Route to Quaternary Oxaprolinol Derivatives as Masked Precursors of Disubstituted β3,β3-Amino Aldehyde

Article abstract of DOI:10.1002/ejoc.201500339

Bicyclic isoxazolidines displaying one or two quaternary stereocenter(s) were formed starting from functional cyclic ketonitrones equipped with a phenyl glycinol chiral auxiliary. The products were engaged in stereocontrolled 1,3-dipolar cycloaddition reactions with a range of electron-rich and electron-poor dipolarophiles. A new reductive removal of the phenyl glycinol chiral auxiliary was introduced and was shown to afford chemoselectively a quaternary isoxazolidine derivative (of oxaprolinol-type) without cleaving the N-O isoxazolidine bond. Keeping the aldehyde function masked as a cyclic pseudo-acetal, the liberated oxy-amine function was shown to be available for a pseudo-peptide coupling with various N-protected amino acids. The isoxazolidine ring was opened by a reductive N-O bond cleavage, giving a pseudo-dipeptide that was C-terminated with an aldehyde function. Isoxazolidines displaying a quaternary stereocenter were formed starting from functional cyclic ketonitrones through a highly stereocontrolled 1,3-dipolar cycloaddition. Chemoselective reductive chiral auxiliary removal gives quaternary oxaprolinol derivatives, which were further transformed into dipeptides terminated directly with an aldehyde function.

Full text of DOI:10.1002/ejoc.201500339

FULL PAPER
DOI: 10.1002/ejoc.201500339
[3+2] Route to Quaternary Oxaprolinol Derivatives as Masked Precursors of
Disubstituted β3,β3-Amino Aldehyde
Pavlo Shpak-Kraievskyi,[a] Amelle Mankou Makaya,[a] Anne Beauchard,[a] Arnaud Martel,[a]
Mathieu Y. Laurent,*[a] and Gilles Dujardin[a]
Keywords: Asymmetric synthesis / Cycloaddition / Chiral auxiliaries / Chemoselectivity / Quaternary center / Amino
aldehydes
Bicyclic isoxazolidines displaying one or two quaternary
stereocenter(s) were formed starting from functional cyclic
ketonitrones equipped with a phenyl glycinol chiral auxil-
iary. The products were engaged in stereocontrolled 1,3-di-
idine derivative (of oxaprolinol-type) without cleaving the N–
isoxazolidine bond. Keeping the aldehyde function
masked as a cyclic pseudo-acetal, the liberated oxy-amine
function was shown to be available for a pseudo-peptide cou-
O
polar cycloaddition reactions with a range of electron-rich pling with various N-protected amino acids. The isoxazolid-
and electron-poor dipolarophiles. A new reductive removal
of the phenyl glycinol chiral auxiliary was introduced and
was shown to afford chemoselectively a quaternary isoxazol-
ine ring was opened by a reductive N–O bond cleavage, giv-
ing a pseudo-dipeptide that was C-terminated with an alde-
hyde function.
underlined that the isoxazolidine ring remained intact dur-
ing the N-deprotection step with the aldehyde function still
masked under a cyclic pseudo-acetal form. For instance, as-
partic aldehyde derivatives (R = CH2CO2Alk, Figure 1)
were obtained by using either chiral aspartic nitrones[5b] or
chiral vinyl ethers[5c] in efficient exo and asymmetrically
controlled 1,3-DC reactions.[7]
Introduction
1,3-Dipolar cycloaddition (1,3-DC) of nitrones is a very
powerful reaction that is used to form five-membered rings
with up to three contiguous stereocenters[1] as shown by the
various examples of total syntheses for which 1,3-DC is a
key-step.[2] Moreover, the 1,3-DC adducts could be trans-
formed into β-amino acids[3] or, when the nitrone is directly
equipped with an ester function, into oxaproline-type,[4,5] or
other unnatural mono- or disubstituted amino acid deriva-
tives.[5,6]
If vinyl ethers are used as dipolarophiles, we showed pre-
viously that quaternary β-amido aldehydes II could also be
accessed via 5-alkoxy-isoxazolidines I (Scheme 1).[5a] It was
Figure 1. Comparison of thermal cycloadditions of acyclic vs. cy-
clic nitrones with ethyl vinyl ether.[8,9]
With smaller substituents such as hydrogen (R = H[8]) or
methyl (R = Me[9]), diastereoselectivity is limited even in the
case of methyl ketonitrones of stable E geometry (Figure 1).
Interestingly, Tamura et al.[10a–10e] and then Baldwin et
al.[10f,10g] demonstrated that cyclic glycine-derived aldoni-
trones incorporating an (R)-phenylglycinol unit (3a; Fig-
ure 1) with a fixed E geometry, could be involved in efficient
1,3-DC reactions with different types of dipolarophiles.[11]
Such cycloadditions proceed with good to total trans selec-
tivity,[12] significantly higher than those observed from the
corresponding acyclic aldonitrones (Figure 1). In addition,
such chiral cyclic nitrones were found to induce high facial
Scheme 1. Access to substituted oxaprolines I and disubstituted
amino aldehydes II with vinyl ethers as dipolarophiles.
[a] Institut des Molécules et Matériaux du Mans, IMMM – CNRS
UMR 6283, LUNAM Université du Maine,
Avenue Olivier Messiaen, 72085 Le Mans Cedex, France
E-mail: mathieu.laurent@univ-lemans.fr
http://immm.univ-lemans.fr/fr/equipes/mso.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500339.
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M. Y. Laurent et al.
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selectivity. However, removal of the chiral auxiliary under (3b–e), yields of nitrones so obtained ranged from 39 to
reductive conditions does not preserve the isoxazolidine 85%.
ring,[10] which would be necessary to access a β-amino alde-
The reactivity of cyclic ketonitrones 3 was first tested in
hyde in a convenient N-protected form. In the cyclic ketoni- inverse 1,3-DC reactions with vinyl ethers, which were en-
trones series, the only examples, developed by Heaney et gaged in cycloaddition reactions with various electron-rich
al.,[13] concerned 1,3-DC reactions of racemic nitrones, dipolarophiles (Table 2). Microwave conditions were em-
which was never investigated in an asymmetric version.
ployed to shorten reaction times of cycloaddition with ke-
In the present work, we report the results of our study tonitrones, which are usually longer than with the corre-
on 1,3-DC reactions of new cyclic enantiopure ketonitrones sponding aldonitrones. The reaction of 3a with ethyl vinyl
such as 3 (Figure 1) towards representative electron-rich ether (entry 1) gave similar results to those obtained by Ta-
and electron-poor dipolarophiles. A main objective was to mura under thermal nonmicrowave conditions.[10c] For
obtain evidence for a gain of diastereocontrol with cyclic nitrone 3b, bearing a methyl substituent, yields were high
ketonitrones as observed by Tamura in the aldonitrone (94–96%) and the major diastereoisomer was formed in the
series. Moreover, we describe the unprecedented removal of range of 67 to 84%.
this type of chiral auxiliary that conserves the isoxazolidine
Table 2. Cycloaddition of nitrones 3a–e with electron-rich di-
polarophiles.
ring by applying the chemoselective conditions that we pre-
viously disclosed in acyclic versions[5a] to obtain enantio-
pure N-deprotected, quaternary-containing isoxazolidines.
Synthetic extensions to this synthon will be revealed to
demonstrate its utility in peptide incorporation by 1) cou-
pling this isoxazolidine with different N-protected amino
acids and 2) showing the possible release of the aldehyde
function after reductive N–O opening reaction.
Entry Nitrone R
RЈ
X
Product Yield (%) dr[f]
1
2
3
4
5
6
7
8
3a
3b
3b
3b
3b
3c
3c
3e
H
H
H
H
H
H
H
H
OEt
OEt
OtBu
SEt
OAc
OEt
OtBu
4a
4b
4c
4d
4e
4f
65[a,b]
96
84:8:8:0
Me
Me
Me
Me
Et
78:6:16:0
81:9:10:0[g]
67:11:22:0
84:6:10:0
75:5:20:0
76:13:11:0
80:20:0:0
Results and Discussion
94
44[c,d]
75[e]
79
Cyclic nitrones 3a–e were synthesized in five steps
(Table 1) by adaptation of Tamura’s procedure that was pre-
viously described for cyclic aldonitrone 3a.[10] Starting from
aminoalcohol 1a or 1b,[14] the imine of p-anisaldehyde was
formed, which was subsequently oxidized to the corre-
sponding oxaziridine. This latter compound was treated
with hydroxylamine hydrochloride to give substituted hy-
droxylamines 2a–b. Cyclic nitrones 3a–e were produced by
reacting hydroxylamines 2a–b either with hydrated glyoxylic
acid (3a) or with the corresponding substituted pyruvic acid
Et
4g
4h
93
47
Me Me OEt
[a] Yield was 76% when the reaction was conducted in benzene at
30 °C. The same dr was obtained under both conditions. [b] Lit.
87% yield, dr 83:8:9.[10c] [c] Reaction conditions: 115 °C for 12 h.
[d] Conversion was 63%. [e] Reaction conditions: 100 °C for 5 h.
[f] dr expressed as trans I/trans II/cis I/cis II was measured by
NMR spectroscopic analysis of the crude product. [g] dr could be
improved by recrystallization to 93:7:0:0 (ca. 50% of enriched 4c
adduct).
Reaction of ethyl-substituted nitrone 3c gave the ex-
pected cycloadducts in good yields (79–93%), albeit in
slightly lower yield than for methyl-substituted compounds,
which shows the deleterious steric effect of the substituent
at the nascent quaternary center. This is more strongly
marked with phenyl-substituted nitrone 3d, which reacted
sluggishly under these reaction conditions. The constrained,
dimethyl-substituted nitrone 3e reacted in 47% yield.
All these reactions gave a major trans adduct.[15] Overall
trans/cis selectivities are usually high as a result of a strong
exo-selective approach, which is typical for vinyl ethers.[7]
In this case, they are better than the typical 75:25 diastereo-
selectivities observed for the corresponding open nitro-
nes[5a] (84:16 for 4b, entry 2; up to 90:10 for 4c and 4e),
showing that the lactonic cycle, which imposes a strict (E)-
nitrone configuration, is also beneficial.
Table 1. Synthesis of cyclic nitrones 3a–e.
Entry
R
RЈ
Product
Yield (%)[a]
1
2
3
4
5
H
Me
Et
Ph
Me
H
H
H
H
3a
3b
3c
3d
3e
80[b,c]
85
43
58
Me
39[d,e]
[a] Isolated yield. [b] It was shown that, compared with Tamura’s
protocol, the yield of cyclic nitrone 3a was maximized by using a
glyoxylate solution dried by prior azeotropic distillation. [c] Ref.[10c]
85% yield. [d] The modest yield was due to partial decomposition
of the nitrone in the acidic medium. [e] Synthesis of the dimeth-
ylated cyclic nitrone derived from glyoxylic acid was attempted but
this compound was very unstable.
The absolute configuration was assigned for compound
4c, for which the structure of a derivative was obtained by
X-ray crystallography (see compound 5c in Scheme 2). Ad-
ditionally, all major diastereoisomers 4a–h exhibit similar
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[3+2] Route to Quaternary Oxaprolinol Derivatives
characteristic NOESY correlations (for example on 4c, Fig- to obtain 5a and 5c with 68 and 81% yield, respectively.
ure 2) showing that H-7, H-2, and H-3α are all located on Importantly, it was possible to separate the diastereoiso-
the lower side of the bicyclic structure, and that Me-3a and mers at this stage.[17] The major diastereoisomer of 5c could
H-3β are both on the upper side, confirming the trans struc- be crystallized and its structure was determined by X-ray
ture for all compounds. The facial selectivity results from crystallography, which provided the absolute configuration
an approach opposite to the phenyl moiety on the Si-face (2S,3aS,7S) for 4c. As the direct hydrogenolysis of com-
of the nitrone.
pounds 5 did not work, the diol functions were protected
as acetates.
Figure 2. NOE correlations for the major diastereoisomer of cy-
cloadduct 4c, and exo-approach on the nitrone; NOE correlations
for the second diastereoisomer of cycloadducts 4b and 4h.
Scheme 2. Opening of the chiral auxiliary and structure of open
cycloadduct 5c determined by X-ray crystallography.
The second diastereoisomer was attributed on the basis
of characteristic NOESY correlations between H-7 and H-
3α on one hand and between Me-3a and H-3β on the other
hand, showing that it is an epimer in the C-2 position (no
correlation between H-7 and H-2) with a cycloadduct of cis
configuration. Additionally, we noticed a large chemical
shift difference between both H-4 for the trans cycloadducts
and a small shift difference for cis cycloadducts, which is
typical for these types of isoxazolidines.[7]
Formic acid mediated hydrogenolysis occurred for 6c
with 60% yield to form oxaprolinol derivative 7c. The same
reaction conditions applied to compound 6a did not afford
the N-deprotected product (Scheme 3).
In contrast, NOESY analysis of the second diastereoiso-
mer of 4h showed correlations between H-3α with both Me-
3a and H-7, proving that the second diastereoisomer has a
trans configuration with opposite stereochemistry. This
shows that the steric effect exerted by the dimethyl groups
favored the exo-approach but was also deleterious for the
facial selectivity.
Scheme 3. Removal of the chiral auxiliary.
