MiPNO, a new chiral cyclic nitrone for enantioselective amino acid synthesis: The cycloaddition approach

Article abstract of DOI:10.1039/b918612c

The resolution of chiral nitrones via derivatization of hydroxylamines was applied to MiPNO, a new, stable, easily prepared chiral cyclic nitrone. The application of MiPNO in totally regio- and diastereo-selective 1,3-dipolar cycloaddition reactions provides an expeditious enantioselective access to unusual γ-hydroxy α-amino acids. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b918612c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
MiPNO, a new chiral cyclic nitrone for enantioselective amino acid synthesis:
the cycloaddition approach†
Maryse Thiverny, Christian Philouze, Pierre Yves Chavant and Ve´ronique Blandin*
Received 8th September 2009, Accepted 11th November 2009
First published as an Advance Article on the web 22nd December 2009
DOI: 10.1039/b918612c
The resolution of chiral nitrones via derivatization of hydroxylamines was applied to MiPNO, a new,
stable, easily prepared chiral cyclic nitrone. The application of MiPNO in totally regio- and
diastereo-selective 1,3-dipolar cycloaddition reactions provides an expeditious enantioselective access
to unusual g-hydroxy a-amino acids.
Introduction
The regio- and diastereo- selective 1,3-dipolar cycloaddition
reaction of chiral nitrones with dipolarophiles is a powerful tool
for obtaining chiral nitrogenated compounds.1 In particular, when
a-alkoxycarbonyl or a-alkylaminocarbonyl nitrones are used,
the cycloaddition reaction with alkenes followed by cleavage
of the N–O bond leads to side chain-functionalized chiral a-
amino acid derivatives.2 In order to gain a high stereoselectivity
in the cycloaddition reaction, overcoming the problem of E/Z
isomerization around the nitrone double bond is important.3
Small-ring endocyclic chiral nitrones are thus good candidates
and their more rigid cyclic skeleton compared to acyclic nitrones
is another asset in obtaining high stereoselectivity. Several five-4
and six-5membered chiral cyclic nitrones of this type have been
previously designed.6
In parallel to our work in the field of N-hydroxy peptide
synthesis and application,7 we sought access to N-hydroxy amino
acids via the addition of functionalized organometallic reagents8
on to properly designed enantiopure nitrones. To this end, we
designed a series of chiral nitrones4d,e obtained by oxidation of
imidazolidinones and based on the self-regeneration of stereo-
centers principle.9 In our continuing efforts to provide storable
reagents and intermediates using inexpensive starting materials
and scalable syntheses,10 we developed the new chiral nitrone 1
Scheme 1 Preparation of MiPNO 1.
(MiPNO) that turned out to feature an excellent thermal stability.
Condensation of amino amide 2 with 3-methyl-butanone led
This made 1 a good candidate for 1,3-dipolar cycloaddition
exclusively to the desired cyclic product 3. Oxidation of 3 was
reactions that usually require prolonged heating. We report herein
performed using urea–hydrogen peroxide (UHP) complex in the
the synthesis of 1 and its evaluation as a successful substrate for
presence of inexpensive sodium tungstate as the catalyst.11 The
whole process was routinely carried out on a 200 mmole scale.
diastereoselective 1,3-dipolar cycloaddition reactions.
After recrystallization the yield of 1, over three steps, was typically
54%. Nitrone 1 could be stored at room temperature for months
without noticeable degradation.
Results and discussion
Nitrone 1 was conveniently prepared in three steps according
to Scheme 1, starting from glycine ethyl ester hydrochloride.
X-Ray analysis of 112 showed a planar ring with one side
hindered by the isopropyl group. In order to evaluate its level
of diastereoinduction, nitrone 1 was engaged in 1,3-dipolar
cycloaddition reactions with a wide range of alkenes (Table 1),
either in neat conditions or using toluene as the solvent.13 The
reaction was highly regio- and diastereo-selective, the nitrone
reacting from the less hindered side in an exo mode to give
cycloadducts 5a–h.14 The NMR and LC/MS analysis of the crude
products indicated an isomeric purity of more than 98% in all cases
except in the case of the acetal 5d (Table 1, entry 4). Nevertheless,
De´partement de Chimie Mole´culaire, UMR-5250, ICMG FR-2607, CNRS,
Universite´ Joseph Fourier, BP-53, 38041, Grenoble, Cedex 9, France. E-mail:
Veronique.Blandin@ujf-grenoble.fr
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra for all new compounds, NOESY spectra for 5f and 5h,
description of the microwave irradiation parameters, ORTEP drawings
of 1 and 10a. CCDC reference numbers 747517 and 747518. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b918612c
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Table 1 1,3-Dipolar cycloaddition of racemic nitrone 1 to alkenes 4a–h and alkyne 6
Entry
1
Dipolarophile 4 or 6
Cycloadducta
Yield (%)b
87 (94)c
4a
4b
4c
5a
5b
5c
2
3
94 (86)c
90
4
5
6
4d
4e
4f
5d
5e
5f
88d
84
80 (80)c
7
8
4g
4h
5g
5h
74 e(65)c,e
90f
9
6
7
73g
a Unless otherwise stated, reactions were performed in a sealed vessel at 80 ◦C for 3–16 h, using 10 equiv. 4 or 6 without solvent. The main isomer,
representing ≥98% of the cycloadducts in the crude product (LC/MS), is shown. b Yield of the isolated main isomer. c Starting from (-)-(R)-1. d Isomeric
purity of the crude product ≥95%. e Toluene was used as a cosolvent. Reaction time: 48 h, 90% conversion. f 1.2 equiv. alkene were used, in toluene.
g 2 equiv. alkyne were used, in toluene. The monocyclic isomer 7¢ resulting from b-elimination was isolated in 20% yield.
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after chromatographic purification all compounds were isolated
as pure cycloadducts in excellent yield.
Alkyne dipolarophiles are seldom reported in the reaction with
nitrones1a and the cycloadducts are prone to rearrangement.5c In
our hands, no reaction occurred between nitrone 1 and propargylic
alcohol or protected derivatives thereof. However, phenylacetylene
reacted smoothly to give the expected cycloadduct 7 in 73%
isolated yield (entry 9). An open-chain enol-imine or keto-enamine
by-product 7¢ derived from 7 through b-elimination15 was also
isolated in 20% yield (Scheme 2).
Scheme 4 Resolution of MiPNO: derivatization of hydroxylamine 9.
and imine. Nevertheless, submitting the mixture of diastereomers
to medium pressure liquid chromatography allowed the isolation
of the first eluted diastereomer 10a as a solid in 32% yield.
On the basis of the relative configuration obtained by X-ray
analysis of recrystallized 10a (Fig. 1),19 the stereochemistry of
the imidazolidinone moiety is (R).
Scheme 2 Tautomeric structures of by-product 7¢.
To elaborate the amino acid side chain further, reductive cleav-
age of the N–O bond was investigated (Scheme 3). Hydrogenolysis
of 5e and 5f under transfer conditions afforded amino alcohols 8e
and 8f in good isolated yield. In the case of 5f, a 9 : 1 mixture of
diastereomers was obtained.16 For the styrene-derived cycloadduct
5c, the reductive cleavage was performed using zinc in acetic acid,
leading to amino alcohol 8c in excellent yield.
Fig. 1 ORTEP drawing of 10a. The ellipsoids are plotted at the 25%
probability level.
