Organocatalytic Multicomponent Synthesis of α/β-Dipeptide Derivatives

Article abstract of DOI:10.1002/chem.202001214

A straightforward multicomponent Knoevenagel-aza-Michael-cyclocondensation reaction involving readily available hydroxamic acid-derived from naturally occurring α-amino acids allows a diversity-oriented synthesis of novel isoxazolidin-5-ones possessing an N-protected α-amino acid pendant with good to high diastereoselectivities thanks to a match effect with a chiral organocatalyst. These diversely substituted heterocycles, easily isolated as a single diastereoisomer, proved to be versatile platforms for the formation of an array of α/β-dipeptide fragments.

Full text of DOI:10.1002/chem.202001214

A Journal of
Accepted Article
Title: Organocatalytic Multicomponent Synthesis of α/β-Dipeptide
Derivatives
Authors: Thomas Martzel, Julien Annibaletto, Pierre Millet, Etienne
Pair, Morgane Sanselme, Sylvain Oudeyer, Vincent Levacher,
and Jean-François Brière
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To be cited as: Chem. Eur. J. 10.1002/chem.202001214
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COMMUNICATION
Organocatalytic Multicomponent Synthesis of α/β-Dipeptide
Derivatives
Thomas Martzel,[a,c] Julien Annibaletto,[a,c] Pierre Millet, Etienne Pair, Morgane Sanselme, Sylvain
[a]
[a]
[b]
[
a]
[a]
[a]
Oudeyer, Vincent Levacher and Jean-François Brière*
Dedication ((optional))
Abstract:
A
straightforward multicomponent Knoevenagel-aza-
acids (βAA) derivatives (Scheme 1A).[6] Bode and co-workers
have made a major achievement in this field, by developing the α-
ketoacid–hydroxylamine (KAHA) ligation between two pre-
synthesized AA derivatives, one bearing a α-keto acid pendant
and another possessing an hydroxylamine N-terminus functional
group.[7] Recently, Takemoto expended the portfolio of
hydroxylamine-derived βAA to aspartic acid derivatives thanks to
Michael-Cyclocondensation reaction involving readily available
hydroxamic acid-derived from naturally occurring α-amino acids
allows a diversity-oriented synthesis of novel isoxazolidin-5-ones
possessing an N-protected α-amino acid pendant with good to high
diastereoselectivities thanks to
a match effect with a chiral
organocatalyst. These diversely substituted heterocycles, easily
isolated as a single diastereoisomer, proved to be versatile platforms
for the formation of an array of α/β-dipeptide fragments.
an organocatalytic aza-Michael addition to fumaric monoacid
electrophiles.[
8]
This elegant strategy, making use of
hydroxylamine functions as key building blocks for the elaboration
of βAA, was applied to the elaboration of α/β-dipeptides albeit with
moderate diastereoselective ratio (dr).
Naturally occurring peptides currently hold a privileged place for
the development of bio-inspired ingredients in pharmaceutical
industry.[1] In order to overcome the inherently sensitivity to
proteolytic degradation of native peptides, while giving the
opportunity to afford new properties and bio-tools to probe protein
functions, synthetic chemists have tackled the elaboration of
peptide analogues. In that peptidomimetic context, β-amino acids
proved to be excellent building blocks for the elaboration of either
β-peptides and hybrid α/β-polyamino acids having not only an
improved stability towards peptidases but also displaying unique
secondary structures and
pharmacological activities.[2]
Furthermore, the α/β-dipeptide fragments are not only a key
elements of naturally occurring products,[3] but have met
important successes in medicinal chemistry either in a linear form
in case of cardiovascular diseases target for instance,[2b] or to
construct cyclic-peptide architectures in which the 1,4-diazepane-
2,5-diones, and heterocycles derived thereof, proved to be
privileged platforms in
a large array of pharmaceutical
applications.[ The attractiveness of these frameworks has fueled
4]
numerous research efforts dealing with the asymmetric synthesis
of β-amino acids, and the elaboration of original derivatives is still
of high added value.[3a],[5]
Scheme 1. A new entry to β-amino acid derivatives.
