Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones

Article abstract of DOI:10.1021/acs.orglett.5b02755

An unprecedented multicomponent organocatalyzed Knoevenagel-aza-Michael-cyclocondensation reaction between Meldrum's acid, hydroxylamines, and aldehydes afforded a straightforward entry to a large array of racemic and syn-diastereoenriched isoxazolidinone

Full text of DOI:10.1021/acs.orglett.5b02755

Letter
pubs.acs.org/OrgLett
Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones
Christophe Berini,† Muriel Sebban,†,§ Hassan Oulyadi,†,§ Morgane Sanselme,‡ Vincent Levacher,†
and Jean-Franco̧
is Briere*,†
̀
†Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnier
̀
e, 76821 Mont Saint
Aignan Cedex, France
‡Normandie Univ, Laboratoire SMS- EA3233, Univ Rouen, F-76821, Mont Saint Aignan, France
S
* Supporting Information
ABSTRACT: An unprecedented multicomponent organocata-
lyzed Knoevenagel−aza-Michael−cyclocondensation reaction
between Meldrum’s acid, hydroxylamines, and aldehydes
afforded a straightforward entry to a large array of racemic and
syn-diastereoenriched isoxazolidinones as synthetically useful
scaffolds. This process revealed a markedly facile aza-Michael−
cyclocondensation sequence as a key domino reaction between
RCO2NHOH and transient alkylidene Meldrum’s acid upon Brønsted base catalysis.
he construction of chiral heterocyclic architectures making
use of organocatalytic multicomponent reactions (MCRs)
Nevertheless, the direct catalytic construction of isoxazolidinone
derivatives 1 using a MCR process remains elusive. Relevant to
this context, the multicomponent synthesis of isoxazolidine
compounds developed by Bode allowed,7 in few subsequent
steps, the formation of enantiopure N-Boc isoxazolidin-5-one
derivatives 1.
T
not only shortened the synthetic efforts toward chemical
diversity but paved the way for sustainable chemistry.1
Nonetheless, the achievement of these modern domino
processes ought to challenge (1) an orchestration of orthogonal
organocatalytic modes of activation, (2) functional-group
compatibility, and (3) a successful stereoselective outcome.2
Isoxazolidin-5-ones 1 (Scheme 1, X = O) are valuable motifs
We recently discovered an enantioselective formation of
bicyclic pyrazolidinone derivatives 2 (X = NR3) based on a
multicomponent Knoevenagel−aza-Michael−cyclocondensa-
tion (KaMC) reaction making use of the reactivity of Meldrum’s
acid 3 (Scheme 1).8 This process highlighted an unprecedented
asymmetric and chemoselective aza-Michael reaction to NHR1 of
pyrazolidinones 6 (R1 = EWG) to highly reactive transient
alkylidene Meldrum’s acids 7,9,10 unusually catalyzed at room
temperature by a dedicated tertiary Brønsted base, namely
(DHQ)2PHAL.8 This MCR complements racemic domino
hetero-Michael−cyclocondensation reactions involving alkyli-
dene Meldrum’s acid 7, which usually leads to six-membered
rings and, in many cases, requires harsh conditions.11−13
Nonetheless, we were not able to extrapolate this sequence to
noncyclic hydrazine showing a specific reactivity in action. We
are pleased to report herein a novel development of the
organocatalytic multicomponent KaMC reaction between
hydroxylamines 5 and Meldrum’s acid 3, achieving a
straightforward construction of isoxazolidin-5-one derivatives
1. Furthermore, this MCR process is performed under mild
conditions and tolerates various chiral aldehydes 4, allowing a
new entry to diastereo- and enantioenriched scaffolds 1 as useful
building blocks.
