New chiral nitrones as precursors of α,α-disubstituted amino-acids, according to the SRS principle

Article abstract of DOI:10.1016/j.tetasy.2006.06.046

The preparation of new enantiopure cyclic nitrones based on the 1-oxy-2,3-dihydro-imidazol-4-one ring is described. The addition of arylmagnesium or alkynylzinc reagents to these nitrones can be achieved with total enantio- and diastereoselectivity, leadi

Full text of DOI:10.1016/j.tetasy.2006.06.046

Tetrahedron: Asymmetry 17 (2006) 1969–1974
New chiral nitrones as precursors of a,a-disubstituted
amino-acids, according to the SRS principle
´ ´
Astrid Pernet-Poil-Chevrier, Frederic Cantagrel, Karel Le Jeune,
Christian Philouze and Pierre Yves Chavant*
L.E.D.S.S., UMR CNRS-UJF, Universite´ Joseph Fourier, BP 53X, 38041 Grenoble, France
Received 23 May 2006; accepted 16 June 2006
Abstract—The preparation of new enantiopure cyclic nitrones based on the 1-oxy-2,3-dihydro-imidazol-4-one ring is described. The
addition of arylmagnesium or alkynylzinc reagents to these nitrones can be achieved with total enantio- and diastereoselectivity, leading
to a,a-disubstituted amino-acid precursors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
H
Me
N
t-Bu
t-Bu
O
Me
O
Me
N
N
N
The de novo design of peptides or peptidomimetics is a
major tool for the exploration and understanding of the
proteome.1 Thus, the need for efficient synthetic methods
for the preparation of ‘tailor-made’2 a-amino-acids with
elaborate side chains or specific geometries3 is continuous,
and a large array of methods have been designed to achieve
this goal. Among them, the addition to properly designed
a-carboxyl-nitrones4 has received attention. Several enan-
tiopure chiral cyclic nitrones have been prepared and used
as substrates for 1,3-dipolar cycloadditions,5–10 radical
additions11 or Grignard addition.12 We have recently ap-
plied13 for the first time the SRS principle to the prepara-
tion of 5-substituted oxazolidin-4-one-N-oxides 1 starting
from natural amino-acids as the only source of chirality.
Highly enantioselective nucleophilic addition to these re-
agents can be achieved. Nevertheless, the acidity of the H
atom at the 2-position, as well as some stability issues for
the product nitrones 1, prompted us to develop a second
series 2, in which the C-2 atom is made quaternary. More-
over, related a-quaternary nitrones feature interesting
applications as spin-trap agents.14 Herein, we report our
first results on the preparation of some enantiopure nitro-
nes 2, and the feasibility of the diastereoselective addition
of Grignard and alkynylzinc reagents to 2.
R1
R1
O
O
1
2
2. Results and discussion
2.1. Preparation of the imidazolidinones
N-Methyl-amide hydrochloride 3 was prepared from the
corresponding amino-acid ester.15 In our previous work,
the reaction of pivalaldehyde with 3 led only to the corre-
sponding acyclic imine. Under the same conditions, the
reaction of pinacolone with 3 led to a mixture of open-
chain amide 4 and cyclic imidazolidinone 5 (about 70%).
Treatment of this mixture with dry HCl in ethanol, fol-
lowed by evaporation of the solvent and precipitation in
acetonitrile, provided pure 5ÆHCl in limited yields (Table
1), but in diastereomerically pure form.
This cyclization appeared to be very easily reversible. We
found that as HCl salts, imidazolidinones 5 were very much
prone to solvolysis to yield 3ÆHCl back. When we repeated
the sequence thrice: dissolution of pure 5ÆHCl in ethanol
followed by concentration on the rotary evaporator, we
recovered pure 3ÆHCl as the sole product.16 Attempts to
displace the equilibrium by adding an excess of pinacolone
led only to a larger amount of crotonization by-product.
*
Corresponding author. Fax: +33 476635983; e-mail: Pierre-Yves.
Chavant@ujf-grenoble.fr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.046

1970
A. Pernet-Poil-Chevrier et al. / Tetrahedron: Asymmetry 17 (2006) 1969–1974
Table 1. Preparation of imidazolidinones 5
because the enantioselectivity of these methods had been
confirmed. Our first tests, using 2.1 equiv of m-CPBA, led
efficiently to product 2b, without any side reactions.