Unfortunately, the chiral auxiliary of cycloadducts 4a–h
could not be selectively removed by simple hydrogenolysis
As a precursor of a disubstituted amino acid, it was
because debenzylation occurs with concomitant cleavage of interesting to couple isoxazolidine 7c with an N-protected
the N–O bond, releasing together incompatible amino and amino acid. Classical peptidic coupling failed on this highly
aldehyde groups. We disclosed previously a debenzylation bulky oxy-amine, giving only starting material.[18] On the
method (Pd/C, HCO2H, MeOH, room temp.) that proved other hand, compound 7c was found to be reactive towards
to be chemoselective over the N–O cleavage.[5a] When this acylation with acetic or propionic anhydride. For this
method was tested on 4a or 4c, the starting materials were reason, we turned to more electrophilic acylating agents
recovered even after prolonged reaction time. We assume such as acyl chlorides.[19] When these were reacted with 7c
that the blocked conformation of their bicyclic structure in toluene under microwave irradiation, the desired cou-
makes 4a and 4c highly constrained around the N–C bond, pling product was formed as the only product (Scheme 4).
hindering hydrogenolysis.
Various pseudo-dipeptides could be formed with moderate
To increase the accessibility of the benzylic bond, we de- yields. Importantly, this base-free reaction worked without
cided to open the chiral auxiliary cycle (Scheme 2). After any noticeable epimerization,[20] even for phthalyl-protected
the failure of lithium hydroxide-mediated saponification,[16] amino acyl chloride. The only exception was the highly epi-
lactone reduction was performed with lithium borohydride merizable phenylglycine (Phg) residue.
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M. Y. Laurent et al.
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Scheme 4. Coupling with protected amino acids.
Figure 3. Comparison of cycloaddition reactions of acyclic vs. cy-
clic nitrones with electron-poor dipolarophiles.[6d,22]
At this point, it was possible to perform a classical pept-
ide synthesis by N-elongation while keeping the oxaprolinol
derivative on the C-terminus. However, this moiety also
contains an aldehyde function in a masked cyclic pseudo-
acetal form. We showed previously that cleavage of the N–
O bond could be achieved with reducing agents such as
Mo(CO)6 or SmI2 when the nitrogen is equipped with an
electron-withdrawing group such as acetyl or trifluoroace-
tyl, giving access to the aldehyde or the ester.[5] This reac-
tion, which has been shown to be sensitive to steric hin-
drance,[5c] has never been done previously on isoxazolidines
with an aminoacyl group on the nitrogen. When 8a was
treated with SmI2, no reaction occurred. In contrast, reac-
tion with Mo(CO)6 gave the opened product terminated by
an aldehyde function, albeit in moderate yield (Scheme 5).
This shows that the isoxazolidine route can be used effec-
tively to obtain pseudo-peptides with a terminal quaternary
β3,β3-amino aldehyde unit, which display the valuable prop-
erty of unepimerizability.[21]
Table 3. Cycloaddition of nitrones 3b–d with electron-poor di-
polarophiles.
Entry Nitrone R
EWG
Product Yield (%)
dr[a]
1
2
3
4
5
6
3b
3b
3c
3c
3d
3d
Me CHO
Me CO2Me
10a
10b
10c
10d
10e
10f
79
71
84
Ͼ95
78
Ͼ95
100:0:0:0
97:3:0:0
96:4:0:0
97:3:0:0
99:1:0:0
91:9:0:0
Et
Et
CHO
CO2Me
Ph CHO
Ph CO2Me
[a] dr expressed as cis I/cis II/trans I/trans II was measured by
NMR spectroscopic analysis of the crude product.
are both located on the lower side of the bicyclic structure
and that Me-3a, H-3β and Me-2 are all on the other side,
confirming the cis structure for all compounds.
Scheme 5. Access to dipeptide aldehyde by reductive ring-opening.
The reactivity of electron-poor dipolarophiles towards
cyclic ketonitrones 3 was then screened because a lack of
diastereoselectivity is also observed with 1,3-DC reactions
with acyclic nitrones (Figure 3). In the case of cyclic aldoni-
trones, Tamura et al. showed in this series a complete cis
diastereocontrol.[6d]
Cyclic nitrones 3b–d were engaged in 1,3-DC reaction
with methacrolein or methyl methacrylate[23] under micro-
wave conditions (Table 3). In both cases, one major dia-
stereoisomer is formed with a very high selectivity in high
yields, showing nearly no steric effect of the nitrone substit-
uent.
All these reactions were found to be completely endo-
selective and gave a major cis adduct with excellent facial
control, with de ranging from 82 to 100%. The absolute
configuration was attributed for compound 10b, for which
a structure was obtained by X-ray crystallographic analysis
(Figure 4). Additionally, all compounds 10a–f exhibit char-
Figure 4. endo-Approach on the nitrone, NOESY correlations on
major diastereoisomer of 10b and structure determined by X-ray
acteristic NOESY correlations showing that H-7 and H-3α crystallographic analysis of 10b.
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[3+2] Route to Quaternary Oxaprolinol Derivatives
with 200 and 400 MHz spectrometers. Chemical shifts are reported
in parts per million (ppm) relative to tetramethylsilane (TMS) as
reference for 1H and 13C. Infrared spectra were performed with an
FT spectrophotometer. High-resolution mass spectra were per-
formed with a GCT Premier Micromass. Compounds 1b,[14] 2a,
and 3a,[10c] and amino acyl chlorides[19] were fully described.
The total endo selectivity is probably governed by the
conjunction of the steric repulsive effect of the methyl sub-
stituent of the dipolarophile and the positive orbital over-
lapping between the carbonyl group and the nitrone. It cor-
responds to a reversal of selectivity compared with the 1,3-
DC adducts obtained from the corresponding acyclic nitro-
nes (Figure 3). As for electron-rich dipolarophiles, the facial
selectivity results from an approach opposite to the phenyl
moiety on Si-face of the nitrone.
As a first illustration of its synthetic potential and in-
spired from a sequence developed by Tamura in the aldo-
nitrone series,[10a] the bis-quaternary center containing bicy-
clic adduct 10b could be N-deprotected by hydrogenolysis,
leading, after protection with Boc2O, to lactone 11 in 60%
yield (Scheme 6).
(S)-1-Hydroxyamino-2-methyl-1-phenylpropan-2-ol (2b): A solution
of amino alcohol 1b (100 mg, 0.6 mmol, 1 equiv.), and para-anis-
aldehyde (88 mg, 0.64 mmol, 1.1 equiv.) in toluene (2.5 mL) was
heated at reflux with a Dean–Stark apparatus for 2 h. After cooling
to room temperature, the mixture was concentrated under reduced
pressure to give a red oil (194 mg, quantitative yield). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 8.27 (s, 1 H), 7.71–7.76 (m, 2 H),
7.30–7.50 (m, 5 H), 6.93 (d, J = 10.0 Hz, 2 H), 4.22 (s, 1 H), 3.84
(s, 3 H), 1.23 (s, 3 H), 1.17 (s, 3 H) ppm. The crude imine was dis-
solved in dichloromethane (2 mL), and a solution of meta-chloro-
perbenzoic acid (75%, 181 mg, 0.82 mmol, 1.2 equiv.) in dichloro-
methane (6 mL) was added dropwise at 0 °C over 1.5 h. The mix-
ture was stirred for 30 min and the white precipitate was then fil-
tered off. The filtrate was washed with a 10% solution of K2CO3
(70 mL), dried with MgSO4, and concentrated under reduced pres-
sure to give a red oil (161 mg, 78% yield). 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.26–7.40 (m, 5 H), 6.77–7.08 (m, 4 H), 6.93 (d,
J = 10.0 Hz, 2 H), 4.44 (s, 1 H), 3.75 (s, 3 H), 1.37 (s, 3 H), 1.29 (s,
3 H) ppm. The oxaziridine was dissolved in methanol (2 mL) and
hydroxylamine hydrochloride (181 mg, 1.07 mmol, 2 equiv.) was
added. The mixture was stirred overnight. Concentrated hydrochlo-
ric acid (1 mL) was added and the mixture was concentrated under
reduced pressure. The residue was dissolved in water and ether and
the aqueous phase was washed with diethyl ether until no nonpolar
compounds were observed by TLC analysis. The aqueous phase
was neutralized with sodium carbonate, saturated with sodium
chloride, and then extracted with chloroform (8ϫ 5 mL). The or-
ganic phases were combined, dried with MgSO4, and concentrated
under reduced pressure to give a yellow oil (45 mg, 45% yield).
This crude product was engaged in the next step without further
Scheme 6. Overall N-deprotection of 10b.
Conclusions
A novel route to enantiopure disubstituted oxaprolinol
derivatives through diastereoselective [3+2]-cycloaddition
of chiral cyclic ketonitrones was successfully demonstrated
and its efficiency for the diastereocontrol of the cycload-
dition was established. The new quaternary isoxazolidine
derivatives can be seen as masked β-amino aldehydes. A
chemoselective reductive N-deprotection was developed
that liberates the oxyamine without cleaving the N–O bond,
keeping the aldehyde function protected. The oxy-amine
was coupled with other N-protected amino acids. The
masked aldehyde function can be released at a later stage
and after coupling to allow the required transformations on
the isoxazolidine framework. The diastereoselective [3+2]-
cycloaddition was also studied with dipolarophiles of meth-
acrylate-type and proved to be completely cis-selective, in
contrast to the 1,3-DC reaction of acyclic nitrones, with
high facial control.
purification. [α]2D0 = +3.4 (c = 0.15, CH2Cl2). H NMR (200 MHz,
1
CDCl3, 25 °C): δ = 7.29–7.36 (m, 5 H), 4.01 (s, 1 H), 1.17 (s, 3 H),
1.15 (s, 3 H) ppm. IR (neat): ν = 3340, 2974, 2922, 1604, 1453,
˜
1367, 1242 cm–1.
General Procedure for the Synthesis of Cyclic Ketonitrones (3b–e):
A solution of hydroxylamine (1 equiv.) and keto-acid (1.1 equiv.) in
dichloromethane (2.5 mL/mmol of hydroxylamine) was stirred at
room temperature overnight. Monohydrated para-toluenesulfonic
acid (1.1 equiv.) was added to the solution, which was brought to
reflux overnight. After cooling, the mixture was extracted with
water, the aqueous layer was extracted with dichloromethane, and
the organic phases were gathered, washed with a saturated solution
of NaHCO3, dried with MgSO4, and concentrated under reduced
pressure. Nitrones 3b–e were purified by chromatography on silica
gel column (cyclohexane/ethyl acetate, 1:1).
Experimental Section
General Information: Reagents were purchased from commercial
suppliers and used without additional purification. Methacrolein
was distilled before use. Dichloromethane and THF were dried on
a column of activated alumina in DRY STATION Glass Technol-
ogy GTS 100 glassware. All reactions were conducted in oven-dried
glassware under an inert atmosphere and were monitored by TLC
with UV 254 silica gel-coated plates. Reactions under microwave
conditions were performed with a CEM-Discover apparatus. Flash
column chromatography was performed with silica gel (230–
400 mesh) under medium pressure (1 bar). All melting points are
uncorrected. Optical rotation measurements were performed in a
10 cm glass cell using a digital polarimeter equipped with a Peltier
(S)-3-Methyl-4-oxy-5-phenyl-5,6-dihydro[1,4]oxazin-2-one (3b): Ob-
tained by following the general procedure, starting from hydroxyl-
amine 2a (0.482 g, 3.15 mmol), yield 0.550 g (2.68 mmol, 85%); yel-
low solid; m.p. 98.6–100.0 °C; Rf 0.25 (cyclohexane/ethyl acetate,
1:1; UV visualization); [α]2D0 = –34.3 (c = 1.1, CH2Cl2). H NMR
1
(400 MHz, CDCl3, 25 °C): δ = 7.40–7.44 (m, 3 H), 7.32–7.37 (m,
2 H), 5.13 (t, J = 4.0 Hz, 1 H), 4.70, 4.83 (2dd, J = 4.0, 12.3 Hz,
2 H), 2.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
158.1, 136.2, 132.2, 129.6 (CH), 129.1 (2CH), 127.1 (2CH), 70.5
(CH), 66.8 (CH ), 11.9 (CH ) ppm. IR (neat): ν = 2985, 1716, 1552,
˜
2
3
1301, 1127, 1071 cm–1. HRMS (CI, NH3): m/z calcd. for
1
thermostated cell holder. H and 13C NMR spectra were recorded
C11H11NO3 [M + H+] 206.0817; found 206.0818.
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M. Y. Laurent et al.
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(S)-3-Ethyl-4-oxy-5-phenyl-5,6-dihydro[1,4]oxazin-2-one (3c): Ob-
tained by following the general procedure, starting from hydroxyl-
amine 2a (0.630 g, 3.9 mmol), yield 0.363 g (1.66 mmol, 43%); yel-
1
visualization). H NMR (400 MHz, CDCl3, 25 °C): δ (major trans
diastereoisomer) = 7.44–7.50 (m, 2 H), 7.30–7.44 (m, 3 H), 5.16
(dd, J = 0.9, 5.7 Hz, 1 H), 4.28 (dd, J = 4.0, 9.9 Hz, 1 H), 4.23 (dd,
low solid; m.p. 122.2–123.5 °C; Rf 0.46 (cyclohexane/ethyl acetate, J = 9.9, 11.9 Hz, 1 H), 4.09 (dd, J = 4.0, 9.9 Hz, 1 H), 3.69 (dq, J
1:1, UV/vanilline visualization); [α]2D0 = –24.5 (c = 1.04, CH2Cl2).
