Multicomponent Catalytic Enantioselective Synthesis of Isoxazolidin-5-Ones

Article abstract of DOI:10.1002/adsc.202100719

We report herein a strategy to afford a multicomponent catalytic enantioselective synthesis of β-substituted isoxazolidin-5-ones via a KMC process promoted by a suited cupreine used as bifunctional organocatalyst. The hydroxamic acid component, with a ste

Full text of DOI:10.1002/adsc.202100719

UPDATES
doi.org/10.1002/adsc.202100719
Multicomponent Catalytic Enantioselective Synthesis of
Isoxazolidin-5-Ones
Julien Annibaletto,a Thomas Martzel,a Vincent Levacher,a Sylvain Oudeyer,a and
Jean-François Brièrea,*
a
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France
E-mail: jean-francois.briere@insa-rouen.fr
Manuscript received: June 9, 2021; Revised manuscript received: July 25, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100719
knowledge, this is the single catalyst-controlled asym-
Abstract: We report herein a strategy to afford a
multicomponent catalytic enantioselective synthesis
of β-substituted isoxazolidin-5-ones via a KMC
process promoted by a suited cupreine used as
metric CÀ N bond formation on such markedly electro-
philic and thereby challenging Michael acceptors.[9]
We recently disclosed an unprecedented multi-
component synthesis of β-substituted isoxazolidin-5-
bifunctional organocatalyst. The hydroxamic acid
one derivatives (Scheme 1B),[10] which are useful
component, with a sterically hindered amide moiety,
proved to be key for the successful formation and
precursors of valuable β3-amino acid derivatives
subsequent to the easy NÀ O bond cleavage.[11] How-
transformation of the obtained original N-amide
ever, the development of an enantioselective version of
isoxazolidin-5-ones.
this unique multicomponent Knoevenagel-aza-Mi-
chael-Cyclocondensation (KMC) reaction, via the N-
BocNHOH addition to alkylidene MA intermediates,
Keywords: Meldrum’s acid; Multicomponent reac-
proved to be very challenging thus far.[10a,12] Indeed,
tion; Organocatalysis; Cupreine; Isoxazolidinone
few groups succeeded in the direct catalytic enantiose-
The synthetic strategy of multicomponent reaction
(MCR) paves the way to versatile, straightforward and
atom-economic
construction
of
heterocyclic
architectures.[1] Nevertheless, the development of cata-
lytic enantioselective MCR, in order to tackle the
synthesis of valuable chiral heterocycles while afford-
ing the opportunity of exploring the 3D-chemical
space, remains a challenging endeavor in research.[2]
The design of a catalyst and a catalytic manifold
capable of orchestrating the selectivity issues within
the complex reaction pathways of MCR is not a trivial
task.[3] In that field, the Meldrum’s acid (MA) based
MCRs, in particular generating in situ the highly
electrophilic alkylidene MA species (AMA),[4] have
encountered a myriad of applications for heterocycles
elaboration (Scheme 1).[5] Nevertheless, the catalytic
enantioselective MC-transformations of alkylidene MA
have essentially focused on the formation of CÀ C bond
in processes such as Michael reactions and (2+n)
annulation (n=1, 3–4) sequences (Scheme 1A).[4,6,7]
Recently, we successfully devised an unprecedented
enantioselective catalytic aza-Michael reaction of pyr-
azolidinones to alkylidenes MA.[8] To the best of our
Scheme 1. Context of the investigation.
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lective construction of valuable β-substituted isoxazoli- embarked in the development of an enantioselective
din-5-ones having a versatile N-EWG pendant such as multicomponent KMC from N-amide hydroxylamine
a Boc group.[11,13,14,15] Very recently, the group of 1b (Scheme 2B).