However, the large amounts of m-CBA by-product caused
difficulties in the recovery of 2b in good yields. Since the
oxidation of the intermediate hydroxylamine with MnO2
was particularly easy in this series, we preferred to use
1.3 equiv m-CPBA18 in order to ensure a total conversion
of secondary amine 5 into hydroxylamine 8 (containing
0.15 equiv of nitrone 2). The transformation of 8 into
O
t-Bu
Me
ClH3N
+
NHMe
O
Me
Et3N
19
Me
N
O
t-Bu
2 was completed with excess MnO2 (DCM, 20 ꢁC, 2 h;
Table 2).
t-Bu
N
Me
Et3NHCl
HN
+
+
NHMe
Me
Me
O
Table 2. Oxidation of amines 5 to nitrones 2
5
4
Me
N
Me
N
Me
N
t-Bu
t-Bu
t-Bu
HCl/EtOH
30°C, evaporator
Me
Me
Me
HO N
O N
HN
R1
O
R1
O
R1
O
Me
t-Bu
5
8
2
O
Me
HClN
ClH2N
N
+
Nitrone 2
R1
Yield
NHMe
3 HCl
.
.
Me
5 HCl
a
b
c
H
Me
CH2Ph
3-Indolyl
60b
Me
O
92a(29b)
80a
precipitated in CH3CN
d
0a,b
Entry
R1
H
Yield
a 1.3 equiv MCPBA, then MnO2.
b 1.2 equiv UHP/MTO, then MnO2.
a
b
c
32
45
27
22
28
Me
CH2Ph
d
e
3-Indolyl
CH2OH
This procedure proved relatively inefficient in the case of
nitrone 2a (based on glycine), because the hydrophilicity
of 2a made the separation of m-CBA even more trouble-
some. We turned to UHP/MTO20 for the first step. We
noticed in our case that with these conditions, the first
oxidation step from 5 to 8 was much quicker (less than
1 h) than the second from 8 to 2. During the slow second
step, catalyst decomposition required repeated additions.20
Thus, we again found it more convenient to use only
1.1 equiv UHP in DCM in the presence of MTO to yield
8a, then filter off the urea after 1 h and complete the oxida-
tion with MnO2 in DCM. Curiously, both procedures
failed to transform the tryptophane derivative 5d (starting
material was recovered).
NOE experiments of 5b, 5c, 5e and X-ray analysis of 5b
proved that the stereochemistry of 5 is cis. This result is
the inverse of that obtained with pivalaldehyde13,15 that
led to the more stable trans imidazolidinones. Examination
of the crystal structure of cis-5b showed that there is no
consequent steric interaction between the tert-butyl and
the 5-methyl groups. Thus, the final recovery of a single
isomer cannot be explained with basic thermodynamic con-
siderations. Most likely, the diastereoselectivity of the
cyclization is dictated by the allylic-1,3 strain17 favouring
the reactive rotamer of 4 that leads to the cis product
(Scheme 1).
The two-step procedure also allowed us to check the diaste-
reopurity of the intermediate hydroxylamine 8b (>95% H
NMR).
disfavoured rotamer
Me
H
tBu
MeNHCO
1
H
N
MeNHCO
tBu
N
Me
Me
Me
3. Addition of Grignard reagents
The addition of Grignard reagents to nitrones 221 easily
took place in THF at 0 ꢁC with aryl- or vinyl-magnesium
halides. The product was always isolated as a single diaste-
reoisomer (NMR detection), in yields ranging from 64% to
78% (Table 3). Adduct 9b of 4-methoxy-phenylmagnesium
bromide and 2c was a solid and X-ray analysis of 9b proved
that the newly introduced aryl group was trans to the tert-
butyl group. The same stereochemical relationship in 9a
was confirmed by NOE experiments.
cis
trans
Scheme 1. Allylic 1,3-strain in cyclization.
2.2. Oxidation
For the oxidation of amines 5 into nitrones 2, we kept to
methods developed in our earlier works on nitrones 1,

A. Pernet-Poil-Chevrier et al. / Tetrahedron: Asymmetry 17 (2006) 1969–1974
1971
Table 3. Addition of organomagnesium reagents
spectrometers, in CDCl3 with tetramethylsilane as the
internal standard. Mass spectra were recorded with a Ther-
moFinnigan PolarisQ ion-trap spectrometer using DCI
(ammonia/isobutane 63/37). IR spectra were recorded with
a Nicolet Impact-400 FTIR spectrometer, from sintered
KBr discs. HRMS (chemical ionization) and elemental
analyses were performed at the Service Central d’Analyses
du CNRS, Vernaison, France. Analytical samples for ele-
mental analysis were obtained by chromatography. Thin
layer chromatography (TLC) was carried out on Merck
precoated silica gel 60 F-254 plates. Spots were visualized
with UV or by basic permanganate revelation, or by basic
1% triphenyl tetrazolium chloride (TTC): a strong perma-
nent red colour is characteristic of N-hydroxylamines.
