Solid-phase synthesis of piperazinones via disrupted ugi condensation

Article abstract of DOI:10.1021/ol5023118

The first application of aziridine aldehyde dimers in solid-phase synthesis is reported. The solid-supported disrupted Ugi condensation between an aziridine aldehyde dimer, isonitrile, and backbone-anchored amino acids delivered N-acyl aziridine intermediates, which were reacted with nucleophiles to yield the corresponding piperazinones. Subsequent cleavage from the resin provided a diverse set of 2,3,6-trisubstituted piperazinones starting from various amino acids, aziridine aldehydes, and nucleophiles.

Full text of DOI:10.1021/ol5023118

Letter
pubs.acs.org/OrgLett
Solid-Phase Synthesis of Piperazinones via Disrupted Ugi
Condensation
Adam P. Treder,† Marie-Claude Tremblay,† Andrei K. Yudin,‡ and Eric Marsault*,†
†Dep
5N4
́
artement de Pharmacologie, Institut de Pharmacologie de Sherbrooke, Universite
́
de Sherbrooke, Sherbrooke, QC, Canada J1H
‡Department of Chemistry, University of Toronto, Davenport Building, rm. 362, 80 St. George, Toronto, ON, Canada M5S 3H6
S
* Supporting Information
ABSTRACT: The first application of aziridine aldehyde dimers in solid-phase synthesis is reported. The solid-supported
disrupted Ugi condensation between an aziridine aldehyde dimer, isonitrile, and backbone-anchored amino acids delivered N-acyl
aziridine intermediates, which were reacted with nucleophiles to yield the corresponding piperazinones. Subsequent cleavage
from the resin provided a diverse set of 2,3,6-trisubstituted piperazinones starting from various amino acids, aziridine aldehydes,
and nucleophiles.
he Ugi multicomponent reaction plays an important role in
drug discovery, natural products synthesis, and combina-
activities such as serine protease inhibitors,17 cytostatic,18
antibacterial,19 and immunomodulating agents20 (Figure 2).
T
torial chemistry as a source of peptidomimetic scaffolds.1
Recently, the Yudin group reported novel aziridine aldehyde
dimers (Figure 1)2 as a new class of amphoteric reagents, which
Figure 1. Synthesis of (S)-aziridine aldehyde dimer derived by Serine.
has found utility in a wide variety of applications in organic
synthesis, including multicomponent reactions.3 Aziridine
aldehydes lead to disrupted Ugi four-component condensations,
generating cyclic products that do not correspond to conven-
tional Ugi-type outcomes, thereby improving the diversity of
accessible structures. The resulting bicyclic aziridines can be
reacted with nucleophiles under mild conditions. This approach
offers four diversity elements on pharmaceutically important
scaffolds such as macrocycles and piperazinones.4
The piperazine moiety has been frequently used in drug
discovery and introduced in many valuable biologically active
compounds,5 including antineoplastics,6 antivirals,7 coagulation
regulators,8 insecticides,9 and antischisostomal agents.10 They
have been applied to a variety of targets such as elastase,11
fibrinogen,12 oxytocin,13 melanocortin-4,14 dopamine recep-
tors,15 or GABAA chloride ion channel.16 The piperazinone ring
is also found in multiple natural products (Figure 2) possessing
Figure 2. Representative biologically active piperazinones.
Recent efforts by the Yudin group in the field of parallel
synthesis of piperazinones have focused on the application of
microfluidics.21 On the other hand, solid-phase synthesis
represents a powerful tool to support the rapid generation of
diversity, both via parallel synthesis or split-pool combinatorial
chemistry.22 In order to further exploit the potential of aziridine
aldehydes, we embarked on the development of a solid-phase
synthetic method to enable the parallel synthesis of piper-
azinones.
Received: August 4, 2014
Published: August 25, 2014
© 2014 American Chemical Society
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Letter
Several approaches to solid-supported Ugi reactions have been
reported.23 Synthesis of substituted piperazinones on solid-phase
has also been explored. Among the known methods of piperazine
ring formation are polyamine cyclization on MBHA resin,24
cyclization of dipeptides immobilized on BAL resin to
diketopiperazines,25 or traceless synthesis of piperazinones on
Wang resin.26 Applications of Merrifield,27 Rink,28 and trityl29
resins as well as a polymer-supported trialkylsilylethyl linker30
have also been reported.
Table 1. Piperazinones Obtained in This Study
We sought a solid-supported precursor displaying free amino
and carboxylate ends, turning our attention to the immobiliza-
tion of amino acids by anchoring the backbone on FMP resin
using reductive amination.25,31,32 This site of resin anchoring was
expected to enhance the nucleophilicy of the amine, and to
facilitate chain folding for cyclization.
Direct reductive amination of unprotected amino acids and
resin aldehyde proved difficult due to the poor solubility of
unprotected amino acids in organic solvents. We thus chose allyl
esters, which are subsequently deallylated on solid phase
(Scheme 1). As described previously,4 the cyclization reaction
Scheme 1. Representative Synthesis of Piperazinones
is best performed in TFE as a solvent, yet the physical properties
of polystyrene-based resins precluded the use of neat TFE due to
poor swelling. To ensure appropriate swelling of the resin, a
variety of solvent and solvent mixtures were tested to finally
identify a mixture of TFE and DCM (1:1) as the best
