Cycloadditions of chiral nitrones to racemic 3-substituted butenes: A direct access with kinetic resolution to enantiopure dihydroxylated amino acids

Article abstract of DOI:10.1055/s-2006-951534

1,3-Dipolar cycloadditions of racemic 3-substituted 1-butenes to nitrones derived from (-)- or (+)-menthone occurred via exo-approach of the alkene onto the nitrone's less hindered face. This process afforded bicyclic spiroheterocycles as epimers, with se

Full text of DOI:10.1055/s-2006-951534

LETTER
3299
Cycloadditions of Chiral Nitrones to Racemic 3-Substituted Butenes: A Direct
Access with Kinetic Resolution to Enantiopure Dihydroxylated Amino Acids
Cycloadditions of
a
Chiral
N
itro
i
nes to
s
R
acemic
3
-SubstitutedBu
A
tenes ouadi,a,b Sébastien Vidal,a Moncef Msaddek,b Jean-Pierre Praly*a
a
Université Claude Bernard Lyon 1, CPE-Lyon, Bât. 308, Laboratoire de Chimie Organique 2 – Glycochimie, UMR-CNRS 5181,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: jean-pierre.praly@univ-lyon1.fr
b
Université de Monastir, Faculté des Sciences de Monastir, Laboratoire de Synthèse Hétérocyclique et Photochimie, Avenue de l’Envi-
ronnement, Monastir 5000, Tunisia
Received 22 July 2006
to the reaction center, so as to exploit the potential of
cycloaddition with menthone-derived nitrones.
Abstract: 1,3-Dipolar cycloadditions of racemic 3-substituted 1-
butenes to nitrones derived from (–)- or (+)-menthone occurred via
exo-approach of the alkene onto the nitrone’s less hindered face.
This process afforded bicyclic spiroheterocycles as epimers, with
selectivities £ 4:1, depending on the 3-substituent (R) on the alkene.
The selectivity appeared to be influenced by hydrogen bonding
(R = OH) or the bulkiness of the R group (R = OBz, Br), as a result
of kinetic resolution. The cycloadducts obtained led, after a reduc-
tive step and cleavage of the chiral auxiliary, to enantiopure dihy-
droxylated non-natural amino acids in high overall yield.
From the structures of the cycloadducts obtained, and in
particular from the absolute configuration of the three
asymmetric centers (C-3 and C-5 in the isoxazoline ring
and C-6 on the alkyl chain, Scheme 1), it should be possi-
ble to establish the cycloaddition selectivity. Depending
on the mode of approach (face selection, endo/exo-mode
of approach) regio- and diastereoisomers may be formed,
respectively. Racemization or equilibration may occur
by heating over prolonged times,9c while identification of
the cycloadducts by NMR spectroscopy may be problem-
atic.9a Nevertheless, many reactions are reported to occur
selectively, via a preferred transition state favored for
steric or electronic reasons.11
Key words: 1,3-dipolar cycloadditions, nitrones, isoxazolidines,
dihydroxy amino acid, kinetic resolution
Selectivity control is the corner stone for the chemical
synthesis of elaborated molecules by economically viable
processes with minimized impact on the environment.
Much effort has led to improved synthetic methodologies
and in particular to the development of concerted
reactions1,2 which may create simultaneously several
chemical bonds and stereogenic centers under smooth
conditions. [3+2] Cycloadditions of nitrones3 to alkenes
and related reactions of azomethine ylides4 are attracting
much interest,5 due to the availability of structurally di-
verse dipoles2d,6 and opportunities to further elaborate the
resulting cycloadducts.