Forced-flow column chromatography was performed using
Macherey-Nagel Silica Gel 60, 230–400 mesh. Melting
Me
Me
N
t-Bu
t-Bu
R2MgX
Me
Me
O N
N
HO N
R1
R2
0 °C
R1
O
O
2b,c
Nitrone 2: R1 =
9a-d
9
R2MgBr
Yield (%)
a
b
c
Me
CH2Ph
Me
p-MeOPhMgBr
p-MeOPhMgBr
Vinyl-MgBr
78
64
68
4. Enantioselectivity of the process
We resolved the racemate of adduct 9a on a CHIRALPAK
AD-RH column. The enantiopurity of a sample prepared
from optically active 2a was found superior to 98%. There-
fore, the whole process, from starting Alanine to the Grig-
nard adduct, was totally enantioselective.
points were determined on a Buchi B-545 apparatus and
¨
are uncorrected. All reactions were performed under nitro-
gen in oven-dried glassware, with magnetic stirring. All
reagents were purchased from Aldrich, Acros or Fluka
and used as received. Dichloromethane (DCM) was
distilled from CaH2. Toluene was distilled from sodium.
Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication numbers CCDC
605989 (9b), 605990 (10a) and 605991 (5b). Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
5. Addition of alkynes
In our preceding work,13 we have shown that the addition
of alkynylzinc reagents prepared in situ from 1-alkynes and
dimethylzinc led smoothly and efficiently to the bicyclic
products 10 (Table 4). We extended this process to 2b
to produce 10a–c with excellent yields and total
diastereoselectivity.
7.2. Imidazolidinones 5
Table 4. Alkynylation of 2b
The preparation of 5b is typical. In a 250 mL flask fitted
with a reflux condenser were introduced the aminoamide
3bÆHCl15 (14.54 g, 105 mmol), pinacolone (26 mL,
t-Bu
Me
N
Me
N
t-Bu
1.3 eq. Me2Zn,
Tol., t.a., 18h
˚
Me
O N
210 mmol), activated 4 A molecular sieves (beads, 60 g),
O N
R2
triethylamine (14.7 mL, 105 mmol) and EtOH (100 mL).
After 16 h at reflux, the sieves were filtered off and the sol-
vent was evaporated under reduced pressure. The crude
white slurry was taken in ethyl acetate (150 mL), the pre-
cipitated triethylamine hydrochloride was filtered off and
the solvent removed under reduced pressure. A solution
of 150 mmol of dry HCl in ethanol (150 mL) was prepared
by addition of 11.2 mL of acetyl chloride in the solvent.
After 30 min, the crude mixture was dissolved in this solu-
tion and the solvent was evaporated in vacuo (bath temper-
ature 30 ꢁC; a prolonged heating at this stage decreased the
yield). A mixture of 3bÆHCl and 5bÆHCl was obtained. The
crude mass was stirred in acetonitrile (50 mL) and filtered.
The solid was 3bÆHCl. The solution was concentrated un-
der reduced pressure, and the crude oil was taken in ethyl
acetate and treated with a 4 M aqueous solution of NaH-
CO3. After drying over Na2SO4 and concentration, 5b
(8.648 g, 47 mmol, 45% yield) was recovered as a yellow
oil, which crystallized on standing. All imidazolidinones 5
were obtained as single isomers (NMR detection).
O
Me
10a-c
Me
O
2b
10
Alkyne: R2 =
Yield (%)
a
b
c
Ph
n-Bu
CH2–OAc
95
98
98
6. Conclusion
In conclusion, we have demonstrated the great potential of
a new family of enantiopure nitrones, available in a few
steps from cheap common amino-acids as the only source
of chirality. These compounds can be reacted with organo-
metallic reagents under very mild conditions, leading to
a,a-disubstituted amino-acids in protected form with total
enantio- and diastereoselectivity.
7. Experimental
7.2.1. rac-2-tert-Butyl-2,3-dimethylimidazolidin-4-one 5a.
