Organocatalysed synthesis of isoxazolines initiated by a chemoselective oxa-Michael reaction of N-BocNHOH

Article abstract of DOI:10.1039/c3ob42406e

An organocatalysed and chemoselective one-pot oxa-Michael-cyclocondensation reaction of N-BocNHOH to unsaturated α-ketoesters is reported which affords an original entry to enantioenriched 3-isoxazoline carboxylate derivatives as biorelevant heterocyclic

Full text of DOI:10.1039/c3ob42406e

Organic &
Biomolecular Chemistry
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Organocatalysed synthesis of isoxazolines initiated
by a chemoselective oxa-Michael reaction of
N-BocNHOH†
Cite this: Org. Biomol. Chem., 2014,
12, 1245
R. Noël, V. Gembus, V. Levacher and J.-F. Brière*
Received 2nd December 2013,
Accepted 2nd January 2014
An organocatalysed and chemoselective one-pot oxa-Michael-cyclocondensation reaction of
N-BocNHOH to unsaturated α-ketoesters is reported which affords an original entry to enantioenriched
3-isoxazoline carboxylate derivatives as biorelevant heterocyclic frameworks.
DOI: 10.1039/c3ob42406e
www.rsc.org/obc
Introduction
The organocatalysed hetero-Michael reaction emerged as a
powerful synthetic methodology to create enantioselectively
C–N or C–O bonds.1,2 By means of bisnucleophiles such as
hydroxylamines, a subsequent cyclisation step is allowed to
construct, in a straightforward fashion, non-racemic isoxazolidine
derivatives,3 important heterocyclic frameworks frequently
found in biologically active compounds (Fig. 1).4,5
In this context, few research groups have achieved an asym-
metric organocatalysed domino hetero-Michael-cyclisation
reaction towards the elaboration of isoxazolidine derivatives by
addressing the NH versus OH chemoselectivity of hydroxyl-
amine bisnucleophiles (Scheme 1).6 Shibata and colleagues
reported that native hydroxylamine led to a domino oxa-
Michael-cyclocondensation reaction onto activated fluorinated-
enones upon the asymmetric phase transfer catalytic regime
with strong bases (Scheme 1a).7 Pihko and collaborators ele-
gantly used oximes as transient-nitrogen protected NH2OH
nucleophiles to form 3-unsubstituted 2-isoxazolines via an
iminium catalysed oxa-Michael reaction followed by an acid
promoted trans-imination cyclisation (Scheme 1a).8 On the
other hand, the group of Córdova performed an efficient
iminium catalysed domino aza-Michael-hemiacetal formation
reaction starting from commercially available N-BocNHOH 1a
(Scheme 1b).9
Fig. 1 Bioactive 3-isoxazolecarboxylate derivatives.
Alternatively, we would like to report here on an original
domino oxa-Michael-hemiaminal formation reaction of
N-BocNHOH 1a making use of unsaturated α-ketoesters 2,
Scheme 1 Domino aza- versus oxa-Michael-cyclisation reaction.
Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS,
IRCOF, 1 rue Tesnière, 76821 Mont Saint Aignan Cedex, France.
E-mail: jean-francois.briere@insa-rouen.fr; Fax: +33 235522464;
namely the 4-substituted 2-oxo-3-butenoates, upon Brønsted
base catalysis (Scheme 1c).10 This sequence not only reveals an
uncommon O-chemoselectivity during the conjugated addition
reaction of N-BocNHOH 1a bisnucleophile, giving rise to
Tel: +33 235522962
†Electronic supplementary information (ESI) available: Further experimental
optimisations, procedures and compound characterisation data. See DOI:
10.1039/c3ob42406e
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Table 1 Towards an enantioselective approacha
intermediate 3, but eventually leads to a concise elaboration of
biologically important isoxazolines 4 flanked by a carboxylate
functional group at C3 after a simple acid promoted Boc
removal (Scheme 1c versus Fig. 1).11 Despite some seminal
experimental observations concerning the oxa-Michael
outcome of hydroxyurea NH2CONHOH with enals by Petrus
and co-workers,12 the asymmetric developments remain to be
achieved. Towards this goal, we are pleased to describe the pre-
liminary results towards an original asymmetric organo-
catalytic synthesis of 3-isoxazoline carboxylate derivatives.