= 7.1, 9.6 Hz, 1 H), 3.38 (dq, J = 7.1, 9.6 Hz, 1 H), 2.92 (dd, J =
5.7, 13.6 Hz, 1 H), 2.45 (dd, J = 0.9, 13.6 Hz, 1 H), 1.78 (s, 3 H),
1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.42 (m, 3 H), 7.33 (m,
2 H), 5.11 (t, J = 3.9 Hz, 1 H), 4.67, 4.82 (2dd, J = 3.9, 12.5 Hz, 1.18 (t, J = 7.1 Hz, 3 H) ppm. δ (cis diastereoisomer) = 7.44–7.50
2 H), 2.81 (m, 2 H), 1.18 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(m, 2 H), 7.30–7.42 (m, 3 H), 5.18 (dd, J = 2.4, 6.0 Hz, 1 H), 4.67
(100 MHz, CDCl3, 25 °C): δ = 158.8, 140.9, 132.3, 129.7 (CH), (dd, J = 3.9, 10.2 Hz, 1 H), 4.21 (dd, J = 3.9, 11.6 Hz, 1 H), 4.17
129.4 (2CH), 127.0 (2CH), 70.7 (CH), 67.0 (CH2), 19.3 (CH2), 9.2 (dd, J = 10.2, 11.6 Hz, 1 H), 3.44 (dq, J = 7.1, 9.6 Hz, 1 H), 3.28
(CH ) ppm. IR (neat): ν = 2986, 2935, 1715, 1553, 1301, 1126,
(dq, J = 7.1, 9.6 Hz, 1 H), 2.95 (dd, J = 2.4, 13.9 Hz, 1 H), 2.68 (dd,
˜
3
1072 cm–1. HRMS (CI, NH3): m/z calcd. for C12H14NO3 [M + H+] J = 6.0, 13.9 Hz, 1 H), 1.66 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H) ppm. δ
220.0974; found 220.0976.
(characteristic signals of minor trans diastereoisomer) = 5.08 (t, J
= 10.8 Hz, 1 H), 2.27 (dd, J = 3.2, 13.9 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ (major trans diastereoisomer) = 173.2,
136.2, 128.7 (2CH), 128.4 (CH), 127.4 (2CH), 100.7 (CH), 69.3
(CH2), 67.1, 65.4 (CH), 63.4 (CH2), 46.5 (CH2), 27.4 (CH3), 15.2
(CH3) ppm. δ (cis diastereoisomer) = 172.1, 136.3, 128.4 (2CH),
127.9 (CH), 127.6 (2CH), 104.3 (CH), 70.2, 68.8 (CH2), 64.8 (CH),
(S)-4-Oxy-3,5-diphenyl-5,6-dihydro[1,4]oxazin-2-one (3d): Obtained
by following the general procedure, starting from hydroxylamine 2a
(0.23 g, 1.5 mmol), yield 0.30 g (0.9 mmol, 58%); pink solid; m.p.
147.0–148.1 °C; Rf 0.49 (cyclohexane/ethyl acetate, 1:1, UV/vanil-
line visualization); [α]2D0 = +24.7 (c = 1.1, CH2Cl2). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.77 (m, 2 H), 7.45 (m, 8 H), 5.28
(t, J = 3.7 Hz, 1 H), 4.83, 4.99 (2dd, J = 3.7, 12.5 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 158.7, 135.5, 132.1, 130.3
(CH), 130.1 (2CH), 129.7 (CH), 129.3 (2CH), 127.9 (2CH), 127.2,
63.9 (CH ), 48.5 (CH ), 27.3 (CH ), 14.8 (CH ) ppm. IR (neat): ν
˜
2
2
3
3
= 2977, 2933, 1747, 1455, 1147, 1041 cm–1. HRMS (CI, NH3): m/z
calcd. for C15H19NO4 [M + H+] 278.1392; found 278.1392.
127.1 (2CH), 72.0 (CH), 66.4 (CH ) ppm. IR (neat): ν = 2924,
˜
(2S,3aS,7S)-2-tert-Butoxy-3a-methyl-7-phenyl-tetrahydroisox-
azolo[3,2-c][1,4]oxazin-4-one and Its Diastereomers (4c): Obtained
by following the general procedure (100 °C, 7 h, MW), starting
from nitrone 3b (7.27 g, 35.4 mmol) and tert-butyl vinyl ether
(14 mL, 106 mmol, 3 equiv.). Purified by chromatography on silica
gel (cyclohexane/diethyl ether, 1:1) and recrystallization [hexane/
diethyl ether, 95:5 (100 mL)] as a solid, yield 10.16 g (33.3 mmol,
94%); crude dr 81:9:10:0. Major trans diastereoisomer could be
enriched up to dr 93:7:0:0 by a second recrystallization. Rf 0.53
(cyclohexane/diethyl ether, 1:1, vanilline and UV visualization). 1H
NMR (400 MHz, CDCl3, 25 °C): δ (major trans diastereoisomer)
= 7.44–7.50 (m, 2 H), 7.28–7.42 (m, 3 H), 5.45 (dd, J = 0.9, 6.1 Hz,
1 H), 4.27 (dd, J = 4.2, 11.9 Hz, 1 H), 4.22 (dd, J = 9.9, 11.9 Hz,
1 H), 4.06 (dd, J = 4.2, 9.9 Hz, 1 H), 2.90 (dd, J = 6.0, 13.3 Hz,
1 H), 2.35 (dd, J = 0.9, 13.3 Hz, 1 H), 1.79 (s, 3 H), 1.16 (s,
9 H) ppm. δ (minor trans diastereoisomer) = 7.44–7.50 (m, 2 H),
7.28–7.42 (m, 3 H), 5.45 (dd, J = 0.9, 6.1 Hz, 1 H), 4.72 (dd, J =
3.5, 10.6 Hz, 1 H), 4.15–4.30 (m, 2 H), 2.82 (dd, J = 3.2, 14.1 Hz,
1 H), 2.68 (dd, J = 6.5, 14.1 Hz, 1 H), 1.64 (s, 3 H), 1.00 (s,
9 H) ppm. δ (characteristic signals of cis diastereoisomer) = 5.10 (t,
J = 11.2 Hz, 1 H), 3.22 (dd, J = 6.6, 13.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ (major trans diastereoisomer) = 173.4,
136.2, 128.6 (2CH), 128.3 (CH), 127.5 (2CH), 96.2 (CH), 74.9, 69.4
(CH2), 67.5, 65.1 (CH), 47.2 (CH2), 28.7 (3CH3), 27.3 (CH3) ppm.
2
1712, 1551, 1361, 1199, 1013 cm–1. HRMS (CI, NH3): m/z calcd.
for C12H14NO3 [M + H+] 220.0974; found 220.0976.
(S)-3,6,6-Trimethyl-4-oxy-5-phenyl-5,6-dihydro[1,4]oxazin-2-one
(3e): Obtained by following general procedure, starting from hy-
droxylamine 2b (0.20 g, 1.1 mmol) and pyruvic acid (106 mg,
1.2 mmol, 1.1 equiv.). Purified by chromatography, yield 0.10 g
(0.43 mmol, 39%); glassy solid; [α]2D0 = +171 (c = 0.09, CH2Cl2);
Rf 0.27 (cyclohexane/ethyl acetate, 1:1, UV/vanilline visualization).
1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.36–7.44 (m, 3 H), 7.22–
7.28 (m, 2 H), 4.78 (s, 1 H), 2.33 (s, 3 H), 1.67 (s, 3 H), 1.23 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 159.3, 134.7,
132.3, 129.9 (CH), 129.2 (2CH), 128.1 (2CH), 80.4 (CH), 78.9, 27.4
(CH ), 25.3 (CH ), 11.9 (CH ) ppm. IR (neat): ν = 2920, 2852,
˜
3
3
3
1712, 1563, 1344, 1120 cm–1. HRMS (CI, NH3): m/z calcd. for
C13H15NO3 [M + H+] 234.1130; found 234.1132.
General Procedure for the [3+2] Cycloaddition of Cyclic Ketonitrones
(3a–e) with Electron-Rich Dipolarophiles: Nitrone 3 (1 equiv.) and
dipolarophile were heated under the specified conditions with mi-
crowave irradiation. The reaction mixture was then concentrated
under reduced pressure and the residue was purified by chromatog-
raphy on silica gel.
(2S,3aS,7S)-2-Ethoxy-7-phenyl-tetrahydroisoxazolo[3,2-c][1,4]-
oxazin-4-one and Its Diastereomers (4a):[10c] Obtained by following
the general procedure (50 °C, 4 h, MW), starting from nitrone 3a
(100 mg, 0.52 mmol) and ethyl vinyl ether (0.5 mL, 5 mmol,
9 equiv.). Purified by chromatography on silica gel (hexane/ethyl
acetate, 3:2), yield 89 mg (0.34 mmol, 65%); yellow oil; dr 84:8:8:0;
Rf 0.54 (hexane/ethyl acetate, 3:2, vanilline and UV visualization).
1H NMR (200 MHz, CDCl3, 25 °C): δ = 7.32–7.51 (m, 5 H), 5.17
(d, J = 4.3 Hz, 1 H), 4.47 (t, J = 8.0 Hz, 1 H), 4.05–4.37 (m, 3 H),
3.63–3.78 (m, 1 H), 3.32–3.49 (m, 1 H), 3.08 (m, 1 H), 2.59–2.85
(m, 2 H) ppm.
IR (neat): ν = 2969, 2934, 1748, 1127, 971 cm–1. HRMS (CI, NH ):
˜
3
m/z calcd. for C17H23NO4 [M + H+] 306.1705; found 306.1703.
(2S,3aS,7S)-2-Ethylsulfanyl-3a-methyl-7-phenyl-tetrahydroisox-
azolo[3,2-c][1,4]oxazin-4-one and Its Diastereomers (4d): Obtained
by following the general procedure (115 °C, 12 h, toluene, MW),
starting from nitrone 3b (52 mg, 0.25 mmol) and ethyl vinyl thio-
ether (0.03 mL, 0.29 mmol, 1.1 equiv.). Purified by chromatography
on silica gel (cyclohexane/ethyl acetate, 7:3) as a brown oil, yield
32 mg (0.11 mmol, 44%); crude dr 67:11:22:0; Rf 0.51 (cyclohexane/
ethyl acetate, 7:3, vanilline and UV visualization). 1H NMR
(2S,3aS,7S)-2-Ethoxy-3a-methyl-7-phenyl-tetrahydroisoxazolo[3,2- (400 MHz, CDCl3, 25 °C): δ (major trans diastereoisomer) = 7.47
c][1,4]oxazin-4-one and Its Diastereomers (4b): Obtained by follow-
ing the general procedure (100 °C, 5 h, MW), starting from nitrone
3b (300 mg, 1.46 mmol) and ethyl vinyl ether (1 mL, 10 mmol,
7 equiv.). Purified by chromatography on silica gel (cyclohexane/
(m, 2 H), 7.36 (m, 3 H), 5.35 (dd, J = 5.8, 8.3 Hz, 1 H), 4.30 (dd,
J = 3.4, 11.2 Hz, 1 H), 4.21 (m, 2 H), 3.30 (dd, J = 8.3, 13.9 Hz,
1 H), 2.57 (q, J = 7.5 Hz, 2 H), 2.34 (dd, J = 5.9, 13.9 Hz, 1 H),
1.76 (s, 3 H), 1.17 (t, J = 7.3 Hz, 3 H) ppm. δ (major cis dia-
diethyl ether, 1:1) as a solid, yield 389 mg (1.40 mmol, 96%); dr stereoisomer) = 7.47 (m, 2 H), 7.36 (m, 3 H), 5.39 (t, J = 7.1 Hz,
78:16:6:0; Rf 0.51 (cyclohexane/diethyl ether, 1:1, vanilline and UV 1 H), 4.91 (dd, J = 4.9, 9.5 Hz, 1 H), 4.22 (m, 2 H), 2.92 (dd, J =
3928
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3923–3934

[3+2] Route to Quaternary Oxaprolinol Derivatives
7.6, 13.7 Hz, 1 H), 2.84 (dd, J = 6.6, 13.7 Hz, 1 H), 2.40–2.52 (m,
2 H), 1.68 (s, 3 H), 1.07 (t, J = 7.6 Hz, 3 H) ppm. δ (characteristic
signals of minor trans diastereoisomer) = 5.43 (dd, J = 5.4, 8.3 Hz,
1 H), 4.84 (dd, J = 3.9, 12.5 Hz, 1 H), 5.09 (t, J = 4.6 Hz, 1 H),
4.75 (dd, J = 4.9, 12.5 Hz, 1 H), 3.43 (dd, J = 8.1, 13.4 Hz, 1 H),
2.65–2.75 (m, 2 H), 2.34 (dd, J = 5.4, 13.7 Hz, 1 H), 1.67 (s, 3 H),
10 mmol, 33 equiv.). Purified by chromatography on silica gel (cy-
clohexane/ethyl acetate, 8:2) as a colorless oil, yield 95 mg
(0.3 mmol, 93%); crude dr 76:13:11:0; Rf 0.30 (cyclohexane/ethyl
1
acetate, 8:2, vanilline and UV visualization). H NMR (400 MHz,
CDCl3, 25 °C): δ (major trans diastereoisomer) = 7.47 (m, 2 H),
7.35 (m, 3 H), 5.48 (dd, J = 1.7, 6.4 Hz, 1 H), 4.18 (m, 2 H), 4.05
1.28 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3, 25 °C): δ (dd, J = 5.6, 8.3 Hz, 1 H), 2.88 (dd, J = 6.4, 13.4 Hz, 1 H), 2.37
(major trans diastereoisomer) = 172.3, 135.5, 128.8 (2CH), 128.4
(CH), 127.5 (2CH), 81.2 (CH), 69.4 (CH2), 68.7, 62.9 (CH), 47.7
(CH2), 27.1 (CH2), 26.2 (CH3), 15.1 (CH3) ppm. δ (major cis dia-
stereoisomer) = 171.5, 135.6, 128.8–127.5 (5CH), 82.9 (CH), 70.3
(dd, J = 1.7, 13.4 Hz, 1 H), 2.28 (dq, J = 7.3, 14.0 Hz, 1 H), 2.08
(dq, J = 7.3, 14.0 Hz, 1 H), 1.14 (s, 9 H), 1.10 (t, J = 7.3 Hz,
3 H) ppm. δ (characteristic signals of major cis diastereoisomer) =
2.78 (dd, J = 3.4, 14.2 Hz, 1 H), 2.69 (dd, J = 6.6, 14.2 Hz,
(CH2), 67.5, 63.3 (CH), 47.3 (CH2), 26.1 (CH2), 25.9 (CH3), 14.6 1 H) ppm. δ (characteristic signals of minor trans diastereoisomer)
(CH ) ppm. IR (neat): ν = 2928, 1738, 1115, 1030 cm–1. HRMS = 3.08 (dd, J = 6.6, 13.4 Hz, 1 H), 2.24 (dd, J = 3.9, 13.4 Hz,
˜
3
(CI, NH3): m/z calcd. for C15H20NO3S [M + H+] 294.1163; found
294.1152.