Treatment of 10a with basic aqueous hydrogen peroxide
overnight allowed the one-pot liberation of the hydroxylamine and
its oxidation into the nitrone (-)-(R)-1. More efficiently, MnO2
may be added as soon as the first step is completed in order to
accelerate the process (Scheme 5).
Scheme 3 Reductive cleavage of the N–O bond.
In order to obtain MiPNO 1 in enantiomerically pure form, we
decided to use a strategy under development in our group, namely
the resolution of secondary hydroxylamines via O-acylation with
a chiral carboxylic acid.17 The nitrone 1 was thus converted
into the N-hydroxy-imidazolidinone 9 by reduction with sodium
borohydride (Scheme 4).
Interestingly, this reduction was clean when THF was the
solvent, whereas the reduction in MeOH was accompanied by
the formation in large amounts (30%) of the imine resulting
from dehydration of 9. Moc-Phe-OH18 was chosen as the chiral
derivatizing agent for its ability to provide chromatographically
separable diastereomers. The 1 : 1 mixture of diastereomers 10 was
obtained in high yield.
Scheme 5 Resolution of MiPNO: one-pot removal of resolving agent and
oxidation.
Unfortunately, the O-acylated hydroxylamine proved to be very
sensitive to silica gel and partially decomposed into Moc-Phe-OH
The enantiomeric excess of (-)-1 was above 99% as deter-
mined by chiral HPLC analysis. The nitrone (-)-1 proved to be
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configurationally stable when purified◦by chromatography on silica
gel4c or when heated in toluene at 80 C for 16 h.
equipped with a gas addition kit. Melting points were deter-
mined in capillary tubes with a Bu¨chi B-540 apparatus. Optical
rotations were measured on a Perkin Elmer 341 polarimeter, the
corresponding concentration is given in g per 100 cm3. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Varian 400MR spectrometer in CDCl3 (dH 7.26 ppm; dC
77.2 ppm; standard for 1H spectra: tetramethylsilane dH 0.0 ppm).
NOESY experiments were run on a Unity Plus 500 MHz Varian.
Multiplicities are reported as follows: s = singlet, d = doublet,
t = triplet, q = quadruplet, quint = quintuplet, hept = heptuplet,
m = multiplet, br = broad, coupling constants J are reported
The 1,3-dipolar cycloaddition of enantiopure MiPNO (-)-1
with several alkenes gave results consistent with those obtained
for the racemic series (Table 1, entries 1, 2, 6 and 7). The N–O
bond of (-)-5f was cleaved using method A (Scheme 2) and (+)-8f
was obtained in 67% yield. Next, the tricyclic compound (+)-5g
was chosen to investigate the transformation of cycloadducts into
conveniently N-protected amino acids (Scheme 6). We developed
a microwave-assisted procedure where acidic hydrogenolytic con-
ditions allow the one-pot cleavage of the N–O, amide, and N–C–N
bonds.20 The crude a-amino-g-lactone21 was Boc-protected to give
after chromatography (-)-11 as a single isomer in 42% yield from
(+)-5g. This is to our knowledge the first preparation of 11 in
enantiopure form.
1
in Hz. H and 13C resonance assignments were performed using
conventional 1D and 2D techniques (DEPT, COSY, HMQC and
HMBC experiments). Relative stereochemistry was assigned using
NOESY experiments. Infrared spectra (IR) were obtained either
from a thin film or from a dispersion of the compound in a
KBr pellet. IR spectra were recorded on a Nicolet Impact-400
FT-IR spectrometer and the data are reported as absorption
maxima in cm-1. Mass spectra (LRSM) were recorded on an
Esquire 300 Plus Bruker Daltonics spectrometer (ESI). High
resolution mass spectra (HRMS) were recorded on a Thermoquest
Orbitrap spectrometer at the LCOSB, UMR 7613, Universite´
Pierre et Marie Curie, Paris, France. Experimental errors for
HRMS data are estimated between 1 and 2 ppm.
Scheme 6 One-pot conversion of cycloadduct 5g to N-protected a-amino
g-lactone (-)-11.
(rac)-2-Isopropyl-2,3-dimethyl-imidazolidin-4-one 3
The aminoamide 2 was prepared according to ref. 22: in a
250 mL Erlenmeyer flask under magnetic stirring, methylamine
(125 mL, 8M in ethanol, 1.0 mol) was added to glycine ethyl
ester hydrochloride (27.92 g, 200 mmol) in ethanol (80 mL). After
stirring for 16 h at room temperature, and concentration, the crude
product was taken up in ethanol (200 mL) and the solvent and
excess methylamine were removed under vacuum. This operation
was repeated twice to give pure 2 (24.91 g, 200 mmol, quantitative
yield) as an amorphous solid.
Conclusion
The new nitrone MiPNO 1, easily prepared on large scale in
three inexpensive steps and one recrystallization, has proven
to exhibit a high degree of facial differentiation, making it a
promising new building block for the synthesis of a-amino acids.
The cycloaddition reaction with alkenes features excellent regio-
and stereo- selectivity, affording a single enantiopure isomer
in high yields. From there, one operation provides a-amino
g-lactones, a masked form of g-hydroxy a-amino acids. We are
currently studying improved resolutions of MiPNO, as well as its
applications to other addition reactions.
In a 500 mL flask fitted with a reflux condenser were introduced
the aminoamide hydrochloride 2 (24.91 g, 200 mmol), ethanol
(200 mL), 3-methyl-2-butanone (42.8 mL, 400 mmol), triethy-
˚
lamine (28.1 mL, 200 mmol) and activated 4 A molecular sieves
(beads, 60 g). The reaction mixture was heated for 16 h at reflux
without stirring, then the sieves were filtered off and the solvent
was evaporated under reduced pressure. The crude white slurry was
taken up in ethyl acetate (150 mL), the precipitated triethylamine
hydrochloride was filtered off and the solvent evaporated under
reduced pressure to yield 24.15 g of crude material 3 (theoretical:
31.25 g); Rf 0.33 (ethyl acetate–ethanol 80 : 20); nmax (KBr pellet):
3327, 2970, 2942, 2876, 1685, 1432, 1404 and 1124; dH (400 MHz;
CDCl3; Me4Si) 3.53 (d, J 16.0, 1H), 3.42 (d, J 16.0, 1H), 2.74 (s,
3H), 1.91 (qq, J 6.4 and 6.8, 1H), 1.71 (br s, 1H), 1.34 (s, 3H), 0.96
(d, J 6.4, 3H), 0.79 (d, J 6.8, 3H); dC (100 MHz, CDCl3) 172.7,
82.0, 49.4, 34.7, 25.2, 24.2, 16.6, 16.2 ppm; MS (ES+): m/z 335
(2M + Na+, 30%), 179 (M + Na+, 55), 157 (M + H+, 100); HRMS:
m/z 157.13329 (M + H) C8H17N2O requires 157.13354.
Experimental
General
THF was freshly distilled from sodium benzophenone ketyl.