R
O
*
6
N
O
*
N2
HO
R
5
4
3
1
O
N
H
CO2
+
*
dipolar
*
*
O
cycloaddition
N
OH
NH3
Scheme 1 Nitrone cycloaddition as a route to dihydroxy amino
acids
While working on the synthesis of C-glycosyl compounds
as stable glycomimics,7 we noticed a recent approach to
C-glycosylated 4-hydroxy amino acids, based on the cy-
cloaddition of the chiral nitrone (–)-1 [derived from (–)-
menthone] to C-1 allyl or C-1 vinyl carbohydrates.8 Sug-
ar-based cycloadducts were obtained with excellent selec-
tivities (82–92% yield). As the subsequent removal of the
chiral auxiliary occurred in high yield under smooth con-
ditions and as stereoisomers can be formed by use of (+)-
1 [derived from (+)-menthone], this method appeared to
have great potential for stereocontrolled synthesis.9,10 As
an application to the synthesis of non-natural amino acids,
we considered racemic 3-substituted 1-butenes as dipo-
larophiles displaying an asymmetric allylic carbon close
Commercially available 3-hydroxy-1-butene (2a) and its
derivatives [3-tert-butyldimethylsilyloxy 2b, 3-benzyl-
oxy 2c, 3-benzoyloxy 2d, and 3-bromo-1-butene (2e)]
appeared to be suitable.12 Due to the cycloaddition condi-
tions (several hours in refluxing toluene) and the use of
volatile alkenes, dipolarophiles 2a–d were added in
excess (2–9 equiv); the reaction was stopped once all the
nitrone (–)-1 was consumed, as indicated by TLC.13 The
cycloadducts (Scheme 2) were separated by column chro-
matography and fully characterized. Indeed, 3-bromo-1-
butene (2e) is not commercially available, while 1-bromo-
2-butene (crotyl bromide) is available as a mixture of cis/
trans isomers (ca. 15% and 70%) and 3-bromo-1-butene
(ca. 15%), as shown by 1H NMR spectroscopy of the pur-
chased batch.14 We found by serendipity that nitrone (–)-
1 and commercial crotyl bromide in excess (four experi-
ments with 2.7, 6.0, 66.0, and 69.4 equiv, respectively)
reacted with complete conversion of the nitrone within a
few days (24 h/69 equiv; 72 h/2.7 equiv) in refluxing
SYNLETT 2006, No. 19, pp 3299–3303
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951534; Art ID: G24006ST
© Georg Thieme Verlag Stuttgart · New York

3300
K. Aouadi et al.
LETTER
toluene to afford two major diastereoisomers 3e and 4e in under standard conditions (TBAF, THF; NaOMe, MeOH
60–74% and 17–20% yields, respectively. Their struc- respectively) to afford 5a and 6a, which were found to be
tures were determined to be the cycloadducts derived identical in all respects (NMR spectra, optical rotations)
from nitrone and 2e, a dipolarophile more reactive than with similar samples obtained from either 3a and 4a or 3c
crotyl bromide, probably because of the higher accessibil- and 4c.
ity of the monosubstituted double bond in 2e. When using
commercial crotyl bromide in large excess, a sufficient
amount of 2e was present in the reaction mixture for the
The cycloadducts obtained were stable compounds, in
several cases amenable to crystallization, so that X-ray
diffraction gave unambiguous proof of the structures for
reaction to occur. Otherwise, 2e could result from in situ
3a, 4a, and 3e.19 The three rings were found to be roughly
isomerization of crotyl bromide15 over 72 hours at 110 °C.
perpendicular at the spiro- and fused-junctions of the cy-
cloadducts.
1H NMR spectroscopy provided additional information,
based on the vicinal coupling constants of the protons at-
The cycloaddition of nitrone (–)-1 to crotyl bromide was
negligible, affording the corresponding product in trace
amounts (< 4%).
