One-Pot Quinine-Catalyzed Synthesis of α-Chiral γ-Keto Esters: Enantioenriched Precursors of cis-α,γ-Substituted-γ-Butyrolactones

Article abstract of DOI:10.1002/adsc.201600427

A highly enantioselective one-pot synthesis of important building blocks, α-chiral γ-keto esters, has been developed by combining a quinine-catalyzed Michael addition of malononitrile to trans-enones followed by magnesium monoperoxyphthalate (MMPP) oxidat

Full text of DOI:10.1002/adsc.201600427

UPDATES
DOI: 10.1002/adsc.201600427
One-Pot Quinine-Catalyzed Synthesis of a-Chiral g-Keto Esters:
Enantioenriched Precursors of cis-a,g-Substituted-g-Butyrolac-
tones
Sara Meninno,a Chiara Volpe,a and Alessandra Lattanzia,*
a
Dipartimento di Chimica e Biologia “A. Zambelli”, Universitꢀ di Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy
E-mail: lattanzi@unisa.it
Received: April 22, 2016; Revised: May 27, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600427.
Abstract: A highly enantioselective one-pot synthe-
sis of important building blocks, a-chiral g-keto
esters, has been developed by combining a quinine-
catalyzed Michael addition of malononitrile to
trans-enones followed by magnesium monoperoxy-
Recently, we disclosed an efficient and highly enan-
tioselective Michael addition of malononitrile to
trans-enones 1 catalyzed by 10 mol% of quinine
[Scheme 1, Eq. (1)].[8] Since all reagents and catalyst
involved are low cost, commercially or easily avail-
able compounds, we were prompted to investigate fur-
ther the potential of this transformation. Indeed, we
envisioned adducts 2 could be useful intermediates
for a facile synthesis of challenging acyclic targets
such as a-chiral g-keto esters.
ACHTUNGTRENNUNGphthalate (MMPP) oxidation. These synthons
proved to be useful reagents for a simple access to
challenging cis-a,g-disubstituted g-butyrolactones in
good diastereoselectivity and high enantiocontrol.
Helmchen and co-workers demonstrated the feasi-
bility of a clean oxidative degradation of racemic 2-
(3-oxo-1,3-diphenylpropyl)malononitrile with magne-
sium monoperoxyphthalate (MMPP) to give methyl
4-oxo-2,4-diphenylbutanoate in good yield [Scheme 1,
Eq. (2)].[9] Considering the synthetic importance of a-
Keywords: asymmetric synthesis; butyrolactones;
Michael addition; organocatalysis; oxidation
Modern synthetic approaches to produce organic mol-
ecules need to take into account the development of
environmentally benign reaction conditions on one
hand and the reduction of practical operations in
order to cut the costs, minimize waste production and
save time. Hence, with a view to set up green and
convenient procedures, chemists have created useful
concepts to follow such as step-economy,[1] atom-
economy,[2] and pot-economy.[3]
In the area of asymmetric organocatalyzed
reactions, an increasing number of processes follows
these guidelines, especially one-pot sequential or
multicomponent reactions focused on the preparation
of pharmaceuticals and biologically active com-
pounds.[4]
Over the last years we have been interested in the
development of new asymmetric organocatalytic
methods to prepare acyclic and heterocyclic com-
pounds. According to the principles expressed above,
we disclosed simple one-pot domino diastereo- and
enantioselective reactions to access different class of
compounds such as tetrahydrothiophenes,[5] tetrasub-
stituted 2-pyrrolines, 3-substituted piperazin-2-ones,[6]
and g-butyrolactones.[7]
Scheme 1. Asymmetric quinine-catalyzed approach to a-
chiral g-keto esters 3 and cis-a,g-disubstituted g-butyrolac-
tones 4.
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Table 1. Scope of the one-pot organocatalytic enantioselec-
chiral g-keto esters and the paucity of asymmetric ap-
proaches reported to obtain these building blocks,[10]
we thought that malononitrile could be used as an
acyl anion equivalent to develop an asymmetric one-
pot synthesis of a-chiral g-keto esters 3 by combining
a quinine-catalyzed Michael addition of malononitrile
to trans-enones followed by oxidation with cheap and
commercially available MMPP [Scheme 1, Eq. (3)].