It is important to note that some of these chiral structures 4
were previously only directly accessible in a non-racemic
form through enzymatic resolution or diastereoselective
reaction.13–15
Entry Cat.
R1
R3
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
0
CO2tBu (1a) CO2Et (2a)
0 (4a)
—
—
—
5
—
1
0
34 (S)
55 (S)
(60)e 73f
35(S)
58(S)
—
Results and discussion
Quinuclidine CO2tBu (1a) CO2Et (2a) 63 (4a)
TFAd
5
6
7
8
CO2tBu (1a) CO2Et (2a)
0 (4a)
At the onset of this project, it was shown that an a priori chemo-
selective oxa-Michael reaction of N-BocNHOH 1a smoothly
took place with unsaturated keto-ester 2a in the presence of
quinuclidine after 24 hours in toluene (Table 1, entry 2).
Indeed, the starting materials 1a and 2a were recovered
without Brønsted base (entry 1). The analyses of the crude
reaction products mainly revealed two compounds which were
CO2tBu (1a) CO2Et (2a) 86 (4a)
CO2tBu (1a) CO2Et (2a) 61 (4a)
CO2tBu (1a) CO2Et (2a) 90 (4a)
CO2tBu (1a) CO2Et (2a) 98 (4a)
CO2tBu (1a) CO2Et (2a) 82 (4a)
CO2tBu (1a) CO2Et (2a) 82 (4a)
CO2tBu (1a) CO2Et (2a) 87 (4a)
CO2Bn (1b) CO2Et (2a) 10 (4a)g
CONH2 (1c) CO2Et (2a) 16 (4a)h
9
9
10
10
10
10
10
10
11
12
assumed to be a mixture of cyclized hemi-aminal epimers 3a 13
(Scheme 1c, R = (CH2)2Ph) due to the absence of a ketone func-
tional group by 13C NMR (see ESI†). Next, the one-pot addition
of trifluoroacetic acid (TFA) in excess easily provided the
corresponding isoxazoline 4a through a formal sequence involv-
ing both dehydration and Boc-removal events with an overall
63% yield. It is worthy of note that no isoxazoline 4a formation
was noticed in the presence of TFA alone (entry 3). This rules
out an acid catalyzed formation of isoxazolidine 3a from 2a
(Scheme 1c). With this original one-pot sequential oxa-
CO2tBu (1a) H (2b)
0 (4b)
a N-protected hydroxylamines 1 (0.11 mmol, 1.1 equiv.) as a solid were
added in one-portion into a solution of unsaturated ketoesters 2a–b
(0.10 mmol, 1 equiv.), catalyst (0.01 mmol, 0.1 equiv.) in toluene (0.05
M); then TFA (1.0 mmol, 10 equiv.). b Isolated yield after column
chromatography. c Determined by chiral HPLC. d In the presence 0.1 or
30 equivalents of TFA. e The N-Boc hydroxylamine 1a was added into a
solution in one-portion. f The N-Boc hydroxylamine 1a was added
dropwise into a solution over 4 hours. g TFA was replaced by TMSI.
h TFA was replaced by HCl in MeOH.