Scheme 1. Context of the Methodology
encountered in bioactive compounds,3 and they have emerged as
useful building blocks for the elaboration of β-amino acids,3c,f
nucleoside mimics,3e and amino sugar derivatives,3a to name a
few.3b The construction of chiral scaffolds 1 elicited recent
developments of catalytic syntheses both racemic4 and
asymmetric.4d−f,5,6 In particular, Sibi achieved the enantiose-
lective 1,4-addition of BnNHOH to activated acrylamides upon
A model reaction was carried out with a stoichiometric mixture
of Meldrum’s acid 3, dihydrocinnamaldehyde 4a, and N-
the catalytic influence of magnesium complexes.5 Cor
́
dova
benzylhydroxylamine 5a in the presence of Hunig base (20
̈
performed a chiral iminium promoted conjugated addition of
BocNHOH to enals giving 5-hydroxyisoxazolidines, some of
them being subsequently oxidized into isoxazolidin-5-ones 1.6
Received: September 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02755
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Organic Letters
Letter
mol %) in toluene (Table 1, entries 1 and 2). A sluggish process
was observed, and the corresponding N-Bn isoxazolidinone
Scheme 2. Scope and Limitation
a
Table 1. Proof and Optimization
b
entry
R1
R3N
temp (°C) time (h)
yield (%)
c
1
2
Bn (5a)
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
20
40
20
20
20
20
20
20
20
20
14
14
1
11 (1aa)
Bn (5a)
50 (1aa)
75 (1ab)
0 (1ab)
3
Boc (5b)
Boc (5b)
Boc (5b)
Boc (5b)
Boc (5b)
Boc (5b)
Boc (5b)
Boc (5b)
4
1
5
DMAP
1
61 (1ab)
82 (1ab)
79 (1ab)
82 (1ab)
28 (1ab)
96 (1ab)
6
DBU
1
7
piperidine
pyrrolidine
proline
1
8
1
9
1
10
DABCO
1
a
Reaction performed at 0.1 M on 0.25 mmol scale with 1 equiv of each
b
components. NMR yield determined by an internal standard.
c
Formation of 3% of nitrone 8a.
product 1aa was obtained up to 50% NMR yield even at 40 °C
(entries 1 and 2). In line with our previous observations, the
presence of nitrone 8a at rt showed that a slow and concurrent (3
+ 2)-cycloaddition between 8a and Meldrum’s acid 3 might
occur (entry 1).4d We turned our attention to the electron-poor
N-Boc hydroxylamine 5b in order to prevent the in situ
formation of dipole species.14 Furthermore, this approach is
meant to furnish directly N-carbamate isoxazolidin-5-ones 1ab,
useful precursors for β-peptides elaboration or total synthesi-
s.6a,7,3b To our delight, the rapid formation of the N-Boc
isoxazolidinone 1ab took place at 20 °C in 75% NMR yield upon
donating methoxy functional groups was reluctant to react under
these conditions (13% after 2 h at rt). However, heating at 40 °C
during 14 h restored the efficiency of the MCR process to give
products 1qb−rb with electron-rich aryl moieties in 86 and 59%
yield, respectively. In these conditions, isoxazolidinones flanked
by a heterocyclic ring such as 3-pyridyl 1sb and N-Boc-indole 1tb
were easily obtained with 81% yield. We found that
cinnamaldehyde 4u underwent a slow transformation into the
novel allylic isoxazolidinone 1ub (42% yield). Nevertheless,
improved 76% isolated yield was obtained by starting from the
Meldrum’s acid (MA) aza-Michael acceptor 7u.9
Despite previous occurrences of diastereoselective Michael
reaction onto γ-chiral alkylidene Meldrum’s,15 even upon
organocatalytic MCR conditions,16 the stereoselective N−C
bond formation has yet to be developed.17 To our delight, the
stereoselective multicomponent KaMC reaction took place
smoothly upon DABCO catalysis. Glyceraldehyde 4v and Ley’s
aldehyde 4w18 led to γ-chiral N-Boc and NCbz isoxazolidinones
1vb−wc with high dr >96:4 as testified by 1H NMR of the crude
mixture (Scheme 3). An erosion of the enantiopurity of products
1vb−vc was observed (88−91% ee) due to the configurational
fragility of glyceraldehyde 4v. However, the use of pyrrolidine
instead of DABCO minimized the racemization, likely via an
iminium-catalyzed Knoevenagel condensation,15b,16b,19 and
furnished products 1vb and 1vc with ee of 99% and 96%,
respectively, and a slight erosion of dr (80/20 and 90/10). The
major syn-isomers 1vb−wc were easily obtained with 65−88%
isolated yields and at least 98/2 dr after flash column
chromatography. Importantly, the use of electron-rich
BnNHOH 5a led to low dr and sluggish reaction rates and
demonstrated the uniqueness of our conditions (see the SI for
more details).17 Along this line, 10 mol % of pyrrolidine allowed
the transformation of Garner’s aldehyde 4x (85% and 59% for
1xb−xc), 2-pyrrolidine carboxaldehyde 4y (72% and 70% for
1yb−yc), and thiazolidine carboxaldehyde 4z (78% and 73% for
1zb−zc) into the corresponding syn-isoxazolidinones (dr >95/
5−98/2 after purification) with ee’s ranging from 95 to 99%.