1
7.1. General remarks
Yield 32%. White solid, mp 88 ꢁC. H NMR (300 MHz,
CDCl3): d = 3.48 (s, 2H), 2.90 (s, 3H), 1.37 (s, 3H), 0.99
(s, 9H). 13C NMR (75 MHz, CDCl3): d = 174.2 (C), 84.8
(C), 49.6 (CH2), 41.0 (C), 29.1 (CH3), 26.3 (CH3), 21.3
1H NMR (200 or 300 MHz) and 13C NMR (50 or 75 MHz)
spectra were recorded on Bruker AC200 or Advance300

1972
A. Pernet-Poil-Chevrier et al. / Tetrahedron: Asymmetry 17 (2006) 1969–1974
(CH3). IR (KBr pellet): 3329, 2952, 1674, 1436, 1126 cmꢀ1
.
7.3. Imidazolidinones N-oxides 2
MS (DCI): 172 (11), 171 (100). Anal. Calcd for C9H16N2O:
C, 63.50; H, 10.66; N, 16.46. Found: C, 62.96; H, 10.59; N,
16.01.
7.3.1. rac-2-tert-Butyl-1-hydroxy-2,3-dimethyl-imidazolid-
in-4-one 8a. In a 250 mL fitted flask, aminoamide 5a
(0.723 g, 4.3 mmol) and the urea:hydroperoxide complex
(UHP; 1.39 g, 5.16 mmol, 1.2 equiv) were introduced in
20 mL of dichloromethane (DCM). Methyltrioxorhenium
(MTO, 5 mg) was added at 20 ꢁC. A yellow coloration
developed, then slowly faded over 30 min. Fresh fractions
of 5 mg MTO were added every other 30 min. After a total
of 1.5 h, anhydrous magnesium sulfate was added, and the
reaction mixture filtered. After concentration, chromatog-
raphy over 50 g silica gel (eluent EtOH/DCM 4/96) yielded
0.477 g (60%) of hydroxylamine 8a. White solid, mp
125 ꢁC. 1H NMR (300 MHz, CDCl3): d = 3.89 (d,
J = 16.8 Hz, 1H), 3.56 (d, J = 16.8 Hz, 1H), 2.89 (s, 3H),
1.40 (s, 3H), 0.99 (s, 9H). 13C NMR (75 MHz, CDCl3):
d = 171.7 (C), 91.7 (C), 61.1 (CH2), 40.7 (C), 29.1 (CH3),
26.5 (CH3), 14.2 (CH3). IR (KBr pellet): 3283, 2967,
1680, 1126 cmꢀ1. MS (DCI): 187 (74), 186 (27), 171 (86),
169 (100). Anal. Calcd for C9H18N2O2: C: 58.04, H: 9.74,
N: 15.04. Found C: 58.28, H: 9.71, N: 14.87.
7.2.2. (2S,5S)-2-tert-Butyl-2,3,5-trimethylimidazolidin-4-one
5b. Yield 42%. Pale yellow solid, mp 81–83 ꢁC. 1H NMR
(300 MHz, CDCl3): d = 3.56 (q, J = 6.8 Hz, 1H), 2.88 (s,
3H), 1.34 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H), 1.02 (s, 9H).
13C NMR (75 MHz, CDCl3): d = 175.8 (C), 82.6 (C),
53.1 (CH), 38.2 (C), 29.0 (CH3), 26.1 (CH3), 18.9 (CH3),
18.0 (CH3). IR (KBr pellet): 3348, 2979, 2930, 2866,
1695, 1475, 1127 cmꢀ1. MS (DCI) 186 (12), 185 (100),
183 (4). Anal. Calcd for C10H20N2O: C, 65.18; H, 10.94;
N, 15.20. Found: C, 65.69; H, 10.97; N, 15.19.
25
½aꢁD ¼ þ50:7 (c 1.03, CH2Cl2). Crystal description CCDC
605991.
7.2.3. (2S,5S)-2-tert-Butyl-5-benzyl-2,3-dimethylimidazol-
idin-4-one 5c. Yield after chromatography is 27% (in
EtOAc 80/EtOH 20, f.r. = 0.57). Oil. 1H NMR
(300 MHz, CDCl3): d = 7.32–7.18 (m, 5H), 3.73 (dd,
J = 4.5, 6.5 Hz, 1H), 3.13 (dd, J = 4.5, 13.7 Hz, 1H), 3.02
(dd, J = 6.5, 13.7 Hz, 1H), 2.86 (s, 3H), 1.25 (s, 3H), 0.82
(s, 9H). 13C NMR (75 MHz, CDCl3): d = 173.7 (C),
137.6 (C), 129.6 (CH), 128.5 (CH), 126.6 (CH), 82.0 (C),
58.0 (CH), 37.8 (C), 37.2 (CH2), 28.4 (CH3), 25.4 (CH3),
18.5 (CH3). IR (KBr pellet): 3334, 3051, 2957, 1690,
1478, 1131 cmꢀ1. MS (DCI) 262 (16), 261 (100), 259 (8).