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ (major trans dia-
stereoisomer) = 172.3, 136.3, 128.6 (2CH), 128.4 (CH), 127.6
(2CH), 96.4 (CH), 75.0, 72.6, 69.7 (CH2), 64.4 (CH), 46.1 (CH2),
(2S,3aS,7S)-3a-Methyl-4-oxo-7-phenyl-hexahydroisoxazolo[3,2-c]-
[1,4]oxazin-2-yl Acetate and Its Diastereomers (4e): Obtained by fol-
lowing the general procedure (100 °C, 5 h, MW), starting from
nitrone 3b (40 mg, 0.19 mmol) and vinyl acetate (0.1 mL, 1.1 mmol,
6 equiv.). Purified by chromatography on silica gel (cyclohexane/
diethyl ether, 1:1) as an oil, yield 34 mg (0.12 mmol, 60%); crude
dr 84:6:10:0; Rf 0.51 (cyclohexane/diethyl ether, 1:1, vanilline and
UV visualization). 1H NMR (400 MHz, CDCl3, 25 °C): δ (major
trans diastereoisomer) = 7.30–7.45 (m, 5 H), 6.40 (dd, J = 0.5,
5.7 Hz, 1 H), 4.32 (dd, J = 4.0, 12.2 Hz, 1 H), 4.27 (dd, J = 9.8,
12.2 Hz, 1 H), 4.12 (dd, J = 4.0, 9.8 Hz, 1 H), 3.11 (dd, J = 5.7,
14.2 Hz, 1 H), 2.56 (dd, J = 0.5, 14.2 Hz, 1 H), 2.07 (s, 3 H), 1.78
(s, 3 H) ppm. δ (characteristic signals of minor trans diastereoiso-
mer) = 3.37 (dd, J = 6.9, 14.2 Hz, 1 H), 2.41 (dd, J = 3.0, 14.2 Hz,
1 H) ppm. δ (characteristic signals of cis diastereoisomer) = 2.78
(dd, J = 5.9, 14.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ (major trans diastereoisomer) = 172.3, 169.7, 135.4, 128.8
(2CH), 128.6 (CH), 127.4 (2CH), 94.5 (CH), 69.1 (CH2), 66.7, 65.3
32.2 (CH ), 28.7 (3CH ), 9.7 (CH ) ppm. IR (neat): ν = 2969, 1746,
˜
2
3
3
1128, 975 cm–1. HRMS (CI, NH3): m/z calcd. for C18H26NO4 [M
+ H+] 320.1862; found 320.1857.
(2R,3aR,7R)-2-Ethoxy-3a,6,6-trimethyl-7-phenyl-tetrahydro-
isoxazolo[3,2-c][1,4]oxazin-4-one and Its Diastereomers (4h): Ob-
tained by following the general procedure (110 °C, 5 h, MW), start-
ing from nitrone 3e (32 mg, 0.14 mmol) and ethyl vinyl ether
(0.13 mL, 1.4 mmol, 10 equiv.). Purified by chromatography on sil-
ica gel (cyclohexane/diethyl ether, 1:1) as a solid, yield 20 mg
(0.065 mmol, 47%); dr 81:19:0:0; Rf 0.71 (cyclohexane/diethyl ether,
1
1:1, vanilline and UV visualization). H NMR (400 MHz, CDCl3,
25 °C): δ (major trans diastereoisomer) = 7.20–7.55 (m, 5 H), 5.18
(dd, J = 0.6, 6.2 Hz, 1 H), 3.79 (s, 1 H), 3.64 (dq, J = 7.0, 9.5 Hz,
1 H), 3.31 (dq, J = 7.0, 9.5 Hz, 1 H), 2.84 (dd, J = 6.2, 13.6 Hz,
1 H), 2.49 (dd, J = 0.6, 13.6 Hz, 1 H), 1.86 (s, 3 H), 1.40 (s, 3 H),
1.23 (s, 3 H), 1.14 (t, J = 7.0 Hz, 3 H) ppm. δ (minor trans dia-
stereoisomer) = 7.20–7.55 (m, 5 H), 5.15 (dd, J = 3.7, 6.2 Hz, 1 H),
4.53 (s, 1 H), 3.10 (dq, J = 7.0, 9.5 Hz, 1 H), 3.04 (dq, J = 7.0,
9.5 Hz, 1 H), 2.81 (dd, J = 3.7, 14.2 Hz, 1 H), 2.76 (dd, J = 6.2,
14.2 Hz, 1 H), 1.65 (s, 3 H), 1.42 (s, 3 H), 1.27 (s, 3 H), 0.99 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ (major
trans diastereoisomer) = 172.3, 136.5, 129.0 (2CH), 128.2 (CH),
128.1 (2CH), 101.9 (CH), 83.6, 72.9 (CH), 67.5, 64.3 (CH2), 45.8
(CH2), 27.1 (CH3), 25.7 (CH3), 22.1 (CH3), 15.2 (CH3) ppm. δ
(minor trans diastereoisomer) = 172.3, 136.7, 128.9 (2CH), 128.3
(CH), 127.9 (2CH), 104.7 (CH), 84.2, 71.9 (CH), 68.7, 64.2 (CH2),
48.5 (CH2), 26.9 (CH3), 26.1 (CH3), 21.8 (CH3), 14.7 (CH3) ppm.
(CH), 46.2 (CH ), 27.1 (CH ), 21.2 (CH ) ppm. IR (neat): ν = 1746,
˜
2
2
3
1456, 1234, 1125 cm–1. HRMS (CI, NH3): m/z calcd. for
C15H18NO5 [M + H+] 292.1185; found 292.1193.
(2S,3aS,7S)-2-Ethoxy-3a-ethyl-7-phenyl-tetrahydroisoxazolo[3,2-
c][1,4]oxazin-4-one and Its Diastereomers (4f): Obtained by follow-
ing the general procedure (90 °C, 4 h, MW), starting from nitrone
3c (53 mg, 0.24 mmol) and ethyl vinyl ether (1.5 mL, 15 mmol,
64 equiv.). Purified by chromatography on silica gel (cyclohexane/
ethyl acetate, 7:3) as a yellow solid, yield 57 mg (0.19 mmol, 79%);
crude dr 75:5:20:0; Rf 0.59 (cyclohexane/ethyl acetate, 7:3, vanilline
and UV visualization). 1H NMR (400 MHz, CDCl3, 25 °C): δ
(major trans diastereoisomer) = 7.48 (m, 2 H), 7.37 (m, 3 H), 5.20
(dd, J = 0.3, 6.4 Hz, 1 H), 4.18 (m, 2 H), 4.05 (dd, J = 6.4, 8.1 Hz,
1 H), 2.87 (dd, J = 6.1, 13.7 Hz, 1 H), 2.49 (dd, J = 0.3, 13.7 Hz,
1 H), 2.29 (dq, J = 7.3, 14.0 Hz, 1 H), 2.07 (dq, J = 7.3, 14.0 Hz,
1 H), 1.15 (t, J = 7.1 Hz, 3 H), 1.09 (t, J = 7.5 Hz, 3 H) ppm. δ
(characteristic signals of major cis diastereoisomer) = 2.87 (m,
1 H), 2.70 (dd, J = 6.4, 14.2 Hz, 1 H) ppm. δ (characteristic signals
of minor trans diastereoisomer) = 3.10 (dd, J = 6.4, 13.7 Hz, 1 H),
2.32 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ (major
trans diastereoisomer) = 172.1, 136.3, 128.8 (2CH), 128.5 (CH),
127.4 (2CH), 101.1 (CH), 72.2, 69.6 (CH2), 65.0 (CH), 63.9 (CH2),
IR (neat): ν = 2982, 2937, 1736, 1373, 1273, 1171, 1110 cm–1
.
˜
HRMS (CI, NH3): m/z calcd. for C17H24NO4 [M + H+] 306.1705;
found 306.1694.
(2S)-2-[(3S,5S)-5-Ethoxy-3-(hydroxymethyl)isoxazolidin-2-yl]-2-
phenylethanol (5a): The 84:8:8 mixture of cycloadducts 4a (220 mg,
0.84 mmol) was dissolved in anhydrous THF (8 mL) under argon,
and a solution of LiBH4 (4 m in THF, 0.5 mL, 2.09 mmol,
2.5 equiv.) was added dropwise. The mixture was stirred at room
temperature for 2 h, then water (5 mL) was added and the mixture
was extracted with ethyl acetate (3ϫ 15 mL). Organic phases were
dried on MgSO4 and concentrated under reduced pressure. The
white solid was purified by chromatography on silica gel (toluene/
methanol, 9:1) to give a white solid, yield 150 mg (0.56 mmol,
68%); Rf 0.32 (toluene/methanol, 9:1, UV and vanilline visualiza-
tion); m.p. 136.0–137.0 °C; [α]2D0 = +86.1 (c = 0.29, CHCl3). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.30–7.38 (m, 5 H), 5.28 (dd,
J = 2.4, 5.6 Hz, 1 H), 5.13 (br. s, 2 H), 4.31 (t, J = 4.9 Hz, 1 H),
4.11 (dd, J = 4.9, 11.2 Hz, 1 H), 3.98 (dd, J = 5.1, 11.5 Hz, 1 H),
3.90 (dd, J = 7.1, 9.3 Hz, 1 H), 3.57 (dd, J = 7.1, 9.5 Hz, 1 H), 3.40
(m, 1 H), 3.24 (dd, J = 6.1, 11.2 Hz, 1 H), 3.08 (dd, J = 4.4,
45.3 (CH ), 32.1 (CH ), 15.1 (CH ), 9.7 (CH ) ppm. IR (neat): ν =
˜
2
2
3
3
2977, 1728, 1148, 1079, 1043 cm–1. HRMS (CI, NH3): m/z calcd.
for C16H22NO4 [M + H+] 292.1549; found 292.1551.
(2S,3aS,7S)-2-tert-Butoxy-3a-ethyl-7-phenyl-tetrahydroisoxazolo-
[3,2-c][1,4]oxazin-4-one and Its Diastereomers (4g): Obtained by fol-
lowing the general procedure (100 °C, 4 h, MW), starting from
nitrone 3c (69 mg, 0.32 mmol) and tert-butyl vinyl ether (1.4 mL,
Eur. J. Org. Chem. 2015, 3923–3934
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3929

M. Y. Laurent et al.
FULL PAPER
11.0 Hz, 1 H), 2.37 (ddd, J = 2.4, 7.6, 13.4 Hz, 1 H), 2.28 (ddd, J
310.2005; found 310.2018. Minor diastereoisomer: Rf 0.25 (cyclo-
= 4.9, 5.6, 13.4 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR hexane/ethyl acetate, 9:1, UV and vanilline visualization).
(100 MHz, CDCl3, 25 °C): δ = 138.6, 135.2, 128.9, 128.4, 128.3,
(2S)-2-[(3S,5S)-3-(Acetoxymethyl)-5-tert-butoxy-3-methylisox-
128.2 (4CH), 125.1 (CH), 105.8 (CH), 72.8 (CH), 66.6 (CH2), 64.6
azolidin-2-yl]-2-phenylethyl Acetate (6c): To a solution of diol 5c
(CH2), 63.7 (CH), 63.4 (CH2), 37.7 (CH2), 15.2 (CH3) ppm. IR
(180 mg, 0.58 mmol) in pyridine (4.5 mL) were added dimethylami-
(neat): ν = 3407, 2974, 1604, 1454, 1375, 1056 cm–1. MS (DCI,
˜
nopyridine (10 mg, 0.09 mmol, 0.15 equiv.) and acetic anhydride
(0.16 mL, 1.74 mmol, 3 equiv.). The solution was stirred for 5 h at
room temperature, then the solvent was removed in vacuo and the
residue was poured into cold water (7 mL) and extracted with
dichloromethane (2ϫ 10 mL). The combined organic layers were
dried with MgSO4 and concentrated under reduced pressure.
