Asymmetric synthesis of α-keto esters via Cu(II)-catalyzed aerobic deacylation of acetoacetate alkylation products: An unusually simple synthetic equivalent to the glyoxylate anion synthon

Article abstract of DOI:10.1021/ol200649u

Chemical equations presented. A simple and efficient method for the preparation of β-stereogenic α-keto esters is described using a copper(II)-catalyzed aerobic deacylation of substituted acetoacetate esters. The substrates for the title process arise fro

Full text of DOI:10.1021/ol200649u

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2426–2429
Asymmetric Synthesis of r-Keto Esters
via Cu(II)-Catalyzed Aerobic Deacylation
of Acetoacetate Alkylation Products: An
Unusually Simple Synthetic Equivalent to
the Glyoxylate Anion Synthon
Kimberly M. Steward and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
jsj@unc.edu
Received March 12, 2011
ABSTRACT
A simple and efficient method for the preparation of β-stereogenic R-keto esters is described using a copper(II)-catalyzed aerobic deacylation of
substituted acetoacetate esters. The substrates for the title process arise from catalytic, enantioselective conjugate additions and alkylation
reactions of acetoacetate esters. The mild conditions do not induce racemization of the incipient enolizable R-keto ester. The reaction is tolerant of
esters, certain ketones, ketals, and nitro groups and utilizes inexpensive, readily available materials.
Formal nucleophilic glyoxylation of π-functional
groupsthrough theapplication of glyoxylate anion equiva-
lents in principle defines a direct entry into R-keto esters,
compounds of considerable importance in biochemistry1
and organic synthesis.2 This unique and versatile func-
tional group provides access to useful building blocks such
as R-hydroxy and R-amino esters.3 Despite positive attri-
butes, the existing reagents and strategies highlighted in
Figure 1 are not amenable to widespread adoption of the
“glyoxylate anion” tactic in organic synthesis due to case-
dependent disadvantages and/or limitations.4 A compell-
ing case can be made that the full potential of R-keto esters
has not been realized due to the absence of a general and
convenient synthetic method for their preparation.
(1) Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471.
(2) (a) Cooper, A; Meister, G. A. Chem. Rev. 1983, 83, 321. (b)
Kovacs, L. Rec. Trav. Chim. Pays-Bas 1993, 112, 471.
(3) (a) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527. (b) Kang, Q.;
Zhao, Z. A.; You, S. L. Adv. Synth. Catal. 2007, 349, 1657.
(4) Select examples of R-keto ester synthesis: (a) Eliel, E.; Hartman,
A. J. Org. Chem. 1972, 37, 505. (b) Takahashi, T.; Okano, T.; Harada,
T.; Imamura, K.; Yamada, H. Synlett 1994, 38, 121. (c) Yao, W.; Wang,
J. Org. Lett. 2003, 5, 1527. (d) Enders, D.; Bonten, M. H.; Raabe, G.
Synlett 2007, 51, 885. (e) Enders, D; Bonten, M. H.; Raabe, G. Angew.
Chem., Int. Ed. 2007, 46, 2314. (f) Radosevich, A. T.; Chan, V. S.; Shih,
H.-W.; Toste, F. D. Angew. Chem., Int. Ed. 2008, 47, 3755. (g) Trost,
B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674. (h)
Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.; Sodeoka,
M. J. Am. Chem. Soc. 2010, 132, 4036. (i) Steward, K. M.; Johnson, J. S.
Org. Lett. 2010, 12, 2864. For catalytic, enantioselective synthesis of
R-keto amides via umpolung catalysis with glyoxamides, see: (j) Liu, Q.;
Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066. (k) Liu, Q.;
Rovis, T. Org. Lett. 2009, 11, 2856.
Figure 1. Synthetic equivalents for the glyoxylate anion
synthon.
r
10.1021/ol200649u
Published on Web 04/12/2011
2011 American Chemical Society