7.3.2. rac-2-tert-Butyl-2,3-dimethyl-2,3-dihydro-imidazol-4-
one-1-oxide 2a. Hydroxylamine 8a (0.477 g) was stirred
for 30 min with activated MnO2 (Fluka, ref. 63548,
0.334 g, 1.5 equiv) in 10 mL of DCM, Then the mixture
was diluted with ethyl acetate and anhydrous Na2SO4
was added. The solid was filtered over Celite and repeat-
edly rinsed with ethyl acetate. Concentration of the gath-
ered filtrates yielded 0.471 g (2.56 mmol) of 2b (60% yield
from 8a) as a yellow solid. Mp 127 ꢁC. 1H NMR
(300 MHz, CDCl3): d = 7.03 (s, 1H), 3.06 (s, 3H), 1.68 (s,
3H), 1.09 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 164.9
(C), 125.1 (CH), 97.2 (C), 40.0 (C), 30.1 (CH3), 25.5
(CH3), 18.3 (CH3). IR (KBr pellet): 2962, 1705, 1550,
1121 cmꢀ1. MS (DCI) 186 (15), 185 (100), 169 (27), 129
(66). Anal. Calcd for C9H16N2O2: C: 58.68, H: 8.76, N:
15.21. Found: C: 58.81, H: 8.80, N: 15.19.
Anal. Calcd for C16H24N2O: C, 73.81, H, 9.30, N, 10.76.
25
Found: C, 74.46, H, 9.48, N, 10.78. ½aꢁD ¼ ꢀ48:8 (c 1.05,
CH2Cl2).
7.2.4.
(2S,5S)-5-((1H-Indol-3-yl)methyl)-2-tert-butyl-2,3-
dimethylimidazolidin-4-one 5d. Yield after chromatogra-
phy is 32% (in EtOAc 80/EtOH 20, f.r. = 0.53). White so-
1
lid, mp 177 ꢁC. H NMR (300 MHz, CDCl3): d = 7.3–7.1
(m, 5H), 3.76 (dd, J = 4.5, 5.6 Hz, 1H), 3.34 (dd, J = 4.5,
14.7 Hz, 1H), 3.25 (dd, J = 5.6, 14.7 Hz, 1H), 2.82 (s,
3H), 1.22 (s, 3H), 0.66 (s, 9H). 13C NMR (75 MHz,
CDCl3): d = 175.2 (C), 136.6 (C), 128.6 (C), 127.5 (CH),
123.8 (CH), 120.1 (CH), 119.3 (CH), 111.5 (CH), 111.3
(C), 82.8 (C), 58.7 (CH), 37.9 (C), 28.9 (CH3), 26.3
(CH2), 25.7 (CH3), 18.6 (CH3) cmꢀ1. IR (KBr pellet):
3329, 3053, 2957, 1680, 1426, 1090. MS (DCI) 301 (21),
300 (100). Anal. Calcd for C18H25N3O: C, 72.21; H, 8.42;
7.3.3. (S)-2-tert-Butyl-2,3,5-trimethyl-2,3-dihydro-imidazol-
4-one-1-oxide 2b. In a 250 mL flask, m-chloroperbenzoic
acid (7.77 g, shipping grade, 70% purity, 21 mmol) was
added in portions at 0 ꢁC to 5b (3.851 g, 21 mmol) in
50 mL of DCM. After 30 min at 20 ꢁC, MnO2 (2.75 g,
31.5 mmol) was added and stirring continued for 2 h at
20 ꢁC. The reaction mixture was then filtered over Celite
and the precipitate repeatedly rinsed with EtOAc. The
organic phase was extracted with a 2 M Na2CO3 solution,
dried over Na2SO4 and concentrated to yield pure nitrone
N, 14.04. Found: C, 71.45; H, 8.58; N, 13.71.
25
½aꢁD ¼ ꢀ70:1 (c 1.01, CH2Cl2).