Eventually, the purity of the crude product allowed its use without
further purification. Otherwise, it could be purified by chromatog-
raphy on silica gel (cyclohexane/ethyl acetate, 2:1), yield 217 mg
(95% yield); Rf 0.57 (cyclohexane/ethyl acetate, 2:1, UV and vanil-
line visualization); [α]2D0 = +45.3 (c = 2.1, CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.46–7.36 (m, 2 H), 7.35–7.25 (m,
3 H), 5.47 (dd, J = 4.3, 6.7 Hz, 1 H), 4.75 (dd, J = 2.1, 8.6 Hz,
1 H), 4.45 (dd, J = 2.1, 7.3 Hz, 1 H), 4.39 (dd, J = 7.3, 8.6 Hz,
1 H), 3.85 (d, J = 10.9 Hz, 1 H), 3.78 (d, J = 10.9 Hz, 1 H), 2.44
(dd, J = 6.7, 13.8 Hz, 1 H), 2.07 (dd, J = 4.3, 13.8 Hz, 1 H), 2.03
(s, 3 H), 1.87 (s, 3 H), 1.28 (s, 9 H), 0.93 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 170.8, 170.7, 140.4, 128.5 (2CH),
128.0 (2CH), 127.5 (CH), 98.9 (CH), 75.1, 68.7 (CH2), 67.6, 67.1
(CH2), 64.8 (CH), 45.5 (CH2), 28.6 (3CH3), 20.9 (CH3), 20.8 (CH3),
CH4): m/z = 268.32 [M + H+]. HRMS (ESI): m/z calcd. for
C14H22NO4 [M + H+] 268.1543; found 268.1541; m/z calcd. for
C14H21NNaO4 [M + Na+] 290.1363; found 290.1367.
(3S,5S)-2-[(1S)-2-Acetoxy-1-phenylethyl]-5-ethoxyisoxazolidin-
3-ylmethyl Acetate (6a): Acetic anhydride (16 mL, 1.69 mmol,
3 equiv.) and DMAP (100 mg, 0.085 mmol, 0.15 equiv.) were added
to cycloadduct 5a (150 mg, 0.56 mmol). Pyridine (3.8 mL) was
added after complete dissolution. The mixture was stirred at room
temperature for 18 h, then the solution was concentrated under re-
duced pressure and transferred onto iced water (10 mL). The aque-
ous phase was extracted three times with dichloromethane and the
organic phases were combined, dried with Na2SO4, and concen-
trated under reduced pressure. The product was purified by
chromatography on silica gel (hexane/ethyl acetate, 2:1) to give a
yellow oil, yield 151 mg (77%); Rf 0.43 (hexane/ethyl acetate, 2:1,
UV and vanilline visualization). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.30–7.40 (m, 5 H), 5.31 (dd, J = 2.4, 6.1 Hz, 1 H), 4.72
(dd, J = 2.9, 10.0 Hz, 1 H), 4.42 (m, 2 H), 3.95 (dd, J = 7.1, 9.5 Hz,
1 H), 3.76 (dd, J = 2.9, 6.6 Hz, 2 H), 3.58 (dd, J = 7.1, 9.5 Hz,
1 H), 3.50 (m, 1 H), 2.43 (ddd, J = 2.7, 8.1, 13.7 Hz, 1 H), 2.20
(ddd, J = 3.7, 6.1, 13.7 Hz, 1 H), 1.95 (s, 3 H), 1.90 (s, 3 H), 1.27
(t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 170.4, 138.3, 128.6, 128.3, 128.1 (5CH), 105.5 (CH), 69.6 (CH),
20.0 (CH ) ppm. IR (neat): ν = 2977, 1743, 1374, 1234, 1045 cm–1.
˜
3
HRMS (FD): m/z calcd. for C21H31NO6 [M+] 393.2151; found
393.2186.
[(3S,5S)-5-(tert-Butoxy)-3-methylisoxazolidin-3-yl]methyl Acetate
66.2 (CH2), 65.3 (CH2), 64.4 (CH2), 60.6 (CH), 37.9 (CH2), 20.6 (7c): Under argon, to a stirred solution of adduct 6c (590 mg,
(2CH ), 14.9 (CH ) ppm. IR (neat): ν = 2978, 1737, 1370, 1231,
1.5 mmol) in methanol (1.7 m) and Pd/C (10%, 103 mg) was added
dropwise formic acid (2.5 mL, 45 equiv.). After 16 h stirring at
room temp., the reaction mixture was diluted with EtOAc (10 mL)
and filtered through Celite. The filtrate was concentrated under
reduced pressure, the viscous residue was partitioned between
EtOAc (10 mL) and aqueous saturated NaHCO3 (7 mL), and the
aqueous phase was separated and extracted with EtOAc (2 ϫ
7 mL). The combined EtOAc phases were washed with brine
(15 mL), dried with MgSO4, filtered, and concentrated under vac-
uum. The crude product was purified by silica gel chromatography
(cyclohexane/ethyl acetate, 95:5), yield 208 mg (0.9 mmol, 60%); Rf
0.46 (petroleum ether/ethyl acetate, 1:1, UV and vanilline visualiza-
tion); [α]2D0 = +149 (c = 1.02, CH2Cl2). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 5.58 (br. s, 1 H), 5.52 (dd, J = 1.4, 5.6 Hz, 1 H), 3.93
(d, J = 10.9 Hz, 1 H), 3.89 (d, J = 10.9 Hz, 1 H), 2.22 (dd, J = 5.6,
13.4 Hz, 1 H), 2.09 (s, 3 H), 1.79 (dd, J = 1.4, 13.4 Hz, 1 H), 1.31
(s, 3 H), 1.25 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 171.1, 100.7 (CH), 74.9, 68.6 (CH2), 62.4, 46.8 (CH2), 28.9
˜
3
3
1042 cm–1. MS (DCI, CH4): m/z = 352.39 [M + H+]. HRMS (ESI):
m/z calcd. for C18H26NO6 [M + H+] 352.1755; found 352.1762.
(2S)-2-[(3S,5S)-5-tert-Butoxy-3-(hydroxymethyl)-3-methylisox-
azolidin-2-yl]-2-phenylethanol (5c): The 93:7 mixture of cycload-
ducts 4c (780 mg, 2.55 mmol) was dissolved in anhydrous THF
(37 mL) under argon, and a solution of LiBH4 (2 m in THF,
3.7 mL, 7.40 mmol, 3.0 equiv.) was added dropwise. The mixture
was stirred at room temperature for 16 h, then water (20 mL) was
added and the mixture was extracted with ethyl acetate (2 ϫ
50 mL). The organic phases were dried on MgSO4 and concen-
trated under reduced pressure. The product was purified by
chromatography on silica gel (cyclohexane/ethyl acetate, 9:1 to 5:5)
to give the major diastereoisomer (478 mg, 1.5 mmol) and the
minor diastereoisomer (50 mg, 0.16 mmol) as white solids (65%
combined yield). Hemiacetal (130 mg, 0.4 mmol, 17% yield) was
also obtained and could be converted into diol (95% yield) by ad-
ditional reduction with LiBH4 (2 equiv.) with a global yield of 81%.
Major diastereoisomer: Rf 0.27 (cyclohexane/ethyl acetate, 9:1, UV
and vanilline visualization); m.p. 78.5 °C; [α]2D0 = +87 (c = 1.01,
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.40–7.25 (m,
5 H), 5.47 (dd, J = 4.5, 6.5 Hz, 1 H), 4.28 (dd, J = 3.1, 6.5 Hz,
1 H), 4.03 (ddd, J = 4.1, 6.5, 11.5 Hz, 1 H), 3.71 (ddd, J = 3.1, 9.1,
11.5 Hz, 1 H), 3.41 (dd, J = 4.1, 9.1 Hz, 1 H), 3.31 (dd, J = 5.8,
10.7 Hz, 1 H), 2.98 (dd, J = 6.8, 10.7 Hz, 1 H), 2.45 (dd, J = 6.5,
13.5 Hz, 1 H), 2.25 (dd, J = 5.8, 6.8 Hz, 1 H), 2.10 (dd, J = 4.5,
13.5 Hz, 1 H), 1.29 (s, 9 H), 1.00 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 140.5, 128.7 (2CH), 127.8 (CH),
127.7 (2CH), 98.8 (CH), 75.6, 68.5 (CH), 68.4, 67.8 (CH2), 67.4
(3CH ), 20.9 (CH ), 20.3 (CH ) ppm. IR (neat): ν = 3227, 2976,
˜
3
3
3
1744, 1461, 1372, 1239, 1044 cm–1. HRMS (FD): m/z calcd. for
C11H21NO4 [M+] 231.1471; found 231.1478.
General Procedure for the Coupling of Compound 7c with Protected
Amino Acyl Chlorides: The corresponding amino acyl chloride
(1.25 equiv.) and 7c (1.0 equiv.) were dissolved in anhydrous tolu-
ene (0.05 m), and the mixture was heated under the specified condi-
tions under microwave irradiation and then evaporated under vac-
uum. Purification of the residue by preparative silica gel
chromatography (cyclohexane/EtOAc, 1:1 or hexane/THF, 7:3) af-
forded the pure product.
(CH ), 45.5 (CH ), 28.5 (3CH ), 19.4 (CH ) ppm. IR (neat): ν = (3S,5S)-5-tert-Butoxy-2-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonyl-
˜
2
2
3
3
3435, 2981, 2930, 2371, 1452, 1395, 1239, 1192, 1070, 1055, amino)-3-phenylpropionyl]-3-methylisoxazolidin-3-ylmethyl Acetate
970 cm–1. HRMS (DCI, NH3): m/z calcd. for C17H27NO4 [M + H+] (8a): Obtained according to the general procedure (70 °C, 30 min,
3930
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3923–3934

[3+2] Route to Quaternary Oxaprolinol Derivatives
MW), from 7c (145 mg, 0.63 mmol) as an oil, yield 208 mg MW), from 7c (135 mg, 0.58 mmol) as an oil, yield 103 mg
(0.35 mmol, 55%); Rf 0.18 (hexane/THF, 7:3, UV and vanilline vi-
sualization); [α]2D0 = +8.35 (c = 2.24, CH2Cl2). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.75 (d, J = 7.6 Hz, 2 H), 7.54 (dd, J = 5.9,
(0.19 mmol, 32%); Rf 0.32 (hexane/THF, 7:3, UV and vanilline vi-
1
sualization); [α]2D0 = –3.28 (c = 3.9, CH2Cl2). H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.61 (d, J = 7.6 Hz,
6.5 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.32–7.12 (m, 7 H), 5.52 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 2 H), 5.51 (d, J
(dd, J = 0.3, 5.5 Hz, 1 H), 5.52 (d, J = 8.6 Hz, 1 H), 4.98 (ddd, J = 9.4 Hz, 1 H), 5.48 (dd, J = 2.5, 5.6 Hz, 1 H), 4.62 (dd, J = 4.5,
= 4.7, 7.4, 8.6 Hz, 1 H), 4.46 (d, J = 11.2 Hz, 1 H), 4.38 (dd, J = 9.4 Hz, 1 H), 4.52 (d, J = 11.3 Hz, 1 H), 4.41 (dd, J = 7.4, 10.1 Hz,
10.1, 13.4 Hz, 1 H), 4.24 (d, J = 11.2 Hz, 1 H), 4.15 (dd, J = 7.7,
13.4 Hz, 1 H), 4.15 (dd, J = 7.7, 10.1 Hz, 1 H), 3.16 (dd, J = 4.8,
13.8 Hz, 1 H), 2.87 (dd, J = 7.4, 13.8 Hz, 1 H), 2.58 (dd, J = 5.5,
1 H), 4.30 (dd, J = 7.0, 10.1 Hz, 1 H), 4.26 (d, J = 11.3 Hz, 1 H),
4.24 (dd, J = 7.0, 7.4 Hz, 1 H), 2.58 (dd, J = 5.6, 12.7 Hz, 1 H),
2.05 (dd, J = 2.5, 12.7 Hz, 1 H), 2.30–2.22 (m, 1 H), 2.01 (s, 3 H),
12.7 Hz, 1 H), 2.08 (s, 3 H), 2.06 (dd, J = 0.3, 12.7 Hz, 1 H), 1.70 1.63 (s, 3 H), 1.27 (s, 9 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.90 (d, J =
(s, 3 H), 1.31 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.5,
= 170.5, 166.0, 155.5, 144.0, 143.9, 141.3 (2 C), 136.5, 129.6 (2CH),
128.3 (2CH), 127.6 (2CH), 127.0 (2CH), 126.8 (CH), 125.2 (2CH),
166.7, 156.5, 144.0 (2 C), 141.3 (2 C), 127.6 (2CH), 127.0 (2CH),
125.2 (2CH), 119.9 (2CH), 96.7 (CH), 76.0, 66.9 (CH2), 65.9 (CH2),
119.9 (2CH), 96.8 (CH), 76.0, 66.8 (CH2), 65.8 (CH2), 63.5, 53.3 63.3, 56.7 (CH), 47.2 (CH), 45.9 (CH2), 30.5 (CH), 28.6 (3CH3),
(CH), 47.1 (CH), 45.7 (CH2), 38.1 (CH2), 28.6 (3CH3), 21.5 (CH3), 21.3 (CH ), 20.7 (CH ), 19.8 (CH ), 16.5 (CH ) ppm. IR (neat): ν
˜
3
3
3
3
20.8 (CH ) ppm. IR (neat): ν = 2976, 1724, 1640, 1451, 1242, = 2972, 1743, 1639, 1450, 1238, 1057 cm–1. HRMS (ESI): m/z
˜
3
1054 cm–1. HRMS (ESI): m/z calcd. for C35H41N2O7 [M + H]+ calcd. for C31H41N2O7 [M + H]+ 553.2908; found 553.2885; calcd.