Michael-cyclocondensation reaction in hand, we sought an hydroxylamine derivatives 1b and 1c were related to the deli-
asymmetric version but a screening of a large array of chiral cate acid-promoted isoxazoline 4a formation requiring
Brønsted bases was required (see ESI† for an overview of adapted reaction conditions which eventually led to modest
screened conditions). Neither quinine derivatives 5, 6 (C9–OH isolated yields lower than 16% (entries 11 and 12). Impor-
or C9–OBz) nor the 9-epi-amino homologues 7, 8 (C9–NH2 or tantly, it was shown that no reaction occurred with enal 2b in
C9–NHAc) were able to achieve a significant enantioselective the presence of organocatalyst 10. Accordingly, the required
transformation, although these organocatalysts furnished 4a ester moiety on the 2-oxo-3-butenoate 4a structure is probably
in good yields (Table 1; entries 4–7). To our delight, the bifunc- an activated EWG for both unsaturated enone towards the oxa-
tional 9-epi-aminoquinines 9–10 led to improved enantio- Michael process with catalyst 10 and the ketone functional
selective excesses ranging from 34% ee with C9-thiourea group during the hemi-aminal 3 formation.10 In all likelihood
derived catalysts 9 to 55% ee with the C9-squaramide one a kinetically driven O-alkylation is occurring, evidently of the
QN-SQ 10 with good (82%) overall yields (entries 8 and 9).16 less sterically hindered moiety of N-BocNHOH 1a,17,18 and this
Interestingly, increased enantiomeric excesses were measured C–O bond formation is secured by the subsequent cyclization
by adding N-BocNHOH 1a dropwise in solution to give up to to stable intermediate 3 (Scheme 1b versus 1c).9a
73% ee (entry 10). The origin of this phenomenon has not
Next, we investigated the reaction conditions through the
been fully understood so far, but constitutes a reproducible direct addition of N-BocNHOH 1a in solution for practical
procedure in any subsequent reactions. The N-CbzNHOH 1b reasons (Table 2). It was found that quinidine derived squara-
and NH2CONHOH 1c nucleophiles were also evaluated in the mide organocatalyst 11 (QD-SQ) (entry 1) could be employed
presence of squaramide catalyst 10 but lower selectivities of instead of quinine QN-SQ with a slightly better ee but a reverse
35% and 58% ee respectively were measured (entries 11 and 12). enantioselectivity (see Table 1, entry 10). The use of various
But the most tedious issues with these N-functionalized aromatic solvents (entries 2 and 3, Table 2) did not improve
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Table 2 Screening of conditionsa
provided more general conditions for the formation of isoxazoli-
dines with various enones 2. First of all, with this optimized
protocol, it was found that quinine 10 or quinidine squaramide
pseudo-enantiomer catalysts 11 could be used with a similar
efficiency in order to furnish both S- or R-enantiomer of isox-
azoline 4a with 74–76% ee (entries 1 and 2).19 Both methyl and
ethyl ester isoxazolines 4a and 4c were synthesized with rather
similar enantiomeric excesses (entries 1 versus 3). Although
4-iso-butyl 2-oxo-3-butenoate 2d led to respectable 68% ee, the
α-branched cyclohexyl pendant 2e underwent a smooth trans-
formation into 4e in 73% yield albeit with lower 31% ee
(entries 4 and 5). However, a longer n-heptyl alkyl chain was
well tolerated giving rise to 77% ee (entry 6). Moreover, enones
2g–i with an alkyl chain flanked by ethers or alkene functional
groups furnished the corresponding isoxazolines 4g–i with
good yields and ee ranging from 67% to 78%. Although 4-alkyl
substituted 2-oxo-3-butenoates 2a–i allowed the formation of
the corresponding isoxazolines 4a–i with high yield and mod-
erate to good enantiomeric excesses (entries 1–9), 4-aryl substi-
tuted derivatives 2j–k revealed a slow oxa-Michael reaction rate
with low enantiomeric excess (entries 10 and 11). This
outcome has not been fully studied at the moment, but the
more stable 4-aryl substituted enones 4j–k might undergo an
oxa-Michael addition under thermodynamic equilibrated con-
ditions together with featuring a steric issue as seen with the
lower enantiomeric excess obtained with the 4-cyclohexyl
derivative 4e.