Styrene, cyclohexene, methyl crotonate and phenylacetylene were
distilled before use, other purchased reagents were used without
purification. Unless otherwise stated, the indicated reaction tem-
peratures are external ones (oil bath). Reactions were monitored by
thin layer chromatography (TLC) using commercial aluminium-
backed silica gel plates (Merck, Kieselgel 60 F254). TLC spots were
viewed under ultraviolet light and by heating the plate after treat-
ment with an appropriate staining solution (KMnO4, ninhydrin
for amines, basic TTC (2,3,5-triphenyltetrazolium chloride) for
hydroxylamines). Product purification by column chromatography
were performed using Macherey Nagel Silica Gel 60M (230-
400 mesh). Microwave irradiation experiments were conducted
in a CEM Discover S-Class apparatus (single mode technology),
(rac)-2-Isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-imidazol-4-one 1
In a 500-mL flask fitted with a reflux condenser the crude amine
3 (24.15 g, 154.58 mmol) was dissolved in methanol (200 mL)
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◦
and the reaction mixture was heated at 40 C. Sodium tungstate
(rac)- and (2R,3aR,6R)-2-Hydroxymethyl-6-isopropyl-5,6-
dihydrate (5.09 g, 15.46 mmol) suspended in water (1.99 g) was
added, followed by the urea–hydrogen peroxide complex (72.71 g,
772.90 mmol) in two portions. The internal temperature of the
flask was maintained below 50 ◦C (water bath). The reaction was
monitored by TLC (silica gel, ethyl acetate) and was completed
after 3 h. The reaction flask was cooled in an ice bath and
MnO2 (Fluka, ref. 63548, 10.0 g) was added in three portions
to destroy the excess of hydrogen peroxide. The reaction mixture
was vigorously stirred until the end of dioxygen evolution (15
min) and the solvent was removed under vacuum. The residue
was taken up in dichloromethane (100 mL), anhydrous Na2SO4
(40 g) was added, and the reaction mixture was filtered over
Celite. After concentration, the crude product was refluxed in
ethyl acetate (32 mL), the hot reaction mixture was filtered
and cyclohexane (29 mL) was added portionwise to the boiling
solution. The reaction mixture was allowed to cool slowly and
after 4 h at room temperature, filtration yielded the nitrone 1 as
white crystals (18.56 g, 109.04 mmol, 54% from glycine ethyl ester
hydrochloride); mp 113.0–113.1 ◦C; Rf 0.32 (ethyl acetate); nmax
(KBr pellet): 2972, 2803, 1701, 1561, 1259 and 1046; dH (400 MHz;
CDCl3; Me4Si) 7.06 (s, 1H), 2.99 (s, 3H), 2.30 (qq, J 7.2 and 6.8,
1H), 1.66 (s, 3H), 1.00 (d, J 7.2, 3H), 0.97 (d, J 6.8, 3H) ppm;
dC (100 MHz, CDCl3) 162.8, 124.9, 94.1, 34.4, 26.0, 21.5, 16.1,
15.4 ppm; MS (ES+): m/z 363 (2M + Na+, 23%), 341 (2M + H+,
29), 193 (M + Na+, 57), 171 (M + H+, 100); Anal. Found: C,
56.08; H, 8.26; N, 16.59; Calc. for C8H14N2O2: C, 56.45; H, 8.29;
N, 16.46%.
dimethyl-tetrahydro-imidazo[1,5-b]isoxazol-4-one 5b and (-)-5b
5b was prepared as described for 5a using 1 (851 mg, 5.00 mmol)
and allyl alcohol (3.4 mL, 50.00 mmol). The reaction mixture was
heated at 80 ◦C for 3.5 h. Purification by column chromatography
(silica gel, ethyl acetate–ethanol 90 : 10) gave 5b (1.07 g, 4.69 mmol,
94%) as a pale yellow oil which solidified upon standing. An
analytic sample crystallized from t-butyl methyl ether had a mp of
85.0–85.1 ◦C; Rf 0.42 (ethyl acetate–ethanol 80 : 20); nmax (KBr
pellet): 3360, 2974, 2924, 2883, 1685, 1451, 1409, 1381, 1089,
1049 and 881; dH (400 MHz; CDCl3; Me4Si) 4.07 (br d, J 9.2,
1H), 4.04–4.00 (m, 1H), 3.78 (ddd, J 2.8, 5.2 and 12.0, 1H),
3.59 (ddd, J 2.0, 6.8 and 12.0, 1H), 2.80 (s, 3H), 2.63 (ddd, J
1.6, 6.4 and 12.4, 1H), 2.39 (ddd, J 7.2, 9.2 and 12.4, 1H), 2.20
(br t, J 6.0, 1H), 1.86 (hept, J 6.8, 1H), 1.48 (s, 3H), 1.04 (d,
J 6.8, 3H), 0.83 (d, J 6.8, 3H); dC (100 MHz, CDCl3) 172.4,
88.4, 77.3, 66.3, 63.7, 36.5, 33.9, 26.7, 17.8, 17.3, 17.1; MS (ES+):
m/z 479 (2M + Na+, 42%), 251 (M + Na+, 100), 229 (M + H+,
54); HRMS: m/z 251.13580 (M + Na); C11H20N2O3Na: requires
251.13661.
(-)-5b (46 mg, 201 mmol, 86%) was obtained starting from (R)-1
(40 mg, 235 mmol) and allyl alcohol (160 mL, 2.35 mmol) as a
pale yellow oil which solidified upon standing; mp 99.5–99.6 ◦C;
[a]2D0 -32.7 (c 1.08 in CHCl3). Anal. Found: C, 57.55; H, 9.00; N,
12.27; Calc. for C11H20N2O3: C, 57.87; H, 8.83; N, 12.27%. The
enantiomeric purity of (-)-5b (≥ 91% ee) was determined by chiral
HPLC on a Daicel Chiralpak AD-RH column, 4.6 ¥ 100 mm,
eluent water–acetonitrile 60 : 40, 0.5 mL min-1, retention time for
(-)-5b 5.39 min and for (+)-5b 4.54 min.
(rac)- and (2R,3aR,6R) Acetic acid (6-isopropyl-5,6-dimethyl-4-
oxo-hexahydro-imidazo[1,5-b]isoxazol-2-yl)methyl ester 5a and
(-)-5a
(rac)-(2R*,3aR*,6R*)-6-Isopropyl-5,6-dimethyl-2-phenyl-
tetrahydro-imidazo[1,5-b]isoxazol-4-one 5c
5c was prepared as described for 5a using 1 (340 mg, 2.00 mmol)
The preparation of 5a is typical: the reaction was performed in a
sealed vessel. A mixture of nitrone 1 (340 mg, 2.00 mmol) and allyl
acetate (2.16 mL, 20.00 mmol) was heated at 80 ◦C for 16 h. The
major part of the alkene was removed under reduced pressure. The
residue was purified by column chromatography (silica gel, ethyl
acetate–cyclohexane 70 : 30) to yield isoxazolidine 5a (468 mg,
1.73 mmol, 87%) as a yellow oil; Rf 0.35 (ethyl acetate); nmax (KBr
pellet): 2973, 2935, 2890, 1735, 1696, 1407, 1382, 1260, 1235, 1084
and 1047; dH (400 MHz; CDCl3; Me4Si) 4.16–3.98 (m, 4H), 2.77
(s, 3H), 2.65 (ddd, J 1.2, 6.4 and 12.4, 1H), 2.24 (td, J 8.8 and
12.4, 1H), 2.05 (s, 3H), 1.83 (qq, J 6.8 and 7.2, 1H), 1.45 (s, 3H),
1.02 (d, J 6.8, 3H), 0.78 (d, J 7.2, 3H) ppm; dC (100 MHz, CDCl3)
172.1, 170.7, 88.6, 74.5, 66.1, 64.1, 36.4, 35.2, 26.5, 20.9, 17.9,
17.0; MS (ES+): m/z 563 (2M + Na+, 11), 293 (M + Na+, 100), 271
(M + H+, 32); HRMS: m/z 293.14756 (M + Na); C13H22N2O4Na
requires 293.14718.