601.2908; found 601.2901; calcd. for C35H40N2NaO7 [M + Na]+ for C31H40N2NaO7 [M + Na]+ 575.2728; found 575.2715.
623.2728; found 623.2727.
(3S,5S)-5-tert-Butoxy-2-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonyl-
amino)-2-phenylacetyl]-3-methylisoxazolidin-3-ylmethyl Acetate
(8d): Obtained according to the general procedure (70 °C, 30 min,
MW), from 7c (80 mg, 0.35 mmol) as an oil, yield 100 mg
9H-Fluoren-9-ylmethyl (2S)-2-[(3S,5S)-3-(Acetoxymethyl)-5-tert-
butoxy-3-methylisoxazolidin-2-ylcarbonyl]pyrrolidine-1-carboxylate
(8b): Obtained according to the general procedure (70 °C, 30 min,
MW), from 7c (80 mg, 0.34 mmol) as an oil, yield 95 mg
(0.17 mmol, 49%); 80:20 diastereomer ratio; Rf 0.47 (hexane/THF,
(0.17 mmol, 50%); Rf 0.23 (hexane/THF, 7:3, UV and vanilline vi-
1
7:3, UV and vanilline visualization). H NMR (400 MHz, CDCl3,
sualization); [α]2D0 = +2.91 (c = 0.94, CH2Cl2). This compound is a
25 °C): δ (major diastereoisomer) = 7.74 (d, J = 7.6 Hz, 2 H), 7.54
mixture of two rotamers in a 60:40 ratio. 1H NMR (400 MHz,
(dd, J = 5.9, 6.5 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.32–7.12 (m,
CDCl3, 25 °C): δ (major rotamer) = 7.75 (d, J = 7.2 Hz, 2 H), 7.61
7 H), 6.24 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 8.0 Hz, 1 H), 5.37 (dd,
(dd, J = 3.1, 7.2 Hz, 2 H), 7.39 (d, J = 7.2 Hz, 2 H), 7.30 (td, J =
J = 1.0, 5.5 Hz, 1 H), 4.55 (d, J = 11.2 Hz, 1 H), 4.32 (m, 2 H),
1.6, 7.2 Hz, 2 H), 5.47 (dd, J = 1.0, 5.4 Hz, 1 H), 4.74 (dd, J = 2.1,
4.18 (t, J = 7.2 Hz, 1 H), 4.08 (d, J = 11.2 Hz, 1 H), 2.47 (dd, J =
8.6 Hz, 1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.42 (dd, J = 7.5, 10.3 Hz,
5.5, 12.7 Hz, 1 H), 2.00 (dd, J = 1.0, 12.7 Hz, 1 H), 1.76 (s, 3 H),
1 H), 4.29 (dd, J = 7.1, 7.4 Hz, 1 H), 4.22 (d, J = 11.0 Hz, 1 H),
1.71 (s, 3 H), 1.31 (s, 9 H) ppm. δ (characteristic signals of minor
4.19 (dd, J = 7.1, 10.3 Hz, 1 H), 3.73 (m, 1 H), 3.56 (m, 1 H), 2.52
diastereoisomer) = 5.99 (d, J = 8.8 Hz, 1 H), 5.76 (d, J = 8.6 Hz,
(dd, J = 5.4, 10.7 Hz, 1 H), 2.06 (s, 3 H), 2.2–1.9 (m, 4 H), 1.98
1 H), 5.40 (dd, J = 1.7, 5.6 Hz, 1 H), 4.63 (d, J = 11.0 Hz, 1 H),
(dd, J = 1.0, 10.7 Hz, 1 H), 1.69 (s, 3 H), 1.31 (s, 9 H) ppm; δ
2.55 (dd, J = 5.4, 12.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3,
(minor rotamer) = 7.74 (dd, J = 2.6, 7.2 Hz, 2 H), 7.66 (dd, J =
25 °C): δ (major diastereoisomer) = 170.3, 164.1, 155.2, 144.0,
4.1, 7.2 Hz, 2 H), 7.36 (dd, J = 2.6, 7.2 Hz, 2 H), 7.29 (dt, J = 1.6,
143.9, 141.2 (2 C), 138.2, 128.5 (2CH), 127.9 (CH), 127.8 (2CH),
7.2 Hz, 2 H), 5.49 (dd, J = 1.5, 5.5 Hz, 1 H), 4.81 (dd, J = 2.6,
127.6 (2CH), 127.0 (2CH), 125.3 (CH), 125.2 (CH), 119.9 (2CH),
8.8 Hz, 1 H), 4.55 (d, J = 11.0 Hz, 1 H), 4.42 (dd, J = 7.5, 10.3 Hz,
96.7 (CH), 75.9, 67.0 (CH2), 64.9 (CH2), 63.4, 56.2 (CH), 47.1
1 H), 4.29 (dd, J = 7.1, 7.4 Hz, 1 H), 4.28 (d, J = 11.0 Hz, 1 H),
(CH), 45.4 (CH2), 28.7 (3CH3), 21.4 (CH3), 20.4 (CH3) ppm. δ
4.19 (dd, J = 7.1, 10.3 Hz, 1 H), 3.73 (m, 1 H), 3.56 (m, 1 H), 2.55
(characteristic signals of minor diastereoisomer) = 170.6, 164.6,
(dd, J = 5.5, 10.7 Hz, 1 H), 2.07 (s, 3 H), 2.2–1.9 (m, 4 H), 2.03
155.6, 75.8, 67.9 (CH2), 65.7 (CH2), 63.6, 55.7 (CH) ppm. IR
(dd, J = 1.5, 10.7 Hz, 1 H), 1.71 (s, 3 H), 1.19 (s, 9 H) ppm. 1H
(neat): ν = 2976, 1744, 1639, 1450, 1238 cm–1. HRMS (DCI, NH ):
˜
3
NMR (400 MHz, CDCl3, 60 °C): δ (characteristic signals) = 7.75
(d, J = 7.2 Hz, 2 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.61 (d, J = 7.2 Hz,
1 H), 7.39 (d, J = 7.2 Hz, 2 H), 7.30 (d, J = 7.2 Hz, 2 H), 5.47 (m,
1 H), 4.78 (m, 1 H), 4.55–4.15 (m, 5 H), 2.52 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ (major rotamer) = 170.4, 167.4,
154.9, 144.5, 144.0, 141.3, 141.1, 127.3 (2CH), 127.1 (2CH), 125.6
(2CH), 125.5 (2CH), 96.4 (CH), 75.7, 67.3 (CH2), 65.7 (CH2), 63.2,
58.8 (CH), 47.3 (CH), 46.8 (CH2), 45.8 (CH2), 34.2 (CH2), 28.6
(3CH3), 22.7 (CH2), 21.7 (CH3), 20.8 (CH3) ppm; δ (minor rot-
amer) = 170.3, 167.1, 154.8, 144.4, 144.3, 141.2, 135.8, 127.0
(2CH), 126.9 (2CH), 125.4 (2CH), 125.3 (2CH), 96.6 (CH), 75.6,
68.0 (CH2), 65.5 (CH2), 63.3, 58.7 (CH), 47.5 (CH), 47.4 (CH2),
45.9 (CH2), 34.3 (CH2), 28.7 (3CH3), 22.6 (CH2), 22.0 (CH3), 20.8
m/z calcd. for C34H38N2O7 [M + H+] 587.2757; found 587.2745.
(3S,5S)-5-tert-Butoxy-2-[(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-
yl)-3-methylbutyryl]-3-methylisoxazolidin-3-ylmethyl Acetate (8e):
Obtained according to the general procedure (110 °C, 60 min,
MW), from 7c (12 mg, 0.052 mmol) as an oil in an inseparable
60:40 mixture with remaining phthalyl valine (19 mg, 0.030 mmol
8e, estimated yield 58%). Rf 0.45 (cyclohexane/EtOAc, 1:1, UV and
vanilline visualization). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.85 (dd, J = 3.2, 5.4 Hz, 2 H), 7.70 (dd, J = 2.9, 5.4 Hz, 2 H), 5.44
(dd, J = 2.0, 5.4 Hz, 1 H), 4.86 (d, J = 10.0 Hz, 1 H), 4.59 (d, J =
11.2 Hz, 1 H), 4.27 (d, J = 11.2 Hz, 1 H), 3.03 (m, 1 H), 2.51 (dd,
J = 5.4, 12.5 Hz, 1 H), 2.06 (s, 3 H), 1.97 (dd, J = 2.0, 12.7 Hz,
1 H), 1.59 (s, 3 H), 1.17 (s, 9 H), 1.11 (d, J = 6.8 Hz, 3 H), 0.93 (d,
J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
170.5, 168.0, 163.2, 133.9 (CH), 131.9, 123.4 (CH), 96.6 (CH), 75.8,
65.5 (CH2), 63.6, 58.1 (CH), 45.5 (CH2), 28.3 (3CH3), 27.5 (CH),
(CH ) ppm. IR (neat): ν = 2976, 1745, 1707, 1655, 1418, 1239 cm–1.
˜
3
HRMS (ESI): m/z calcd. for C31H38N2O7 [M + H]+ 551.2752;
found 551.2723; calcd. for C31H37N2NaO7 [M + Na]+ 573.2571;
found 573.2555.
(3S,5S)-5-tert-Butoxy-2-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonyl- 21.4 (CH ), 20.8 (CH ), 19.9, 19.8 (2CH ) ppm. IR (neat): ν =
˜
3
3
3
amino)-3-methylbutyryl]-3-methylisoxazolidin-3-ylmethyl Acetate
(8c): Obtained according to the general procedure (70 °C, 30 min,
2973, 1743, 1638, 1450, 1238, 1056 cm–1. HRMS (DCI, NH3): m/z
calcd. for C24H32N2O7 [M + H+] 461.2288; found 461.2294.
Eur. J. Org. Chem. 2015, 3923–3934
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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M. Y. Laurent et al.
FULL PAPER
(2S)-2-[(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-
propionylamino]-2-methyl-4-oxobutyl Acetate (9a): A mixture of ad-
duct 8a (100 mg, 0.166 mmol) and Mo(CO)6 (2 equiv.) was dis-
solved in a mixture of acetonitrile and water (10:3 v/v, 0.07 m). The
mixture was heated for 3 d and then evaporated under vacuum.
The residue was partitioned between ethyl acetate and brine, and
the aqueous phase was extracted three times with ethyl acetate. The
organic phase was dried with MgSO4, filtered, and concentrated
under reduced pressure to give a residue, which is purified by pre-
parative silica gel chromatography (hexane/THF, 1:1) to give 9a as
an oil, yield 33 mg (0.062 mmol, 38%); Rf 0.43 (hexane/THF, 7:3,
UV and vanilline visualization); [α]2D0 = –1.1 (c = 0.52, CH2Cl2).
1H NMR (400 MHz, CDCl3, 25 °C): δ = 9.59 (d, J = 2.0 Hz, 1 H),
7.76 (d, J = 7.5 Hz, 2 H), 7.55 (dd, J = 4.3, 7.6 Hz, 2 H), 7.40 (dd,
J = 7.3, 7.5 Hz, 2 H), 7.35–7.18 (m, 5 H), 7.31 (dd, J = 4.3, 7.5 Hz,
2 H), 6.13 (br. s, 1 H), 5.34 (br. s, 1 H), 4.43 (dd, J = 7.2, 10.4 Hz,
1 H), 4.40–4.25 (m, 2 H), 4.20 (dd, J = 6.9, 7.2 Hz, 1 H), 4.13 (d,
J = 11.3 Hz, 1 H), 4.05 (d, J = 11.3 Hz, 1 H), 3.15–3.05 (m, 1 H),
3.05–2.95 (m, 1 H), 2.92 (dd, J = 2.0, 16.4 Hz, 1 H), 2.84 (dd, J
= 2.0, 16.4 Hz, 1 H), 1.98 (s, 3 H), 1.30 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 199.6, 170.8, 170.6, 155.8, 143.7,
143.6, 141.3 (2 C), 136.3, 129.4–127.1 (9CH), 125.5 (2CH), 120.0
(2CH), 68.3 (CH2), 67.1 (CH2), 56.7 (CH), 54.7, 48.2 (CH2), 47.1
1 H), 4.20 (dd, J = 3.9, 11.7 Hz, 1 H), 4.15 (dd, J = 10.3, 11.5 Hz,
1 H), 3.65 (s, 3 H), 3.57 (d, J = 13.7 Hz, 1 H), 2.42 (d, J = 13.7 Hz,
1 H), 1.75 (s, 3 H), 1.55 (s, 3 H) ppm. δ (characteristic signals of
minor diastereoisomer) = 3.05 (d, J = 13.4 Hz, 1 H), 2.83 (d, J =
13.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 174.4,
171.5, 135.6, 128.7 (2CH), 128.6 (CH), 127.5 (2CH), 83.4, 70.2,
69.9 (CH2), 62.8 (CH), 52.6 (CH3), 49.4 (CH2), 26.4 (CH3), 24.9
(CH ) ppm. IR (neat): ν = 2925, 1748, 1721, 1279, 1147 cm–1
.