Removal of the chiral auxiliary (Scheme 2) was achieved
tached to the isoxazolidine ring and on the NOE experi-
in three high-yielding steps: a) reductive cleavage of the
ments carried out with 3c, 3d, and 4c in acetone-d6. In
one-dimensional NOE experiments (Figure 1), selective
irradiation of 3-H induced enhancements of the vicinal
N–O bond in the isoxazolidine ring of 3a–d and 4a–d
[Pd(OH)2/C (20%), H2, 1 atm, MeOH];16,17 b) acid-cata-
lyzed hydrolysis of the imidazolidinones to liberate (–)-
protons were found to be higher for 4-HproR compared to
menthone; c) base-catalyzed hydrolysis of the resulting N-
4-HproS (3c, 3d, 4c, 2.9:3.7: 2.3). Selective irradiation of
methylamides (two steps carried out in one-pot) to afford
5-H enhanced the signal of 4-HproS more compared to the
pure amino acids 7 and 8, without racemization.18 For the
effect exerted on 4-HproR (3c, 3d, 4c, 2.9:7.3:3). These ob-
benzyloxy derivatives, the benzyl groups underwent hy-
servations clearly indicated that the 3-H and 5-H protons
drogenolysis concomitantly with N–O cleavage so that 3c
attached to the isoxazolidine ring pointed in opposite
directions. Selective irradiation of 3-H also enhanced the
signals of the isopropyl protons, visible as doublets (Me)
and as a multiplet (CHMe2). These results showed conclu-
and 4c led to 5a (73%) and 6a (71%). The brominated cy-
cloadducts 3e and 4e were resistant towards N–O cleav-
age under various conditions [Pd(OH)2/C (20%),16 H2, up
to 10 atm, MeOH; SmI2;8b Zn, AcOH9b], probably for ster-
sively the C-3–H bond pointed towards the isopropyl
ic reasons. The silyl and benzoyl groups in the isolated in-
group (Figure 1); this was also observed in the solid
termediates 5b/5d and 6b/6d were cleaved efficiently
1
state.19 Further arguments came from analysis of the H
R
R
O
O
O
H
H
R
N
N
N
O
O
O
+
2a–e
N
N
N
PhMe, 110 °C
(–)-1
3a–e
4a–e
a R = OH
H2, Pd(OH)2-C
MeOH, r.t.
b R = OTBDMS
c R = OBn
d R = OBz
e R = Br
R
R
Yields (%)
Yields (%)
HO
HN
HO
HN
H
3a 38
3b 55
3c 59
3d 57
3e 74
4a 60
4b 36
4c 30
4d 18
4e 18
H
O
O
N
N
Yields (%)
Yields (%)
5a,b,d
6a,b,d
5a 99a, 73b 6a 99e, 71f
74c, 62d
5b 75
5d 79
5e
74g, 64h
6b 74
6d 80
6e
1) 3N HCl, AcOH, 80 °C
2) LiOH·H2O, THF, H2O, r.t.
84%
from 5a
80%
from 6a
0
0
a from 3a, b from 3c
c from 5b, d from 5d
e from 4a, f from 4c
g from 6b, h from 6d
OH
OH
CO2
+
CO2
+
OH
NH3
OH NH3
7
8
Scheme 2 Access to enantiopure amino acids by cycloaddition
Synlett 2006, No. 19, 3299–3303 © Thieme Stuttgart · New York

LETTER
Cycloadditions of Chiral Nitrones to Racemic 3-Substituted Butenes
3301
NMR spectra and the observed values of the vicinal cou- Therefore, the cycloadducts produced in the reactions
plings: J3,4R ca. 8–9 Hz, J3,4S < 2 Hz, J4R,4S ca. 12 Hz, J4R,5 studied were C-6 epimers (Scheme 2). Depending on the
8.7–11.7 Hz, J4S,5 4.5–6.0 Hz, J5,6 6.6–7.5 Hz, J6,7 6.0–6.6 R substituent at C-6, the ratio of the 6R/6S products
Hz. Finally, the fact that 5a (prepared from 3a and 3c) and ranged from 2:3 (R = OH) to 1.5:1 (R = TBDMSO), 2:1
6a (prepared from 4a and 4c) were found to be identical (R = OBn), 3:1 (R = OBz), 3:1 (R = Br). While the 6S
to samples prepared by desilylation (from 5b and 6b) and epimer predominated when R was a hydroxyl group, 6R
debenzoylation (from 5d and 6d) supported conclusively epimers were favored in the other cases studied, where the
the structures proposed for the cycloadducts.
stereoselectivity increased according to the sequence
TBDMSO < OBn < OBz < Br, thus suggesting steric con-
trol (Table 1). This can be seen from the models proposed
for the approach/transition state (Figure 2), which favors
conformers in which the hydrogen atom is closer to the
nitrone moiety, while Me and R lie in uncrowded posi-
tions.20 To account for the observed 6S-selectivity for
3-hydroxy-1-butene (2a) reacting in toluene with (–)-1, a
hydrogen-bonded transition state is a reasonable model;
this was previously invoked to explain both stereochemi-
cal and regiochemical trends in nitrile oxide cycloaddi-
tions with allylic alcohols.21 Such favored approaches led
to diastereoisomeric transition states with minimal activa-
tion energies associated with faster reaction rates. Kinetic
resolution22,23 could be achieved, in particular with bromi-
nated alkene 2e, leading to C-6 epimeric cycloadducts
with ca. 60% diastereomeric excess, which was shown to
increase slightly with the amount of alkene 2e used
(Table 1).