Introduced herein is an aerobic oxidation reaction for the
preparation of β-stereogenic-R-keto esters that establishes
synthetic equivalence between acetoacetate esters and the
glyoxylate anion synthon in the context of asymmetric
synthesis. The reaction sequences described give structu-
rally diverse enantiomerically enriched products that are
heretofore unknown even in racemic form. Practical attri-
butes include the use of cheap starting materials, an
unmodified commercial catalyst, and air as the oxidant
for a powerful, yet underutilized aerobic cleavage reaction
of β-keto esters.
To bring about the desired synthetic equivalence, a
family of enantioselective reactions was needed that would
deliver products to serve as the R-keto ester progenitor.
The appeal of using β-dicarbonyl nucleophiles with π-elec-
trophiles stems from the range of chiral catalysts that
are available to mediate enantioselective enolate-based
carbonꢀcarbon bond constructions. These reactions offer
significant practical advantages since the pronucleophiles
are commercially available and inexpensive. Moreover,
activation can be achieved under mild and convenient
reaction conditions due to the low pKa of the carbon acid.
Enolates act as d2-reagents and give normal polarity
products with π-electrophiles. The corresponding umpo-
lung products from d1-reagents are more challenging to
achieve5,6 and the only two examples of direct asymmetric
“glyoxylate anion” catalysis employ glyoxamides as the
glyoxylate donor.4j,k The present work capitalizes on an
operationally trivial aerobic cleavage reaction to establish
acetoacetate esters as synthetic equivalents to the glyox-
ylate anion synthon. The tactic parlays the established
advantages of enolate-based reactions into asymmetric
syntheses of many families of chiral R-keto esters that have
not been previously prepared and would not be accessible
via a glyoxylate anion catalysis manifold.4iꢀk
For our preliminary studies we purposely chose a chal-
lenging substrate (2a9) to assess the mildness and func-
tional group compatibility of the reaction. The oxidative
deacylation shown in Scheme 1 (2a f 3a) was initially
conducted under 1 atm of O2, and after 48 h 60% conver-
sion to the R-keto ester was observed. Further optimi-
zation10 revealed that pressurized air (50 psig in a standard
Fisher-Porter bottle) and 20 mol % of Cu(NO3)2 3H2O
3
provided the best results, affording 3a in 83% yield. The
fact that 3a can readily eliminate HNO2 to give the
β,γ-unsaturated-R-keto ester 4 on untreated silica gel
underscores the mildness of these oxidation conditions.11
Indeed, despite the CꢀH acidity of the product 3a and
accompanying possibility of racemization, no loss in en-
antiopurity is observed during the course of the reaction.
i
Conjugate adduct 2b (R = Pr) was not previously de-
scribed using catalyst 1, but efficient enantioselective
catalysis was observed and aerobic deacylation of the
tautomeric and stereoisomeric mixture provided R-keto
ester 3b in good yield without measurable racemization.
Scheme 1. Formal Nucleophilic Glyoxylation of Nitroalkenes
In 2000, Clariant disclosed the conversion of substituted
acetoacetates and malonates to the corresponding R-keto
esters using O2 and catalytic quantities of a Cu(II) or
Fe(III) salt; a ring-cleavage variant had been previously
disclosed by Cossy and co-workers.7 While the products
reported were achiral and unfunctionalized, the transfor-
mation is striking for its simplicity and use of cheap,
unmodified catalysts. To the best of our knowledge, this
reaction has not been employed in asymmetric synthesis.
In light of the fact that the products are strong carbon
acids,8 it was an open question whether the reaction
conditions would be sufficiently mild to avoid base- or
acid-catalyzed racemization.
With the goal of diversifying available product classes,
attention was directed to finding other cases that might be
applicable to aerobic deacylation. Scheme 2 illustrates
formal conjugate glyoxylation of R,β-unsaturated ketones.
Asymmetric addition of methyl acetoacetate to both
2-cyclopenten-1-one12 and 2-cyclohexen-1-one13 using
known chiral catalysts (4 and 5) followed by site-selec-
tive ketalization14 provided 6a and 6b, respectively, with
excellent enantiocontrol. Cu(II)-catalyzed aerobic deacyla-
tion of β-keto ester 6a occurred with concomitant ketal
(5) (a) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239. (b) Johnson,
J. S. Curr. Opin. Drug Disc. Dev. 2007, 10, 691.
(9) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958.
(10) See the Supporting Information for details.
(11) β-Aryl-γ-nitro-R-keto esters like 3a could not be prepared using
an auxiliary-based glyoxylate anion synthetic equivalent because of this
elimination. See ref 4e.
(12) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003,
125, 7508.
(13) Majima, K.; Takita, R.; Okada, A.; Oshima, T.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 15837.
(6) By the Seebach definition, an an- or dn-synthon is, “respectively, a
synthon with an O- or N-heteroatom at C1 and an acceptor or donor
center at Cn.” For donor synthons, normal reactivity corresponds to
d
2,4,6,... (an enolate would correspond to a d2 synthon), while umpolung
reactivity corresponds to d1,3,5,... (an acyl anion is a d1 synthon).
(7) (a) Cossy, J.; Belotti, V.; Bellosta, V.; Brocca, D. Tetrahedron
Lett. 1994, 35, 6089. (b) Vallejos, J.-C.; Capelle, N.; Arzoumanian, H. U.
S. Patent 6,057,474, 2000.
(8) The pKa (H2O) of ethyl pyruvate has been estimated to be 16.6:
Bell, R. P.; Ridgewell, H. F. F. Proc. Royal Soc. London. Ser. A, Math
Phys. Sci. 1967, 298, 178–183.
(14) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357. Subjecting these Michael adducts directly to the aerobic deacyla-
tion conditions afforded a complex mixture of products.
Org. Lett., Vol. 13, No. 9, 2011
2427