1
7.2.5.
rac-(2S*,5S*)-2-tert-Butyl-5-(hydroxymethyl)-2,3-
2b in 74% yield (3.06 g). Pale yellow solid, mp 63 ꢁC. H
dimethylimidazolidin-4-one 5e. Yield after chromatogra-
phy is 28% (in EtOAc 80/EtOH 20, f.r. = 0.37). White so-
lid, mp 108–110 ꢁC. 1H NMR (300 MHz, CDCl3): d = 3.98
(dd, J = 3.9, 11.3 Hz, 1H), 3.77 (dd, J = 4.9, 11.3 Hz, 1H),
3.60 (dd, J = 3.9, 4.9 Hz, 1H), 2.80 (s, 3H), 1.34 (s, 3H),
1.04 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 174.6 (C),
82.6 (C), 61.7 (CH2), 58.3 (CH), 38.1 (C), 28.4 (CH3),
25.7 (CH3), 18.8 (CH3). IR (KBr pellet): 3298, 3205,
2962, 1685, 1478, 1157, 1059 cmꢀ1. MS (DCI) 202 (19),
201 (100). Anal. Calcd for C10H20N2O2: C, 59.98; H,
10.07; N, 13.99. Found: C, 59.71; H, 10.00; N, 13.85.
NMR (300 MHz, CDCl3): d = 2.90 (s, 3H), 1.90 (s, 3H),
1.50 (s, 3H), 0.90 (s, 9H). 13C NMR (75 MHz, CDCl3):
d = 165.3 (C), 134.1 (C), 94.5 (C), 39.8 (C), 29.7 (CH3),
25.2 (CH3), 17.6 (CH3), 7.3 (CH3). IR (KBr pellet): 2964,
1707, 1601, 1126 cmꢀ1. MS (DCI): 200 (12), 199 (100),
25
183 (13), 143 (30). ½aꢁD ¼ ꢀ93:7 (c 4.8, CH2Cl2). Anal.
Calcd for C10H18N2O2: C, 60.59; H, 9.16, N, 14.13. Found:
C, 60.52, H, 9.22, N, 14.06.
7.3.4.
(S)-5-Benzyl-2-tert-butyl-2,3-dimethyl-2,3-dihydro-
imidazol-4-one-1-oxide 2c. Same preparation as 2b. Yield

A. Pernet-Poil-Chevrier et al. / Tetrahedron: Asymmetry 17 (2006) 1969–1974
1973
1
80%. Yellow oil. H NMR (300 MHz, CDCl3): d = 7.41–
(CH2), 82.6 (C), 68.1 (C), 38.2 (C), 29.0 (CH3), 26.5
(CH3), 23.3 (CH3), 14.3 (CH3). IR (KBr pellet): 3376,
7.16 (m, 5H), 3.85 (d, J = 14.10 Hz, 1H), 3.82 (d,
J = 14.10 Hz, 1H), 3.06 (s, 3H), 1.63 (s, 3H), 0.96 (s, 9H).
13C NMR (75 MHz, CDCl3): d = 165.4 (C), 136.0 (C),
134.8 (C), 130.3 (CH), 129.1 (CH), 127.3 (CH), 94.9 (C),
40.3 (C) ; 29.7 (CH3) ; 27.9 (CH2), 26.3 (CH3), 18.1
3081, 2988, 2967, 2920, 1695, 1059 cmꢀ1. MS (DCI): 228
25
(16), 227 (100), 226 (29), 211 (36), 196 (74). ½aꢁD ¼ þ25:2
(c 1.02, CH2Cl2). Anal. Calcd for C12H22N2O2: C: 63.69,
H: 9.80, N: 12.38. Found C: 63.65, H: 9.76, N: 11.91.
(CH3). IR (KBr pellet): 3029, 2962, 1705, 1581, 1126. MS
25
(DCI): 276 (16), 275 (100), 259 (14). ½aꢁD ¼ ꢀ69:8 (a
7.5. Preparation of 10
1.08, CH2Cl2). Anal. Calcd for C16H22N2O2: C: 70.04, H:
8.08, N: 10.21. Found C: 69.82, H: 8.43, N: 10.27.
The preparation of 10a is typical. In a 50 mL Schlenk tube
under a nitrogen atmosphere, 198 mg (1.0 mmol) of nitrone
2b and 306 mg (3 mmol) of phenylacetylene were dissolved
in 2 mL of toluene. At 20 ꢁC, 0.75 mL of a 2 M commercial
solution of dimethylzinc in toluene was added and the mix-
ture was stirred overnight. After hydrolysis with 1 mL sat-
urated NH4Cl and extractive work-up in ethyl acetate, the
excess alkyne was separated on a short column of silica gel,
to yield pure 10a (285 mg, 95%).