The synthesis of the α/β-dipeptide motif essentially relies on
the construction of the amide bond by means of coupling reagents,
essentially stoichiometric, between suitably (orthogonal)
protected and pre-elaborated α-amino acids (αAA) and β-amino
Besides these convergent sequences, we tackled an
alternative divergent approach in order to populate the chemical
space within the biorelevant α/β-dipeptide series (Scheme 1B).
We reasoned that the multicomponent Knoevenagel-aza-
Michael-Cyclocondensation (KMC) reaction would take place
between readily available hydroxamic acids 1,[9] derived from
naturally occurring and enantiopure αAA, various aldehydes 2
[
a]
Dr. T. Martzel, Dr. J. Anniballeto, P. Millet, Dr. E. Pair, Dr. S.
Oudeyer, Dr. V. Levacher and Dr. J.-F. Brière
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000
Rouen, France.
E-mail: jean-francois.briere@insa-rouen.fr
Dr. M. Sanselme
Laboratoire SMS – EA3233, Normandie Univ-University of Rouen,
France.
These authors contributed equally to this work.
and Meldrum’s acid (MA) as a C2-synthon (first point of
diversity).[10],[11] Then, this strategy would afford a straightforward
[
b]
c]
elaboration of novel isoxazolidin-5-ones 3,[12] as masked βAA with
an αAA side chain, providing eventually versatile platforms to
[
elaborate a
diversity).[
13],[14]
library of α/β-dipeptides (second point of
In order to be synthetically useful, this sequence
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
should demonstrate a significant functional group compatibility
and furnish one stereoisomer. Thanks to the marked electrophilic
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COMMUNICATION
reactivity of alkylidene MA intermediates 4,[11],[15] we postulated
that (1) a facile domino addition process of hydroxamic acids 1
would occur and (2) the C-N bond formation between 1 and 4
would be under the influence of both a chiral nucleophile 1 and a
Brønsted base organocatalysts to favor the formation one
stereoisomer (Scheme 1B). We are delighted to report on the
unprecedented diastereoselective multicomponent reaction
entry 2). A large screening of organocatalysts (see SI) showed
that the commercially available and chiral amine (DHQ) PHAL
2
turned out to be the more efficient catalyst leading to good 86:14
dr in 75% yield in 5 hours (entry 3 versus entries 4-7). Early
optimization endeavors (see SI) showed that less polar solvents
like CH
while a mixture of PhMe/CH
2
Cl
2
(entries 8-9) benefited to the level of stereoinduction,
Cl was required for solubility issue
2
2
(
MCR) giving rise to versatile isoxazolidin-5-ones 3 thanks to the
(entries 10-11). Noteworthy, isoxazolidone 3a proved to be
somewhat unstable during the purification by silica-gel column
chromatography but also in the presence of the Brønsted base in
solution (vide infra). Then, some decomposition events occur
during longer or forcing reaction conditions leading to eratic
outcomes. However, the use of more diluted conditions and a
match influence of a suited organocatalyst, en route to the
elaboration of various original α/β-dipeptide derivatives.
Table 1. Proof of principle and optimization.[a]
slight excess of MA prevent the decomposition of product 3a
O)[
11],[16]
even at 30 °C, a
(
thanks to its high acidity, pK
a
= 4.8 in H
2
temperature allowing both a faster process and a decrease of the
amount of catalyst from 20 to 10 mol% while giving improved yield
of 75% and the same dr in 5 hours (entries 3 vs 11, Table 1). This
shows the key role of MA to secure soft reaction conditions.
Interestingly, it was observed a match/mismatch effect between
chiral Cinchona-derived organocatalysts and (S)-Boc-αAlaNHOH
1
a (Table 1, entries 3-4 and 6-7) which demonstrated that quinine
Entry
Deviation from the standard conditions
Yield [%]
dr[b]
versus quinidine derivatives were more competent to give (S,S)-
isoxazolidinone 3a with a good dr. Accordingly, it was proven that
1
2
3
4
Without catalyst
20 (55)[c]
57:43
71:29
86:14
74:26
quinidine derived (DHQD)
the (R)-Boc-αAlaNHOH enantiomer 1a’ into isoxazolidinone
R,R)-3a’ in 71% yield and 82:18 dr contrary to (DHQ) PHAL
2
PHAL catalyst was able to transform
Quinuclidine as catalyst
86
75
82
-
(
2
2
(DHQD) PHAL as catalyst
catalyst giving 3a’ only in 58% yield and 77:23 dr (Scheme 2).