(-)-5a (60 mg, 222 mmol, 94%) was obtained starting from (R)-
1 (40 mg, 235 mmol) and allyl acetate (254 mL, 2.35 mmol) as a
pale yellow oil which solidified upon standing; mp 87.9–88.0 ◦C;
[a]2D0 -37.9 (c 1.06, CHCl3). Anal. Found: C, 57.47; H, 8.43; N,
10.25; Calc. for C13H22N2O4: C, 57.76; H, 8.20; N, 10.36%. The
enantiomeric purity of (-)-5a (≥97% ee) was determined by chiral
HPLC on a Daicel Chiralpak AD-RH column, 4.6 ¥ 100 mm,
eluent water–acetonitrile 60 : 40, 0.5 mL min-1, retention time for
(-)-5a 7.67 min and for (+)-5a 6.76 min.
and styrene (2.3 mL, 20.00 mmol). The reaction mixture was
heated at 80 C for 3 h. Purification by column chromatography
◦
(silica gel, ethyl acetate–cyclohexane 70 : 30) gave 5c (494 mg,
1.80 mmol, 90%) as a colourless oil; Rf 0.48 (ethyl acetate); nmax
(KBr pellet): 3084, 3067, 3028, 2974, 2939, 2885, 1696, 1452, 1404,
1082, 1049, 760, 700; dH (400 MHz; CDCl3; Me4Si) 7.38–7.30 (m,
5H), 4.73 (dd, J 5.0 and 10.6, 1H), 4.20 (br d, J 8.6, 1H), 2.95 (dd,
J 5.0 and 12.2, 1H), 2.85 (s, 3H), 2.52 (ddd, J 8.6, 10.6 and 12.2,
1H), 1.92 (hept, J 6.8, 1H), 1.55 (s, 3H), 1.09 (d, J 6.8, 3H), 0.83
(d, J 6.8, 3H); dC (100 MHz, CDCl3) 172.1, 137.8, 128.7, 128.4,
126.7, 89.3, 79.1, 67.6, 41.4, 36.3, 26.4, 18.6, 17.0, 16.8; MS (ES+):
m/z 571 (2M + Na+, 57%), 297 (M + Na+, 100), 275 (M + H+,
54); HRMS: m/z 297.15803 (M + Na); C16H22N2O2Na requires
297.15735.
(rac)-(2R*,3aR*,6R*)-2-Butoxy-6-isopropyl-5,6-dimethyl-
tetrahydro-imidazo[1,5-b]isoxazol-4-one 5d
5d was prepared as described for 5a using 1 (340 mg, 2.00 mmol)
and n-butyl vinyl ether (2.6 mL, 20.00 mmol). The reaction
mixture was heated at 80 ◦C for 16 h. Purification by column
chromatography (silica gel, ethyl acetate–cyclohexane 70 : 30)
gave 5d (476 mg, 1.76 mmol, 88%) as a colourless oil which
solidified upon standing; mp 54.7–54.8 ◦C; Rf 0.40 (ethyl acetate–
cyclohexane 70 : 30); nmax (KBr pellet): 2958, 2921, 2873, 1691,
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1458, 1432, 1401, 1386; dH (400 MHz; CDCl3; Me4Si) 5.01 (dd,
J 1.4 and 6.2, 1H), 4.06 (dd, J 2.8 and 9.6, 1H), 3.68 (td, J 6.8
and 10.0, 1H), 3.40 (td, J 6.8 and 10.0, 1H), 2.80 (s, 3H), 2.76
(ddd, J 2.8, 6.2 and 13.4, 1H), 2.46 (ddd, J 1.4, 9.6 and 13.4,
1H), 1.85 (hept, J 7.2, 1H), 1.56 (quint, J 6.8, 2H), 1.43 (s, 3H),
1.42-1.35 (m, 2H), 1.03 (d, J 7.2, 3H), 0.91 (d, J 7.2, 3H), 0.91
(t, J 7.4, 3H); dC (100 MHz, CDCl3) 173.5, 99.8, 87.3, 67.6, 64.1,
39.0, 37.0, 31.8, 27.3, 19.4, 18.1, 17.3, 17.0, 13.9; MS (ES+): m/z
563 (2M + Na+,68%), 293 (M + Na+, 100), 271 (M + H+, 30);
Anal. Found: C, 62.36; H, 9.78; N, 10.40; Calc. for C14H26N2O3:
C, 62.20; H, 6.70; N, 10.37%.
(rac)- and (1R,3aR,3bS,7aS)-1-Isopropyl-1,2-dimethyl-octahydro-
8-oxa-2,8a-diaza-cyclopenta[a]inden-3-one 5g and (+)-5g
5g was prepared as described for 5a using 1 (340 mg, 2.00 mmol),
cyclohexene (2.0 mL, 20.00 mmol) and toluene (0.5 mL). The
reaction mixture was heated at 80 ◦C for 48 h (90% conversion).
Purification by column chromatography (silica gel, ethyl acetate–
cyclohexane 65 : 35) gave 5g as a pale yellow oil (376 mg,
1.48 mmol, 74% yield); Rf 0.29 (ethyl acetate–cyclohexane 70 : 30);
nmax (KBr pellet): 2973, 2939, 2883, 1685, 1449, 1406, 1084 and
1050; dH (400 MHz; CDCl3; Me4Si) 3.78–3.76 (m, 1H), 3.66 (br s,
1H), 2.75 (s, 3H), 2.63 (ddd, J 2.4, 6.4 and 12.0, 1H), 1.99-1.96 (m,
1H), 1.83 (qq, J 6.4 and 7.2, 1H), 1.80–1.76 (m, 1H), 1.70–1.66
(m, 1H), 1.55–1.41 (m, 4H), 1.46 (s, 3H), 1.24–1.13 (m, 1H), 1.04
(d, J 6.4, 3H), 0.74 (d, J 7.2, 3H); dC (100 MHz, CDCl3) 172.1,
89.3, 74.8, 73.7, 45.1, 36.4, 27.3, 26.1, 25.5, 24.3, 19.8, 18.7, 17.1,
16.7; MS (ES+): m/z 527 (2M + Na+, 26%), 275 (M + Na+,42), 253
(M + H+, 100); HRMS: m/z 275.17304 (M + Na); C14H24N2O2Na
requires 275.17300.
(rac)-(2R*,3aS*,6R*)-6-Isopropyl-5,6-dimethyl-4-oxo-hexahydro-
imidazo[1,5-b]isoxazole-2-carboxylic acid ethyl ester 5e
5e was prepared as described for 5a using 1 (340 mg, 2.00 mmol)
and ethyl acrylate (2.2 mL, 20.00 mmol). The reaction mixture was
◦
heated at 80 C for 4 h. Purification by column chromatography
(+)-5g (72 mg, 285 mmol, 65% yield) was obtained starting from
(R)-1 (75 mg, 441 mmol) and cyclohexene (447 mL, 4.41 mmol) as
a pale yellow oil; [a]2D0 +8.9 (c 1.04 in CHCl3). The enantiomeric
purity of (+)-5g (≥99% ee) was determined by chiral HPLC
on a Daicel Chiralpak AD-RH column, 4.6 ¥ 100 mm, eluent
water–acetonitrile 68 : 32, 0.5 mL min-1, retention time for (-)-5g
19.30 min and for (+)-5g 17.70 min.