Birman exploited the readily availability of racemic N-
At the onset, the regular Cinchona alkaloid derived
Boc isoxazolidin-5-ones by means of the multicompo- organocatalysts such as quinine derivatives 6a or 6b,
nent KMC reaction,[10a] to perform an elegant while together with Takemoto bifunctional cyclohexanedi-
efficient kinetic resolution of these products through amine 6c led to isoxazolidinone 5ba with enantio-
an alcoholysis sequence.[16] This work prompts us to meric excesses (ee) lower than 24% and good NMR
report our effort towards the development of an yields ranging from 76% to 96% (see SI for the overall
unprecedented catalytic enantioselective multicompo- screening conditions). In spite of the fully O-substi-
nent synthesis of isoxazolidin-5-ones (Scheme 1C). tuted quinine 6d furnished low 12%ee in moderate
This achievement sheds light on (1) the key reactivity 61% yield, the counterpart 6e, with the two free
modulation (through N-EWG) of hydroxamic acid hydroxyl functional groups gave improved 52%ee and
component (2) and the use of a suitable bifunctional excellent 99% yield.[17] The use of cupreine O-
chiral organocatalyst, in order to successfully secure protected at C9 (6f–g, R2=Bn, Bz and PYR) benefited
the asymmetric construction of original N-amide to the selectivity of the MCR, and the most sterically
isoxazolidin-5-ones.
hindered PYR-derivative 6h developed by Deng
Our working hypothesis was based on the initial provided product 5ba with good 75%ee.[18] Eventually,
observation that N-Boc hydroxylamine 1a leads to a the original and bulky benzhydryl-derived cupreine 6i,
rather facile domino addition-cyclocondensation se- that we have recently developed for an asymmetric
quence to alkylidene Meldrum’s acid 4a even in the decarboxylative protonation reaction,[19] turned out to
absence of a Brønsted base (Scheme 2A). This marked be the best organocatalyst giving rise to the formation
background process might compete with an asymmet- of 5ba with 81%ee and excellent 99% yield.
ric sequence. Interestingly, the analogous N-amide
Having this competent catalyst 6i in hands, we
hydroxylamine 1b did not show any uncatalyzed subsequently investigated the influence of the amide
reaction, although a smooth formation of isoxazolidi- moiety of a series of hydroxamic acids (Scheme 3). At
none 5ba occurred in 63% yield (2 hours) in the first, it was confirmed that N-Boc-NHOH 1a was not a
presence of 10 mol% of DABCO. Importantly, these suited nucleophile even in the presence of the most
types of N-amide isoxazolidinone 5ba are not well efficient cupreine catalyst 6i (5% ee). On the other
investigated in the literature and constitute a novel hand, the morpholine precursor 5c led to the corre-
platform in this series on their own. Then, we sponding isoxazolidinone 5ca with a decreased ee of
73% and aniline type hydroxylamine 5e gave a poor
selectivity (14%ee), which tends to demonstrate that a
pronounced electron-poor property of the amide
function does not benefit to ee. Then, we moved to the
bulkier bis-iso-propyl derivative 5d which advanta-
geously allowed an improved selectivity of 85%ee
while securing a good 94% yield. Eventually, the
reagents having a secondary amine moiety (1f–h) were
unable to be engaged into the MCR, showing the subtle
topology prerequisite for achieving the successful
Scheme 2. (A) Working hypothesis and (B) proof of principle.
Scheme 3. Evaluation of various hydroxamic acids.
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enantioselective catalytic multicomponent KMC reac- benzothiophene 5do derivatives were isolated in
tion. 76%ee (26% yield) and 81%ee (58% yield). Interest-
Next, we probed the scope and limitation of this ingly, the more sensitive aliphatic aldehydes 2p–2q,
unprecedented catalytic enantioselective multicompo- leading to rather unstable transient alkylidene MA,[4,20]
nent synthesis of β-substituted isoxazolidin-5-ones 5 still allowed the construction of the corresponding
with various aldehydes and hydroxamic acid 1d isoxazolidinones 5dp and 5dq in 84%ee (73% yield)
(Scheme 4). The model reaction with benzaldehyde and 77%ee (58% yield) respectively, thanks to the
allowed to obtain the corresponding product 5da with MCR procedure.