deprotection to provide dione 7a (82%, er 96:4). Conversely,
the ketal remained intact for the cyclohexanone ketal 6b,
yielding 7b (78%, er 96:4) with all three oxygenated
functional groups differentiated.
Even more value-added products can be obtained by
utilizing the second nucleophilic site on methyl acetoacetate.
Withanambident electrophile suchas2-cyclohexen-1-one,
methyl acetoacetate undergoes (3 þ 3)-annulation18 pro-
viding bicyclo[3.3.1]nonanone 10 (Scheme 4). Oxidative
deacylation of (()-10 led to a ring-cleavage reaction7a that
yielded cyclohexanol 11 as a single isomer (87% yield)
with all four oxygenated functional groups differentiated.
Notably, the product is the synthetic equivalent of two
challenging reactions: enone conjugate glyoxylation and
diastereoselective ketone acetate aldolization. The reaction
was operationally trivial on a 10 g scale, and the product
was isolated in pure form without the need for chromato-
graphy by precipitation from Et2O using hexanes as
the antisolvent. The acetoacetate/cyclohexenone (3 þ 3)-
annulation has only been reported in racemic form, but
aldolization of the enantioenriched 1,4-adduct13 under
modified conditions (NaOMe, MeOH, rt) led to (ꢀ)-10
in good yield. Aerobic deacylation provided (ꢀ)-11 with no
loss of enantiopurity (er 95:5).
Scheme 2. Formal Conjugate Glyoxylation of Cyclic Enones
Scheme 4. Formal Conjugate Glyoxylation/Ketone Acetate
Aldolization Sequence
Because R-keto esters are potential substrates for
dynamic kinetic resolution,4i it is not a prerequisite that the
acetoacetate-based bond construction have an associated
asymmetric variant. Enantioselective acetoacetate additions
to acyclic R,β-unsaturated carbonyls await discovery, but the
easily accessible adducts (()-8a15 and (()-8b16 provide their
derived R-keto esters (()-9a and (()-9b in the presence of
Cu(II)/air (Scheme 3). The utility of these racemic products
in subsequent stereodynamic processes is under investiga-
tion. Conjugate addition of dimethyl malonate to chalcone
using a chiral strontium catalyst has been reported,17 but the
use of this catalyst with methyl acetoacetate provided race-
mic product. The Clariant patent described the aerobic
cleavage of simple linear malonates; however, in our hands
the oxidative cleavage of the branched and more highly
functionalized malonate derivatives to the R-ketoesters has
to date been unsuccessful.
Dual functionalization was also achieved with the un-
saturated β-keto ester derived from the asymmetric allylic
alkylation of benzyl acetoacetate with cyclohexen-3-yl
acetate (12, Scheme 5).19 Under the standard conditions,
both aerobic deacylation and epoxidation occurred, pro-
viding 13 with >95:5 diastereoselection. The syn-stereo-
chemical relationship strongly implicates participation of
the R-keto ester or a precursor thereto in the epoxida-
tion.20,21 The conversion of 12 to 13 also establishes the
feasibility of employing other acetoacetate starting materi-
als (i.e., benzyl ester).
Scheme 3. Formal Conjugate Glyoxylation of Acyclic Michael
Acceptors
(15) Saidi, M. R.; Azizi, N.; Akbari, E.; Ebrahimi, F. J. Mol. Catal.
Chem-A. 2008, 292, 44.
(16) Xian, M.; Alaux, S.; Sagot, E.; Gefflaut, T. J. Org. Chem. 2007,
72, 7560.
(17) Agostinho, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130,
2430.
(18) Momose, T; Muraoka, O. Chem. Pharm. Bull. 1978, 26, 288.
(19) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. It is
interesting to note that the reaction of malonate esters with cyclohexen-
3-yl acetate is a standard test for new allylic alkylation catalysts, but the
analogous asymmetric reaction with acetoacetate esters was to the best
of our knowledge unknown.
2428
Org. Lett., Vol. 13, No. 9, 2011