(silica gel, ethyl acetate–cyclohexane 70 : 30) gave 5e (454 mg,
1.68 mmol, 84%) as a colourless oil; Rf 0.42 (ethyl acetate); nmax
(KBr pellet): 2973, 2918, 2883, 1740, 1686, 1459, 1399, 1378, 1088,
1049 and 881; dH (400 MHz; CDCl3; Me4Si) 4.33 (t, J 6.8, 1H),
4.24–4.10 (m, 2H), 4.04 (dd, J 1.8 and 9.2, 1H), 2.83 (ddd, J 1.8,
7.2 and 12.6, 1H), 2.78 (s, 3H), 2.74 (ddd, J 2.2, 9.2 and 12.6, 1H),
1.82 (qq, J 6.8 and 7.2, 1H), 1.47 (s, 3H), 1.26 (t, J 6.8, 3H), 1.01
(d, J 6.8, 3H), 0.82 (d, J 7.2, 3H); dC (100 MHz, CDCl3) 172.1,
170.4, 88.2, 74.3, 65.3, 61.5, 36.7, 35.8, 26.9, 17.6, 17.5, 17.1, 14.2;
MS (ES+): m/z 563 (2M + Na+, 16%), 293 (M + Na+, 100), 271
(M + H+, 21); HRMS: m/z 293.14783 (M + Na); C13H22N2O4Na
requires 293.14718.
(rac)-(1R*,3aR*,3bS*,4S*,7R*,7aS*)-1-Isopropyl-1,2-dimethyl-
octahydro-4,7-methano-8-oxa-2,8a-diaza-cyclopenta[a]inden-3-
one 5h
5h was prepared as described for 5a using 1 (170 mg, 1.00 mmol), 2-
norbornene (113 mg, 1.20 mmol) and toluene (1 mL). The reaction
mixture was heated at 80 ◦C for 16 h. Purification by column
chromatography (silica gel, ethyl acetate–cyclohexane 65 : 35) gave
5h as a white solid (238 mg, 900 mmol, 90%); mp 79.7–79.8 ◦C; Rf
0.32 (ethyl acetate–cyclohexane 65 : 35); nmax (KBr pellet): 2958,
2873, 2360, 2339 and 1685; dH (400 MHz; CDCl3; Me4Si) 3.99
(br d, J 6.8, 1H), 3.61 (d, J 2.4, 1H), 2.76 (s, 3H), 2.72–2.70 (m,
1H), 2.27–2.25 (m, 2H), 1.87–1.85 (m, 1H), 1.78 (hept, J 6.8, 1H),
1.47–1.42 (m, 2H), 1.39 (s, 3H), 1.18–1.13 (m, 1H), 1.10–1.07 (m,
1H), 1.01 (d, J 6.8, 3H), 0.99–0.94 (m, 1H), 0.83 (d, J 6.8, 3H);
dC (100 MHz, CDCl3) 171.8, 87.8, 86.0, 70.8, 55.8, 41.9, 41.0,
36.6, 33.0, 27.5, 26.7, 23.5, 17.8, 17.5, 17.1; MS (ES+): m/z 551
(2M + Na+, 42), 287 (M + Na+, 20), 265 (M + H+, 100). Anal.
Found: C, 68.12; H, 9.25; N, 10.58; Calc. for C15H24N2O2: C, 68.15;
H, 9.15; N, 10.60%.
(rac)- and (2S,3R,3aR,6R)-6-Isopropyl-2,5,6-trimethyl-4-oxo-
hexahydro-imidazo[1,5-b]isoxazole-3-carboxylic acid methyl ester
5f and (-)-5f
5f was prepared as described for 5a using 1 (340 mg, 2.00 mmol)
and trans-methyl crotonate (2.1 mL, 20.00 mmol). The reaction
mixture was heated at 80 ◦C for 16 h. Purification by column
chromatography (silica gel, ethyl acetate–cyclohexane 70 : 30) gave
5f as a colourless oil (435 mg, 1.61 mmol, 80%); Rf 0.41 (ethyl
acetate); nmax (KBr pellet): 2971, 2934, 2885, 1743, 1697, 1437,
1403, 1374, 1086 and 1050; dH (400 MHz; CDCl3; Me4Si) 4.27
(d, J 9.2, 1H), 4.08 (qd, J 6.0 and 10.4, 1H), 3.78 (s, 3H), 3.20
(t, J 9.2, 1H), 2.75 (s, 3H), 1.86 (qq, J 6.4 and 6.8, 1H), 1.49
(s, 3H), 1.28 (d, J 6.0, 3H), 1.03 (d, J 6.4, 3H), 0.73 (d, J
6.8, 3H); dC (100 MHz, CDCl3) 169.2, 168.9, 89.1, 74.9, 68.0,
56.1, 52.2, 36.1, 26.2, 18.5, 16.9, 16.6, 16.5; MS (ES+): m/z
563 (2M + Na+, 26%), 293 (M + Na+, 100), 271 (M + H+,
16); HRMS: m/z 293.14770 (M + Na); C13H22N2O4Na requires
293.14718.
(-)-5f (84 mg, 311 mmol, 80%) was obtained starting from (R)-1
(66 mg, 388 mmol) and trans-methyl crotonate (411 mL, 3.88 mmol)
as a colourless oil; [a]2D0 -96.1 (c 1.00, CHCl3).
The enantiomeric purity of (-)-5f (≥99% ee) was determined
by chiral HPLC on a Daicel Chiralpak AD-RH column, 4.6 ¥
100 mm, eluent water–acetonitrile 60 : 40, 0.5 mL min-1, retention
time for (+)-5f 8.21 min and for (-)-5f 7.47 min.
(rac)-(3aR*,6R*)-6-Isopropyl-5,6-dimethyl-2-phenyl-5,6-dihydro-
3aH-imidazo[1,5-b]isoxazol-4-one 7
7 was prepared as described for 5a using 1 (170 mg, 1.00 mmol),
phenylacetylene (220 mL, 2.00 mmol) and toluene (1 mL). The
reaction mixture was heated at 80 ◦C for 16 h. Purification
by column chromatography (silica gel, ethyl acetate–cyclohexane
75 : 25) gave 7 as a beige solid (199 mg, 730 mmol, 73%); mp 146.8–
146.9 ◦C; Rf 0.33 (ethyl acetate); nmax (KBr pellet): 3089, 3067,
3037, 2963, 2937, 2898, 2872, 1702, 1451, 1422, 1391, 823 and
733; dH (400 MHz; CDCl3; Me4Si) 8.04 (dd, J 1.2 and 7.2, 2H),
7.61 (tt, J 1.2 and 7.2, 1H), 7.51 (t, J 7.2, 2H), 3.52 (d, J 5.2, 1H),
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3.18 (d, J 5.2, 1H), 2.64 (s, 3H), 1.92 (qq, J 6.4 and 6.8, 1H), 1.16
(s, 3H), 1.10 (d, J 6.4, 3H), 0.90 (d, J 6.8, 3H); dC (100 MHz,
CDCl3) 194.2, 168.9, 137.8, 134.0, 129.0, 128.7, 84.1, 45.3, 42.3,
38.7, 26.0, 20.7, 16.4, 16.2; MS (ES+): m/z 567 (2M + Na+, 52%),
545 (2M + H+, 32), 295 (M + Na+, 100), 273 (M + H+, 65); Anal.
Found: C, 70.17; H, 7.58; N, 10.29; Calc. for C16H20N2O2: C, 70.57;
H, 7.41; N, 10.29%.