˜
3
HRMS (ESI): m/z calcd. for C16H19NNaO5 [M + Na+] 328.1155;
found 328.1154.
(2R,3aS,7S)-3a-Ethyl-2-methyl-4-oxo-7-phenyl-hexahydroisox-
azolo[3,2-c][1,4]oxazine-2-carbaldehyde (10c): Obtained by follow-
ing the general procedure (90 °C, 4 h, MW), starting from nitrone
3c (72 mg, 0.33 mmol) and methacrolein (1.5 mL, 18 mmol,
55 equiv.). Purified by chromatography on silica gel (cyclohexane/
ethyl acetate, 7:3) as a white solid, yield 80 mg (0.28 mmol, 84%);
dr 96:4:0:0; Rf 0.48 (cyclohexane/ethyl acetate, 7:3, UV visualiza-
1
tion). H NMR (400 MHz, CDCl3, 25 °C): δ (major diastereoiso-
mer) = 9.48 (s, 1 H), 7.37–7.40 (m, 5 H), 4.13 (m, 2 H), 3.88 (dd, J
= 5.4, 8.2 Hz, 1 H), 3.37 (d, J = 13.7 Hz, 1 H), 2.27 (d, J = 13.7 Hz,
1 H), 2.09 (m, 2 H), 1.37 (s, 3 H), 1.13 (t, J = 7.1 Hz, 3 H) ppm. δ
(characteristic signals of minor diastereoisomer) = 9.60 (s, 1 H),
4.27–4.34 (m, 3 H), 2.85 (d, J = 13.4 Hz, 1 H), 2.73 (d, J = 13.9 Hz,
1 H), 1.34 (s, 3 H), 1.02 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 200.8, 170.8, 135.1, 129.1 (2CH),
128.9 (CH), 127.7 (2CH), 86.5, 76.0, 70.1 (CH2), 62.7 (CH), 44.9
(CH), 38.5 (CH ), 22.2 (CH ), 20.7 (CH ) ppm. IR (neat): ν = 3065,
˜
2
3
3
2927, 1721, 1661, 1539, 1236, 1043 cm–1. HRMS (DCI, NH3): m/z
calcd. for C31H33N2O6 [M + H+] 529.2339; found 529.2347.
General Procedure for the [3+2] Cycloaddition of Cyclic Ketonitrones
(3b–e) with Electron-Poor Dipolarophiles: Nitrone (1 equiv.) and di-
polarophile were heated under the specified conditions with micro-
wave irradiation. The reaction mixture was then concentrated un-
der reduced pressure and the residue was purified by chromatog-
raphy on silica gel.
(CH ), 32.2 (CH ), 21.4 (CH ), 10.0 (CH ) ppm. IR (neat): ν =
˜
2 2 3 3
2942, 1728, 1182, 1042 cm–1. HRMS (CI, NH3): m/z calcd. for
C16H20NO4 [M + H+] 290.1392; found 290.1382.
Methyl (2R,3aS,7S)-2,3a-Dimethyl-4-oxo-7-phenyl-hexahydroisox-
azolo[3,2-c][1,4]oxazine-2-carboxylate (10d): Obtained by following
the general procedure (90 °C, 4 h, MW), starting from nitrone 3c
(2R,3aS,7S)-2,3a-Dimethyl-4-oxo-7-phenyl-hexahydroisoxazolo- (76 mg, 0.35 mmol) and methyl methacrylate (1.5 mL, 14 mmol,
[3,2-c][1,4]oxazine-2-carbaldehyde (10a): Obtained by following the
general procedure (90 °C, 7 h, MW), starting from nitrone 3b
(63 mg, 0.31 mmol) and methacrolein (0.15 mL, 1.8 mmol,
6 equiv.). Purified by chromatography on silica gel (cyclohexane/
40 equiv.), as a white foam (0.84 g). Purified by chromatography on
silica gel (cyclohexane/ethyl acetate, 7:3) as a white foam, yield
0.115 g (0.35 mmol, Ͼ95%); dr 97:3:0:0; Rf 0.42 (cyclohexane/ethyl
acetate, 7:3, UV visualization). 1H NMR (400 MHz, CDCl3,
ethyl acetate, 9:1) as a yellow oil, yield 43 mg (0.20 mmol, 79%); 25 °C): δ (major diastereoisomer) = 7.33–7.43 (m, 5 H), 4.28 (dd,
dr 100:0:0:0; Rf 0.43 (cyclohexane/ethyl acetate, 7:3, UV visualiza-
tion); [α]2D0 = +5.5 (c = 1.14, CH2Cl2); GC (Restek β-Dex-sm
30 mϫ0.25 mm 0.25 μm, Helium, 120 °C 1 min, 2 °C/min, 200 °C
J = 3.7, 10.0 Hz, 1 H), 4.14 (dd, J = 3.9, 11.7 Hz, 1 H), 4.10 (dd,
J = 10.5, 11.5 Hz, 1 H), 3.65 (s, 3 H), 3.56 (d, J = 13.7 Hz, 1 H),
2.42 (d, J = 13.9 Hz, 1 H), 2.06 (m, 2 H), 1.52 (s, 3 H), 1.11 (t, J =
30 min, 3 mL/min, Tdet = 220 °C, Tinj = 220 °C): tR = 42.93 min. 7.3 Hz, 3 H) ppm. δ (characteristic signals of minor diastereoiso-
1H NMR (400 MHz, CDCl3, 25 °C): δ = 9.47 (s, 1 H), 7.36–7.40 mer) = 3.15 (d, J = 13.7 Hz, 1 H), 2.78 (d, J = 13.4 Hz, 1 H) ppm.
(m, 5 H), 4.17 (d, J = 6.8 Hz, 2 H), 3.89 (t, J = 6.8 Hz, 1 H), 3.36 13C NMR (100 MHz, CDCl3, 25 °C): δ = 174.7, 171.2, 135.8, 128.8
(d, J = 13.6 Hz, 1 H), 2.29 (d, J = 13.6 Hz, 1 H), 1.79 (s, 3 H), 1.41
(2CH), 128.6 (CH), 127.5 (2CH), 83.2, 75.3, 70.1 (CH2), 62.4 (CH),
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 200.6, 52.7 (CH3), 49.0 (CH2), 32.1 (CH2), 25.1 (CH3), 10.0 (CH3) ppm.
171.1, 134.8, 129.1 (2CH), 128.9 (CH), 127.7 (2CH), 86.8, 71.0, IR (neat): ν = 2931, 1733, 1719, 1151 cm–1. HRMS (CI, NH ): m/z
˜
3
70.1 (CH2), 62.9 (CH), 45.0 (CH2), 26.4 (CH3), 21.4 (CH3) ppm. calcd. for C17H22NO5 [M + H+] 320.1498; found 320.1494.
IR (neat): ν = 2931, 1728, 1455, 1395, 1144, 1071 cm–1. HRMS
˜
(2R,3aS,7S)-2-Methyl-4-oxo-3a,7-diphenyl-hexahydroisoxazolo-
[3,2-c][1,4]oxazine-2-carbaldehyde (10e): Obtained by following the
general procedure (90 °C, 4 h, MW), starting from nitrone 3d
(CI, NH3): m/z calcd. for C15H18NO4 [M + H+] 276.1236; found
276.1223.
Methyl (2R,3aS,7S)-2,3a-Dimethyl-4-oxo-7-phenyl-hexahydroisox- (42 mg, 0.16 mmol) and methacrolein (1.2 mL, 14.5 mmol,
azolo[3,2-c][1,4]oxazine-2-carboxylate (10b): Obtained by following
the general procedure (100 °C, 5 h, MW), starting from nitrone 3b
(53 mg, 0.26 mmol) and methyl methacrylate (0.16 mL, 1.54 mmol,
10 equiv.). Purified by chromatography on silica gel (cyclohexane/
90 equiv.). Purified by chromatography on silica gel (cyclohexane/
ethyl acetate, 8:2) as a brown oil, yield 42 mg (0.12 mmol, 78%);
dr 99:1:0:0; Rf 0.33 (cyclohexane/ethyl acetate, 8:2, UV visualiza-
1
tion). H NMR (400 MHz, CDCl3, 25 °C): δ (major diastereoiso-
ethyl acetate, 9:1) as a yellow solid, yield 51 mg (0.17 mmol, 65%); mer) = 9.50 (s, 1 H), 7.90 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 7.1 Hz,
dr 97:3:0:0. A crystal of pure major diastereomer was obtained by
long standing storage and was used for m.p. and X-ray analysis. Rf
0.67 (cyclohexane/ethyl acetate, 1:1, UV visualization); m.p. 130.0–
131.1 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ (major dia-
stereoisomer) = 7.30–7.45 (m, 5 H), 4.33 (dd, J = 3.9, 10.0 Hz,
2 H), 7.30–7.50 (m, 6 H), 4.42 (dd, J = 3.9, 11.0 Hz, 1 H), 4.22 (dd,
J = 3.9, 12.0 Hz, 1 H), 4.14 (dd, J = 11.0, 12.0 Hz, 1 H), 3.71 (d,
J = 13.6 Hz, 1 H), 2.71 (d, J = 13.6 Hz, 1 H), 1.16 (s, 3 H) ppm. δ
(characteristic signals of minor diastereoisomer) = 4.54 (d, J =
5.4 Hz, 1 H), 3.85 (d, J = 6.1 Hz, 1 H), 3.54 (dd, J = 4.6, 5.0 Hz,
3932
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3923–3934

[3+2] Route to Quaternary Oxaprolinol Derivatives
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 199.3 (CH), 7.1 Hz, 2 H), 3.98 (d, J = 13.9 Hz, 1 H), 3.51 (dd, J = 6.8, 9.5 Hz,
169.7, 138.7, 135.7, 130.0 (2CH), 128.9 (2CH), 128.8 (CH), 128.6
(CH), 127.6 (2CH), 126.7 (2CH), 86.5, 75.5, 69.4 (CH2), 65.1 (CH), 1 H), 1.29 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H) ppm. δ (minor dia-
48.6 (CH ), 20.2 (CH ) ppm. IR (neat): ν = 2925, 1735, 1455, stereoisomer) = 9.56 (s, 1 H), 7.26–7.41 (m, 5 H), 4.11 (m, 1 H),
1 H), 2.83 (dd, J = 6.8, 12.7 Hz, 1 H), 2.28 (dd, J = 9.8, 13.0 Hz,
˜
2
3
1043 cm–1. HRMS (CI, NH3): m/z calcd. for C20H20NO4 [M + H+] 4.20 (q, J = 7.1 Hz, 1 H), 4.01 (d, J = 13.4 Hz, 1 H), 3.79 (dd, J =
337.1392; found 337.1388.
4.4, 8.3 Hz, 1 H), 2.92 (dd, J = 8.6, 13.0 Hz, 1 H), 2.39 (dd, J =
4.2, 13.0 Hz, 1 H), 1.39 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ (major diastereoisomer) = 204.2 (CH),
169.6, 136.3, 129.0–127.6 (CH), 84.5, 66.7 (CH), 61.4 (CH2), 61.2
Methyl (2R,3aS,7S)-2-Methyl-4-oxo-3a,7-diphenyl-hexahydroisox-
azolo[3,2-c][1,4]oxazine-2-carboxylate (10f): Obtained by following
the general procedure (90 °C, 4 h, MW), starting from nitrone 3d
(40 mg, 0.15 mmol) and methyl methacrylate (1 mL, 9.3 mmol,
60 equiv.). Purified by chromatography on silica gel (cyclohexane/
ethyl acetate, 7:3) as a yellow oil, yield 64 mg (0.15 mmol, Ͼ 95%);
dr 91:9:0:0; Rf 0.43 (cyclohexane/ethyl acetate, 7:3, UV visualiza-
(CH ), 41.0 (CH ), 19.0 (CH ), 14.1 (CH ) ppm. IR (neat): ν =
˜
2
2
3
3
2980, 2934, 1737, 1674, 1454, 1273 cm–1. HRMS (CI, NH3): m/z
calcd. for C15H20NO4 [M + H+] 278.1392; found 278.1393.