Scheme 5. Merged Aerobic Deacylation/Epoxidation
Scheme 6. Current Substrate Limitations
Scheme 6 summarizes initial observations that help
define the method’s limitations at the current level of
development. While investigating the aerobic ring cleavage
of substrate 14, a retro-aldol reaction was found to be
operative under the reaction conditions, providing
Michael adduct 8a. The related trimethylsilyl ether 15
decomposed in the presence of Cu(II)/air, perhaps due to
the formation of the benzylic carbocation 16. Decomposi-
tion of allylic silyl ether 17 was also observed, presumably
through a similar pathway. Addressing these limitations
and extending the scope of the aerobic deacylation are
current areas of interest.
In summary, a simple protocol for the preparation of
β-stereogenic R-keto esters has been established through
the aerobic deacylation of substituted acetoacetate deriva-
tives. A heretofore underdeveloped relationship between
chiral β-keto esters and R-keto esters has been realized that
dramatically simplifies the glyoxylate anion problem. The
strategy described herein captures many characteristics
that are often described in “ideal” synthetic methods:
aerobic deacylation is operationally simple and scalable,
employs starting materials that are commercially available
and cheap, generates an innocuous byproduct, provides
product diversity, and is compatible with a number of
useful functional groups.
Acknowledgment. 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 a BMS Minority Chemist Fellowship and
an NIH NRSA Fellowship to Promote Diversity in
Health-Related Research.
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Komiya, N.; Naota, T.; Oda, Y.; Murahashi, S. J. Mol. Catal.
€
Ribas, X.; Costas, M.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 1425.
(21) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
Chem-A. 1997, 117, 21. (b) Schroder, K; Join, B.; Amali, A. J; Junge, K;
Org. Lett., Vol. 13, No. 9, 2011
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