Most of the 5-alkyl substituted 3-isoxazoline carboxylate
derivatives being novel products, we sought to both determine
their absolute configurations and probe useful chemical trans-
formations (Scheme 2). Inspired by a previous study of
Nishiyama and Pihko, we attempted the fragmentation of the
oxazole ring.20 To our delight, after a facile saponification reac-
tion into carboxylic acid 12, a straightforward decarboxylative-
fragmentation took place on the crude product 12 at 80 °C to
form the β-hydroxy acetonitrile 13 with excellent 78% yield
over the two steps. This S-featuring known alcohol 6 was
obtained without racemization providing accordingly the
absolute configuration of precursor 4a.20b
Entry Solvent
Concentration Temp. (°C) Yieldb (%) eec (%)
1
2
Toluene
m-Xylene 0.05 M
0.05 M
20
20
20
20
20
20
20
20
0
87
62
82
88
77
86
82
79
93
86
82
69
66
63
45
45
55
55
61
69
59
70
3
4
5
6
7
8
9
10
11
PhCF3
MeCy
CH2Cl2
THF
MeCN
EtOH
Toluene
Toluene
Toluene
0.05 M
0.05 M
0.05 M
0.05 M
0.05 M
0.05 M
0.05 M
0.1 M
20
20
0.025 M
a Unsaturated ketoesters 2a (0.10 mmol,
1
equiv.), N-Boc
hydroxylamines 1a (0.11 mmol, 1.1 equiv.) were added in one-portion
into a solution, catalysts 10 or 11 (0.01 mmol, 0.1 equiv.), toluene
(0.05 M); and then TFA (1.0 mmol, 10 equiv.). b Isolated yield after
column chromatography. c Determined by chiral HPLC.
the induction but less polar methylcyclohexane was detrimen-
tal and led to poor solubility issues (entry 4). On the other
hand, moving from dichloromethane to more polar solvents
decreased markedly the enantioselectivities (entries 5–8). The
asymmetric outcome was insensitive to the decrease of temp-
erature (entry 9) but the concentration has to be maintained at
0.05 M; otherwise lower enantiomeric excess was observed
(entries 10–12).
Then, we evaluated this one-pot oxa-Michael-cyclocondensa-
tion sequence on various unsaturated α-ketoester derivatives 2
(Table 3). At that stage, it was found that 30 equivalents of TFA
Table 3 Scope of the reactiona
With this structure in hand, a plausible transition state is
depicted in Fig. 2, stemming from previous proposals of
Jørgensen and co-workers.16,21 The α-ketoester would be recog-
nized and activated through a double hydrogen bonding
network of the squaramide moiety while the R1-pendant is
pointing away from the bulky quinuclidine part. Then, the Si
face approach of the incoming oxygen-nucleophile is assisted
by the top-face position of the tertiary amine.
Entry R1
R2
Catalysta
Prod. Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Ph(CH2)2
Et (2a) QN-SQ (10) 4a
Et (2a) QD-SQ (11) 4a
Me (2c) QN-SQ (10) 4c
Et (2d) QN-SQ (10) 4d
Et (2e) QN-SQ (10) 4e
Et (2f) QN-SQ (10) 4f
Et (2 g) QN-SQ (10) 4g
Et (2 h) QN-SQ (10) 4h
87
82
87
82
73
86
80
68
79
21d
42d
74 (S)
76 (R)
72 (S)
68
31
77
67
72
78
5
Ph(CH2)2
Ph(CH2)2
iso-Butyl
Cyclohexyl
n-Heptyl
EtO(CH2)2
BnOCH2
9
10
11
H2CCH(CH2)2 Et (2i) QN-SQ (10) 4i
Ph
3,4-DiClPh
Me (2j) QN-SQ (10) 4j
Me (2k) QN-SQ (10) 4k
8
a Unsaturated ketoesters (0.250 mmol, 1 equiv.), N-Boc hydroxylamine 1a
(0.275 mmol, 1.1 equiv.) were added dropwise into a solution over
4 hours, catalyst (0.025 mmol, 0.1 equiv.), toluene (0.05 M); then TFA
(7.5 mmol, 30 equiv.). b Isolated yield after column chromatography.
c Determined by chiral HPLC. d Yield after 72 h.
Scheme 2 Transformation and determination of the absolute
configuration.
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0.05 M) in a Schlenk flask was added dropwise over 4 h a solu-
tion of N-Boc hydroxylamine (36.6 mg, 0.275 mmol, 1.1 equiv.)
in toluene (750 µL). After stirring for 24 h at 20 °C, TFA (580
µL, 7.6 mmol, 30 equiv.) was added and the resulting solution
was stirred for 1 h. The reaction mixture was partitioned
between a saturated aqueous NaHCO3 solution (10 mL) and
Et2O (10 mL). The organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, and filtered and con-
centrated under reduced pressure. The crude residue was puri-
fied by silica gel chromatography to give the expected 4a as a
pale yellow oil (54 mg, 87%). Rf = 0.25 (petroleum ether–
EtOAc: 9/1). [α]2D0 = −104.5 (c 1.01, CHCl3, 74% ee). IR (neat)
νmax 3026, 2982, 2938, 2862, 1738, 1721, 1715, 1588, 1454,
Fig. 2 Proposed transition state.
