One-pot decarboxylative acylation of N-, O-, S-nucleophiles and peptides with 2,2-disubstituted malonic acids

Article abstract of DOI:10.1002/chem.201403529

Monocarbonyl activation of 2,2-disubstituted malonic acids with benzotriazole leads to decarboxylation of one of the carboxy groups and formation of a C-H bond. Intermediate carbonyl benzotriazoles then readily acylate nucleophilic reagents and peptides resulting in libraries of conjugates and peptidomimetics.

Full text of DOI:10.1002/chem.201403529

DOI: 10.1002/chem.201403529
Communication
&
Decarboxylative Acylation
One-Pot Decarboxylative Acylation of N-, O-, S-Nucleophiles and
Peptides with 2,2-Disubstituted Malonic Acids
Iryna O. Lebedyeva,*[a, b] Suvendu Biswas,[a] Kevin Goncalves,[a] Sean M. Sileno,[a]
Ashton R. Jackson,[a] Kunal Patel,[a] Peter J. Steel,[c] and the late Prof. Dr. Alan R. Katritzky[a]
Abstract: Monocarbonyl activation of 2,2-disubstituted
malonic acids with benzotriazole leads to decarboxylation
of one of the carboxy groups and formation of a CÀH
bond. Intermediate carbonyl benzotriazoles then readily
acylate nucleophilic reagents and peptides resulting in
libraries of conjugates and peptidomimetics.
The process of decarboxylation has been widely used in Ag-,[1]
Cu-,[2] and Pd-catalyzed[3] CÀC bond formation,[4,5] Pd/Cu-cata-
lyzed[6] cross couplings with aryl halides,[7,8] radical decarboxy-
Scheme 1. Reported and novel reaction conditions that lead to decarboxyla-
tion of malonic acids.
lative CÀH arylation,[9] and protodecarboxylation.[10,11,5] Organo-
catalyzed decarboxylation of naturally occurring cinnamic acid
leads to the flavor enhancement of decarboxylated products
and is therefore of interest to the food chemistry communi-
boxylation or CÀC bond formation in malonic acids. The use of
ty.[12] Decarboxylative CÀC cross-couplings have found their
carbonyldiimidazole (CDI) for the decarboxylative mono-
uses in the synthesis of ketones,[13] biaryls,[7,14] (E)-1,2-diaryl-
carbonylactivation of malonic acids has recently been report-
ethenes,[3] heterocyclic 2,5-diarylsubstituted thiazoles and oxa-
zoles,[15] 3H-pyrazolo[3,4-c]isoquinolines, thieno[3,2-c]isoquino-
lines,[16] and oxothiazolo- and oxazolo-C-C conjugates.[17] In
such processes it is important to suppress parallel reactions
and to minimize the formation of by-products during the
metal-catalyzed decarboxylative CÀC bond formations.[17] De-
carboxylative CÀH arylation provides a high yielding synthesis
of C1–C4 substituted 9H-fluoren-9-ones,[9] whereas radical pro-
todecarboxylation leads to the synthesis of substituted ben-
zenes from benzoic acids.[10]
Decarboxylation of malonates[18] usually requires the pres-
ence of strong bases,[19,20] acids[18,21,22] or high temperatures
(Scheme 1).[23,24] Enzymatic-[24,25–27] organometal-[28] or metal-
catalyzed[21,20] carbon dioxide release also leads to protodecar-
ed.[29] The absence of literature on the effect of the leaving
groups on decarboxylative acylation of malonic acids in the
synthesis of chirally active peptidomimetics or S-nucleophilic
conjugates led to the current study. In this work we have de-
veloped a feasible and straightforward three-step, one-pot syn-
thesis of peptide conjugates and peptidomimetics based on
monocarbonyl activation of malonic acids followed by loss of
carbon dioxide and nucleophilic substitution with benzotria-
zole as a leaving group. This approach allows the synthesis of
acylated chiral products under mild reaction conditions
(Scheme 1, current work).