7.4. Addition of Grignard reagents to nitrones 2
The preparation of 9a is typical. In a 20 mL Schlenk vessel
under an N2 atmosphere, 2b (396 mg, 2 mmol) was
dissolved in 5 mL THF. At ꢀ40 ꢁC, the solution of p-meth-
oxy-phenyl-magnesium bromide in THF (2 mL, 2.4 mmol)
was added dropwise. After 4 h at ꢀ40 ꢁC, the mixture was
quenched with NH4Cl, extracted with EtOAc, the organic
phase dried over Na2SO4 and concentrated. The solid ob-
tained was washed with an EtOAc/cyclohexane mixture
10/90, to yield 477 mg (78% yield) of pure 9a.
7.5.1. (3aS,6R)-6-tert-Butyl-5,6-dimethyl-2-phenyl-5,6-di-
hydroimidazo[1,5-b]isoxazol-4(3aH)-one 10a. Yield 95%.
White solid, mp 103 ꢁC. 1H NMR (CDCl3, 300 MHz):
d = 7.45–7.25 (m, 5H), 5.32 (s, 1H), 2.85 (s, 3H), 1.48 (s,
3H), 1.31 (s, 3H), 1.03 (s, 9H). 13C NMR (CDCl3,
75 MHz) d = 171.3 (C), 154.7 (C), 129.3 (CH), 128.4
(CH), 127.3 (C), 125.5 (CH), 98.0 (CH), 90.5 (C), 74.5
(C), 39.5 (C), 28.8 (CH3), 25.6 (CH3), 24.0 (CH3), 13.5
(CH3). IR (KBr pellet): 3374, 3096, 3062, 2986, 2962,
7.4.1.
(2R,5R)-2-tert-Butyl-1-hydroxy-5-para-methoxy-
phenyl-2,3,5-trimethylimidazolidin-4-one 9a. Yield 78%.
White solid, mp 61 ꢁC. 1H NMR (300 MHz, CDCl3):
d = 7.10–6.74 (m, 4H), 3.72 (s, 3H), 3.02 (s, 3H), 1.63 (s,
3H), 1.06 (s, 3H), 0.95 (s, 9H). 13C NMR (75 MHz,
CDCl3): d = 176.7 (C), 155.3 (C), 130.5 (CH), 130.0 (C),
113.6 (CH), 87.3 (C), 77.9 (C), 54.9 (CH3), 40.5 (C), 28.9
(CH3), 26.4 (CH3), 24.9 (CH3), 13.4 (CH3). IR (KBr pellet):
2924, 1703, 1496, 1481, 1447, 1428, 1392, 1258, 1131,
25
1055, 1003, 916, 763, 737, 694 cmꢀ1. ½aꢁD ¼ ꢀ33 (c 3.2 ;
CH2 Cl2). Anal. Calcd for C18H24N2O2: C: 71.97, H:
8.05, N: 9.33. Found C: 72.36, H: 8.44, N: 9.11. Crystal
description CCDC 605990.
3371, 3014, 2988, 2967, 1690, 1183 cmꢀ1. MS (DCI): 308
25
(9), 307 (56), 306 (8), 291 (44), 192 (100). ½aꢁD ¼ þ77:3 (c
0.75, CH2Cl2). Anal. Calcd for C17H26N2O3: C: 66.64, H:
8.55, N: 9.14. Found C: 66.57, H: 8.71, N: 9.15. HPLC
of enantiomers: Daicel Chiralpak AD-RH column,
4.6 · 150 mm, eluent acetonitrile 60/water 40, 0.3 mL/
min, retention time (2R,5R)-9a 9.7 min, (2S,5S)-9a 12.7
min.
7.5.2.
(3aS,6R)-2-Butyl-6-tert-butyl-5,6-dimethyl-5,6-di-
hydroimidazo[1,5-b]isoxazol-4(3aH)-one 10b. Yield 98%
(835 mg, 6 mol equiv of 1-hexyne were used). Oil. 1H
NMR (CDCl3, 300 MHz): d = 4.62 (t, J = 1.1 Hz, 1H),
2.86 (s, 3H), 2.11–2.05 (m, 2H), 1.49–1.23 (m, 4H), 1.36
(s, 3H), 1.29 (s, 3H), 0.98 (s, 9H), 0.85 (t, J = 7.1 Hz,
3H). 13C NMR (CDCl3, 75 MHz): d = 172.2 (C), 157.6
(C), 97.8 (CH), 90.4 (C), 74.1 (C), 39.6 (C), 28.9 (CH3),
28.6 (CH2), 25.9 (CH3), 25.8 (CH3), 25.1 (CH2), 24.4
(CH3), 22.4 (CH2), 13.9 (CH3). IR (KBr pellet): 3111,
2959, 2928, 2873, 1703, 1446, 1424, 1392, 1372, 1264,
7.4.2.