combination. In the first step of cyclization, a secondary FMP-
anchored amino acid (I) was reacted with an aziridine aldehyde
dimer and t-BuNC to yield the bicyclic aziridine derivative (II).
Our efforts to cleave and isolate the bicyclic aziridine product
(II) were unsuccessful due to the instability of the compounds
under cleavage conditions. Only decomposition products were
observed by LC/MS. In subsequent experiments, the aziridine
was opened in situ with a variety of nucleophiles, including thiol,
azide, and thioacid (Scheme 1, Table 1). The cyclization
reactions (I−II, Scheme 1) occurred in good yields and gave
products in high purity when the amino acid configuration
matched that of the aziridine aldehyde dimer [matched
chemistry: (S)-dimer and L-amino acid, or (R)-dimer and D-
amino acid; mismatched chemistry: (S)-dimer and D-amino acid;
Figure 3]. L- and D-Phe anchored to FMP resin were chosen to
assess the robustness of the cyclization to deliver (S)-(1−6).
In the subsequent step, the corresponding bicyclic aziridine
intermediate (II) was reacted with a series of nucleophiles such
as thiophenol (1−3), thiobenzoic acid (4), and sodium azide (5).
In the case of azido derivative (5), the azide moiety was
subsequently reacted with phenylacetylene in a “click” cyclo-
a
Overall yields for 4−5 steps including RP-HPLC purification and
lyophilization, calculated based on initial resin loading.
addition displaying an alternative method for piperazinone
derivatization (6).33 Several other FMP-attached amino acids
were cyclized with the (S)-aziridine aldehyde dimer and t-BuNC:
L-Leu, D-Leu, L-Ala, D-Ala, L-Tyr, and L-Lys. The bicyclic aziridine
intermediates were further reacted with thiophenol, yielding
thioether derivatives (7−12). Figure 3 shows a representative
chromatogram of a matched (2a) and a mismatched (2b)
cyclization. Matched combinations were typically of superior
purity and gave higher yields. The configurations of newly
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Organic Letters
Letter
For product 2a obtained from FMP-D-Phe and the (S)-
aziridine aldehyde dimer, the coupling constant between protons
in positions 2 and 3 was characteristic of a trans-diaxial
orientation (9.5 Hz). NOESY analysis further confirmed the
configuration as (2R) (Figure 5). As a side product of FMP-D-
Phe cyclization with the (S)-dimer, (2S)-diastereomer 2b was
isolated. For 2b, only a long distance NOE was observed, along
with a low coupling constant (3.1 Hz), which is indicative of an
axial−equatorial relationship (Figure 5). Configurations of other
1
compounds in this series were assigned by comparison of H
NMR coupling constants to 1, 2a,b, and 7.
The configuration at position 2 of the piperazinones obtained
on solid phase was determined by the configuration of the starting
amino acid. By virtue of resin anchoring, which converts the
amino acid into a secondary amine, piperazinones derived from
the solid-phase method yield the cis diastereomer. This is in
contrast to solution phase, which yields the trans diastereomer
predominantly when primary amino acids are cyclized (Figure
6).4a Thus, the solid-phase approach provides complementary
access to the opposite diastereomer for the cyclization of primary
amino acids such as Leu and Phe.
Figure 3. Typical HPLC traces of crude cyclizations in matched (1) and
mismatched (2a, 2b) cases.
synthesized compounds were determined by NMR, particularly
positions 3 and 6 of the piperazinone scaffold (Figure 4).
Figure 6. Comparison of solid-phase and solution-phase outcomes for (S)
matched chemistry.
In summary, we have developed a new and efficient solid-
supported method to synthesize 2,3,6-trisubstituted piperazi-
nones via disrupted Ugi condensation between amine-anchored
amino acids, isocyanides, and aziridine aldehyde dimers. The
cyclization diastereoselectivity strongly depends on the stereo-
chemistry of both the amino acid and the aziridine aldehyde. The
reaction yields a single cis diastereomer when the amino acid and
aziridine aldehyde dimer possess matched stereochemistry. The
solid-phase cyclization approach presented herein represents a
viable method for the synthesis of combinatorial libraries of
piperazinones.
Figure 4. NOESY experiment for (1). Diagnostic crosspeak between
two axial protons (Figure 5) marked by arrow.
The relative configuration of the new stereocenter in position
1
2 was confirmed by analysis of H NMR coupling constants
followed by 2D NOESY experiments for a subset of compounds
1
(1, 2a,b, 7). For product 1, the H NMR coupling constant
between protons in positions 2 and 3 was characteristic of axial−
equatorial or equatorial−equatorial protons (4.7 Hz). A 1H−1H
NOESY experiment (Figures 4 and 5) showed cross-peaks for
axial protons in positions 2 and 6, confirming the (2S)
configuration. Similar results were obtained for 7.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, chromatograms, and NMR and MS
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: eric.marsault@usherbrooke.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CQDM (Consortium Queb
́
ec
́
ois sur la Dec
́
ouverte du Med
́
ica-
ment, www.cqdm.org) is acknowledged for funding. We also
thank Serge Zaretsky and Jennifer L. Hickey (University of
Toronto) for constructive comments.
Figure 5. Structural elucidation of products.
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Organic Letters
Letter
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