J 6.4, 1H), 2.78 (s, 3H), 2.10–2.07 (m, 2H), 1.96 (hept, J 6.8,
1H), 1.40 (s, 3H), 1.29 (t, J 7.2, 3H), 0.99 (d, J 6.8, 3H), 0.80
(d, J 6.8, 3H); dC (100 MHz, CDCl3) 174.2, 173.4, 80.9, 69.5,
61.6, 57.8, 37.1, 35.1, 26.4, 25.5, 16.8, 16.4, 14.3; MS (ES+):
m/z 567 (2M + Na+, 5%), 295 (M + Na+, 29), 273 (M + H+,
100); HRMS: m/z 295.16307 (M + Na); C13H24N2O4Na requires
295.16338.
A monocyclic isomer 7¢ with two possible tautomeric structures
was isolated in 20% yield (yellow oil, 55 mg, 202 mmol): Rf 0.52
(ethyl acetate); dH (400 MHz; CDCl3; Me4Si) 7.97 (d, J 6.8, 2H),
7.48–7.41 (m, 3H), 6.51 (s, 1H), 2.95 (s, 3H), 2.10 (qq, J 6.4 and
6.8, 1H), 1.54 (s, 3H), 1.10 (d, J 6.8, 3H), 0.67 (d, J 6.4, 3H);
dC (100 MHz, CDCl3) 191.2, 162.6, 150.4, 138.9, 131.8, 128.5,
127.5, 86.8, 80.6, 34.7, 25.0, 23.9, 17.1, 15.4; MS (ES+): m/z 567
(2M + Na+, 100%), 295 (M + Na+, 27), 273 (M + H+, 16).
(rac)- and (2S,3R)-3-Hydroxy-2-((2S,4R)-2-isopropyl-1,2-
dimethyl-5-oxo-imidazolidin-4-yl)-butyric acid methyl ester 8f
and (+)-8f
8f was prepared as described for 8e using 5f (83 mg, 307 mmol).
Purification by column chromatography (silica gel, ethyl acetate–
cyclohexane 80 : 20 to 100 : 0) yielded amino alcohol 8f (57 mg,
0.209 mmol, 68%) as a colourless oil which solidified upon
standing; mp 72.3–72.4 ◦C; Rf 0.21 (ethyl acetate–cyclohexane
80 : 20); nmax (KBr pellet): 3373, 2974, 2927, 2883, 1719, 1677,
1438, 1407, 1378, 1088 and 1050; dH (400 MHz; CDCl3; Me4Si)
4.24 (quint, J 6.4, 1H), 4.04 (d, J 6.4, 1H), 3.70 (s, 3H), 2.82–
2.76 (m, 1H), 2.80 (s, 3H), 1.97 (hept, J 6.8, 1H), 1.34 (s, 3H),
1.23 (d, J 6.4, 3H), 0.96 (d, J 6.8, 3H), 0.81 (d, J 6.8, 3H); dC
(100 MHz, CDCl3) 172.9, 172.7, 80.9, 67.2, 59.3, 56.2, 51.7, 35.2,
26.2, 25.5, 21.3, 16.8, 16.4; MS (ES+): m/z 567 (2M + Na+, 5%),
295 (M + Na+, 10), 273 (M + H+, 100); HRMS: m/z 273.18081
(M + H); C13H25N2O4 requires 273.18088.
(rac)-(2S*,5R*)-5-[(2R*)-2-Hydroxy-2-phenylethyl]-2-isopropyl-
2,3-dimethylimidazolidin-4-one 8c
In a 25 mL flask, zinc dust (657 mg, 10.06 mmol) was added in one
portion to a solution of 5c (138 mg, 0.503 mmol) in acetic acid
(1.7 mL). The reaction was monitored by TLC (silica gel, ethyl
acetate) and was completed within 3.5 h at room temperature.
The reaction mixture was filtered and the solid was rinsed with
dichloromethane. After concentration of the filtrate, the crude
product was purified by column chromatography (silica gel, ethyl
acetate–cyclohexane 80 : 20) to yield 8c as a colourless oil (116 mg,
0.420 mmol, 83%) which solidified upon standing; mp 84.8–
84.9 ◦C; Rf 0.32 (ethyl acetate–cyclohexane 80 : 20); nmax (KBr
pellet): 3345, 3066, 3033, 2970, 2873, 1677, 1451, 1405, 764 and
702; dH (400 MHz; CDCl3; Me4Si) 7.41–7.39 (m, 2H), 7.35–7.31
(m, 2H), 7.26–7.22 (m, 1H), 4.95 (dd, J 2.8 and 8.8, 1H), 3.85 (dd, J
4.4, 7.2, 1H), 2.83 (s, 3H), 2.10–1.94 (m, 3H), 1.42 (s, 3H), 1.00 (d,
J 6.8, 3H), 0.83 (d, J 6.8, 3H); dC (100 MHz, CDCl3) 174.1, 144.7,
128.4, 127.3, 125.7, 81.0, 72.6, 59.4, 42.8, 35.3, 26.4, 25.7, 16.9,
16.6; MS (ES+): m/z 575 (2M + Na+, 12%), 277 (M + H+, 100);
Anal. Found: C, 69.54; H, 8.75; N, 10.25; Calc. for C16H24N2O2:
C, 69.54; H, 8.76; N, 10.14%.
(+)-8f (49 mg, 180 mmol, 67%) was obtained starting from (-)-5f
(73 mg, 270 mmol) as a colourless oil which solidified on standing;
◦
mp 89.3–89.4 C; [a]2D0 +47.1 (c 1.06, CHCl3). Anal. Found: C,
57.59; H, 8.90; N, 10.12; Calc. for C13H24N2O4: C, 57.33; H, 8.88;
N, 10.29%.
(rac)-1-Hydroxy-2-isopropyl-2,3-dimethyl-imidazolidin-4-one 9
In a 100 mL flask under an argon atmosphere, nitrone 1 (3.40 g,
20.00 mmol) was dissolved in anhydrous THF (40 mL). Sodium
borohydride (1.51 g, 40.00 mmol) was added in one portion. The
reaction mixture was stirred for 2.5 h at room temperature and
was then treated with H2O (2.9 mL, 160.00 mmol). The reaction
mixture was stirred until the end of dihydrogen evolution (15 min)
and then the solvent was removed under reduced pressure. The
crude product was taken up in ethyl acetate (50 mL), the organic
layer was separated from the aqueous one, dried over anhydrous
Na2SO4 and filtered. The filtrate was concentrated under vacuum
to yield pure 9 (3.44 g, 20.00 mmol, quantitative yield) as a pale
yellow oil; Rf 0.32 (ethyl acetate); nmax (film): 3352, 2970, 2937,
2881, 2838, 1682, 1435 and 1405; dH (400 MHz; CDCl3; Me4Si)
5.78 (s, 1H), 3.79 (d, J 16.0, 1H), 3.57 (d, J 16.0, 1H), 2.77 (s,
3H), 1.86 (hept, J 6.8, 1H), 1.38 (s, 3H), 1.01 (d, J 6.8, 3H),
0.84 (d, J 6.8, 3H); dC (100 MHz, CDCl3) 170.1, 88.3, 59.8, 35.3,
26.1, 17.5, 17.2, 15.8; MS (ES+): m/z 367 (2M + Na+, 58%),
195 (M + Na+, 100), 173 (M + H+, 37); HRMS: m/z 195.11024
(M + Na); C8H16N2O2Na requires 195.11040.