86–87%ee and isolated yields of 73%, which was
We propose a plausible mechanistic pathway
improved to 88% on 1 mmol scale. As a rule of thumb, as depicted in Scheme 5. At first, the organocatalyst 6i
a slight drop in isolated yields was observed due to the catalyzes Knoevenagel condensation between benzal-
likely somewhat hydrolytic sensitivity of these prod- dehyde 2a and Meldrum’s acid 3 to afford the
ucts during silica gel column chromatography. A large corresponding alkylidene MA 4a.[4] Next, the hydrox-
series of ortho- (5db: 2-Me, 66%, 86%ee), meta- ylamine addition would take place on the Re-face of
(5dc: 3-Me, 74%, 87%ee and 5de: 3-OMe, 62%, the alkylidene MA upon the guidance (through NÀ H
86%ee) and para-substituted (5dd, 5df and 5dg–5dj, activation or deprotonation events)[21] by the quinucli-
59–83%, 86–88%ee) isoxazolidinones 5db–5dj were dine part of cupreine 6i. Thereby, the Ph-moiety of the
easily synthesized from aromatic aldehyde derivatives aza-Michael acceptor is lying away from the catalyst
with homogenous ee of 86–88%, regardless to the (preventing a steric clash), while the phenol moiety of
nature of the R-group, and yields ranging from 59% to 6i would organized the transition state by H-bonding
89%. The product 5dk was obtained in 76% yield and with one of the carbonyl of 4a. In this scenario, we
good 89%ee from 2-naphthaldehyde 2k, and pyridine- suppose that cupreine 6i adopts a preferred anti-
2-carboxaldehyde 2l allowed the construction of the opened conformation as proposed by Cheng during
corresponding product 5dl in 58% yield (99% esti- insightful mechanistic investigations.[22] Then, a rapid
1
mated by H NMR with an internal standard) albeit in cyclocondensation sequence would occur to give the
drop of ee to 76%. Accordingly, a slightly less carboxylate 7da, in order to prevent any equilibrated
homogenous series stemmed from the use of more aza-Michael step leading to racemization. Finally, a
challenging heteroaromatic aldehydes as seen with decarboxylative-protonation sequence furnishes the
quinoline derived product 5dm which was obtained in corresponding S-isoxazolidinone 5da and releases the
82%ee (76% yield), while 5-pyrimidyl 5dn and catalyst.
The N-amide isoxazolidinones 5d are original
compounds on their own whose reactivity remains to
be explored.[23] Thus, we triggered the investigation of
their transformation into valuable β3-amino acid deriv-
atives (Scheme 6). We were especially interested in
recent investigations related to the enhanced reactivity
observed with sterically hindered tertiary-amides and
ureas.[24] At the onset, we carried out regular hydro-
genolysis conditions in the presence of palladium on
Scheme 4. Scope and limitations.
Scheme 5. Proposed catalytic cycle and transition state.
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°
was stirred at 20 C for 20 hours. The crude mixture was then
diluted with an aqueous Na2CO3 solution (10% w/w) and the
aqueous layer was extracted three times with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue
was quickly purified by flash column chromatography on silica
gel to afford isoxazolidin-5-one 5da (38 mg, 73%, 87%ee).
The reaction was carried out on 1.2 mmol to give 5da in 88%
yield (307 mg, 86%ee).
Scheme 6. Functional group transformation.
Acknowledgements
This work has been partially supported by University of Rouen
Normandy, INSA Rouen Normandy, the Centre National de la
Recherche Scientifique (CNRS), European Regional Develop-
ment Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029),
Carnot Institute I2 C, the graduate school for research XL-
Chem (ANR-18-EURE-0020 XL CHEM), and by Region
Normandie. This research was also supported by the French
National Research Agency (ANR) as part of the ANR-16-CE07-
0011-01 project OMaChem.
charcoal of 5da, followed by a TMSCH2N2 promoted
esterification. This sequence afforded a straightforward
elaboration of the phenyl β3-amino acid 8 as crude
product in 94% yield, pure enough for the subsequent
step. Then, after the exploration of reaction conditions,
it was found that substrate 8, under microwave
°
irradiation conditions at 130 C in the presence of an
alcohol (MeOH or BnOH), led to a smooth trans-
formation of the urea moiety into the corresponding
methylcarbamate 10a (73% yield and 84%ee) and the
versatile N-Cbz derivative 10b (85% yield and
83%ee) with almost no loss of ee. This sequence also
allowed us to confirm the absolute configuration of the
isoxazolidinone 5da by chemical analogy with known
compound from the literature (see SI).[25] Based on the
insightful investigations of Lloyd-Jones and Booker-
Milburn,[24b] we propose the formation of an isocyanate
intermediate 9 under neutral conditions, which would
be rapidly trapped by the external alcohol as nucleo-
phile to provide carbamate 10. Nevertheless, this
achievement constitutes a novel application of the
salient reactivity of bulky urea functional groups to the
chemistry of amino acids.
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Multicomponent Catalytic Enantioselective Synthesis of Iso-
xazolidin-5-Ones
Adv. Synth. Catal. 2021, 363, 1–6
J. Annibaletto, T. Martzel, V. Levacher, S. Oudeyer, J.-F.
Brière*