Eventually, it was validated that this MCR took place with no
racemization and provided the major isoxazolidones 3a and 3a’
as a single enantiomer (>99:1 er, see SI).
5
6
7
8
9
(DHQ) Pyr as catalyst
2
62
82:18
81:19
48:52
73:27
86:14
-
Quinine (QN) as catalyst
73
Quinidine (QD) as catalyst
MeCN (0.1 M) as solvent, 20 °C[d]
66
44
CH
PhMe (0.1 M) as solvent, 20 °C[d]
PhMe/CH Cl
(3:1, 0.1 M) as solvent, 20 °C[d]
2
Cl
2
(0.1 M) as solvent, 20 °C[d]
30
1
0
1
traces
68
1
2
2
86:14
[
a] Reaction conditions: 1a (0.1 mmol), PhCHO 2a (1 equiv), MA (1.5 equiv) in Scheme 2. Molecular diversity towards a versatile synthesis of 3a’ - the other
2 2
PhMe/CH Cl
(3:1, 0.025 M) at 30 °C for 5 h. Yields of both diastereoisomers enantiomer of isoxazolidinone 3a. Yields of both diastereoisomers determined
determined by H NMR with an internal standard. [b] dr determined by H NMR by 1H NMR with an internal standard. [a] 47% isolated yield after column
1
1
on the crude product. [c] Bimolecular reaction from benzylidene Meldrum’s acid chromatography.
2
4a. [d] MA (1 equiv), (DHQ) PHAL (20 mol%).
At the onset, it was shown that the model MCR involving the
The scope and limitation of this novel MC-strategy was next
addressed (Table 2). Pleasingly, carrying out the reaction for 24
hours on a larger scale secured the complete transformation of
Boc-αAlaNHOH 1a into isoxazolidinone 3a in 88:12 dr (99% of
NMR yield for both diastereoisomers). Importantly, the two
diastereoisomers of isoxazolidinone 3a could be separated by
flash column chromatography, as a general behavior in this series,
N-Boc alanine hydroxamic acid 1a (Boc-αAlaNHOH), MA and
benzaldehyde 2a furnished after 5 hours the corresponding
1
isoxazolidinone 3a in 20% yield (determined by H NMR) as 57:43
mixture of diastereoisomers namely with virtually no
stereoinduction (entry 1, Table 1). By performing the di-
component reaction with benzylidene Meldrum’s acid 4a, the
putative intermediate involved into the formal domino aza-
Michael-cyclocondensation process (see Scheme 1), similar poor
dr was obtained with a better 55% yield (entry 1). The facility with
which this MCR takes place is worthy of note, likely thanks to the
high electrophilic reactivity of benzylidene MA,[15] but the ability of
leading to the major (S,S)-3a in 71% isolated yield (slight drop of
the theoretical yield of 88%).[17] Starting from isovaleraldehyde 2b,
a facile synthesis of the corresponding isoxazolidinone 3b, having
3
βhLeu backbone (homologated β -Leucine), occurred in excellent
dr > 95:5 and 96% yield for the pure major stereoisomer. As a rule
of thumb, in comparison to the use of aromatic aldehydes such as
a
catalyst to accelerate this process and promote
a
[
10]
stereoselective sequence remains an issue. To our delight the
use of 10 mol% of a Brønsted base like the achiral quinuclidine
allowed to improve significantly the yield to 86% and dr (71:29,
2a, the isoxazolidinones 3 derived from aliphatic aldehydes 2
turned out to be more stable which allows (1) an easy purification
by chromatography and (2) to carry out the reaction in higher
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Chemistry - A European Journal
10.1002/chem.202001214
COMMUNICATION
concentration.[18] The MCR was applied successfully to N-Cbz-
αAlaNHOH 1b (3c-3d, 64-85%, 83:17-89:11 dr)[19] and N-Fmoc-
αAlaNHOH 1c (3e, 86%, 93:7 dr) to provide the corresponding
even with 20 mol% of catalyst, due to the instability of these
aldehydes that results in an incomplete reaction. Although the
homologous tryptophane derivative 3t (βhTrp) could be
constructed with excellent > 95:5 dr, a low conversion was
observed leading to a moderate 19% isolated yield. Worthy of
note, several MCR could be carried out on 1 mmol scale to give
the isoxazolidinones 3b, 3d, 3e and 3r with rather similar yields
3c-3e with good to excellent stereoselectivities and yields. Then,
various βhLeu-derived isoxazolidinones were constructed from
isovaleraldehyde and Boc-protected proteinogenic αAA such as
αPhe (3f, 71%, 89:11 dr), αVal (3f, 93%, >95:5 dr) and αPro (3i,
6
3%, 75:25 dr) with yields ranging from 63% to 93%. It was also
and dr by means of only
organocatalyst.