2,2-Disubstituted malonic acids 1 undergo mild decarboxyla-
tion as a result of monocarbonyl activation with benzotriazole
to form intermediates 3 which then react with nucleophiles 4
to give conjugates 5. In this work, the three-step reaction of
malonic acids with nucleophilic reagents has been studied on
amines 4 that provided products 5a–e in 75–83% yields. As
a result of the reaction of 1 with O- and S-nucleophiles, prod-
ucts 5 f–k have been isolated in 77–88% yields (Scheme 2 and
Table 1). The three-step process proceeded without noticeable
difficulties and gave the expected products 5a–k in high yields
within 2 h. After the microwave-mediated one-step CO-activa-
tion of 1 with 1-(methylsulfonyl)-1H-benzo[d][1,2,3]triazole 2 it
also was possible to isolate decarboxylated intermediates 3a
(R=H, n=0, acyclic) and 3b (R=H, n=2, cyclic) in yields of
[a] Dr. I. O. Lebedyeva, Dr. S. Biswas, K. Goncalves, S. M. Sileno, A. R. Jackson,
K. Patel, Prof. Dr. A. R. Katritzky
Center for Heterocyclic Compounds, Department of Chemistry
University of Florida
Gainesville, FL 32611-7200 (USA)
Fax: (+1)352-392-9199
E-mail: irynal@chem.ufl.edu
[b] Dr. I. O. Lebedyeva
Department of Chemistry and Physics, Georgia Regents University
1120 15th Street SCI W3005, Augusta, GA 30912 (USA)
[c] Prof. Dr. P. J. Steel
Department of Chemistry, University of Canterbury
Christchurch 8140 (New Zealand)
1
89% and 92%, respectively. H spectra for 3a,b confirmed the
formation of the intermediates 3 by the observation of two
doublet and two triplet signals for the hydrogen atoms of the
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403529.
Chem. Eur. J. 2014, 20, 11695 – 11698
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Communication
Reaction of 2,2-disubstituted malonic acids 1 with 1-(methyl-
sulfonyl)-1H-benzo[d][1,2,3]triazole 2 using DMF as solvent and
excess of TEA as base (508C, MW 50 W, 1 h) led to the forma-
tion of decarboxylated CO-activated intermediate 3, which was
then reacted in situ with amino acids, their esters, and di- and
tripeptides. As such, a library of twelve peptidomimetics, 7a–l,
acylated at the N-terminus was synthesized in good to excel-
lent yields (79–90%). Acylation of amino acids and peptides
proceeded in situ in DMF using microwave irradiation (508C,
70 W, 1 h) (Scheme 3, Table 2). A double excess of amino acid
Scheme 2. Decarboxylative acylation of N-, O-, S-nucleophiles with 2,2-disub-
stituted malonic acids.
Table 1. Products 5a–k.
Cmpd
Nu 4
R
n
Yield [%]
5a
5b
5c
5d
5e
5f
5g
5h
5i
NH-nPr
NH-C6H5
NH-Bn
NH-Bn
NH-2,5-(CH3)2-C6H3
O-C6H5
O-l-menthol
O-cholesterol
S-C6H5
CH3
H
H
H
H
H
H
CH3
H
H
0 (acyclic)
3 (cyclic)
0 (acyclic)
3 (cyclic)
0 (cyclic)
2 (cyclic)
3 (cyclic)
0 (acyclic)
2 (cyclic)
0 (cyclic)
2 (cyclic)
75
84
83
78
83
86
81
77
88
83
80
Scheme 3. Benzotriazolyl-activated decarboxylative acylation of peptides.
Table 2. Products 7a–l.
5j
5k
S-Boc-N-l-Cys
S-Cbz-N-l-Cys
Cmpd
AA
R
n
R1
Yield [%]
H
7a
7b
7c
7d
7e
7f
7g
7h
7i
Gly
Gly
l-Leu
L-Val
l-Phe
d-Phe
d,l-Phe
l-Leu-l-Ala
l-Phe-l-Val
l-Ala-l-Leu
b-Ala-l-Cys-S-Ala-NH-Cbz
l-Phe-Gly-Gly
H
H
H
0 (acyclic) OBn 80
1 (cyclic)
0 (cyclic)
OBn 86
H
H
H
H
H
H
79
85
80
84
87
89
90
88
82
90
benzotriazole residue and a multiplet for the hydrogen of the
newly formed CÀH bond (see the Supporting Information).
Two-step couplings were conducted following a general proce-
dure using DMF as solvent at 508C for CO activation and 508C
for the reaction with nucleophiles using a 1.5 excess of triethyl-
amine (TEA) as base. Nucleophilic reagents were used in situ in
1.5 molar excess over the starting dicarboxylic acids 1 and mi-
crowave irradiation (50 W). The isolation of 5a–k was achieved
by extraction with ethyl acetate from saturated sodium car-
bonate solution and purification by column chromatography
as required.