0.59
0.08
H
OBz
0.34
0.37
6
HproS
HproR
0.82
0.47
0.22
H
5
4
H
O
0.91
1
3
0.79
O
N2
H
N
H
3d
Figure 1 One-dimensional NOE observed for cycloadduct 3d
The data collected clearly established the configurations
at C-3 and C-5 as S for the ten cycloadducts considered.
These observations indicated that the reaction proceeded
with complete regioselectivity (due to steric control) and
complete diastereoselectivity with regard to the isoxazoli-
dine ring formation, with all products being formed via an
anticipated exo approach of the alkene from the less hin-
dered face of the nitrone (Figure 2).
Table 1 1,3-Dipolar Cycloadditions of Chiral Nitrone (–)-1 with
Racemic Alkenes 2a–e in Toluene at 110 °C
Alkenes
R
Nitrone/
Time 3a–e 4a–e de
alkene ratio (h)
(%)
(%)
60
36
30
18
(%)
2a
2b
2c
2d
2e
OH
1:9
24
72
48
48
38
22
OTBDMS 1:3
55
21
H
H
R
3-substituted
allylic
alcohol
OBn
OBz
Br
1:5
1:2
59
33
Me
Me
alkene
O
H
H
57
52
H
H
H
H
H
H
H
1:2.7
1:6
1:66
1:69
72
48
24
24
71
60
74
70
20
17
18
18
56
56
61
59
O
O
N
N
Me
Me
Me
Me
O
O
N
N
Me
Me
Me
Me
cyclic nitrone
Experiments performed with nitrone (+)-1 fully con-
firmed the initial observations in terms of yields, regiose-
lectivities, and diastereoselectivities and provided the
corresponding enantiomers identical in all respects with
those derived from (–)-1, except for their optical rotation.
This was valid for the four g,d-dihydroxy amino acids 7–
10 synthesized (Table 2).
H
H
R
Me
Me
HO
R
S
HproR
HproR
HproS
HproS
H
H
H
O
O
H
N
N
Me
Me
Me
Me
In conclusion, 1,3-dipolar cycloadditions of menthone-
based nitrones to a series of racemic 3-substituted 1-
butenes afforded, via the exo-approach and completely
controlled creation of two stereogenic centers, a series of
epimeric isoxazolidines with a 6R or 6S configuration.
Partial kinetic resolution due to one alkene enantiomer re-
acting at a faster rate accounted for the observed epimeric
O
O
N
Me
N
Me
Me
Me
Figure 2 Normal (R ≠ OH) and H-bonded (R = OH) models for the
cycloaddition transition state of nitrone (–)-1 and alkenes in the exo
approach
Synlett 2006, No. 19, 3299–3303 © Thieme Stuttgart · New York

3302
K. Aouadi et al.
LETTER
(9) (a) Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C.
Table 2 Optical Rotations of g,d-Dihydroxy Amino Acids 7–10a
Tetrahedron 1997, 53, 5725. (b) Baldwin, S. W.; Long, A.
Org. Lett. 2004, 6, 1653. (c) Stecko, S.; Pasniczek, K.;
Jurczak, M.; Urbanczyk-Lipkowska, Z.; Chmielewski, M.
Tetrahedron: Asymmetry 2006, 17, 68. (d) Wang, P.-F.;
Gao, P.; Xu, P.-F. Synlett 2006, 1095.
Amino acids
7 (2S,4S,5R)
8 (2S,4S,5S)
9 (2R,4R,5S)
10 (2R,4R,5R)
a c = 1, H2O.
Optical rotations
–23
–27
+22
+28
(10) For other chiral glycine equivalents, see: (a) Katagiri, N.;
Sato, H.; Kurimoto, A.; Okada, M.; Yamada, A.; Kaneko, C.
J. Org. Chem. 1994, 59, 8101. (b) Baldwin, S. W.; Young,
B. G.; McPhail, A. T. Tetrahedron Lett. 1998, 39, 6819.
(c) Tamura, O.; Kuroki, T.; Sakai, Y.; Takizawa, J.-I.;
Yoshino, J.; Morita, Y.; Mita, N.; Gotanda, K.; Sakamoto,
M. Tetrahedron Lett. 1999, 40, 895. (d) Tamura, O.;
Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.;
Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.;
Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000, 65, 8544.