1380, 1257, 1125, 1018, 934, 749 and 701 cm−1 1H NMR
.
(300 MHz; CDCl3) δH 7.32–7.27 (2H, m), 7.23–7.18 (3H, m),
4.85–4.74 (1H, m), 4.35 (2H, q, J = 7.1 Hz), 3.25 (1H, dd, J =
11.0, 17.5 Hz), 2.85 (1H, dd, J = 8.3, 17.5 Hz), 2.84–2.67 (2H, m),
2.17–2.03 (1H, m), 1.96–1.84 (1H, m), 1.37 (3H, t, J =
7.1 Hz). 13C NMR (75.4 MHz; CDCl3) δC 161.0 (C), 151.5 (C),
140.8 (C), 128.7 (2 × CH), 128.5 (2 × CH), 126.3 (CH), 83.2 (CH),
62.2 (CH2), 38.6 (CH2), 36.9 (CH2), 31.5 (CH2), 14.3 (CH3). HRMS
(ESI+): calcd for C14H18NO3 [M + H]+: 248.1281; found: 248.1278.
HPLC analysis: Daicel Chiralpak® AD-H (heptane–iPrOH = 98 : 2,
flow rate 1.0 mL min−1, UV 254 nm, tminor = 15.0 min for R enan-
tiomer; tmajor = 19.9 min for S enantiomer, 74% ee).
Conclusions
In summary, although N-BocNHOH was previously used in the
aza-Michael reaction upon iminium organocatalysis with
enals,9a we report in this paper an enantioselective
oxa-Michael event of this bisnucleophile with unsaturated
α-ketoesters upon Brønsted base catalysis. This original chemo-
selective process followed by a one-pot acid promoted cyclo-
condensation reaction affords a unique entry to non-racemic
bio-relevant 3-isoxazoline carboxylate derivatives. The search
for more efficient squaramide derived organocatalysts is cur-
rently of interest.
Acknowledgements
Experimental section
This work has been partially supported by INSA Rouen,
Rouen University, CNRS, EFRD and Labex SynOrg (ANR-11-
LABX-0029). This work is part of the Immunochim project
(no. 34209) funded by the European Union through a FEDER
support engaged in region Haute-Normandie. We gratefully
acknowledge the French National Research Agency (ANR) for
the support as part of the ANR-08-JCJC-004301 project. We
warmly thank the COST ORCA Action 0905 (Organocatalysis).
Solvents were purchased as dehydrated ones, and toluene or
CH2Cl2 was distilled on CaH2. All reagents were used as received
unless otherwise indicated. Chromatographic purification of
compounds was achieved with silica gel 60 (40–63 μm). Thin
layer chromatography was carried out on silica gel 60 F254
(1.1 mm) with spot detection under UV light or phosphomolyb-
dic acid or ninhydrin or KMnO4 oxidation. 1H NMR spectra
were recorded on a Bruker AVANCE 300 at 300 MHz. Data
appear in the following order: chemical shifts in ppm, number
of protons, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), and coupling constant J in Hz. 13C NMR
spectra were acquired at 75.4 MHz operating with broad band
1H decoupling. The hydrogen multiplicity was obtained by
DEPT135. IR spectra were recorded on a Perkin Elmer IRTF 100
spectrometer using an ATR (Attenuated Total Reflectance)
sampling with a solid dispersed or neat or on a Perkin Elmer
IRFT 1650 with a solid dispersed on KBr pastille. Mp’s were
uncorrected. HRMS analyses were measured on a Q-TOF Micro
WATERS spectrometer. HPLC analyses were performed with
Daicel Chiralpack® or Daicel ChiralCel® columns (4.6 mm ×
25 cm). A spectrosystem UV 1000 thermofisher detector and a
chiral detector (polarimeter) JACSCO OR-1590 were used.
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