CH3 0 (acyclic)
CH3 0 (acyclic)
CH3 0 (acyclic)
CH3 0 (acyclic)
H
1 (cyclic)
CH3 0 (acyclic) CH3
7j
7k
7l
H
H
H
3 (cyclic)
3 (cyclic)
3 (cyclic)
H
H
H
was used to synthesize 7c–g and a 1.5 molar excess of amino
ester and peptide was used to synthesize acylated products
7a,b and 7h–l. Optical rotation for all the chiral products has
Introduction of benzotriazole as a monocarbonyl activating
agent for 2,2-disubstituted malonic acids 1 and the subse-
quent reaction of 3 with amino acids, esters and peptides 6
takes place under mild reaction conditions with moderate
heating and microwave irradiation (50 W, 508C).
The structure of product 7 f was confirmed by single-crystal
X-ray crystallography (Figure 1). It crystallizes in the orthorhom-
bic space group P212121 with two molecules in the asymmetric
unit that are hydrogen-bonded to one another.
1
been measured (see the Supporting Information). H spectra of
7a–l had an additional multiplet signal at approximately d=
4.5 ppm for the proton of the newly formed CÀH bond and
the 13C NMR spectra revealed a signal between d=28–37 ppm.
Analysis of the mechanism of CO2 loss during the synthesis
of acylated nucleophiles and peptidomimetics suggests an
eight-step process that begins with the carbonyl group activa-
tion of 2,2-disubstituted malonic acids 1 with benzotriazole.
We tried several methods of CO-benzotriazolyl activation using
thionyl chloride and DCC-mediated COOH/benzotriazole cou-
plings and the highest yields for the final products 5 or 7 were
identified when the reaction of malonic acids 1 with 1-(methyl-
sulfonyl)-1H-benzo[d][1,2,3]triazole 2 was induced by base,
heating to 508C, and microwave irradiation (Scheme 4).
Activation of 10 occurs through H-bonding between the car-
boxylic group and the amide carbonyl of the benzotriazolide
promoting loss of CO2 with no requirement for the use of
Figure 1. Structure of (2-ethylbutanoyl)-d-phenylalanine 7 f.
Chem. Eur. J. 2014, 20, 11695 – 11698
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11696
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Communication
General procedure for the synthesis of acylated N-, O-, S-
nucleophiles 5, amino acids and peptides 7
1-(Methylsulfonyl)-1H-benzo[d][1,2,3]triazole (0.20 g, 1 mmol) was
added to a solution of 2,2-disubstituted malonic acid (1 mmol) in
DMF (3 mL) followed by addition of TEA (0.21 mL, 1.5 mmol), and
the mixture was subjected to microwave irradiation (20 W, 508C)
for 1 h. After cooling to room temperature the reaction mixture
was treated with the appropriate nucleophile (1.5 mmol for N-, O-,
S-nucleophiles and peptides and 2.0 mmol for amino acids) and
the mixture was subjected to microwave irradiation for 1 h (50 W,
508C). After the reaction was complete, the mixture was added to
4n HCl solution (50 mL) and extracted with ethyl acetate (3ꢁ
30 mL). The organic layers were combined, washed with 4n HCl so-
lution (2ꢁ50 mL), then dried over MgSO4 to give acylated products
5 and 7.
Scheme 4. Mechanism of: i) monocarbonyl-activation; ii) decarboxylation; iii)
acylation for 2,2-disubstituted malonic acids.
Acknowledgements
strong bases[19,20] or acids.[18,21,22] Formation of the CÀH bond
of 3 stabilizes the molecule and allows convenient acylation of
a broad spectrum of nucleophilic reagents and peptides. Addi-
tional HPLC/MS studies of the reaction mixture for 7a revealed
the molecular weight of 7a (m/z [M+H]+ 325.9) present in the
mixture and the absence of dicarboxyl malono-intermediates
or other products. Isolation of decarboxylated benzotriazole-
active intermediates 3a,b agrees with the suggested forma-
tion of 3 after CO2 release from the unstable intermediate 10.
A parallel synthesis where isolated CO-activated intermediate
3a reacted with benzylamine forming 5a confirmed loss of
CO2 prior to reaction with nucleophiles.
The authors thank the University of Florida for financial sup-
port.
Keywords: acylation
· cleavage reactions · conjugates ·
decarboxylation · peptides
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Received: May 14, 2014
Published online on July 25, 2014
Chem. Eur. J. 2014, 20, 11695 – 11698
www.chemeurj.org
11698
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