Chem. 2008, 6, 349–353.
(d) Naka, H.; Kanase, N.; Ueno, M.; Kondo, Y. Chem.;Eur. J. 2008, 14,
5267–5274. (e) Shi, J.; Wang, M.; He, L.; Zheng, K.; Liu, X.; Lin, L.; Feng,
X. Chem. Commun. 2009, 4711–4713. (f) Pansare, S. V.; Lingampally, R.
Org. Biomol. Chem. 2009, 7, 319–324.
(18) Basedon a known procedure:Weigl, U.; Heimberger, M.; Pierik,
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A. J.; Retey, J. Chem.;Eur. J. 2003, 9, 652–660. See SI for details.
(19) For pioneer work on thiourea catalysis, see: (a) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901–4902. (b) Schreiner,
P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217–220. (c) Wittkopp, A.;
Schreiner, P. R. Chem.;Eur. J. 2003, 9, 407–414. (d) Okino, T.; Hoashi,
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J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–4296.
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S. D.; Hardinger, S. A.; Saft, M. S.; Hinney, H. R. J. Chem. Soc., Chem.
Commun. 1980, 287–288. (b) Wade, P. A.; Hinney, H. R.; Amin, N. V.;
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Org. Lett., Vol. XX, No. XX, XXXX

3ꢀ6, Table 1). Oxidative methanolysis of the adduct (3a)
afforded the desired γ-keto ester (4a) with good enantio-
meric ratios (er), indicating the essential stereochemical
stability of the R-carbon in the adduct and the product.
Nevertheless, attempts to improve er by lowering reaction
temperatures resulted in a drastic decrease in yields due to
the insufficient solubility of the substrates under the reaction
conditions (entry 7, Table 1). It is also worth noting that the
solubilities of many enones can marginally reach the re-
quired high concentration (2 M) even at rt, therefore
diminishing the applicability of the reaction conditions.
solvent in the Michael reaction, 4a was obtained in mod-
erate yield via the direct oxidative methanolysis of 3a, thus
streamlining the protocol. Despite the fact that excess 2a
was oxidized to 1,3-diphenyl-2,3-epoxy-1-propanone as a
byproduct, it could be easily separated from 4a via SiO2
column chromatography. It was also found that different
primary amines afforded 4a with similar levels of stereo-
selectivity.
Table 2. One-Pot Synthesis of R-Stereogenic γ-Keto Esters
Catalyzed by Primary Amines
Table 1. Thiourea-Catalyzed Synthesis of γ-Keto Esters
a Isolated yields. b Measured by chiral HPLC.
a Conversions to 3a, determined by 1H NMR. b Isolated yields.
c Performed with 1 at 2 M concn. d Performed without stirring. e Mea-
sured by chiral HPLC. f The oxidative methanolysis was performed after
the completion of the Michael addition. Crude 3a was subjected to the
oxidation without purification.
It has been demonstrated that Brønsted acids can facil-
itate amine-catalyzed reactions by means of iminium
activation23 or mediating H-bonding interactions.24 On
this basis, we surmised that Brønsted acids might also be
effective cocatalysts. Although initial attempts to exploit
phenols and fluorinated alcohols as additives were unsuc-
cessful (see SI for details), benzenesulfonic acid monohy-
drate brought a rather promising result (entry 1, Table 2),
indicating the importance of additive acid strength. How-
ever, the excessive acidity of CF3SO3H was found to have a
detrimental impact on the stereoselectivity (entry 2,
Table 2). Based on these results, a series of carboxylic acids
with moderate acidities was further screened.
Further optimization was achieved through acceleration
of the reaction with cinchona alkaloid-derived primary
amines, which have been widely used as amenable chiral
catalysts.22 While γ-keto ester 4a was obtained with infer-
ior er by the introduction of primary amine catalysts, the
Michael addition was complete within 48 h at a concentra-
tion of 0.5 M (entries 8ꢀ11, Table 1). Notably, the present
Michael additionꢀoxidative methanolysis approach could
also be achieved in a one-pot fashion. After removal of the
€
(23) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416–5470.
(22) Reviews on primary amine catalysis: (a) Bartoli, G.; Melchiorre,
P. Synlett 2008, 1759–1771. (b) Chen, Y.-C. Synlett 2008, 1919–1930.
(c) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807–1821.
(24) (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986–990. (b) Knowles, R. R.; Jacobsen, E. N. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 20678–20685.