(2R,5R)-5-Benzyl-2-tert-butyl-1-hydroxy-5-para-
methoxyphenyl-2,3-dimethylimidazolidin-4-one 9b. Yield
64%. White solid, mp 85 ꢁC. 1H NMR (300 MHz, CDCl3):
d = 7.32–6.78 (m, 9H), 3.73 (s, 3H), 3.39 (d, J = 13.7 Hz,
1H), 3.19 (d, J = 13.7 Hz, 1H), 2.90 (s, 3H), 0.88 (s, 3H),
0.51 (s, 9H). 13C NMR (75 MHz, CDCl3): d = 171.0 (C),
159.5 (C), 138.2 (C), 132.0 (CH), 131.2 (CH), 129.8 (C),
128.2 (CH), 126.7 (CH), 113.5 (CH), 86.6 (C), 74.1 (C),
55.6 (CH3), 42.6 (CH2), 40.1 (C), 28.5 (CH3), 26.2 (CH3),
13.4 (CH3). IR (KBr pellet): 3355, 3005, 2988, 2952,
1135, 1103, 1080, 1050, 983, 954, 936, 855, 822, 756, 719.
25
½aꢁD ¼ ꢀ29 (c 5.3, CH2Cl2). HRMS (EI) calcd for
C16H28N2O2 (M+.) 280.21522. Found 280.21580.
7.5.3. [(3aS,6R)-6-tert-Butyl-5,6-dimethyl-4-oxo-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazol-2-yl]methyl acetate 10c.
Yield 98% (673 mg). Oil. 1H NMR (CDCl3, 300 MHz):
d = 5.05 (s, 1H), 4.65 (s, 2H), 2.91 (s, 3H), 2.07 (s, 3H),
1.44 (s, 3H,), 1.36 (s, 3H), 1.03 (s, 9H). 13C NMR (CDCl3,
75 MHz): d = 170.8 (C), 169.7 (C), 151.5 (C), 102.5 (CH),
90.5 (C), 73.9 (C), 56.1 (CH2), 39.4 (C), 28.7 (CH3), 25.6
(CH3), 23.8 (CH3), 20.3 (CH3), 13.5 (CH3). IR (KBr
pellet): 3116, 2974, 2927, 2875, 1750, 1701, 1483, 1446,
2915, 1679, 1173 cmꢀ1. MS (DCI): 384 (25), 383 (100),
25
382 (7), 367 (22), 268 (80). ½aꢁD ¼ þ93:9 (c 0.83, CH2Cl2).
Anal. Calcd for C23H30N2O3: C: 72.22, H: 7.91, N: 7.32.
Found C: 67.62, H: 8.42, N: 6.36. Crystal description
CCDC 605989.
7.4.3.
(2R,5R)-2-tert-Butyl-1-hydroxy-2,3,5-trimethyl-5-
vinylimidazolidin-4-one 9c. Yield 68%. White solid, mp
128 ꢁC. 1H NMR (300 MHz, CDCl3): d = 6.09 (dd,
J = 10.9, 17.6 Hz, 1H), 5.24–5.16 (m, 2H), 2.87 (s, 3H),
1.37 (s, 3H), 1.33 (s, 3H), 0.93 (s, 9H). 13C NMR
(75 MHz, CDCl3): d = 175.8 (C), 136.9 (CH), 117.2
1427, 1393, 1297, 1245, 1220, 1136, 1050, 1032, 935, 917,
25
857, 819, 727 cmꢀ1. ½aꢁD ¼ ꢀ34 (c 6.9, CH2Cl2). HRMS
(EI) calcd for C15H24N2O4 (M+Å) 296.17361. Found
296.17476.

1974
A. Pernet-Poil-Chevrier et al. / Tetrahedron: Asymmetry 17 (2006) 1969–1974
10. Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetrahedron
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we thank the CNRS and MENR (ACI No. 02 L 0525,
´
´
Molecules et Cibles Therapeutiques) for financial support.
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