Hunig base catalysis (entries 3 and 4). This MCR process was
̈
promoted by various tertiary (entries 5 and 6) and secondary
amines (entries 7 and 8) to give 1ab with yields ranging from 28
to 82%. Among them, DABCO achieved the highest 96% yield
within only 1 h (entry 9; see the SI for further details). This
unprecedented multicomponent construction of isoxazolidi-
nones 1 not only opens a straightforward access to these useful
architectures but also highlights an extremely facile domino
KaMC process involving the unique Meldrum’s acid reactivity.9
A survey of conditions revealed the acceleration of the
multicomponent KaMC reaction in more polar and greener
AcOEt solvent (see the SI), which allowed us to probe a large
array of aldehydes 4 in the presence of 10 mol % of DABCO
catalyst (Scheme 2). After 2 h at room temperature, the MCR
occurred with linear 4a−c, α-branched 4d−f, and an alkene-
derived aliphatic aldehyde 4g to give the corresponding N-Boc-
isoxazolidinones 1ab−gb with isolated yields ranging from 63 to
84%. This reaction also tolerated aliphatic aldehydes flanked by
NHBoc (4h), ether (4i), thioether (4j), and ester (4k) functional
groups furnishing products 1hb−kb with 55−82% yields. This
approach was also carried out from CbzNHOH 5c to afford N-
Cbz isoxazolidinones 1ac and 1hc in 68−70% yields displaying
orthogonal protective groups. Moreover, aromatic- and
benzothiophenone-derived aldehydes 4l−p were easily trans-
formed into N-Boc-5-arylisoxazolidinones 1lb−pb in 65−73%
yield. Aldehyde 4q having an aryl pendant with two electron-
B
DOI: 10.1021/acs.orglett.5b02755
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Organic Letters
Letter
Scheme 3. Diastereoselective Approach
Scheme 4. Useful Chemical Transformations
these sequences, the initial diastereoselective ratio were virtually
preserved.
Since the early observations,22 recent mechanistic inves-
tigations17 have explained the facility with which electron-rich N-
alkyl hydroxylamines add to acrylates due to a noncatalyzed
concerted (3 + 2) cycloaddition-like process. Furthermore, the
high electrophilic character of alkylidene Meldrum’s acid
derivatives 7 (>1011 than the corresponding benzylidene
malonate)9 has been highlighted during model aza-Michael
reactions, which were assumed to be accelerated by an
intramolecular hydrogen bond between the R2N−H nucleophile
and the forming enolate moiety in the transition state (TS).23
Based on this background knowledge, we propose that the N−C
bond formation to alkylidene Meldrum’s acid 7 occurs with the
concomitant hydrogen transfer from OH of 5 to give 13
following a (3 + 2) cycloaddition process (TS 12, Scheme 5).24
a
Yields of the major syn-diastereomer (>98/2 dr except for 1xb, 1zb,
b
and 1zc > 95/5 dr) isolated after flash column chromatography. dr
(in parentheses) determined by 1H NMR on the crude product.
c
d
Determined by single-crystal X-ray diffraction. At 0 °C.
Scheme 5. Mechanistic Proposal
The labile Garner’s aldehyde 4x provided the corresponding
N-Boc products 1xb with somewhat lower 90% ee. Most notably,
the determination of dr ratios of compounds 1xb−zc was not
trivial as these carbamate derivatives displayed rather stable
rotamers. Nonetheless, a complete characterization by NMR,
including variable-temperature NMR and chemical-exchange
NMR experiments (EXSY), allowed the discrimination of
rotamer/diastereoisomer NMR signals (see the SI). Accordingly,
an estimation of the stereoselectivity on the crude mixtures
revealed dr ranging from 77/23 to 88/12 for 1xb−zc in favor of
the syn stereoisomer in all cases. The remarkable general syn
induction was unequivocally proven by a series of six single-
crystal X-ray diffractions (Scheme 3) and chemical trans-
formations (vide infra).