(e) Baldwin, S. W.; Long, A. Tetrahedron Lett. 2001, 42,
5343. (f) Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653.
(11) (a) Osborn, H. M. I.; Gemmel, N.; Harwood, L. M. J. Chem.
Soc., Perkin Trans. 1 2002, 2419. (b) Enderlin, G.;
ratio. Further manipulations of the cycloadducts led to
four stereochemically defined non-natural g,d-dihydroxy-
a-amino acids (2S,4S,5R; 2S,4S,5S; 2R,4R,5S; and
2R,4R,5R), as couples of enantiomers.
Taillefumier, C.; Didierjean, C.; Chapleur, Y. Tetrahedron:
Asymmetry 2005, 16, 2459.
Acknowledgment
(12) (a) Racemic 3-hydroxy-1-butene (2a) was purchased from
Acros Organics. (b) For the preparation of 2b, see: Hoeyer,
T.; Kjaer, A.; Lykkesfeldt, J. Collect. Czech. Chem.
Commun. 1991, 56, 1042. (c) For the preparation of 2c, see:
Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457. (d) For the preparation of 2d see:
Yasui, K.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org.
Chem. 1995, 60, 1365.
Financial support from Région Rhône-Alpes (MIRA Recherche
2001 and stipends to K.A.) is gratefully acknowledged, as well as
funds from Université Claude Bernard Lyon 1 and CNRS. The au-
thors are indebted to Prof René Faure and Erwann Jeanneau (Uni-
versité Claude Bernard Lyon 1) for X-ray analyses. K.A. expresses
warm thanks to Prof. A.-K. Khemiss.
References and Notes
(13) General Procedure: A mixture of nitrone (–)-1 (1.5 mmol)
and alkene 2a–e (for nitrone/alkene ratio see Table 1) was
stirred in toluene (10 mL) at 110 °C [monitored by TLC
(CHCl3–i-PrOH, 98:2)]. When the reaction was complete the
solution was concentrated and the residue was purified by
flash chromatography (CHCl3–i-PrOH, 98:2) to afford the
desired cycloadducts 3a–e and 4a–e. Cycloadduct 3a:
[a]D22 +65 (c 1, CH2Cl2); white solid; mp 97–100 °C (Et2O).
1H NMR (CDCl3, 300 MHz): d = 0.80 (d, 3 H, J = 6.6 Hz,
CH3), 0.86 (d, 3 H, J = 6.9 Hz, CH3), 0.93 (d, 3 H, J = 6.3 Hz,
CH3), 0.93 (m, 1 H), 1.11 (d, 3 H, J = 6.6 Hz, CH3), 1.25 (t,
1 H, J = 12.3 Hz), 1.39 (m, 1 H), 1.44 (m, 1 H), 1.64 (m, 2
H), 1.83 (m, 1 H), 1.99 (m, 1 H), 2.06 (dt, 1 H, J = 3.0 Hz, J
= 12.3 Hz), 2.55 (m, 2 H), 2.74 (s, 3 H, NCH3), 3.78 (dt, 1 H,
J = 3.0 Hz, J = 6.9 Hz), 3.97 (dd, 1 H, J = 3.0 Hz, J = 7.5 Hz),
4.05 (dq, 1 H, J = 3.0 Hz, J = 6.6 Hz). 13C NMR (CDCl3, 75
MHz): d = 18.4, 18.6, 22.2, 22.4, 24.1, 24.2, 25.9 (NCH3),
29.3, 31.5, 34.5, 40.6, 47.9, 65.8, 68.0, 80.1, 88.9, 172.8
(C=O). MS (ESI): m/z = 311 [M + H]+. Anal. Calcd for
C17H30N2O3: C, 65.77; H, 9.74; N, 9.02; O, 15.46. Found: C,
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22
65.66; H, 9.99; N, 8.83; O, 16.01. Cycloadduct 3e: [a]D