X-ray Crystal Data: CCDC-1007248 (5c) and 1007249 (10b) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
tion). H NMR (400 MHz, CDCl3, 25 °C): δ (major diastereoiso-
mer) = 7.85 (m, 2 H), 7.53 (m, 2 H), 7.38 (m, 6 H), 4.96 (dd, J =
3.7, 11.5 Hz, 1 H), 4.16 (dd, J = 3.7, 11.7 Hz, 1 H), 4.06 (t, J =
11.7 Hz, 1 H), 3.75 (s, 3 H), 2.70, 3.88 (2d, J = 13.5 Hz, 2 H), 1.35
(s, 3 H) ppm. δ (characteristic signals of minor diastereoisomer) =
5.15 (d, J = 11.5 Hz, 1 H), 4.83 (d, J = 11.5 Hz, 1 H), 4.65 (d, J =
12.0 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.30 (d, J = 6.4 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.9, 169.9,
139.2, 136.7, 129.0 (2CH), 128.7 (2CH), 128.3 (2CH), 127.9 (2CH),
126.4 (2CH), 83.8, 74.8, 68.8 (CH2), 65.5 (CH), 53.1 (CH2), 52.9
Acknowledgments
Financial support of this study by the Agence Nationale de la Re-
cherche (ANR) (BS-07-00501) is gratefully acknowledged. The au-
thors also wish to thank Q. Blanc and F. Legros for technical assist-
ance, A. Durand for recording NMR spectra, P. Gangnery for re-
cording HRMS spectra, and K. Adil for recording crystallographic
structures.
(CH ), 23.2 (CH ) ppm. IR (neat): ν = 2952, 1741, 1198, 1115 cm–1.
˜
3
3
HRMS (CI, NH3): m/z calcd. for C21H22NO5 [M + H+] 368.1498;
found 368.1488.
Methyl (2R,4S)-4-(tert-Butoxycarbonylamino)-2,4-dimethyl-5-oxo-
tetrahydrofuran-2-carboxylate (11): To a solution of cycloadduct
10b (125 mg, 0.41 mmol) in MeOH (3 mL), was added Pd(OH)2
(10 %mol, C, 125 mg) under Ar. The mixture was placed under
1 atm of H2 and stirred for 5 h at room temp. The resulting mixture
was filtered through Celite and the solvents were evaporated. The
residue was diluted with MeCN (3 mL), then a saturated solution
of NaHCO3 (3 drops) and Boc2O (446 mg, 2 mmol, 5 equiv.) was
added and stirring was continued for 24 h at room temp. The mix-
ture was diluted with H2O (5 mL) and EtOAc (10 mL), and the
aqueous layer was extracted with EtOAc (2ϫ 10 mL). The organic
phases were dried with MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography (cyclo-
hexane/EtOAc, 1:1) to give a white solid, yield 71 mg (0.24 mmol,
60%); m.p. 159.1–160.3 °C; Rf 0.34 (cyclohexane/ethyl acetate, 1:1);
[α]2D0 = –13.4 (c = 0.37, CH2Cl2). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 4.93 (br. s, 1 H), 3.81 (s, 3 H), 2.72 (d, J = 13.6 Hz,
1 H), 2.66 (d, J = 13.6 Hz, 1 H), 1.75 (s, 3 H), 1.44 (s, 9 H), 1.40
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 176.2,
172.9, 154.2, 80.6, 71.2, 57.0, 53.0 (CH3), 44.6 (CH2), 28.3 (3CH3),
[1] For reviews on dipolar cycloaddition of nitrones, see: a) J. N.
Martin, R. C. F. Jones, in: Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
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New York, 2002, chapter 1, p. 1–82; b) K. V. Gothelf, in: Cyclo-
addition Reactions in Organic Synthesis (Eds.: S. Kobayashi,
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Jørgensen), Wiley-VCH, Weinheim, Germany, 2002; chapter 7,
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G. Dujardin, Org. Prep. Proced. Int. 2010, 42, 387–431; e) T. B.
Nguyen, A. Martel, C. Gaulon-Nourry, R. Dhal, G. Dujardin,
Org. Prep. Proced. Int. 2012, 44, 1–81.
[2] For a review on the use of 1,3-DC in total synthesis: a) V. Nair,
T. D. Suja, Tetrahedron 2007, 63, 12247–12275; b) A. Brandi,
F. Cardona, S. Cicchi, F. M. Cordero, A. Goti, Chem. Eur. J.
2009, 15, 7808–7821. For recent examples of total synthesis
including a 1,3-DC as key-step, see: c) D. Yang, G. C. Micali-
zio, J. Am. Chem. Soc. 2012, 134, 15237–15240; d) I. Coldham,
L. Watson, H. Adams, N. G. Martin, J. Org. Chem. 2011, 76,
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ella, Org. Lett. 2007, 9, 1769–1772.
25.1 (CH ), 24.0 (CH ) ppm. IR (neat): ν = 3363, 2983, 1793, 1747,
˜
3
3
1708, 1160, 1083 cm–1. HRMS (CI, NH3): m/z calcd. for
C13H22NO6 [M + H+] 288.1440; found 288.1447.
[3] a) V. K. Aggarwal, S. Roseblade, R. Alexander, Org. Biomol.
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Ethyl (3R*,5S*)-2-Benzyl-5-formyl-5-methylisoxazolidine-3-carb-
oxylate (12): N-(1-Ethoxy-1-oxoethylidene)-1-phenylmethanamine
oxide (106 mg, 0.51 mmol) and methacroleine (0.42 mL, 5.1 mmol,
10 equiv.) were heated at 90 °C for 26 h in a sealed tube. The reac-
tion mixture was then concentrated under reduced pressure and the
residue was purified by chromatography on silica gel (cyclohexane/
ethyl acetate 9:1) as a yellow oil, yield 89.5 mg (0.32 mmol, 63%);
dr 70:30; Rf 0.36 (cyclohexane/ethyl acetate, 8:2, UV visualization).
GC (DB-5MS, 30 m ϫ 0.32 mm 0.25 μm, Helium, 80 °C 1 min,
5 °C/min, 200 °C 30 min, 3.5 mL/min, Tdet = 220 °C, Tinj = 220 °C):
tR = 18.88 (major diastereomer), 19.24 (minor diastereomer) min.
1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) = 9.56 (s,
1 H), 7.26–7.41 (m, 5 H), 4.28 (d, J = 13.9 Hz, 1 H), 4.11 (q, J =
[5] a) T. B. Nguyen, A. Beauseigneur, A. Martel, R. Dhal, M.
Laurent, G. Dujardin, J. Org. Chem. 2010, 75, 611–620; b) X.
Eur. J. Org. Chem. 2015, 3923–3934
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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M. Y. Laurent et al.
FULL PAPER
Zhang, P. Cividino, J.-F. Poisson, P. Shpak-Kraievskyi, M. Y.
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nitrone relative to the functional group of the dipolarophile
(ester, aldehyde, alkoxy substituents).
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Okada, Y. Morishita, C. Kaneko, Chem. Commun. 1996, 2137–
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Aspartic ketonitrones, as other ester ketonitrones, exhibit a sin-
gle and stable E geometry (see ref.[5a,5c]) and proved to favor the
formation of trans isoxazolidines in thermal 1,3-DC reactions
involving vinyl ethers as the dipolarophile, as a result of a pre-
ferred exo-approach. See: T. B. Nguyen, A. Martel, R. Dhal,
G. Dujardin, Org. Lett. 2008, 10, 4493–4496.
Ester aldonitrones exist as an E/Z mixture, which contribute
to a poor diastereoselectivity during cycloaddition, irrespective
of the type of dipolarophile involved. For example, with ethyl
vinyl ether, the trans/cis selectivity is around 78:22 (ref.[8c]), see:
a) Y. Inouye, J. Hara, H. Kakisawa, Chem. Lett. 1980, 1407–
1410; b) Y. Inouye, K. Takaya, H. Kakisawa, Bull. Chem. Soc.
Jpn. 1983, 56, 3541–3542; c) O. Tamura, N. Mita, Y. Imai, T.
Nishimura, T. Kiyotani, M. Yamasaki, M. Shiro, N. Morita, I.
Okamoto, T. Takeya, H. Ishibashi, M. Sakamoto, Tetrahedron
2006, 62, 12227–12236.
[15] The two major diastereoisomers were attributed to both trans
1
adducts, as shown by the typical signals in the H NMR spec-
tra of the CH2 group of the isoxazolidine ring (i.e., 6b 2.92/
2.45 for the major trans diastereomer; 2.95/2.68 for the minor
trans diastereomer).
[16] Saponification attempts include aqueous lithium hydroxide
(1N, 1.2 to 2 equiv. ) in THF or MeOH at 0–36 °C. After 3 d
at room temp., conversion was less than 30%.
[17] Diastereoisomeric purification was only rarely possible from
bicyclic adducts.
[18] Classical peptidic conditions were tested such as EDCI/DMAP,
EDCI/HOBt, IBCF/NMM, HATU/DIPEA. Starting materials
were recovered under all these conditions.
[19] All amino acyl chlorides were prepared by following known
procedures: a) L. A. Carpino, B. J. Cohen, K. E. Stephens, S. Y.
Sadat-Aalaee, J.-H. Tien, D. C. Langridge, J. Org. Chem. 1986,
51, 3734–3736; b) L. A. Carpino, J. Org. Chem. 1988, 53, 875–
878; c) T. Oshikawa, M. Yamashita, Bull. Chem. Soc. Jpn. 1990,
63, 2728–2730.
[20] Epimerization was found to occur when a base, such as pyr-
idine, was added to trap hydrogen chloride or when the solvent
was changed to chloroform or acetonitrile. It was also shown
that, to avoid epimerization, shorter reaction times under mi-
crowave irradiation were preferable to longer thermic reactions.
[21] α-Peptide aldehydes are known to be sensitive to epimerization,
see: a) C. Ganneau, A. Moulin, L. Demange, J. Martinez, J.-
A. Fehrentz, J. Pept. Sci. 2006, 12, 497–501 and references cited
therein. For other nonepimerizable β-amino-aldehydes ob-
tained by a cycloaddition method, see for example: b) P.
Shpak-Kraievskyi, B. Yin, A. Martel, R. Dhal, G. Dujardin,
M. Y. Laurent, Tetrahedron 2012, 68, 2179–2188.
[7]
[8]
[9] Cycloaddition of ester ketonitrones to ethyl vinyl ether show a
clear influence of the steric bulk of the nitrone substituent
(ref.[5a]). For instance, the trans/cis ratio of isoxazolidines vary
from 75:25 (R = Me, ref.[5a]) to 92:8:91:9 (R = CH2CO2Me and
CH2CH2CO2Me, ref.[5a,7]).
[10] a) O. Tamura, K. Gotanda, R. Terashima, M. Kikuchi, T. Mi-
yawaki, M. Sakamoto, Chem. Commun. 1996, 1861–1862; b)
O. Tamura, T. Kuroki, Y. Sakai, J.-I. Takizawa, J. Yoshino, Y.
Morita, N. Mita, K. Gotanda, M. Sakamoto, Tetrahedron Lett.
1999, 40, 895–898; c) O. Tamura, K. Gotanda, J. Yoshino, Y.
Morita, R. Terashima, M. Kikuchi, T. Miyawaki, N. Mita, M.
Yamashita, H. Ishibashi, M. Sakamoto, J. Org. Chem. 2000,
65, 8544–8551; d) O. Tamura, T. Shiro, A. Toyao, H. Ishibashi,
Chem. Commun. 2003, 2678–2679; e) Ref.[6d]; f) S. W. Baldwin,
B. G. Young, A. T. McPhail, Tetrahedron Lett. 1998, 39, 6819–
6822; g) A. Long, S. W. Baldwin, Tetrahedron Lett. 2001, 42,
5343–5345.
[11] For other diastereoselective cycloadditions involving lactone-
or lactam-containing aldonitrones equipped with a chiral auxil-
iary, see: a) ref.[4a,6b–c,6f–h]; b) S. W. Baldwin, A. Long, Org.
Lett. 2004, 6, 1653–1656; c) P.-F. Wang, P. Gao, P.-F. Xu, Syn-
lett 2006, 1095–1099; d) K. Aouadi, S. Vidal, M. Msaddek, J.-
P. Praly, Synlett 2006, 3299–3303; e) K. Aouadi, E. Jeanneau,
M. Msaddek, J.-P. Praly, Synthesis 2007, 3399–3405; f) for in-
tramolecular version of cycloaddition involving a cyclic ester-
nitrone, see: R. E. Looper, M. T. C. Runnegar, R. M. Williams,
Tetrahedron 2006, 62, 4549–4562, and references cited therein.
[12] Throughout this work, trans/cis selectivity refers to the position
in the cycloadduct of the ester function (or lactone) of the
[22] Cycloaddition of N-benzyl ester aldonitrone with methacrolein
gave the trans cycloadduct with a 70:30 diastereoisomeric ratio:
In the case of ester ketonitrones of alanine-type, the diastereo-
isomeric ratio of cycloaddition in thermic conditions was typi-
cally around 70:30 (see ref.[22b]). Notably, efficient catalytic
asymmetric cycloadditions were developed from the same
nitrones with differently substituted enals as dipolarophiles,
see: a) K. B. Selim, A. Beauchard, J. Lhoste, A. Martel, M. Y.
Laurent, G. Dujardin, Tetrahedron: Asymmetry 2012, 23, 1670–
1677; b) K. B. Selim, A. Martel, M. Y. Laurent, J. Lhoste, S.
Py, G. Dujardin, J. Org. Chem. 2014, 79, 3414–3426.
[23] Other electron-poor dipolarophiles as acrolein or crotonalde-
hyde were tested and gave mixtures of regioisomers (3,5 vs.
3,4), see for example: S. Kanemasa, N. Ueno, M. Shirahase,
Tetrahedron Lett. 2002, 43, 657–660.
Received: March 12, 2015
Published Online: May 6, 2015
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