Chiral N-Bn isoxazolidinone derivatives flanked by a δ-C*−X
bond (X = O, N) are known to be high value building blocks for
the elaboration of bioactive compounds.3c,e,20 In order to
highlight the usefulness of our readily available and orthogonal
N-carbamate homologues, it was shown that N-Cbz isoxazolidi-
nones 1vc,xc,yc underwent clean hydrogenolysis reactions to
give various β-amino acids 9a−c (Scheme 4). The cyclization of
9c upon acidic conditions allowed a concise access to
aminopyrrolizidine 10 and complemented literature proce-
dures.21 Eventually, inspired by Merino’s work,20b we showed
that β-amino acid 9b is a useful precursor to functionalized
lactone 11 obtained in 38% yield over two steps but along a one-
pot sequence providing a single anti-diastereoisomer. During
The Brønsted base catalyst may promote the addition reaction of
the N-EWG hydroxylamine 5 leading to the rapid transformation
of the transient Knoevenagel product 7.19 It is also assumed that
the N-EWG facilitates the base catalyzed decarboxylation event
of 14 by stabilizing the corresponding enolate of isoxazolidinones
1 and the TS derived thereof.4e
As a preliminary proposal, the general syn-selectivity could be
rationalized in line with Yamamoto’s model (TS 12),15b,16b,25 in
which the allylic 1,3-strain is minimized when C-H and
Meldrum’s acid moiety faced to each other. Then, the incoming
nucleophile would approach from the same face of the “outside”
positioned γ-heteroatom (Y) of the more reactive conformation.
In summary, we discovered an extremely facile organo-
catalyzed multicomponent KaMC reaction between aldehydes,
Meldrum’s acid 3, and N-carbamate-NHOH 5. This MCR allows
not only a straightforward elaboration of a large array of racemic
C
DOI: 10.1021/acs.orglett.5b02755
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Organic Letters
Letter
(6) (a) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Cor
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́
dova, A. Chem.
isoxazoldin-5-ones 1 but affords a new entry to diastereo- and
enantioenriched scaffolds 1 as useful building blocks in organic
synthesis. The development of an enantioselective MCR is
currently under investigation.26
ASSOCIATED CONTENT
■
(8) Pair, E.; Berini, C.; Noel, R.; Sanselme, M.; Levacher, V.; Brier
̀
e, J.-
̈
S
* Supporting Information
F. Chem. Commun. 2014, 50, 10218.
(9) For an insightful review on Meldrum’s acid and the corresponding
alkylidenes, see: Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43, 440.
(10) For a previous organocatalyzed domino Michael−cycloconden-
sation reaction but through C−C bond formation, see: (a) Wang, J.-Y.;
Zhang, H.; Liao, Y.-H.; Yuan, W.-C.; Feng, Y.-J.; Zhang, X.-M. Synlett
2012, 23, 796. (b) Caruana, L.; Mondatori, M.; Corti, V.; Morales, S.;
Mazzanti, A.; Fochi, M.; Bernardi, L. Chem. - Eur. J. 2015, 21, 6037.
(11) Reviews on Meldrum’s acid in MCRs: (a) Gerencser, J.; Dorman,
́ ́
G.; Darvas, F. QSAR Comb. Sci. 2006, 25, 439. (b) Lipson, V.; Gorobets,
N. Y. Mol. Diversity 2009, 13, 399.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02755.
Experimental procedures and characterization for new
compounds (PDF)
X-ray data for 1vb (CIF)
X-ray data for 1wb (CIF)
X-ray data for 1yb (CIF)
X-ray data for yc (CIF)
X-ray data for 1zb (CIF)
X-ray data for zc (CIF)
(12) Pair, E.; Levacher, V.; Brier
references cited therein.
̀
e, J.-F. RSC Adv. 2015, 5, 46267 and
(13) For a MCR involving an hydrazine derivative and Meldrum’s acid
but requiring hash conditions, see: Saluja, P.; Khurana, J. M.; Sharma, C.;
Aneja, K. R. Aust. J. Chem. 2014, 67, 867.
AUTHOR INFORMATION
Corresponding Author
■
(14) The formation of N-Boc nitrones requires the preformation of α-
*E-mail: jean-francois.briere@insa-rouen.fr.
Author Contributions
§M.S. and H.O. are affiliated with the NMR department of the
laboratory COBRA.
sulfone amide derivatives: Guinchard, X.; Vallee
Lett. 2005, 7, 5147.
(15) (a) Larcheveq
Commun. 1989, 31. (b) Fujimori, S.; Carreira, E. M. Angew. Chem., Int.
Ed. 2007, 46, 4964. (c) Dumas, A. M.; Fillion, E. Org. Lett. 2009, 11,
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́
, Y.; Denis, J.-N. Org.
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ue, M.; Tamagnan, G.; Petit, Y. J. Chem. Soc., Chem.
Notes
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The authors declare no competing financial interest.
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Chem., Int. Ed. 2003, 42, 4233. (b) Dardennes, E.; Gerard, S.;
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ACKNOWLEDGMENTS
■
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-
0029), and region Haute-Normandie (CRUNCh network).
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