2
5 mol% of (DHQ) PHAL as
shown that N-Boc glycine hydroxamic acid afforded the
corresponding isoxazolidinone 3h in excellent 93% yield but low
58:42 er. In line with previous observations, this highlights a
2
moderate capability of (DHQ) PHAL catalyst to promote an
enantioselective process from an achiral αAANHOH.[10a],[20]
Table 2. Scope and limitations.[a]
Scheme 3. Chemical transformations into α/β-dipeptides. Reaction conditions:
a] H , Pd/C (1 atm), i-PrOH, 30 °C for 6a-b;15 atm, RT for 6c, 1 atm, 50 °C for
f and TMSCHN , MeOH, RT. [b] H , Pd(OH) /C (20 atm), i-PrOH/EtOAc (2:1),
0 °C for 6g. [c] Zn (40-80 equiv), THF/H O/AcOH, 40 °C, and TMSCHN
NEt, DMAP (0.5 equiv), DMF, RT.
NEt, EDC•HCl, HOBt, CH Cl , RT. [f] PhSH,
, RT. [g] BnN , Na•Ascorbate, CuSO •5H O (20 mol%), t-
[
2
6
2
2
2
6
2
2
,
MeOH, RT. [d] From 3b, HCl•AlaOt-Bu, iPr
e] From 5b, HCl•AlaOt-Bu, i-Pr
DCC, HOBt, CH Cl
BuOH/H O, RT.
2
[
2
2
2
2
2
3
4
2
2
Having an array of novel isoxazolidinones 3 in hand,
decorated with various functionalities, the transformations of 3
into α/β-dipeptide derivatives was undertaken in order to probe
the versatility of these masked βAA platforms (Scheme 3). By
means of adapted palladium catalyzed N-O bond hydrogenolysis,
followed by esterification of the obtained acids 5, in order to
facilitate the purification step, several syn-α/β-dipeptides-OMe
6a-6c (86-93%),[ together with NHBoc 6f (Boc-αAla-Boc-βhLys,
80%) and SMe 6g (Boc-αAla-Boc-βhMet, 67%) derivatives were
[
a] Reaction conditions: 1 (0.3 mmol), RCHO 2 (1 equiv), MA (1.5 equiv) in
PhMe/CH Cl (3:1, 0.025 M) at 30 °C for 24 h. Isolated yields of the pure
major diastereoisomer after column chromatography. In parentheses, yields
of both diastereoisomers determined by H NMR with an internal standard.
dr determined by H NMR on the crude product. [b] 5 mol% of catalyst on 1
mmol scale gives 3b (89%, 94:6 dr), 3d (86%, 89:11), 3e (80%, 94:6 dr), 3r
(
determined for 3h.
