Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

Article abstract of DOI:10.3762/bjoc.12.166

A sequential three-component process is described, starting from 3-arylmethylene-2,5-piperazinediones and involving a one-pot sequence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziridine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild conditions. Their transformation into β-trifluoroacetamido-α-ketoamide and α,β-diketoamide frameworks was also achieved in a single step.

Full text of DOI:10.3762/bjoc.12.166

Three-component synthesis of highly functionalized aziridines
containing a peptide side chain and their one-step
transformation into β-functionalized α-ketoamides
Lena Huck, Juan F. González, Elena de la Cuesta and J. Carlos Menéndez*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1772–1777.
Departmento de Química Orgánica y Farmacéutica, Facultad de
Farmacia, Universidad Complutense, 28040 Madrid, Spain
doi:10.3762/bjoc.12.166
Received: 09 May 2016
Accepted: 27 July 2016
Published: 08 August 2016
Email:
J. Carlos Menéndez* - josecm@farm.ucm.es
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2016 Huck et al.; licensee Beilstein-Institut.
License and terms: see end of document.
α-ketoamides; aziridines; multicomponent reactions; nitrogen
heterocycles; one-pot reactions; peptide mimics; vicinal tricarbonyl
compounds
Abstract
A sequential three-component process is described, starting from 3-arylmethylene-2,5-piperazinediones and involving a one-pot se-
quence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziri-
dine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild
conditions. Their transformation into β-trifluoroacetamido-α-ketoamide and α,β-diketoamide frameworks was also achieved in a
single step.
Introduction
Aziridine moieties occur in many natural products and are also ing strategy for the design of active site-directed drugs, espe-
encountered in unnatural biologically active compounds includ- cially in the field of chemotherapy [6,7].
ing drugs in clinical use, especially in the field of cancer treat-
ment [1]. In the areas of medicinal chemistry and chemical Aziridines also have an important role in the preparation of
biology, aziridines are of current interest as starting materials further types of nitrogen-containing compounds [8-10]. As a
for the preparation of peptides [2,3] and the synthesis of consequence, the preparation of aziridines is of great impor-
peptide-like compounds comprising the aziridine motif [4,5]. tance [11-13]. The primary synthetic approaches involve either
Furthermore, the incorporation of an electrophilic aziridine the direct aziridination of an olefin [14] or the reaction of an
moiety in peptide or peptidomimetic frameworks is an interest- imine with diazoalkanes. Alternatively, the reaction of imines
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with various nucleophiles, including aza-Darzens mechanisms, tert-butoxide, followed by deacetylation with hydrazine hydrate
can lead to aziridine products [15]. However, few known (see the Supporting Information File 1 for further details). As
methods allow the synthesis of C-trisubstituted aziridines, par- shown in Scheme 2, treatment of these materials with N-bromo-
ticularly for the case of N-unprotected systems [10,16,17].
succinimide and methanol in dioxane followed by the addition
of 1.2 equivalents of a primary or secondary amine or alcohol in
2,5-Diketopiperazines (DKPs) are readily accessible from the presence of 2 equivalents of sodium hydride afforded the
amino acids and are versatile synthetic scaffolds [18,19]. highly substituted and functionalized aziridine derivatives 2.
Consequently, there is considerable interest in the development Under these conditions, it can be assumed that methoxide is the
of synthetic methodology based on the cleavage of suitably predominant base. The optimal reagent concentration was deter-
functionalized DKP derivatives [20-22]. In this context, we mined to be 0.2 M, since higher concentrations led to the
describe here an efficient regio- and diastereoselective one-pot precipitation of reaction intermediates and lower yields.
three-component assembly of trisubstituted aziridines
possessing a free NH group and containing a peptidic or
peptide-like side chain. Furthermore, we describe the conver-
sion of these compounds into functionalized β-amino-α-
ketoamides. This is an important structural fragment that is used
in the design of reversible covalent enzyme inhibitors, includ-
ing the anti-hepatitis C drugs boceprevir and telaprevir, because
the electrophilic keto group is able to react reversibly with
mercapto or hydroxy groups at the active sites of a variety of
enzymes. Existing synthetic approaches to this moiety are
Scheme 2: Synthesis of aziridines 2.
normally quite complex and do not easily allow the presence of
amino acid side chains on the amide nitrogen [23]. Finally, in
order to further underscore the synthetic usefulness of The scope of the reaction was investigated and the results are
these aziridine scaffolds, we examined their one-pot summarized in Table 1. Good yields were obtained indepen-
transformation into α,β-diketoamides and the transformation of dently from the electronic nature of the aryl ring. Bulky R1 aryl
the latter compounds into nitrogen heterocycles bearing a groups were well tolerated, as shown by the presence of ortho-
peptide side chain (Scheme 1).
substituents in many of the examples (Table 1, entries 3–11).