(rac)-(2R*)-2-Hydroxy-3-[(2S*,4R*)-1,2-dimethyl-5-oxo-2-
(propan-2-yl)imidazolidin-4-yl]-propanoic acid ethyl ester 8e
In an argon-flushed 25 mL two-necked flask was introduced
Pd/C 10% (Fluka, ref. 75990, 67 mg), followed by 2 mL of
methanol and then a solution of 5c (114 mg, 422 mmol) in
methanol (2 mL). Ammonium formate (532 mg, 8.43 mmol) was
added in one portion and the argon inlet was removed. The
reaction was monitored by TLC (silica gel, ethyl acetate) and
was completed within 75 min at room temperature. The reaction
mixture was filtered over Celite and the solid was rinsed with
dichloromethane. The filtrate was diluted with water (2.5 mL), the
aqueous layer was separated and extracted with dichloromethane
(5 mL). The gathered organic layers were dried over anhydrous
Na2SO4 and filtered. After concentration under reduced pressure,
purification by column chromatography (silica gel, ethyl acetate–
cyclohexane 80 : 20) yielded amino alcohol 8e (84 mg, 308 mmol,
73%) as a yellow oil; Rf 0.26 (ethyl acetate); nmax (film): 3445,
3348, 2973, 2937, 2880, 1739, 1682, 1473 and 755; dH (400 MHz;
CDCl3; Me4Si) 4.39 (t, J 4.8, 1H), 4.24 (q, J 7.2, 2H), 3.78 (t,
(S)-2-Methoxycarbonylamino-3-phenyl-propionic acid
(R)-2-isopropyl-2,3-dimethyl-4-oxo-imidazolidin-1-yl ester 10a
Moc-Phe-OH (11.41 g, 51.11. mmol, 87%) was prepared from
L-phenylalanine (9.69 g, 58.66 mmol) according to ref. 23.
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In a 100 mL flask, N-(methoxycarbonyl)-L-phenylalanine
(1.34 g, 6.00 mmol) was dissolved in dichloromethane (10 mL)
and solid 1,3-dicyclohexylcarbodiimide (1.24 g, 6.00 mmol) was
added. A solution of hydroxylamine 9 (861 mg, 5.00 mmol) in
dichloromethane (10 mL) was added rapidly at 0 ◦C. The reaction
mixture was stirred for 1 h at 0 ◦C, then the urea was precipitated
by addition of diethyl ether (20 mL) and filtered off. The filtrate
was stirred for 5 min with a 1 M aqueous solution of HCl (20 mL);
the aqueous phase was separated and extracted twice with diethyl
ether (50 mL). The gathered organic layers were washed with
a saturated aqueous solution of NaHCO3 (100 mL), then with
brine (100 mL), dried over anhydrous Na2SO4 and filtered. After
removal of the solvents under reduced pressure, more urea was
precipitated in diethyl ether and filtered off. Concentration of the
filtrate under vacuum yielded the 1 : 1 mixture of diastereoiso-
mers 10 as a white foam (1.55 g, 4.10 mmol). Separation by
medium pressure liquid chromatography (silica gel, diethyl ether–
dichloromethane 10 : 90 to 100 : 0 in 15 min, 15 mL min-1) yielded
the diastereoisomer 10◦a (300 mg, 0.795 mmol, 32%) as a white
solid; mp 121.3–121.4 C; [a]2D0 +21.2 (c 0.98 in CHCl3); Rf 0.38
(dichloromethane–t-butyl methyl ether 70 : 30); nmax (KBr pellet):
3326, 3020, 2963, 2933, 2920, 1776, 1701, 1686, 1540, 1125, 751
and 710; dH (400 MHz; CDCl3; Me4Si) 7.32–7.27 (m, 3H), 7.17 (d,
J 6.4, 2H), 5.22 (br d, J 6.4, 1H), 4.52–4.47 (m, 1H), 3.82 (d, J 17.2,
1H), 3.67 (s, 3H), 3.07 (dd, J 6.8 and 13.6, 1H), 3.01 (d, J 17.2, 1H),
2.98 (dd, J 8.0 and 13.6, 1H), 2.79 (s, 3H), 1.85 (hept, J 6.8, 1H),
1.30 (s, 3H), 0.99 (d, J 6.8, 3H), 0.91 (d, J 6.8, 3H); dC (100 MHz,
CDCl3) 170.4, 169.5, 156.3, 135.3, 129.4, 129.0, 127.6, 89.5, 58.7,
54.1, 52.6, 38.7, 36.1, 26.6, 17.5, 17.2, 16.4; MS (ES+): m/z 777
(2M + Na+, 14%), 400 (M + Na+, 100), 378 (M + H+, 11), 177
(M + Na - Moc-Phe-OH+, 39), 155 (M + H - Moc-Phe-OH+, 84).
Anal. Found: C, 60.67; H, 7.12; N, 11.15; Calc. for C19H27N3O5:
C, 60.47; H, 7.21; N, 11.14%.
(rac)- and (3R,3aS,7aS)-(2-Oxo-octahydro-benzofuran-3-yl)-
carbamic acid tert-butyl ester 11 and (-)-11
In a 10 mL microwave vial were introduced isoxazolidine 5g
(85 mg, 337 mmol), glacial acetic acid (2 mL), a 3 N aqueous
solution of HCl (2 mL) and Pd/C 10% (Fluka, ref. 15990, 20 mg).
The vial was brought into the microwave reactor, evacuated, filled
up with H2 and the reaction mixture was stirred under H2 pressure
(7 bar) for 15 min at 150 ◦C. After filtration through Celite,
the solids were rinsed with acetic acid and concentration under
vacuum yielded the acetate salt of the lactone.
The crude salt was dissolved in methanol (3 mL) and added
to a mixture of triethylamine (0.12 mL, 842 mmol) and methanol
(1 mL), followed by di-t-butyl dicarbonate (147 mg, 674 mmol).
The reaction mixture was stirred for 4.5 h at 45 ◦C, then
concentrated under reduced pressure. Purification by column
chromatography (silica gel, dichloromethane–t-butyl methyl ether
98 : 2) yielded N-Boc lactone 11 (35 mg, 137 mmol, 42%) as a
colourless oil which solidified upon standing; mp 95.6–95.7 ◦C;
Rf 0.26 (dichloromethane–t-butyl methyl ether 97 : 3); nmax (KBr
pellet): 3328, 2994, 2975, 2937, 2663, 1787, 1684, 1527, 1164,
967 cm-1; dH (400 MHz; CDCl3; Me4Si) 5.00 (br s, 1H), 4.54–
4.50 (m, 2H), 2.73–2.68 (m, 1H), 2.26–2.23 (m, 1H), 1.76–1.54 (m,
4H), 1.45 (s, 9H), 1.41–1.29 (m, 1H), 1.19 (qt, J 2.8 and 13.2, 1H),
0.91 (dq, J 3.2 and 13.2, 1H); dC (100 MHz, CDCl3) 175.8, 155.6,
80.4, 76.8, 57.3, 39.4, 28.4, 27.4, 22.8, 22.0, 19.7; MS (ES+): m/z
533 (2M + Na+, 47%), 278 (M + Na+, 100); Anal. Found: C, 60.94;
H, 8.47; N, 5.21; Calc. for C13H21NO4: C, 61.16; H, 8.29; N, 5.49%.
(-)-11 (26 mg, 102 mmol, 42%) was obtained starting from (+)-
5g (62 mg, 243 mmol) as a pale yellow oil which solidified upon
standing; mp 112.4–112.6 ◦C; [a]D20 -78.1 (c 1.04 in CHCl3).