+59 (c 1, CH2Cl2); white crystals, mp 94–95 °C (Et2O). 1H
NMR (CDCl3, 300 MHz): d = 0.81 (d, 3 H, J = 6.9 Hz, CH3),
0.85 (d, 3 H, J = 6.9 Hz, CH3), 0.91 (d, 3 H, J = 6.6 Hz, CH3),
0.93 (m, 1 H), 1.26 (t, 1 H, J = 12.3 Hz), 1.38 (m, 1 H), 1.44
(m, 1 H), 1.63 (m, 2 H), 1.72 (d, 3 H, J = 6.3 Hz, CH3), 1.82
(m, 1 H), 1.98 (m, 1 H), 2.03 (dt, 1 H, J = 2.5 Hz, J = 12.6
Hz), 2.42 (ddd, 1 H, J = 7.2 Hz, J = 12.6 Hz, J = 9.0 Hz), 2.74
(s, 3 H, NCH3), 2.86 (ddd, 1 H, J = 1.8 Hz, J = 5.4 Hz, J =
12.6 Hz), 3.92 (m, 3 H). 13C NMR (CDCl3, 75 MHz): d =
18.4, 22.2, 22.3, 23.1, 24.1, 24.2, 25.9 (NCH3), 29.5, 34.5,
37.8, 40.7, 48.0, 48.8, 65.7, 80.8, 89.2, 172.5 (C=O). MS
(ESI): m/z = 373 [M + H]+, 395 [M + Na]+, 767 [2 M + Na]+.
Cycloadduct 4e: [a]D22 +54 (c 1, CH2Cl2); yellow oil. 1H
NMR (CDCl3, 300 MHz): d = 0.83 (d, 3 H, J = 6.6 Hz, CH3),
0.85 (d, 3 H, J = 6.6 Hz, CH3), 0.92 (m, 1 H), 0.93 (d, 3 H,
Synlett 2006, No. 19, 3299–3303 © Thieme Stuttgart · New York

LETTER
Cycloadditions of Chiral Nitrones to Racemic 3-Substituted Butenes
3303
J = 6.3 Hz, CH3), 1.26 (t, 1 H, J = 12.3 Hz), 1.36 (m, 1 H),
(18) Typical Procedure: A solution of 1,3-imidazolidinone 5a
(100 mg) and AcOH (25 mL) in aq HCl (3 N, 30 mL) was
stirred at 80 °C for 2 h. The reaction mixture was then
evaporated to dryness and LiOH·H2O (200 mg) in THF–H2O
(1:1, 10 mL) was added. The resulting mixture was stirred at
r.t. for 2 h, then concentrated to dryness and purified by
reverse-phase flash chromatography (C18) to afford the
desired amino acid 7. [a]D22 –23 (c 1, H2O); white solid; mp
194–195 °C (MeOH). 1H NMR (D2O, 300 MHz): d = 1.12
(d, 3 H, J = 6.6 Hz, CH3), 1.73 (m, 2 H, H-3), 3.50 (dd, 1 H,
J = 4.8 Hz, J = 7.8 Hz, H-2), 3.65 (m, 1 H, H-4), 3.71 (m, 1
H, H-5). 13C NMR (D2O, 75 MHz): d = 17.0 (CH3), 35.7 (C-
3), 53.4 (C-2), 70.8 (C-5), 72.5 (C-4), 181.3 (C=O). MS
(ESI, negative mode): m/z = 162 [M – H]–. HRMS (CI,
isobutane): m/z calcd for C6H13NO4 [M + H]+: 164.0923;
found: 164.0919.
1.39 (m, 1 H), 1.65 (m, 2 H), 1.67 (d, 3 H, J = 6.6 Hz, CH3),
1.83 (m, 1 H), 2.05 (dt, 1 H, J = 2.5 Hz, J = 12.0 Hz), 2.11
(m, 1 H), 2.22 (ddd, 1 H, J = 9.0 Hz, J = 6.0 Hz, J = 12.3 Hz),
2.69 (ddd, 1 H, J = 5.1 Hz, J = 12.3 Hz), 2.75 (s, 3 H, NCH3),
3.90 (ddd, 1 H, J = 5.1 Hz, J = 4.5 Hz), 4.02 (br d, 1 H, J =
9.0 Hz), 4.02 (dq, 1 H, J = 6.6 Hz, J = 7.2 Hz). 13C NMR
(CDCl3, 75 MHz): d = 18.3, 22.3, 22.3, 22.4, 24.1, 24.3, 26.0
(NCH3), 29.6, 34.5, 36.1, 40.6, 47.8, 48.0, 66.6, 81.2, 90.0,
172.4 (C=O). MS (ESI): m/z = 373.1 [M]+, 769.0 [2 M +
Na]+. HRMS (ESI): m/z calcd for C17H29BrN2O2 [M]+:
373.1491; found: 373.1491.