Both primary (Table 1, entries 1, 3, 4, 5, 6, 9, and 11) and sec-
ondary amines (Table 1, entries 2 and 7) could be employed as
nucleophiles, and the use of oxygen nucleophiles (methanol)
was also possible (Table 1, entries 8 and 10). Nevertheless,
steric limitations existed in the latter case, since the reaction did
not tolerate the use of bulkier alcohols such as ethanol or
propanol, which led only to recovered starting materials. In all
cases, the reaction proceeded with full diastereoselectivity,
affording the product with a cis relationship between the aryl
substituent and the peptide side chain as shown by NOE studies,
which are summarized in Figure 1 for compound 2f. One exam-
ple of a reaction leading to an alkyl substituent at the aziridine
C-3 position (R1 = Et) was attempted, but the yield was poor
(15%) and the resulting aziridine derivative could not be com-
pletely purified.
Mechanistically, the reaction is proposed to proceed by the
pathway summarized in Scheme 3. An initial bromomethoxyla-
tion of the starting materials 1 is expected to afford intermedi-
ates 3. Although 3 may be formed as a mixture of diastereo-
Scheme 1: Summary of the work described in this paper.
Results and Discussion
The starting 3-arylmethylene-2,5-piperazinediones 1 were mers because of the epimerization of the initial adduct, as de-
readily available by aldol condensation of 1,4-diacetyl-2,5- scribed in a literature precedent on a similar reaction [24], this
piperazinedione with aldehydes in the presence of potassium is of no consequence for the outcome of the reaction. The next
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Table 1: Results obtained in the aziridine synthesis.
Entry Compound R1
ZR2
Yield, %
79
1
2
2a
2b
C6H5
C6H5
n-BuNH
58
3
4
5
6
2c
2d
2e
2f
(2,5-MeO)2C6H3 n-BuNH
(2,5-MeO)2C6H3 n-HexNH
75
69
92
73
2-ClC6H4
2-ClC6H4
n-BuNH
n-HexNH
7
2g
2-ClC6H4
61
8
2h
2i
2-ClC6H4
OMe
76
71
57
9
2-NO2C6H4
2-NO2C6H4
n-BuNH
OMe
10
2j
11
2k
n-BuNH
50
Scheme 3: Mechanistic proposal accounting for the chemo- and dia-
stereoselective formation of aziridines 2.
synthetic applications of aziridines have received much atten-
tion [11,25-29] there is little precedent of their opening with
weak nucleophiles such as carboxylate anions [30]. However,
we expected that the presence of the 2-methoxy substituent
would facilitate the desired transformation. The initial study
was carried out on compound 2e, but we found that a variety of
acidic conditions either failed to give any reaction at room tem-
perature or afforded complex mixtures when heated. After some
experimentation, we finally discovered that treatment of com-
Figure 1: NOE effects in compound 2f.
step would involve the base-promoted formation of the bicyclic pound 2e with trifluoroacetic acid in dichloromethane at 45 °C
aziridine 4, where nitrogen conjugation to the adjacent carbon- gave an excellent yield of the β-trifluoroacetamido-α-ketoamide
yl would be geometrically constrained. The associated increase 6d. The method was then applied to a range of representative
in reactivity for this carbonyl would explain the complete selec- aziridines 2, allowing the synthesis of the corresponding com-
tivity of the diketopiperazine ring opening, with concomitant pounds 6 in excellent yields (Scheme 4 and Table 2).
loss of a molecule of methanol, to furnish azirine 5. Finally, ad-
dition of the methanol released in the previous step to the highly The formation of 6 can be explained by the mechanism summa-
strained intermediate 5 would take place anti to the R1 substitu- rized in Scheme 5. The acid-promoted opening of the hemi-
ent, explaining the observed diastereoselection. This proposal aminal ether function existent in aziridine derivatives 2 because
was supported by the isolation of one of its intermediates from of the presence of the 2-methoxy substituent would furnish
the reaction between 3-(2,5-dimethoxybenzylidene)-2,5-piper- oxonium species 7 via a Neber reaction. Its O-demethylation by
azinedione and NBS in dioxane containing methanol at room the trifluoroacetate anion would yield compound 8, whose
temperature. This reaction led to the corresponding compound 3 amino group would finally be trifluoroacetylated by the methyl
in 75% yield, with full regioselectivity but as a 1.7:1 mixture of trifluoroacetate liberated in the previous step, to give 6. Alterna-
diastereomers. When this mixture was treated with butylamine tively, loss of a molecule of methanol from starting compound 2
and sodium hydride under our standard conditions, compound would lead to intermediate 5 (see Scheme 3), whose reaction
2c was isolated in 85% yield.