Acknowledgements
The relative configuration of 10a was determined by X-ray
crystallography of an analytical sample recrystallized in ethanol.
The authors thank Beatrice Gennaro and Corinne Bailly for their
assistance in NMR and X-ray analysis respectively, and Alicia
Contet and Olga N. Burchak for their support. We are grateful to
Universite´ Joseph Fourier and the CNRS for financial support.
(R)-2-Isopropyl-2,3-dimethyl-1-oxy-2,3-dihydro-imidazol-4-one
(R)-1
In a 50 mL flask, 10a (394 mg, 1.04 mmol) was dissolved in
methanol (15 mL). NaHCO3 (877 mg, 10.44 mmol) was added,
followed by a 35% aqueous solution of hydrogen peroxide (1.01 g,
10.44 mmol). The reaction was monitored by TLC (ethyl acetate);
hydrolysis of the ester bond was completed within 4 h at room
temperature. MnO2 (Fluka, ref. 63548, 600 mg) was then added
portionwise, both to destroy the excess of hydrogen peroxide and
complete the oxidation of the intermediate hydroxylamine. The
reaction mixture was stirred for 15 min at room temperature
and was then filtered over Celite. The solid was rinsed with
ethyl acetate and the solvents were removed under vacuum.
Purification by column chromatography (silica gel, ethyl acetate–
cyclohexane 70 : 30), followed by recrystallization from ethyl
acetate–cyclohexane (1.0 mL ; 0.7 mL) yielded the nitrone (R)-
1 as a beige solid (124 mg, 729.5 mmol, 70%); [a]2D0 -28.5 (c
3.96 in CHCl3). The enantiomeric purity of (-)-(R)-1 (≥99% ee)
was determined by chiral HPLC on a Daicel Chiralpak AD-
RH column, 4.6 ¥ 100 mm, eluent acetonitrile–water 70 : 30,
0.5 mL min-1, retention time for (R)-1 6.96 min and for (S)-1
5.94 min.
Notes and references
1 See for instance: (a) I. A. Grigor’ev, in Nitrile Oxides, Nitrones,
and Nitronates in Organic Synthesis, 2nd edn, ed. H. Feuer, Wiley-
Interscience, 2008, pp. 129–434; (b) a recent review on asymmetric
1,3-dipolar cycloadditions: H. Pellissier, Tetrahedron, 2007, 63, 3235–
3285.
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5 (a) O. Tamura, K. Gotanda, R. Terashima, M. Kikuchi, T. Miyawaki
and M. Sakamoto, Chem. Commun., 1996, 1861–1862; (b) S. W.
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Wang, P. Gao and P.-F. Xu, Synlett, 2006, 1095–1099.
R
int: 0.09; refinement vs. F; final R values (observed data): R = 0.0533,
wR = 0.0867. For the ORTEP drawing of 1, see ESI†.
13 The reaction between MiPNO and cyclohexene, sluggish in toluene,
was also performed in a polar solvent, NMP, without any improvement:
48 h, 64% conversion.
14 The stereochemistry of the cycloadducts was assigned on the basis of
their NOESY spectra.
15 Such a ring opening was previously reported: A. Padwa, M. Meske and
Z. Ni, Tetrahedron Lett., 1993, 34, 5047–5050.
16 Attempted NOESY experiments were not conclusive enough to allow
determination of the relative configuration of the minor isomer.
17 O. N. Burchak, C. Philouze, P. Y. Chavant and S. Py, Org. Lett., 2008,
10, 3021–3023.
6 For other enantiopure cyclic nitrones see the review: J. Revuelta, S.
Cicchi, A. Goti and A. Brandi, Synthesis, 2007, 485–504.
7 (a) P. Maire, V. Blandin, M. Lopez and Y. Valle´e, Synlett, 2003, 671–
674; (b) J. Lawrence, L. Cointeaux, P. Maire, Y. Valle´e and V. Blandin,
Org. Biomol. Chem., 2006, 4, 3125–3141; (c) J. Lawrence, M. Jourdan,
Y. Va l l e´e and V. Blandin, Org. Biomol. Chem., 2008, 6, 4575–4581.
8 (a) S. U. Pandya, C. Garcon, P. Y. Chavant, S. Py and Y. Valle´e, Chem.
Commun., 2001, 1806–1807; (b) S. Pinet, S. U. Pandya, P. Y. Chavant, A.
Ayling and Y. Valle´e, Org. Lett., 2002, 4, 1463–1466; (c) S. U. Pandya,
S. Pinet, P. Y. Chavant and Y. Valle´e, Eur. J. Org. Chem., 2003, 3621–
3627.
9 See for instance the review: D. Seebach, A. R. Sting and M. Hoffmann,
Angew. Chem., Int. Ed. Engl., 1996, 35, 2708–2748.
10 (a) N. PraveenGanesh, S. d’Hondt and P. Y. Chavant, J. Org. Chem.,
2007, 72, 4510–4514; (b) N. PraveenGanesh and P. Y. Chavant,
Eur. J. Org. Chem., 2008, 4690–4696.
18 Moc-Phe-OH (N-methoxycarbonyl-L-phenylalanine): (S)-2-methoxy-
carbonylamino-3-phenylpropanoic acid.
19 Crystal data for 10a (C19H27N3O5, enantiopure sample). M:
377.44 g mol-1; crystal system: monoclinic; unit-cell dimensions and
˚
˚
˚
volume: a = 10.080(3) A, b = 9.129(4) A, c = 11.610(3) A, b =
◦
3
˚
112.49(3) , V = 987.2(6) A , temperature of measurement: 293.0 K;
space group symbol: P21; no. of formula units in the unit cell Z = 2;
no. of measured and independent reflections : 2273 and 2174, Rint: 0.07;
refinement vs. F; final R values (observed data): R = 0.0531, wR =
0.0921. The relative streochemistry (R) at C5 was attributed knowing
the (S) configuration at C11 from the starting material Moc-Phe-OH.
20 Note that this step produces only volatile side products (3-methyl-
butanone and methylamine).
11 E. Marcantoni, M. Petrini and O. Polimanti, Tetrahedron Lett., 1995,
36, 3561–3562.
21 For related compounds, see: (a) B. Merla, H.-J. Grumbach and N.
Risch, Synthesis, 1998, 1609–1614; (b) W. Notz, S.-i. Watanabe, N. S.
Chowdari, G. Zhong, J. M. Betancort, F. Tanaka and C. F. Barbas III,
Adv. Synth. Catal., 2004, 346, 1131–1140.
22 R. Fitzi and D. Seebach, Angew. Chem., Int. Ed. Engl., 1986, 25, 345–
346.
12 Crystal data for 1 (C8H14N2O2, racemic sample). M: 170.21 g mol-1;
crystal system: triclinic; unit-cell dimensions and volume◦:
a
=
˚
˚
˚
6.900(2) A, b = 7.365(2) A, c = 11.610(3) A, a = 83.78(2) , b =
◦
◦
3
˚
86.06(2) , g = 84.78(2) , V = 442.9(5) A , temperature of measurement:
¯
293.0 K; space group symbol: P1; no. of formula units in the unit cell
23 M. W. Liladhar, J. J. McKenna, A. Bach, M. Prashad, O. Repic and
T. J. Blacklock, Synth. Commun., 2007, 37, 1445–1454.
Z = 2; no. of measured and independent reflections: 9127 and 2392,
872 | Org. Biomol. Chem., 2010, 8, 864–872
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