2
2
1
19]
1
47%, 94:6 dr). [c] 20 mol% of catalyst. [d] Absolute configuration was not
easily synthesized. This straightforward strategy was also applied
to the formation of (R,R)-dipeptide 6a’ in 92% yield.[19] On the
other hand, by means of orthogonal Zn/AcOH deprotection
conditions, the elaboration of N-Cbz and N-Fmoc αAla-βhLeu
dipeptides 6d (48%) and 6e (74%) respectively was allowed.[
Product 6h, displaying a sensitive but useful terminal alkyne
moiety, was accessible in 50% yield under these reductive
conditions (Zn/AcOH) and successfully transformed into triazole
An array of both aromatic aldehydes (3j-3l, 51-68%, 88:12 to
2:8 dr), linear and cyclic aliphatic aldehydes (3m-3p, 69-91%,
9
8
10b]
5:15 to
> 95:5 dr) proved to be compatible with this
multicomponent KaMC process, encompassing the construction
of βhPhe 3n and βhLeu 3o precursors. Isoxazolidinones with
ether 3q (βhSer, 61%, 83:17 dr), thioether 3r (βhMet, 41%, >95:5
dr) and NHBoc 3s (βhLys, 44%, 89:11 dr) pendants could be
isolated in diastereomeric pure form albeit in slightly lower yields
10 in 82% yield, thanks to the copper-catalyzed 1,3-dipolar
cycloaddition protocol. The readily available Boc-αAla-βhLeu
carboxylic acid 5b (used as a crude product) was subjected to
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Chemistry - A European Journal
10.1002/chem.202001214
COMMUNICATION
peptide-coupling reagents to give rise to the formation of either
thioester 7 (94%), suited for further native ligation processes, or
α/β/α-tripeptide 8 in 91% yield. Interestingly, taking advantage of
the reactivity of the N-EWG isoxazolidinone framework,[12],[7b, 7c]
the direct ring opening event of 3b with tert-butyl-alanine
furnished the α/β/α-tripeptide 9, similar to 8 but with a N-OH
functionality known to be a valuable moiety to complex metal in
bio-environment.[21]
Fanter, C. Müller, D. Schepmann, F. Bracher, B. Wünsch, Bioorg. Med.
Chem. 2017, 25, 4778.
[
5] For review, see: a) J.-A. Ma, Angew. Chem. Int. Ed. 2003, 42, 4290; Angew.
Chem. 2003, 115, 4426; b) B. Weiner, W. Szymański, D. B. Janssen, A. J.
Minnaard, B. L. Feringa, Chem. Soc. Rev. 2010, 39, 1656; c) S. M. Kim, J.
W. Yang, Org. Biomol. Chem. 2013, 11, 4737.
[
[
6] For emerging coupling reagents for amide bond formation, see: a) R. M. de
Figueiredo, J.-S. Suppo, J.-M. Campagne, Chem. Rev. 2016, 116, 12029;
b) K. Hollanders, B. U. W. Maes, S. Ballet, Synthesis 2019, 51, 2261.
7] a) J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem. Int. Ed. 2006, 45,
In summary, we have developed a multicomponent synthesis
of novel isoxazolidin-5-ones possessing an N-α-amino acid.
Thanks to the high reactivity of transient alkylidene Meldrum’s
acids, a smooth and diastereoselective domino addition reaction
takes place upon the match influence of a commercially available
quinine derived organocatalyst allowing to achieve good to
excellent dr. The corresponding isoxazolidin-5-ones, easily
obtained as single diastereoisomer after purification, proved to be
versatile platforms for the diversity-oriented synthesis of an array
of α/β-dipeptides, as useful fragment in medicinal chemistry.
1
248; Angew. Chem. 2006, 118, 1270; b) M. E. Juarez-Garcia, S. Yu, J. W.
Bode, Tetrahedron 2010, 66, 4841; c) Y.-L. Huang, R. Frey, M. E. Juarez-
Garcia, J. W. Bode, Heterocycles 2012, 84, 1179; d) J. W. Bode, Acc.
Chem. Res. 2017, 50, 2104.
[
[
[
8] K. Michigami, H. Murakami, T. Nakamura, N. Hayama, Y. Takemoto, Org.
Biomol. Chem. 2019, 17, 2331.
9] J. Zhu, Q. Wang, M.-X. Wang, in Multicomponent Reactions in Organic
Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2014.
10] For early discovery of the MCR to form racemic isoxazolidin-5-ones from
achiral aldehydes and N-oxycarbonyl-hydroxylamines, see: a) C. Berini, M.