with trifluoroacetic acid would furnish 9. Neber-type chemistry
would afford the oxonium species 10, which would finally be
With compounds 2 in hand, we next examined their transformed into the observed product 6 by intramolecular
transformation into β-amino-α-ketoamide derivatives. While the transfer of the trifluoroacetyl group.
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Scheme 4: Transformation of aziridines 2 into β-trifluoroacetamido-α-ketoamides 6.
tion from compounds 2, together with their application to the
synthesis of nitrogen heterocycles bearing a peptide side chain.
We discovered that treatment of representative aziridines 2 with
perchloric acid in a THF–water reaction medium led to the
isolation of the corresponding compounds 11, which were then
transformed into pyrazines 12 and quinoxalines 13 via straight-
forward cyclocondensation reactions with ethylenediamine and
o-phenylenediamine, respectively (Scheme 6 and Table 3).
Table 2: Results of the synthesis of
β-trifluoroacetamido-α-ketoamides 6.
Entry Compound R1
ZR2
Yield, %
1
2
3
4
6a
6b
6c
6d
C6H5
n-BuNH
90
87
(2,5-MeO)2C6H3 n-BuNH
(2,5-MeO)2C6H3 n-HexNH 92
2-ClC6H4
2-ClC6H4
2-ClC6H4
n-BuNH
97
93
98
5
6
6e
6f
OMe
Finally, bearing in mind the interest of 1,2,3-tricarbonyl com-
pounds (vicinal tricarbonyl compounds, VCTs) both as struc-
tural fragments of protease inhibitors [31] and synthetic inter-
mediates [32,33], we also explored briefly their direct prepara-
Scheme 6: Transformation of aziridines 2 into vicinal tricarbonyl com-
pounds 11 and transformation of the latter into nitrogen heterocycles
12 and 13, containing a peptide side chain.
The transformation of 2 into 11 can be explained by the mecha-
nism summarized in Scheme 7, starting with the formation of
the previously mentioned intermediate 8, followed by hydroly-
sis of its imino tautomer to give 14 and a final oxidation by per-
chloric acid. One of the proposed intermediates (compound
14b) was isolated by lowering the amount of perchloric acid,
and was transformed into 11b under the general conditions em-
ployed for the preparation of 11 from 2.
Scheme 5: Two mechanistic proposals explaining the formation of
compounds 6.
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to an important pharmacophore in the design of enzyme inhibi-
tors. Furthermore, the aziridines could also be transformed into
α,β-diketoamides, which were suitable precursors for nitrogen
heterocycles bearing a peptide side chain.
Table 3: Results of the synthesis of vicinal tricarbonyl compounds 11
and the nitrogen heterocycles 12 and 13 arising from them.
Entry Compound R1
ZR2
Yield, %
1
2
3
4
5
6
7
11a
11b
12a
12b
13a
13b
13c
2-ClC6H4
n-BuNH
67
64a
64
67
61
74
74
(2,5-MeO)2C6H3 n-BuNH
2-ClC6H4 n-BuNH
(2,5-MeO)2C6H3 n-BuNH
2-ClC6H4 n-BuNH
(2,5-MeO)2C6H3 n-BuNH
2-ClC6H4 OMe
Supporting Information
Supporting Information File 1
Experimental section, copies of 1H NMR, 13C NMR and
ESIMS spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-166-S1.pdf]
aTwo equivalents of perchloric acid were required in this case. The
normal reaction conditions (1 equiv HClO4) led to 13% yield of 11b and
52% of compound 14b (see below the mechanistic discussion associ-
ated to Scheme 7).
Acknowledgements
Financial support from MINECO (grants CTQ2012-33272-
BQU and CTQ2015-68380-R) and UCM (fellowship to LH) is
gratefully acknowledged. We also thank Dr. Paul A. Clarke
(York University, UK) for helpful mechanistic discussions.
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