Due to their interesting and manifold biological ac-
tivities,[11] chiral substituted g-butyrolactones are
among the most relevant building blocks for the syn-
thesis of natural products, such as flavours,[12] phero-
mones,[13] and alkaloids.[14]
tive Michael addition/oxidation.[a]
Although several investigations focused on their
asymmetric synthesis, only few synthetic approaches
have been reported to obtain enantioenriched cis-a,g-
tri- and disubstituted g-butyrolactones, relying on
a chiral auxiliary approach[15] or asymmetric metal-
based[16] catalysis and organocatalysis.[17] To the best
of our knowledge, no general methodology for the
enantioselective synthesis of cis-a,g-diaryl-substituted
g-butyrolactones has been reported. Hence, the devel-
opment of a simple and convenient route to obtain
this class of compounds is highly desirable. We antici-
pated that the NaBH4-mediated reduction of enantio-
merically enriched products 3 followed by acid-cata-
lyzed lactonization would afford cis-a,g-diaryl-substi-
tuted g-butyrolactones 4 with good diastereoselectiv-
ity and high ee value [Scheme 1, Eq. (3)].
We commenced our investigation by reacting a vari-
ety of trans-enones 1 with 10 mol% of quinine under
our previously reported conditions at À208C in tolu-
ene (Table 1).[8]
At the end of the reaction, toluene was evaporated
from the reaction vessel and the crude product was
reacted with MMPP under basic conditions in anhy-
drous MeOH.[9] The reaction was performed at
À208C, to prevent eventual racemization and poten-
tial Baeyer–Villiger side reaction.[18] The feasibility of
the one-pot protocol has been successfully demon-
strated starting from chalcones substituted with elec-
tron-withdrawing or electron-donating groups at both
aromatic rings. A heteroaromatic moiety is also toler-
[a]
Conditions: 1 (0.4 mmol), malononitrile (0.48 mmol), qui-
nine (0.04 mmol) in toluene (4 mL) at À208C. For the
second step, after solvent evaporation, MeOH (3 mL),
Li2CO3 (0.6 mmol) and MMPP (0.4 mmol) were added at
À208C. The product was isolated after flash chromatog-
raphy; the ee was determined via chiral HPLC analysis.
[b]
Reaction carried out with 20 mol% of quinine.
ated as well as aliphatic groups at the b-position of before, only a few methodologies enable the asym-
the starting enone. In all the examples, a-chiral g-keto metric synthesis of cis-a,g-dialkyl-substituted g-
esters 3 were isolated in fairly good overall yield and butyroACTHNUTRGNEUNG
lactones[16] and cis-a-alkyl-g-aryl-substituted g-
high enantioselectivity. No racemization occurred butyroACTHNUTRGNEUNG
lactones,[17] by derivatization of enantiomeri-
during the oxidation step as attested by the ee values cally enriched intermediates.
measured for compounds 3, found to be in line with
those obtained for compounds 2.
Literature precedents, showed the reduction of
compounds 3 or amide derivatives by (R)-MeCBS/
or by (t-BuO)3AlHLi[21] to proceed with
[20,10b]
The synthetic utility of enantioenriched compounds BH3
3 was further explored with the aim to access cis-a,g- poor or good diastereoselectivity, respectively. Unex-
disubstituted butyrolactones via a reduction and lac- pectedly, Bahr et al. found that NaBH4 in MeOH at
tonization sequence. Enantiomerically enriched trans- room temperature simultaneously reduced both car-
a,g-disubstituted g-butyrolactones can be synthesized bonyl groups of 4-aryl-4-oxo esters to yield 1-aryl-1,4-
by diastereoselective a-alkylation of enantioenriched butanediols.[22] A preliminary investigation on the re-
g-aryl-substituted butyrolactones.[19] As mentioned action of model racemic compound 3a with different
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reducing agents followed, after aqueous work-up, by
p-toluenesulfonic acid-catalyzed lactonization, was
carried out.[23] Interestingly, NaBH4 in THF/MeOH at
À408C proved to be the most effective and conven-
ient reducing system.
Under these conditions, the reduction of the ester
group was disfavored and racemic product 4a was iso-
lated in 82% overall yield and cis/trans 85/15 ratio.
This protocol, applied on a range of enantioen-
riched compounds 3, afforded cis-a,g-diaryl-substitut-
ed and cis-a-alkyl-g-aryl-substituted g-butyrolactones
in high yield, good diastereoselectivity and high ee
(Table 2). The relative and absolute configurations of
products 4 were confirmed by comparison with litera-
ture data.[17,21,24]
Scheme 2. Scale-up asymmetric synthesis of cis-a,g-diphen-
yl-substituted butyrolactone 4a.