(14) Sample purchased from Acros Organics.
(15) (a) Young, W. G.; Winstein, S. J. Am. Chem. Soc. 1935, 57,
2013. (b) Winstein, S.; Young, W. G. J. Am. Chem. Soc.
1936, 58, 104.
(16) Cardona, F.; Valenza, S.; Picasso, S.; Goti, A.; Brandi, A. J.
Org. Chem. 1998, 63, 7311.
(19) Crystallographic data for 3a, 3e, and 4a have been deposited
with the Cambridge Crystallographic Data Centre, under the
following reference numbers: CCDC 606452 (3a); CCDC
601858 (3e); CCDC 606451 (4a). Copies of these data can
be obtained on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).
(20) (a) Ito, M.; Maeda, M.; Kibayashi, C. Tetrahedron Lett.
1992, 33, 3765. (b) Ina, H.; Ito, M.; Kibayashi, C. J. Org.
Chem. 1996, 61, 1023.
(17) General Procedure: A suspension of cycloadduct 3a–d or
4a–d (100 mg) and Pd(OH)2/C (20%, 15 mg) was stirred in
MeOH (10 mL) at r.t. under H2 (1 atm). When the reaction
was complete (TLC) (CHCl3–i-PrOH, 98:2), the mixture
was filtered over Celite, concentrated, and purified by flash
chromatography (CHCl3–i-PrOH, 98:2) to afford the desired
spiro-imidazolidinones 5a, 5b, 5d or 6a, 6b, 6d.
Imidazolidinone 5a: [a]D22 +13 (c 1, CH2Cl2); colorless oil.
1H NMR (CDCl3, 300 MHz): d = 0.87 (d, 3 H, J = 6.9 Hz,
CH3), 0.89 (d, 3 H, J = 6.9 Hz, CH3), 0.90 (m, 1 H), 0.93 (d,
3 H, J = 6.3 Hz, CH3), 1.16 (d, 3 H, J = 6.3 Hz, CH3), 1.38
(m, 2 H), 1.50 (m, 2 H), 1.58 (t, 1 H, J = 6.9 Hz), 1.68 (m, 2
H), 1.76 (m, 1 H), 1.81 (m, 1 H), 1.88 (ddd, 1 H, J = 2.1 Hz,
J = 3.9 Hz, J = 13.1 Hz), 2.17 (br s, 1 H, OH), 2.76 (s, 3 H,
NCH3), 3.72 (m, 2 H), 3.83 (m, 1 H), 5.57 (br s, 1 H, NH).
13C NMR (CDCl3, 75 MHz): d = 17.5, 18.4, 22.1, 22.2, 23.9,
24.6, 25.4 (NCH3), 28.8, 34.0, 34.4, 46.6, 48.0, 58.3, 70.1,
73.4, 81.3, 174.6 (C = O). MS (ESI): m/z = 313 [M + H]+,
647.0 [2 M + Na]+. HRMS (CI, isobutane): m/z calcd for
C17H32N2O3 [M + H]+: 313.2491; found: 313.2490.
(21) (a) Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J. Am.
Chem. Soc. 1986, 108, 2754. (b) Curran, D. P.; Gothe, S. A.
Tetrahedron 1988, 44, 3945.
(22) Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2001,
2999.
(23) For recent [3+2] cycloadditions with kinetic resolution, see:
(a) Socha, D.; Jurczak, M.; Frelek, J.; Klimek, A.; Rabiczko,
J.; Urbanczyk-Lipkowska, Z.; Suwinska, K.; Chmielewski,
M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron:
Asymmetry 2001, 12, 3163. (b) Suárez, A.; Downey, C. W.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244. (c) Meng,
J.-c.; Fokin, V. V.; Finn, M. G. Tetrahedron Lett. 2005, 46,
4543.
Synlett 2006, No. 19, 3299–3303 © Thieme Stuttgart · New York