Sebban, H. Oulyadi, M. Sanselme, V. Levacher, J.-F. Brière, Org. Lett.
2015, 17, 5408−5411; b) A. Le Foll Devaux, E. Deau, E. Corrot, L. Bischoff,
V. Levacher, J.-F. Brière, Eur. J. Org. Chem. 2017, 3265.
11] For reviews on catalytic transformations of alkylidene Meldrum’s acids, see:
a) A. M. Dumas, E. Fillion, Acc. Chem. Res. 2010, 43, 440; b) E. Pair, T.
Cadart, V. Levacher, J.-F. Brière, ChemCatChem 2016, 8, 1882.
12] For a review on catalytic enantioselective synthese of isoxazolidin-5-ones,
see: J. Annibaletto, S. Oudeyer, V. Levacher, J.-F. Brière, Synthesis 2017,
49, 2117.
[
[
[
Acknowledgements
This work has been partially supported by INSA Rouen Normandy,
University of Rouen Normandy, the Centre National de la
Recherche Scientifique (CNRS), EFRD, and Labex SynOrg
13] For rare examples of catalytic enantioselective synthesis (dicomponant) of
(
ANR-11-LABX-0029), and by Region Normandie (CRUNCh

-substituted N-EWG isoxazolidin-5-ones, see: a) S. Postikova, T. Tite, V.
network). This research was also supported by the French
National Research Agency (ANR) as part of the ANR-16-CE07-
Levacher, J.-F. Brière, Adv. Synth. Catal. 2013, 355, 2513; b) S. Izumi, Y.
Kobayashi, Y. Takemoto, Org. Lett. 2016, 18, 696.
0
011-01 project OMaChem.
[
14] For dicomponant but two steps catalytic synthesis of -substituted N-EWG
isoxazolidin-5-ones, see: a) I. Ibrahem, R. Rios, J. Vesely, G.-L. Zhao, A.
Córdova, Chem. Commun. 2007, 849 (two steps); b) A. Pou, A. Moyano,
Eur. J. Org. Chem. 2013, 3103 (two steps); c) H.-T. Jiang, H.-L. Gao, C.-S.
Ge, Chinese Chem. Lett. 2017, 28, 471 (two steps); d) J. Lai, S. Sayalero,
A. Ferrali, L. Osorio-Planes, F. Bravo, C. Rodríguez-Escrich, M. A. Pericàs,
Keywords: amino acid • asymmetric synthesis • isoxazolidinone
Meldrum’s acid • organocatalysis
•
[
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chromatography. This shows the clear advantage of working with
isoxazolidinone 3a whose pure major (S,S)-diastereoisomer could be
isolated. This easy separation of the mixture of diastereoisomers of
isoxazolidinones 3 is a general rule in this series.
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[
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94:6 dr; 0.2 M, 99% NMR yield, 93:7 dr).
19] CCDC 1983122, 1983125, 1983123, 1983124 contains the supplementary
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diastereoisomer), 6a (the two diastereoisomers both originated from major
and minor stereoisomers 3a), 6a'.
[
[
20] For a rare example of enantioselective catalytic C-N bond formation to
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Chemistry - A European Journal
10.1002/chem.202001214
COMMUNICATION
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COMMUNICATION
Thomas Martzel, Julien Annibaletto,
Pierre Millet, Etienne Pair, Morgane
Sanselme, Sylvain Oudeyer, Vincent
Levacher and Jean-François Brière
Page No. – Page No.
Organocatalytic Multicomponent
Synthesis of α/β-Dipeptide
Derivatives
The diversity: A straightforward organocatalyzed multicomponent reaction (MCR)
involving readily available hydroxamic acids-derived from naturally occurring α-amino
acids (αAA) allows a stereoselective and diversity-oriented synthesis of novel
isoxazolidin-5-ones as versatile platforms for the elaboration of α/β-dipeptide
fragments.
This article is protected by copyright. All rights reserved.
[
a]
Dr. T. Martzel, J. Anniballeto, P. Millet, Dr. E. Pair, Dr. S. O