Finally, a scale-up asymmetric synthesis of cis-g-bu-
tyrolactone 4a has been carried out starting from
3 mmol of trans-chalcone 1a (Scheme 2). The com- compounds, that is, a-chiral g-keto esters and cis-a,g-
bined four-step sequence involving one-pot Michael disubstituted g-butyrolactones by using readily acces-
addition/oxidation followed by reduction and acid- sible, inexpensive reagents and quinine as the organo-
catalyzed lactonization required two aqueous work-up catalyst. The four-step approach represents a first gen-
steps and one final column chromatography. The de- eral and efficient asymmetric protocol to prepare cis-
sired cis-g-butyrolactone 4a was isolated in 51% over- a,g-diaryl-substituted g-butyrolactones. The entire
all yield and 90% ee.
process, which includes only two aqueous work-up
In summary, we developed a simple highly stereose- and one chromatographic purification step can be per-
lective one-pot approach to two classes of challenging formed on a large scale starting from trans-enones.
Table 2. Reduction/lactonization of enantioenriched 3 to cis-
Experimental Section
a,g-disubstituted g-butyrolactones.[a]
General One-Pot Procedure for the Synthesis of a-
Chiral g-Keto Esters 3
Enone 1 (0.40 mmol) and quinine (13.0 mg, 0.040 mmol)
were dissolved in dry toluene (4 mL). Malononitrile (32 mg,
0.48 mmol) was added, and the reaction stirred at À208C.
After completion, toluene was removed, then anhydrous
methanol (2.7 mL) and Li2CO3 (44.3 mg, 0.6 mmol) were
added. The suspension was cooled to À208C and MMPP
(80% technical grade 248 mg, 0.4 mmol) was added portion-
wise. The reaction mixture was stirred at À208C overnight.
After completion, the reaction was quenched by the addi-
tion of water (15 mL) and diluted with ethyl acetate
(15 mL). The aqueous layer was extracted with ethyl acetate
(2ꢂ15 mL) and the combined organic layers were washed
with water (2ꢂ15 mL). The organic layer was dried over an-
hydrous Na2SO4 and concentrated under reduced pressure.
The reaction mixture was purified by flash chromatography
(PE/ethyl acetate 98/2 to 95/5) to afford the products.
General Procedure for the Reduction/Lactonization
of g-Keto Esters 3 to cis-a,g-Disubstituted g-
Butyrolactones 4
[a]
Conditions: reduction step,
3
(0.2 mmol) NaBH4
(1.2 mmol) in MeOH/THF 1/1 (2 mL), À408C. Lactoni-
zation step, crude mixture in CH2Cl2 (1.2 mL), p-TsOH
(0.02 mmol), room temperature. The dr ratio was deter-
mined by 1H NMR analysis of the crude reaction mix-
ture. Isolated yield of cis/trans-diastereosiomers; the ee
was determined via chiral HPLC analysis.
g-Keto ester 3 (0.2 mmol) was dissolved in dry THF/MeOH
1/1 (2 mL) in a dried round-bottomed flask under a nitrogen
atmosphere and the solution was cooled at À408C. After
10 min, NaBH4 was added in 6 portions (1.2 mmol) waiting
10 min between two subsequent additions. The reaction mix-
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ture was stirred at À408C until completion. Then, the reac-
tion was quenched with brine (10 mL) and the mixture ex-
tracted with ethyl acetate (3ꢂ10 mL). The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
crude mixture was dissolved in CH2Cl2 (1.2 mL) and p-
TsOH·H2O (3.8 mg, 0.02 mmol) was added. The reaction
mixture was stirred overnight at room temperature. The dia-
stereoisomeric ratio of g-butyrolactones 4 was determined
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1
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Acknowledgements
We thank the University of Salerno and MIUR for financial
support. We thank Dr. P. Iannece for assistance with the mass
spectral analyses.
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One-Pot Quinine-Catalyzed Synthesis of a-Chiral g-Keto
Esters: Enantioenriched Precursors of cis-a,g-Substituted-g-
Butyrolactones
5
Adv. Synth. Catal. 2016, 358, 1 – 5
Sara Meninno, Chiara Volpe, Alessandra Lattanzi*
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!