Org. Lett., Vol. XX, No. XX, XXXX
C

Asoutlined inFigure 1, variousenoneswereinvestigated
in the one-pot Michael additionꢀoxidative methanolysis
protocol. In general, both electron-rich and -deficient
chalcone derivatives underwent the reaction smoothly,
affording R-stereogenic γ-keto esters in moderate yields
with high enantiomeric selectivities (entries 1 and 4ꢀ11,
Figure 1). Similar to the previous reaction using a fluori-
nated pronucleophile,16a the present reaction has also
demonstrated R-facial discrimination on the R-carbon.
However, when 4-(2-furyl)-3-buten-2-one was subjected
to the reaction, only a complex mixture was obtained,
possibly due to the lability of the furan ring under the
oxidation conditions (entry 3, Figure 1).25 Although
methyl styryl ketone participated in the reaction, the er
was found to be rather low, indicating the limitation of the
present protocol (entry 2, Figure 1).
To demonstrate the synthetic utility of the present
protocol, 4i was subjected to a tandem reductionꢀreduc-
tive amination reaction.26 As depicted in Scheme 3, synthe-
tically useful tetrahydroquinoline-4-carboxylic ester 5 was
obtained as a single diastereomer in good yield without
significant loss of optical purity.27
Figure 1. Investigation of substrate scope. aIsolated yields.
bMajor/minor, measured by chiral HPLC. cPerformed in
THF/CH2Cl2 (1:2, v/v) due to the low solubilities of enones in
Scheme 3. Stereoselective Synthesis of Tetrahydropyridine
d
THF. Performed in CH2Cl2 due to the low solubilities of the
enone in THF. eThe absolute configuration determined by
X-ray crystallography; see SI.
The er of the reaction gradually increased as the acid
strength of the additive increased (entries 4ꢀ7, Table 2).
Excellent stereoselectivity was obtained via the employ-
ment of trichloroacetic acid. Presumably, such a trend can
be rationalized by strong acidity facilitating the iminium
catalysis pathway more efficiently than weak acidity.
Meanwhile, by decreasing the concentration of free pri-
mary amines, enhanced acidity also suppressed the less
stereoselective reaction pathway mediated by neutral pri-
mary amines (entry 9, Table 1). Similar to triflic acid, the
high acidity of CF3CO2H also impaired the stereoselectiv-
ity of the reaction (entry 8, Table 2). Although increasing
the amount of ClCH2CO2H did slightly enhance the er,
thisled todramaticdecreasesin reaction yields (entries 5, 9,
and 10, Figure 1). Further screening of catalysts showed
QD-2 to be a superior catalyst over CN-2. Under the
catalysis of QD-2, the solvent effects on the stereoselectiv-
ity were also investigated, which revealed THF to be the
optimal solvent (entry 26, Table 2). The optimized reaction
conditions were eventually achieved using 10 mol % of
QD-2 as the catalyst along with 10 mol % of Cl2CHCO2H
(DCA) in THF (entry 26, Table 2).
In summary, a feasible protocol has been achieved for
the enantioselective preparation of R-stereogenic γ-keto
esters via an umpolung strategy. By exploiting nitro-
(phenylsulfonyl)methane (NSM) as an acyl anion pre-
cursor, various γ-keto esters were obtained in moderate
yields with good enantioselectivities. The large-scale
preparation of NSM has also been achieved, making
the protocol operationally simple. In particular, the
protocol is significantly streamlined by merging the
asymmetric organocatalyzed Michael addition and the
subsequent oxidative methanolysis into a one-pot reac-
tion. Further investigation of NSM as an acyl anion
equivalent in the Mannich reaction is currently under-
way in our laboratory.
Acknowledgment. Support of our work by the Loker
Hydrocarbon Research Institute is gratefully acknowl-
edged. We acknowledge NSF CRIF Grant 1048807 for
the acquisition of an X-ray diffractometer.
Supporting Information Available. Experimental de-
tails, HPLC data, X-ray crystal structures, and copies of
1H and 13C spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Badovskaya, L. A.; Povarova, L. V. Chem. Heterocycl. Compd.
2009, 45, 1023–1034.
(26) Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S. V.
J. Org. Chem. 2001, 66, 2822–2827.
(27) Differing from the description in ref 25, 5 underwent a demethyl-
carboxylation reaction under the hydrogenation conditions. Such a side
reaction was essentially evitable by shortening the reaction time to 1 h.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX