Preparation of 2-alkenylperhydro-1,3-benzoxazines and application for 2-isoxazolines synthesis

Article abstract of DOI:10.1016/j.tetasy.2009.10.033

Various 2-substituted-N-benzyl-4,4,7-trimethyl-trans-octahydro-1,3-benzoxazines 2 were prepared from the condensation of (-)-8-benzylaminomenthol 1 derived from (+)-pulegone, with acrolein, crotonaldehyde, cinnamaldehyde, 2(E)-N,N-diisopropyl-4-oxobut-2-e

Full text of DOI:10.1016/j.tetasy.2009.10.033

Tetrahedron: Asymmetry 20 (2009) 2447–2461
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of 2-alkenylperhydro-1,3-benzoxazines and application
for 2-isoxazolines synthesis
*
Carl Poisson, Jean-Éric Lacoste, Fernande D. Rochon, Livain Breau
Département de Chimie, Université du Québec à Montréal, Case Postale 8888 Succursale Centre-Ville Montréal (Québec), Canada H3C 3P8
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2009
Accepted 28 October 2009
Various 2-substituted-N-benzyl-4,4,7-trimethyl-trans-octahydro-1,3-benzoxazines 2 were prepared from
the condensation of (ꢀ)-8-benzylaminomenthol 1 derived from (+)-pulegone, with acrolein, crotonalde-
hyde, cinnamaldehyde, 2(E)-N,N-diisopropyl-4-oxobut-2-enamide, ethyl (2E)-4-oxobut-2-enoate, and
2-furaldehyde in 71–96% yield. The 1,3-dipolar cycloaddition with aceto- and benzonitrile oxide gave
the corresponding 2-isoxazoline cycloadducts. The origin of the stereoselectivity (40S, 50S-cycloadducts
up to 64% de) arises from the cycloaddition of the dipole to the top of the Re,Re-alkene face of dipolarophile 2.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
the synthesis of polyketide building blocks9 or for the synthesis
of b-aminoacids.10
The synthesis of chiral 2-isoxazolines has advanced consider-
ably over the last decade.1 The most direct route to generate this
five-membered heterocycle consists of a 1,3-dipolar cycloaddition
reaction involving a dipolarophile with a nitrile oxide as dipole.
Both the regio- and stereoselectivity can, in principle, be controlled
by the use of the enantiomerically pure form of at least one of these
two reagents, or by the use of a chiral catalyst. An important dis-
covery was made by Kanemasa et al. which involved Mg2+ direc-
However, those applications requiring a 2-isoxazoline with a
non-propionic substitution pattern or those with reversed regio-
chemistry still rely on the use of other asymmetric processes. Var-
ious chiral dipolarophiles,11–14 when reacted with more stable
nitrile oxides (benzo-, mesito-, and pivalo-), produced cycload-
ducts with good diastereoselectivity.
A 1,3-dipolar cycloaddition reaction involving a variety of aro-
matic and aliphatic nitrile oxides was developed by Lassalata
et al.,15 who found that complete control of the regio- and stere-
oselectivity was possible when a bulky C-2 symmetric pyrolidine
was used as the chiral auxiliary. However, under harsh acidic con-
ditions (6 N HCl, AcOH, reflux 100 °C, 48 h), only three cycload-
ducts could be cleaved from their chiral auxiliary. A mixture of
2-isoxazoline regioisomers usually results if unsymmetrical 1,2-
ted nitrile oxide cycloadditions with chiral allylic2 and
a-silylallyl
alcohols.3 The use of chiral catalysts prepared from dialkyl zinc
and diisopropyl (R,R)-tartrate allowed Inomata et al.4 to prepare
asymmetric isoxazolines up to 93% de from achiral allylic alcohols.
Furthermore, Sibi et al. employed magnesium iodide and a chiral
bisoxazoline to catalyze the cycloaddition of mesityl nitrile oxide
with achiral pyrazolidinone crotonates5 and
a
,b-disubstituted
disubstituted olefins including
are used. The diastereoselectivity of these 1,3-dipolar cycloaddi-
tion reactions is also lower.16 Free
,b-unsaturated aldehydes are
a,b-unsaturated esters and ketones
acrylimidines6 providing various 2-isoxazolines with both high re-
gio- and enantioselectivities. These studies have so far been limited
to the use of the more stable pivalo- and aryl nitrile oxides.
Aliphatic nitrile oxides are considerably more capricious than their
aromatic counterparts because of their propensity to dimerise,
generating furoxanes. A breakthrough was achieved by Carreira
et al.,7 who extended the Kamenasa hydroxy-directed nitrile oxide
cycloaddition to the use of chiral aliphatic nitrile oxides at ꢀ78 °C.
Under their conditions, the integrity of the aliphatic nitrile oxide is
preserved and 2-isoxazoline cycloadducts with complete regio-
and stereoselectivity were obtained from chiral allylic alcohols.8
The substituents on these 2-isoxazolines are ideally placed for
a
precluded because they tend to form bis-cycloadducts via nitrile
oxide attack on the aldehyde of the initial 2-isoxazoline product.17a
This problem can be avoided using the corresponding acetals or
thioacetals. Indeed, some of these reactions are highly regioselec-
tive; for example, using an acetal18,19 versus a dithioacetal19
reverses the regioselectivity in the nitrile oxide 1,3-dipolar
cycloaddition reaction to cinnamaldehyde and crotonaldehyde
derivatives. However, the use of an aminal in a 1,3-dipolar cycload-
dition reaction has not been reported.
8-Benzylaminomenthol20 acts as a protecting group and chiral
adjuvant for acrolein in 2a.21 We report here the use of aminals
such as perhydrobenzoxazines 2b–2g to control the regio- and ste-
reoselectivity of those 1,3-dipolar cycloaddition reaction using
* Corresponding author. Tel.: +1 514 987 3000; fax: +1 514 987 4054.
E-mail address: breau.livain@uqam.ca (L. Breau).
b-substituted, a,b-unsaturated aldehydes.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.033

2448
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
H
NH
OH
O
R
O
Eliel
procedure20
N
2
R
Tol,
Δ
X
10
O
9
X
71-96%
7
H
(+)-Pulegone
2a-2g
(-)-8-benzylaminomenthol 1
Scheme 1. Synthesis of perhydrobenzoxazines 2 from (ꢀ)-8-benzylaminomenthol 1
Table 1
Preparation of octahydrobenzoxazines 2a–2g
Entry
1
Aldehyde (equiv)
Methoda,b,c
Time (h)
Product 2
Yield (%)
H
2
24
15
A
B
C
12
10
20
15
22
84
2a (R = X = H)
O
H
2
8
A
C
12
15
18
81
2
3
2b (R = CH3, X = H)
2c (R = H, X = CH3)
2d (R = CO2Et, X = H)
O
CH3
H
2
15
A
C
12
24
—
—
O
CH3
H
H
H
4
5
1.2
1
A
A
48
60
71
73
O
O
O
CO2Et
2e (R = CON(iPr)2, X = H)
2f (R = CHCH–O = X)
CON(iPr)2
O
6
7
3
2
A
A
48
24
88
96
H
2g (R = Ph, X = H)
O
a
b
c
Method A: a solution of aldehyde in toluene is added in one portion to 1.
Method B: a solution of 1 in neat acrolein (24 equiv) is heated to reflux.
Method C: a solution of aldehyde in toluene is added slowly over 15–20 h to 1.
of volatile aldehyde, slowly added to the reaction mixture under re-
flux (entries 1 and 2, method C). Under these conditions, the prema-
ture polymerization of the aldehyde in the condenser is reduced. The
yields ranged from 71% to 96%, with the exception of methacrolein
which failed to produce 2c (entry 3). The presence of a methyl group
2. Results and discussion
2.1. Preparation of perhydrobenzoxazines 2
In order to study the regio- and stereoselectivity of the 1,3-
dipolar cycloaddition reaction of disubstituted alkenes derived
a
to the carbonyl hampers the nucleophilic addition of the nitrogen
and oxygen atoms.
from (+)-pulegone, derivative
2 was prepared as shown in
Scheme 1. The trans-fused octahydrobenzoxazines 2d–2g were ob-
tained in good yield from the condensation of 8-N-benzylamino-
menthol 1, with 1–3 equiv of the less volatile aldehydes which
were added at once in refluxing toluene (Table 1, entries 4–7,
method A).20c More volatile aldehydes such as acrolein and croton-
aldehyde had lower conversion yields (entries 1 and 2, method A).
A gas chromatography analysis of the latter reactions revealed that
they plateaued at 15% after 12 h. A similar result was obtained
using neat acrolein (Table 1, method B). Compounds 2a and 2b
were best prepared from the condensation of 1 with a large excess
2.2. Structural analysis of dipolarophiles 2
All of the optical rotations for 2 had negative values; smaller
groups, 2a,b,f: ꢀ24 to ꢀ30 and bigger groups, 2d,e,g: ꢀ63 to
ꢀ69. These amplitudes are consistent with a somewhat rigid struc-
ture having increasing mass in the same geometrical quadrant.
The rigorous establishment of the stereochemistry of these chi-
ral auxiliaries is of paramount importance to the understanding of
olefin facial discrimination. In general, tetrahydro-1,3-oxazines
have been found to be mainly in a chair conformation and in room
temperature solutions, an N-inversion occurs rapidly between
equatorial and axial positions.23,24 The position of the N-alkyl
group has not been clearly defined for similar 2-substituted perhy-
drobenz-2H-1,3-oxazine derivatives. Eliel and Pedrosa first
reported an equatorial;20a,b,25 and later an axial;20c,d stereochemis-
The use of a Lewis acid (MgBr2) allowed the reaction time to be reduced to 6 h;
however, the yield did not improve (21%). Furthermore, the use of a stronger Lewis
Acid, BF3ꢁEt2O only led to premature polymerization of the acrolein. The reaction of
the bis-N,O-trimethylsilyl derivative of 1 with acrolein in the presence of a catalyst,
trimethylsilyl trifluoromethanesulfonate, failed.22

C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
2449
EtO
EtO
EtO
EtO
Ts
Ts
N
N
O
H
SO2
NH
OH
H
O
BBr3
CH2Cl2
BF3
Et2O
H
3
4
5 (X-ray)
Scheme 2. Synthesis of 3-N-tosylperhydrobenzoxazines in an all chair 4 and in a chair-boat 5 conformation; the nitrogen atom has a planar geometry.
try for the N-benzyl and N-methyl groups in compounds such as
2g. Pedrosa et al. suggested that their N-acryloyl derivative was
equatorial.26 However, since the more significant resonance of
the nitrogen lone pair is with the carbonyl, the nitrogen atom
should be planar. An equatorial N-tosyl group was also cited by
Ko et al.,27 for trans-3-N-tosyl-2-benzoyloctahydro-1,3,5-benzdi-
oxazine, but no spectroscopic evidence was presented. Ko’s results
clearly contrast with our findings for 4 and 5, in which the nitrogen
atom had a planar geometry (Scheme 2).28 In addition, while com-
pound 4 was found to have an all chair conformation, in 5, the tet-
rahydro-1,3-oxazine ring is a boat in both the solid state and in
solution (CDCl3).
both showed NOEs with H2ax (Fig. 2b–d). Coplanarity of the phen-
ylethenyl with H2ax can be ruled out, since an NOE was observed
between H27 and H2ax. Also, if the phenylethenyl moiety were
coplanar with H2ax, this would place H27 in an anti geometry with
respect to H2ax and no NOE would have been seen. Furthermore, the
coupling constant, J2–27, (4.9 Hz), is consistent with a torsion angle
of 130° for H2 and H27.30 Irradiation of the H2 of 2a also results in
NOEs with its corresponding H27 (7%) and H28 (2%) but the inten-
sities are switched as compared to those shown in Figure 2b. In this
case, a coupling constant, J2–27, of 4.3 Hz, is consistent with a torsion
angle of only 40° between these protons (Fig. 2a, R = H). This confor-
mation differs from that previously proposed.21
Considering the scarcity of rigorous studies of the stereochem-
istry of these heterocycles, we were interested in obtaining an X-
ray crystal structure of 2. A crystal suitable for X-ray analysis
was obtained for (ꢀ)-2g, derived from cinnamaldehyde.
Irradiation of the benzylic proton, N–CHAPh, in 2g caused an
NOE which enhanced the signals attributed to H10ax and to the
equatorial methyl at C4 (Fig. 2e). We also observed an NOE
enhancement of the signals assigned to H27 and H28 (weak) upon
irradiation of the other benzylic proton, N–CHBPh (Fig. 2f). Based
on these results, we conclude that the N-benzyl substituent is
mainly axial at room temperature, which is consistent with the
conformation found in the solid state for (ꢀ)-2g.
Figure 1 clearly shows the absolute configuration of C2, N3, C7,
C9, and C10 and an almost perfect chair conformation for the fused
rings. The trans-junction was established by torsion angles C5–
C10–C9–01 = 178.9(3)° and C8–C9–C10–C4 = ꢀ173.4(3)°. The N3
is pyramidal, the N-benzyl is axial and the two phenyl rings are al-
most perpendicular to each other, dihedral angle = 91.1(1)°. This is
the first example of a trans-fused octahydro-2H-1,3-benzoxazine
ring system having an axial N-benzyl substituent. The H2 is axial,
while the phenylethenyl group is equatorial and coplanar with
the chair–chair ring, (i.e., H28 is eclipsed with O1) with torsion
angles N3–C2–C27–C28 = ꢀ142.5(3)° and O1–C2–C27–C28 =
ꢀ16.0(3)°. Note that the alkene function is not coplanar with H2
thus allylic 1,3-strain29 between O1 and H28, and steric interaction
between N3 and H27, are avoided. If H2 and H28 were eclipsed, the
H27 and benzyl CH2 interaction would be more destabilizing.
On the other hand, an NMR study showed that the N-benzylic
protons, AB doublets (3.6 and 4.0 ppm), separated into three sets
of doublets at temperatures below ꢀ70 °C, presumably due to
additional rotamers of the phenethenyl residue. A weak (1%) but
reciprocal NOE also exists between the CH3ax–C4 and one of the
N–CH2–Ph protons (Fig. 2e). The only possible explanation for this
observation is that the latter is equatorial. Thus, a rapid pyramidal
inversion at the nitrogen occurs at higher temperatures.
2.3. Syntheses of 2-isoxazolines 6–9
Dipolarophiles (ꢀ)-2 were then used in 1,3-dipolar cycloaddi-
tion reactions with both acetonitrile oxide and benzonitrile oxide;
the benzonitrile oxide was generated from three different precur-
sors: oximoyl chloride (method A),31 nitro (method B),32 and oxime
functional groups (method C).33 These reactions gave cycloadducts
6–9, as shown in Table 2. The 1,3-dipolar cycloaddition reaction
was optimized using 2-vinyl benzoxazine (ꢀ)-2a and benzonitrile
oxide because the cycloaddition with (ꢀ)-2a is known to be regio-
specific.21 In order to evaluate the role played by the base, method
A was used since N-hydroxybenzenecarboimidoyl chloride is more
stable.31a When 5 equiv of this chloride was used with no added
baseà or when Et3N was added dropwise, the conversion yield and
stereoselectivity were low (22% and 36%, respectively; Table 2, en-
tries 1 and 2). Similarly, poor results were obtained if phenylnitrom-
ethane was used as the precursor (entry 6). An improvement was
noted if the Et3N (15 equiv) was added first to the reaction vessel,
in which case the diastereoselectivity was 77:23 in favor of the
(+)-6a isomer (entries 4, 5, and 7). There are several possible expla-
nations for this result: (1) in the absence of excess base, part of the
Figure 1. The structure of (ꢀ)-2g showing the atom-labeling scheme. Displacement
ellipsoids are drawn to 30% probability level and selected H atoms are shown as
spheres of arbitrary radii.
Since the stereochemistry of the H9ax proton has been previ-
ously established,20a NOEs readily confirmed a trans-chair-chair
configuration in solution for the benzoxazine ring of (ꢀ)-2 when
this proton was irradiated (Fig. 2a); H5ax, H7ax, H8eq and, particu-
larly, H2 (9%) were also enhanced. However, no NOE was observed
for the alkene proton signals. Therefore, the stereochemistry for H2
is axial. Irradiation of H2 led to NOE enhancements of the signals
assigned to H9ax and the axial methyl, that is, C4, H27 and H28
(Fig. 2b). Thus, H27 and H28 are almost orthogonal to H2ax, since
à
A comparison of two 1H NMR spectra of one of the crude reaction mixture
separated by 24 h in wet CDCl3, indicated that the cycloadduct had undergone partial
hydrolysis to give some of the free chiral auxiliary 1. However, the free aldehyde of
the 2-isoxazoline moiety was not observed since they are known to be unstable.17

2450
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
4%
7%
4%
3%
3%
9%
3%
H
15%
3% CH3
6%
10%
H
CH 3
H
CH 3
7%
H
H
27
H
H
H
H
2
27
27
1%
N
H
9
2
H
N
4
R
N
H
H
2
O
9
H
10
Ph
O
28
9
O
H
28
H
8
1%
H
H
HB
H
HB
a) irradiation at H-9
b) irradiation at H-2
c) irradiation at H-27
4%
H
1%
3%
H
27
N
3%
O
N
N
O
O
10
H
28
H
28
H
H
H
8
1%
25%
AH
H
6%
H
H
HB
25%
1%
6%
6%
d) irradiation at H-28
e) irradiation at N-CHA-Ph
f) irradiation at N-CHB-Ph
Figure 2. Summary of average NOE observed for (a) compounds 2a–2g by irradiation at H9, and for compound 2g by irradiation at: (b) H2, (c) H27, (d) H28, (e) N–CHA–Ph, (f)
N–CHB–Ph.
auxiliary itself serves as an internal weaker base and thus generation
of the nitrile oxide is not as efficient as it would be with Et3N; (2) the
corresponding ammonium salt undergoes cycloaddition more slowly
than does 2a; or (3) cycloaddition occurs for one of the two ammo-
nium salts fixed with respect to N-pyramidal inversion. Such fixed
geometries would result in lower overall olefin facial discrimination
(Scheme 3). When a large excess of external base is used, the equi-
librium shifts to the free base 2a. Rapid N-pyramidal inversion shifts
the position of the benzyl group, so that the less bulky alkene face is
free to be attacked by the dipole. This allows for a higher ee.
Under these conditions, the reaction of disubstituted dipolaro-
philes 2d, 2e, and 2g with benzonitrile oxide gave all four possible
diastereomers, 6–9, with the exception of 8e for which only three
diastereomers were produced from 2e (Table 2, entries 10–12). The
diastereomeric ratios for 6–9 were determined by careful analysis
of the C50 signals of the crude reaction mixture (13C NMR, see
Section 4). The calculated ratios were in agreement with those iso-
lated and the combined yields for the cycloadducts averaged 55%.
Use of a Lewis acid, MgBr2, as previously described by Yamamoto
et al.,34 did not affect the cycloadduct distribution ratio for the
reaction of benzonitrile oxide and 2g.
tuted one (Fig. 3a and b). The stereochemistry for each product was
established via the following key NOEs: for all derivatives, irradia-
tion of the signal assigned to H9 established that these compounds
have a chair-chair conformation. Irradiation of the signal assigned
to H2 of 6a and 6b showed that H2 is gauche with respect to H50
(4% NOE), J2–5 = 3.6 Hz and their torsion angle is 50°.30
0
Irradiation of H40a and H50 enhanced the signals assigned to the
N–CH2 and o-Ph protons. These results demonstrate that H40a and
H50 are oriented toward the N-benzyl and therefore, both major
isomers 6a and 6b have a 50S-stereochemistry.§ Significant NOEs
were obtained for the N–CH2 protons with both H2 and H10, even
though they are geometrically opposed. In fact, based on the various
NOEs, rapid N-pyramidal inversion is general to all cycloadducts 6–9
as shown in Figures 3 and 4 (dashed lines).
0
For minor isomers 8a and 8b, J2–5 = 8.4 Hz but no NOE was ob-
served between H2 and H50. This suggests these protons are almost
anti. Irradiation of H2 enhanced the signals attributed to H9,
CH3ax–C4 and H40 while irradiation of H40b showed NOEs with H2
b
(5%) and the o-Ph (3%) protons. Thus, the C50 of 8a and 8b is R.
2.4.2. Characterization of 3,4,5-trisubstituted cycloadducts
6–9d,e,g
The stereochemistry was established by rigorous NOEs while
that for 9g was established unequivocally by X-ray diffraction.
We were surprised to find a definite trend in the optical rotations.
We observed positive rotations for (+)-6 and (+)-7; due to Re,Re al-
kene facial addition, while attack on the alkene via its Si,Si face,
produced levrorotary (ꢀ)-8 and (ꢀ)-9.
2.4.2.1. Regiochemistry studies. Figure 4 shows a summary of
the significant NOEs observed for 6–9, d–g. For cycloadducts 6d–
6g and 8d–8g, irradiation of the o-Ph–C30 proton signal enhanced
that attributed to H40, as well as the signal for the o-Ph proton at
C40, 2% for 6g and 8g, but no NOE was observed for H2. Therefore,
the C30 phenyl substituent is more distant from the N-benzylox-
azine moiety than in 7d–7g or 9d–9g.
2.4. Characterization of 2-isoxazolines cycloadducts 6–9
For regioisomers 7d–7g and 9d–9g the enhancements were re-
versed. That is, NOEs were observed between the signals attributed
to the o-Ph–C30 and those for H2 and H40. However, none was seen
for the proton signals attributed to the C50 substituents (R = Ph and
CON(CHMe2)2) upon irradiation of those for o-Ph–C30.
For all substituents, each of the four diastereoisomers, 6–9,
adopts a similar spatial arrangement. Therefore, the regio- and
stereochemistries of these cycloadducts will be discussed as four
diastereomer groups rather than by substituent. 1H and 13C assign-
ments were based on COSY, DEPT, and HMQC cross peak
correlations.35
The above C50 phenyl regiochemistry for 7g and 9g is consistent
with a mass peak at 106 m/z, corresponding to benzaldehyde less
2.4.1. Characterization of 3,5-disubstituted cycloadducts 6- and
8a,b
§
An initial study found a configuration of 50R for 6b and a 50S for 8b.21 However,
further investigations of the NOEs arising from the irradiation of H40 and H4b0 have
For 6a and 6b, the chemical shifts of their C40 methylene pro-
tons were shielded (d 2.4 and d 3.3 ppm) relative to the C50
methine proton (d 4.5 ppm) for both isomers. This is consistent
with a 3,5-disubstituted 2-isoxazoline but not with a 3,4-disubsti-
a
now shown them to be 50S and 50R, respectively. All the NOEs observed previously are
consistent with the current proposed structures. The higher diastereomeric ratio
initially reported for 6b was based on isolated yields and not on the 13C NMR of the
crude reaction mixture.

Table 2
Syntheses of 2-isoxazolines 6–9 from several octahydrobenzoxazines 2a, 2d, 2e, 2g with aceto- and benzonitrile oxides
R'
N
N
R'
N
N
-
O
–
O
+N C – R'
O
H
R'
O
R'
O
O
N
R
R
N
N
+
+
N
+
R
O
R
N
H
O
R
51-
79%
O
O
H
H
H
H
H
(-)-2
(+)-7
(-)-8
(+)-6
(-)-9 (9g, R=Ph; X-ray)
Entry
Benzoxazines (ꢀ)-2
Nitrile oxide (O–N„C–R0)
Methoda,b,c
Et3N (equiv)
Isolated yield (%)
2-Isoxazolines distribution (% isolated)
Selectivityd
Regio-
Stereo-
(+)-6
(+)-7
(ꢀ)-8
(ꢀ)-9
6+8:7+9
6+7:8+9
50S:50R
1
2
3
4
5
6
7
8
9
a R = H
a R = H
a R = H
a R = H
a R = H
a R = H
a R = H
a R = H
R0 = Ph
R0 = Ph
R0 = Ph
R0 = Ph
R0 = Ph
R0 = Ph
R0 = Ph
R0 = Ph
R0 = CH3
R0 = Ph
R0 = Ph
R0 = Ph
A
A
A
A
A
B
B
C
B
A
A
Af
—
5e
5
15
20
2
15
0
1.6
20
20
20
22
36
68
70
70
52
75
68
27
59
51
52
6a (62)
6a (62)
6a (73)
6a (77)
6a (77)
6a (71)
6a (78)
6a (77)
6b(75)
6d (31)
6e (6)
—
—
—
—
—
—
—
—
8a (38)
8a (38)
8a (27)
8a (23)
8a (23)
8a (29)
8a (22)
8a (23)
8b (25)
8d (7)
—
—
—
—
—
—
—
—
—
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
64:36
12:88
28:72
62:38
62:38
73:27
77:23
77:23
71:29
78:22
77:23
75:25
82:18
71:29
55:45
a R = H
—
—
10
11
12
d R = CO2Et
e R = CO N(iPr)2
g R = Ph
7d (16)
7e (30)
7g (20)
9d (5)
9e (15)
9g (18)
6g (8)
8g (6)
a
b
c
d
e
f
Method A: to 2 (1 equiv) and Et3N (0–20 equiv) in CH2Cl2 was added PhCCl@NOH (5 equiv) dropwise over 8 h).
Method B: to 2a (1 equiv) and Et3N (1.6–15 equiv) in CH2Cl2 was added a nitroalkane (2–5 equiv) and phenylisocyanate (4–10 equiv).
Method C: to 2a (0.2 mmol) and benzaldehyde oxime (3 equiv) in CH2Cl2 (4 mL) was added a 5% NaOCl solution (3 mL) and was stirred for 48 h.
13
Determined from the integration of the C NMR0s of the crude reaction mixture.
Dropwise addition.
Heated to reflux.

2452
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
H
H+
H+
N
N
N
H
O
O
O
2a
Reduced facial descrimination
Scheme 3. Protonation of dipolarophile 2a. Distribution of the two ammonium salts with either an N-equatorial or N-axial benzyl group.
4.6 %
7 %
9 %
8 %
9.4 %
3 %
4%
3.3%
3 %
4%
R'
N
3%Hβ
H
H
H
3 %
6%
CH3
3.4 % CH3
5%
H
2
H
2
3'
O
4'
H
Hα
H
3.5%
Hα
H
H
O
8 %
H
H
5
H
H
4
8
4
3 %N
N
5'
5'
N
3 %
H
H
6.5 %
2 %
2%
H
O
O
Hα1.5%
9
5
9
10
10
HH
H
4' 3'
7
7
H
H
H
7 %
22%
8
H
H
Hβ
R'
5 %
5 %
Figure 3. (a) Summary of average NOE for major (50S)-6a (R0 = Ph) and 6b (R0 = CH3). (b) Summary of average NOE for minor (50R)-8a (R0 = Ph) and 8b (R0 = CH3). Note:
Pyramidal inversion of the N-benzyl group is indicated by dashed lines.
3.6 %
7 %
2 %
2 %
9 %
H
H
H
H
2
H
H
4
4%
H
4.5% H
H
O
H
2
N
2 %
5'
N
3'
N
3.5%
4'
N
0.7%
O
2.7%
O
4' 3'
R
5'
O
H
H
H
H
H
H
R
4%
8
H
H
5%
3 %
13 %
H
2%
0.4 %
5 %
8 %
10%
3 %
6 %
7%H
H
12%
4%
O
R
5'
H
CH3
H
N
H
H
3'
H
H
4'
2
1.5%
2 %
6 %
4
N
3 %
R
5'
2
4'
N
H
H
13%
H
3.5%
3'
O
H
3.5%
9
1%
O
H
HH
O
H
N
8
H
9 %
H
Figure 4. (a) Summary of average NOE for (40S, 50S)-6d, (R = CO2Et), 6e (R = CONiPr2), and 6g (R = Ph). (b) Summary of average NOE for (40S, 50S)-7d, (R = CO2Et), 7e
(R = CONiPr2) and 7g (R = Ph). (c) Summary of averaged NOE for (40R,50R)-8d, (R = CO2Et) and 8g (R = Ph). (d) Summary of averaged NOE for (40R,50R)-9d, (R = CO2Et), 9e
(R=CONiPr2) and 9g (R = Ph). Note: Pyramidal inversion of the N-benzyl group is indicated by dashed lines.
one proton. This ion arises from the fragmentation of the 2-isoxaz-
oline ring at C50–C40 and N–O;17,36 however, it was not seen for 6g
and 8g.
C50 stereocenters is (R), which is in agreement with the X-ray
structure for 9g (Fig. 5).
Figure 5 shows one of the two independent molecules seen in
the crystallographic results. The two molecules are almost identi-
cal, except for the dihedral angle between the phenyl ring located
on C30 and the plane formed by four of the atoms of the five-mem-
bered ring. The five-membered ring has an envelope conformation
with the C50 pointing out of the plane and toward its phenyl sub-
stituent. The fused rings adopt chair conformations with a trans-
junction as shown in Figure 5. The environment around the N3
atom is pyramidal and the N-benzyl group is axial, as observed
in crystal of 2g.
2.4.2.2. Stereochemistry studies at C40 and C50. Since the trans
geometry of the alkene is transposed in the cycloadducts, this sec-
tion will focus on the isoxazoline carbon directly linked to the ben-
zoxazine moiety. For 9d, -e and -g, strong mutual NOEs were
observed for the signals assigned to H2 and H50 and those assigned
to H50 and the peak for the o-NBn protons (Fig. 4d). However, there
was no NOE between H2 and H40 and J2–4 averaged 10 Hz, hence
0
H2 and H40 are anti. A significant NOE was also observed between
the signal for H40 and one of the doublets associated with the ben-
zylic protons. Therefore, the absolute configuration at both C40 and
0
J2–4 for isomer 7 was found to be small (ave. 1.7 Hz); therefore,
the torsion angle between H2 and H40 should be 65°.30 Also, irradi-

C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
2453
N
O
C
HH
N
H
O
H
Si
Si,
-Cycloadduct
Figure 5. The structure of one of the two independent cycloadduct (ꢀ)-9g, showing the atom-labeling scheme. Displacement ellipsoids are drawn to 30% probability level and
selected H atoms are shown as spheres of arbitrary radii.
ation of the signal assigned to H40 led to strong NOEs with the res-
onances assigned to o-NBn, N–CH2Ph, H2, and H50 (Fig. 4b). Hence,
H40 is oriented toward the N-benzyl moiety. Long range NOEs
(weak) were observed between the signals for H50 and H8eq there-
fore, H50 must be oriented toward H8eq. Since the structure for 9
has been established by X-ray crystallography and 7 has the same
regiochemistry as 9, the stereocenters C40 and C50 of 7 must be (S).
Isomer 6 has the reverse regiochemistry relative to 7 and 9 and
similar enhancements were observed for its corresponding proton
signals. But, the positions of protons H40 and H50 of 6 are reversed
(Fig. 4a). The torsion angle between protons H2 and H50 should be
tiary crotonamides independently studied by Weidner-Wells
et al.36 and, particularly elegantly by Caramella et al.38 For their
amide, the reaction is under the steric control of one of the N-al-
kyl substituents of the almost exclusively cisoid amide rotamer
and the phenyl of the benzonitrile oxide. Steric hindrance modi-
fies the frontier orbital interactions which, in turn, cause a drift
in the regiochemistry to increasingly favor the C5 acyl cycload-
duct of 7.3:1.
As reported, in the case of cinnamaldehyde, the choice of an
acetal versus a dithioacetal reverses the regioselectivity of the
1,3-dipolar cycloaddition reaction with nitrile oxide.18,19 We found
that the benzoxazine moiety of dipolarophile 2 acts as an acetal,
giving cycloadducts 7g + 9g derived from benzonitrile oxide
(C4:C5 aminal ratio: 2.6:1; Table 2 entry 12). The aminal or acetal
is favored at C4, since this best avoids steric repulsion between the
two phenyl substituents as was observed for 2e.
25° since the coupling constant J2–5 = 7.5 Hz.30 Also, NOEs were
0
observed between the signals for H50 and N–CH–Ph (strong) and
between those for H50 and H2. Irradiation of the signal attributed
to H40 led to the enhancement of the peaks for the H2 and N–
CH–Ph protons. Therefore, the absolute configuration at both C40
and C50 is (S).
For isomer 8, H50 produced a strong NOE with the signal for one
of the benzylic protons as well as one (weak) NOE with the o-NBn
2.5.2. Stereochemistry rational
The preferred conformation of the C2 alkenyl moiety of 2 is
orthogonal to H2 (Figs. 1, 2, and 6); and, to avoid steric hindrance,
cycloaddition of the nitrile oxide likely occurs from the top of the
auxiliary, opposite the N-benzyl. When attack of the nitrile oxide
occurs on the Re,Re-face of olefin 2 (Fig. 6, parallel to H2), major
isomers 6 + 7 (40S,50S) are obtained. Otherwise, rapid N-pyramidal
inversion allows for a 180° rotation of the 2-alkenyl moiety and at-
tack occurs via the Si,Si-face of the alkene, which gives minor
(40R,50R) isomers 8 + 9.
peak (Fig. 4c). For 8, the average J2–5 = 7.4 Hz between H2 and H50,
0
which corresponds to a torsion angle of 155°.30 Therefore, H40
should be coplanar with H2. This conclusion is further supported
by the observation of NOEs for the H2 and o-NBn signals upon
irradiation of the H40 doublet. H50 is also oriented toward the N-
benzyl group and, therefore, the stereochemistry for C40 and C50
of 8 is (R).
Preliminary energy minimization calculations for the alkene
rotamers of 2 (Fig. 6) supports the proposed rational for facial
discrimination, with the favored rotamer having the Re,Re alkene
face pointing to H2: 0.8 kJ/mol for 2g (R = Ph), 1.7 kJ/mol for 2e
(R = CON(iPr)2), and 2.4 kJ/mol for 2d (R = CO2Et). The order of in-
crease in the calculated energy differences for these rotamers is
consistent with the observed increase in stereoselectivities of
dipolarophiles 2g, 2e, and 2d (de for (40S,50S): 10%, 42%, and 64%,
respectively).
2.5. Isomeric control of the cycloaddition
2.5.1. Regiochemistry rational
The reaction involving the monosubstituted dipolarophile 2a,
being under steric control, gives regiospecifically the C5 aminal
cycloadducts 6a + 8a (Table 2, entries 1–9). Using disubstituted,
a
,b-unsaturated amides and esters, Weidner-Wells,36 Huisgen,37
and Caramella38 have shown that the nitrile oxide attacks prefer-
entially via the oxygen onto the b-center of the alkene. This allows
the preferred orbital match to occur, greater HOMO coefficient of
the oxygen of the dipole with the greater LUMO coefficient located
3. Conclusion
at the b-carbon of the
using the ,b-unsaturated ester 2d, are consistent with this trend;
a
,b-unsaturated ester.39 Our own results,
a
(ꢀ)-8-Benzylaminomenthol 1, was used as a chiral adjuvant in
affording preferentially C4 acyl cycloadducts 6d + 8d (C4:C5 acyl,
1.7:1; Table 2, entry 10). In addition, Rosella and Harper40 observed
that this effect was greatly magnified for ethyl cinnamate when
dissolved in an ionic liquid (ratios up to 15:1).
However, the use of a bulky amide favors the opposite regio-
chemistry (Table 2, entry 11), which is consistent with the ter-
the cycloaddition of
a,b-unsaturated 1,3-dipolarophiles. The con-
densation of 1 with various
a,b-unsaturated aldehydes gave the
corresponding aminal 2 with an average isolated yield of 84%. X-
ray diffraction of (ꢀ)-2g showed a chair–chair conformation for
the hetero-ring, with stereocenters C2 and N being S. The phenyl-
ethenyl moiety is equatorial and coplanar to the trans-octahydro-

2454
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
N
O
H
C
N
C
R
O
H
2
2
N
N
O
Major (4'S,5'S)-
Stereoisomers
6 + 7
R
O
Minor (4'R,5'R)-
Stereoisomers
8 + 9
H
H
Re,Re-Addition
Si,Si -Addition
Figure 6. Suprafacial Re,Re- and Si,Si-addition of benzonitrile oxide onto dipolarophile 2.
2H-1,3-benzoxazine ring; pointing away from the N-benzyl group.
Our results in solution were consistent with the X-ray structure.
However, rapid pyramidal inversion of the NBn group was ob-
served along with the concomitant rotation of the alkenyl moiety.
1,3-Dipolar cycloadditions with nitrile oxide are regiospecific for
2a, generating (50S)-6a in up to 56% de when excess base is used.
For 2d–g, the substituent R greatly influenced the regio- and ste-
reochemical course of the reaction. The stereochemistry for all
compounds was determined by rigorous NOEs; and was unequiv-
ocally established crystallographically for (ꢀ)-9g. Regioselectivity
is under steric control for 2a, 2e, and 2g and the favored 2-isoxaz-
oline regioisomers had the least steric interaction between the
substituent derived from nitrile oxide and the substituents on
the alkene (R = H, CON(iPr)2 and Ph, respectively). Electronic
control governs 1,3-dipolar cycloaddition reaction with 4d
(R = CO2Et), favoring cycloadducts 6d + 8d, that is, the phenyl sub-
stituent is oriented toward the alkanoyl ester. The observed stere-
oselectivity (up to 64% de in favor of cycloadducts 6 and 7 arises
from the addition of the dipole to the top of the Re,Re-alkene face
of 2.
circular chromatography (chromatotronÒ, model 7924, Harrison
Research; E. Merck silica gel 7749).
4.1.2. Materials
Acrolein, acetaldehyde oxime, benzaldehyde oxime, benzyl
bromide, borontribromide, borontrifluoride etherate, N-choro-
succinimide, cinnamaldehyde, crotonaldehyde, diisopropyl amine,
2-furaldehyde, fumaric acid monoethyl ester, methacrolein, and
(+)-pulegone were all obtained from Aldrich Chemical Co. and
were used without further purification. Phenylisocyanate was
freshly distilled before use (bp 46 °C/10 mmHg). (ꢀ)-8-N-benzy-
laminomenthol 1,20a N-hydroxybenzene-carboimidoyl chloride,31
methyl 4-hydroxycrotonate41 as well as methyl 4-oxo-2(E)-bute-
noate42 were prepared as previously reported while ethyl 2(E)-4-
(diisopropylamino)-4-oxo-butenoate was prepared from an adap-
tation of a general procedure previously reported.36
Solvents were dried by distillation as follows: THF and diethyl
ether from sodium/benzophenone; dichloromethane, and toluene
from P2O5; and finally, triethylamine from CaH2. Unless otherwise
stated, all syntheses were carried out under dry nitrogen. After
reaction work-up, solutions were dried using Na2SO4 and the sol-
vents were subsequently removed by rotary evaporation.
4. Experimental
4.2. Experimental procedures
4.1. General information
4.2.1. Typical condensation procedures for the synthesis of
perhydrobenzoxazines 2a–g
Crystallographic data (CIF tables excluding structure factors) for
the two structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation numbers CCDC-707015 and CCDC-707016. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cabridge CB2 1EZ, UK, (fax: +44 (0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.Uk).
Method A. Typical condensation procedure A, when less volatile
aldehydes are used. To a solution of 1 (1.000 g, 3.83 mmol, 1 equiv)
in toluene (10 mL), was added, all at once, 2-furaldehyde (1.10 g,
0.95 mL; 11.5 mmol, 3 equiv). The reaction was heated to reflux
for 48 h or until it had finished as indicated by TLC (CH2Cl2–MeOH,
90:10; see times indicated in Table 1). The reaction was stopped at
8 h intervals and any condensed water was removed from the
inside of the condenser. The solvent was removed under reduced
pressure and the product purified by chromatography using pet-
rol–CH2Cl2 (65:35). 1.144 g (88% yield) of 2f, a yellow oil was
isolated.
Method B. Typical procedure when volatile aldehydes are used.
(ꢀ)-8-N-Benzylaminomenthol (1.00 g, 3.83 mmol, 1 equiv) was
dissolved in toluene (5 mL). The solution was heated to reflux
and a solution of acrolein (3.218 g, 3.80 mL, 57.46 mmol, 15 equiv)
in toluene (1 mL) was slowly added with stirring over 8 h using a
syringe pump. At 5 h intervals, the solution was cooled and any
deposited water or white polymeric material was removed from
the condenser. The reaction mixture was then heated again to re-
flux and followed by TLC (CH2Cl2, MeOH; 9:1); approx. 20 h in to-
tal. The resultant mixture was cooled, concentrated and the
residue purified by chromatography using petrol–Et2O (9:1) to give
2a (0.963 g, 84% yield) as a pale yellow oil.
4.1.1. Instrumentation
Melting points were determined with a Fisher-Johns melting
point apparatus and are uncorrected. Infrared spectra were re-
corded on a Perkin–Elmer 1600 FTIR instrument. 1H NMR spectra
were recorded using a Varian 300 BB, 300 MHz or on a Brüker
AMX 2-500 MHz spectrometer. 13C NMR spectra were recorded
at 75 or 125 MHz. Chemical shifts are reported in parts per million
(d). 1H Chemical shifts in CDCl3 were referenced to residual CHCl3
(7.27 ppm) while 13C chemical shifts were referenced to the sol-
vent (CDCl3, 77.03 ppm). Mass spectra were obtained using a GC–
MS (GCD plus gas chromatography-electron ionization detector,
HPG 1800A GCD system) equipped with a 5% crosslinked PhMe sil-
icone HP 19091 J-433 column. Elemental analyses were carried out
at the chemistry department of the Université de Montréal, Mont-
réal, P.Q., Canada; on a Fisons Instrument SPA, model EA1108.
Thin-layer chromatography was performed on Silica Gel F254 (E.
Merck precoated glass plates). Separations were carried out using

C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
2455
4.2.1.1. (ꢀ)-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyl-2-ethe-
nyloctahydro-2H-1,3-benzoxazine 2a. See general condensation
(m, 1H, H10), 1.61–1.67 (m, 1H, H6eq), 1.70–1.78 (m, 1H, H5eq),
1.96 (d app., J = 12.4 Hz, 1H, H8eq), 3.58 (td, J = 10.4, 3.8 Hz, 1H,
H9), 3.79 (AB-d, J = 17.3 Hz, 1H, NCH2Ph), 3.93 (AB-d, J = 17.3 Hz,
1H, NCH2Ph), 4.08 (q, J = 7.3 Hz, 2H, O–CH2–CH3), 5.29 (br s, 1H,
method B. Rf = 0.79 (petrol–CH2Cl2, 1:1); ½a D23
¼ ꢀ23:6 (c 0.865,
ꢂ
MeOH); IR (film)
m 3088, 3061, 3023, 2978, 2923, 2867, 1603,
1493, 1452, 1409, 1385, 1095, 947, 940, 722, 695 and 688 cmꢀ1
;
H2), 6.07 (dd, J = 15.7, 1.7 Hz, 1H, H2 ), 6.63 (dd, J = 15.7, 3.4 Hz,
0
1H NMR (CDCl3, 300 MHz): d 0.90–1.03 (m, 2H, H5ax, 6ax), 0.92 (d,
J = 5.9 Hz, 3H, CH3–C7), 0.98 (s, 3H, CH3eq–C4), 1.15 (q, J = 11.0 Hz,
1H, H3 ), 7.11 (t, J = 7.5 Hz, 1H, Hp-Ph), 7.22 (t, J = 7.5 Hz, 2H, Hm-
0
Ph), 7.29 (d app., J = 7.5 Hz, 2H, Ho-Ph); 13C NMR (CDCl3, 75 MHz):
d 14.09 (O–CH2–CH3), 20.97 (CH3ax–C4), 22.24 (CH3–C7), 24.95
(CH2, C6), 27.10 (CH3eq–C4), 31.37(CH, C7), 35.06 (CH2, C5), 41.28
(CH2, C8), 45.42 (CH, C10), 47.75 (NCH2Ph), 57.04 (Cq, C4), 60.14
(O–CH2–CH3), 76.07 (CH, C9), 85.48 (CH, C2), 123.07 (CH, C2‘),
125.91 (CH, Cp-Ph), 127.04 (2CH, Cm-Ph), 127.99 (2CH, Co-Ph),
143.50 (Cq, CPh), 146.25 (CH, C3‘),166.02 (Cq, C@O); GC–MS
(70 eV, m/z, %): 326 (M+ꢀC2H5O, 2); 272 (M+ꢀHC@CH–CO2Et,
13); 91 (C7H7þ, 100); Anal. Calcd for C23H33NO3: C, 74.36; H;
8.95; N, 3.77. Found: C, 74.03; H, 8.94; N, 3.76.
1H, H8ax), 1.23 (s, 3H, CH3ax–C4), 1.43–1.78 (m, 4H, H5eq, H6eq
,
H10, H7), 1.97 (br d, J = 11.6 Hz, 1H, H8eq), 3.55 (td, J = 11.0,
4.0 Hz, 1H, H9), 3.75 (AB-d, J = 11.7 Hz, 1H, NCH2Ph), 4.05 (AB-d,
0
J = 11.7 Hz, 1H, NCH2Ph), 5.09 (dt, J = 10.6; 1.7; Hz, 1H, H2 ), 5.14
0
(dt, J = 4.3, 1.7 Hz, 1H, H2), 5.37 (dt, J = 17.4; 1.7 Hz, 1H, H2 ), 5.69
0
(ddd, J = 17.4, 10.6, 4.3 Hz, 1H, H1 ), 7.15 (t, J = 7.1 Hz, 1H, Hp-Ph),
7.26 (t, J = 7.0 Hz, 2H, Hm-Ph), 7.37 (d, J = 7.0 Hz, 2H, Ho-Ph); 13C
NMR (CDCl3, 75 MHz): d 19.78 (CH3ax–C4), 22.30 (CH3–C7), 25.06
(CH2, C5), 27.07 (CH3eq–C4), 31.43 (CH, C7), 35.11 (CH2, C6), 41.49
(CH2, C8), 46.32 (CH, C10), 47.18 (N–CH2), 56.79 (Cq, C4), 75.79
0
(CH, C9), 87.46 (CH, C2), 117.43 (CH2, C2 ), 125.72 (CH, Cp-Ph),
4.2.1.4. Ethyl (2E)-4-(diisopropylamino)-4-oxobut-2-enoate (pre-
cursor to acid). In a flask mounted with a drying tube, ethyl
hydrogenofumarate (0.500 g, 3.47 mmol, 1 equiv) was dissolved
in CH2Cl2 (4 mL) and thionyl chloride (0.802 g, 6.8 mmol,
0.492 mL, 2 equiv) was added all at once. The reaction mixture
was stirred for 2 h and then diisopropylamine (0.911 g, 9.02 mmol,
1.18 mL, 2.6 equiv) was added in small amounts, to allow for safe
gas evolution, over about 20 min. The resultant brown mixture was
stirred at room temperature for 2 h then carefully quenched with
small portions of a saturated Na2CO3 solution (2 mL), diluted with
1 mL of water, and extracted with CH2Cl2 (3 ꢃ 5 mL). The com-
bined extracts were washed with 5 mL of water, dried over Na2SO4,
and the solvent was removed under vacuum. The crude product
was purified by chromatography (CH2Cl2–MeOH, 99:1) to give
0.733 g (93% yield) of the desired enoate as a yellow oil. Rf = 0.52
(CH2Cl2–MeOH, 96:4); IR (nujol): 2971, 2935, 2827, 1710 (O–
0
126.93 (2CH, Co-Ph), 127.90 (2CH, Cm-Ph), 137.72 (CH, C1 ), 144.28
(Cq, CPh); GC–MS (70 eV, m/z, %): 299 (M+, 1.5), 284 (M+ÅꢀCH3,
5.5), 272 (M+ÅꢀC2H3, 25), 228 (10), 208 (M+ÅꢀPhCH2, 3), 146
(PhCH2N+ÅH@CH–CH@CH2, 45), 91 (C7H7þ, 100).
4.2.1.2. (ꢀ)-(10E)-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyl-2-
(prop-10-enyl)octahydro-2H-1,3-benzoxazine 2b. Using general
condensation procedure B: 1 (1.500 g, 5.74 mmol; 1 equiv) was
dissolved in toluene (10 mL) and to this was added, over 15 h, a
solution of crotonaldehyde (3.214 g, 3.80 mL; 45.92 mmol, 8 equiv)
in toluene (2 mL). The crude product was purified by chromatogra-
phy using petrol–Et2O (96:4) giving 1.457 g (81% yield) of 2b as a
yellow oil. Rf = 0.42 (petrol–Et2O, 96:4); ½a D23
¼ ꢀ31:3 (c 0.193,
ꢂ
CH2Cl2); IR (film)
m 3083, 3061, 3027, 2982, 2868, 1493, 1452,
986, 956, 727, 692 and 667 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
0.97 (d, J = 6.6 Hz, 3H, CH3–C7), 0.96–1.01 (m, 2H, H5ax + H6ax),
1.04 (s, 3H, CH3-eq–C4), 1.16 (q, J = 11.7 Hz, 1H, H8ax), 1.22 (s, 3H,
CH3ax–C4), 1.46–1.52 (m, 2H, H10 + H7), 1.54 (d, J = 6.6 Hz, 3H,
C@C_CH3), 1.62–1.70 (m, 1H, H5eq), 1.70–1.79 (m, 1H, H6eq), 1.99
(d app., J = 12.5 Hz, 1H, H8eq), 3.56 (td, J = 10.3, 3.7 Hz, 1H, H9),
3.66 (AB-d, J = 17.1 Hz, 1H, NCH2Ph), 4.05 (AB-d, J = 17.1 Hz, 1H,
NCH2Ph), 5.04 (d, J = 5.0 Hz, 1H, H2), 5.28 (br dd, J = 15.4, 5.0 Hz,
1H, H1 ), 5.81 (dq, J = 15.4, 6.6 Hz, 1H, H2 ), 7.17 (t, J = 7.2 Hz, 1H,
p-Ph), 7.28 (t, J = 7.3 Hz, 2H, Hm-Ph), 7.37 (d, J = 7.3 Hz, 2H, Ho-Ph);
13C NMR (CDCl3, 75 MHz): d 17.63 (CH3, C@C_CH3), 18.52 (CH3ax
C@O), 1626 (N–C@O), 1216 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
1.26 (50%, d, J = 6.9 Hz, 6H, N–CH–(CH3)2), 1.32 (t, J = 7.1 Hz, 3H,
O–CH2–CH3), 1.40 (50%, d, J = 6.9 Hz, 6H, N–CH–(CH3)2), 3.72
(sep., J = 6.9 Hz, 1H, N–CH–(CH3)2), 4.00 (sep., J = 6.9 Hz, 1H, N–
CH–(CH3)2), 4.25 (q, J = 7.1 Hz, 2H, O–CH2–CH3), 6.63 (d,
J = 15.4 Hz, 1H, H2), 7.37 (d, J = 15.4 Hz, 1H, H3); 13C NMR (CDCl3,
75 MHz): d 14.16 (CH3, O–CH2–CH3), 20.34 (50%, N–CH–(CH3)2),
21.30 (50%, N–CH–(CH3)2), 46.03 (N–CH–(CH3)2), 47.94 (CH, N–
CH–(CH3)2), 60.95 (CH2, O–CH2–CH3), 129.00 (CH, C2), 137.28
(CH, C3), 164.33 (Cq, CON), 166.04 (Cq, COO); GC–MS (70 eV, m/z,
%): 227.1 (M+, 1.4), 212.1 (M+ꢀCH3, 5.3), 127.0 (M+ꢀC6H14N, 37),
100.0 (C6H14N+, 52), 86.1 (M+ꢀC5H12N, 100).
0
0
H
–
C4), 22.28 (CH3–C7), 25.10 (CH2, C5), 27.27 (CH3eq–C4), 31.39 (CH,
C7), 35.09 (CH2, C6), 41.50 (CH2, C8), 46.98 (CH, C10), 47.50
(NCH2Ph), 56.75 (Cq, C4), 75.56 (CH, C9), 88.00 (CH, C2), 125.66
(CH, Cp-Ph), 127.19 (2CH, Co-Ph), 127.81 (2CH, Cm-Ph), 128.83 (CH,
4.2.1.5. (2E)-4-(Diisopropylamino)-4-oxobut-2-enoic acid (pre-
cursor to aldehyde). Ethyl (2E)-4-(diisopropylamino)-4-oxobut-
2-enoate (0.638 g, 2.81 mmol, 1 equiv) was dissolved in a mixture
of ethanol (95%, 2 mL) and NaOH(aq) (2 M, 1.4 mL). The resultant
mixture was stirred for 15 min, acidified to pH 2, and extracted
with ethyl acetate (3 ꢃ 15 mL). The combined organic layers were
dried over MgSO4, filtered, and the solvent was removed under re-
duced pressure. The corresponding acid was purified by chroma-
tography using CH2Cl2–MeOH (9:1) to give 0.504 g (90% yield) as
a light brown solid. Mp = 112 °C; Rf = 0.72 (CH2Cl2–MeOH, 4:1);
0
C2‘), 131.15 (CH, C1 ), 144.38 (Cq, CPh). GC–MS (70 eV, m/z, %):
313.2 (M+, 0.8), 272.2 (M+ꢀHC@CH–CH3, 9), 228 (M+ꢀC4H7NO,
6), 160 (C10H10NO+, 18), 148 (C9H10NO+, 39), 91 (C7H7þ, 100); Anal.
Calcd for C21H31NO: C, 80.46; H, 9.97; N, 4.47. Found: C, 80.18; H,
10.01; N, 4.48.
4.2.1.3. (ꢀ)-(2E)-[(2S,7R,9R,10S)-Ethyl-3-3-(benzyl)-4,4,7-trim-
ethyloctahydro-2H-1,3-benzoxazin-2-yl-prop-2-enoate
2d. Using general condensation procedure A: 1, (1.500 g,
5.75 mmol, 1 equiv) was dissolved in toluene (12 mL) and ethyl
(2E)-4-oxobut-2-enoate (0.861 g, 6.73 mmol, 1.2 equiv) was added.
The compound, 2d, was isolated by chromatography, using petrol–
Et2O (95:5) leaving 1.451 g (68% yield) as a white solid. mp: 102 °C;
IR (KBr)
m
3099 (COO–H), 1731 (OC@O), 1603 (NC@O), 1250 and
;
1170 cmꢀ1
1H NMR (CDCl3, 300 MHz): d 1.24 (50%, d, J = 6.6 Hz,
6H, (CH3)2CH–N), 1.38 (50%, d, J = 6.6 Hz, 6H, (CH3)2CH–N), 3.71
(b sep., J = 6.6 Hz, 1H, N–CH–(CH3)2), 3.98 (sep., J = 6.6 Hz, 1H, N–
CH–(CH3)2), 6.60 (d, J = 15.7 Hz, 1H, H2), 7.38 (d, J = 15.7 Hz, 1H,
H3), 10.91 (br s, 1H, COOH); 13C NMR (CDCl3, 75 MHz): d 20.19
(50%, ((CH3)2CH–N), 21.10 (50%, (CH3)2CH–N), 46.28 (N–CH–
(CH3)2), 49.25 (N–CH–(CH3)2), 128.99 (CH, C2), 137.99 (CH, C3),
164.95 (Cq, CON(iPr)2), 169.11 (Cq, COOH); GC–MS (70 eV, m/z,
%): 199 (M+, 0.9), 184 (M+ꢀCH3, 16), 181 (M+ꢀH2O, 16), 142
Rf = 0.52 (petrol–Et2O, 90:10); ½a D23
¼ ꢀ69:0 (c 0.114, CH2Cl2); IR
ꢂ
(KBr)
m 3084, 3061, 3029, 2979, 2861, 1718 (C@O); 1661, 1495,
1200, 950, 737, 696, 648 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 0.92
;
(d, J = 6.3 Hz, 3H, CH3–C7), 0.96 (s, 3H, CH3eq–C4), 0.95–1.05 (m,
2H, 5ax + 6ax), 1.14 (t, J = 7.2 Hz, 3H, O–CH2–CH), 1.11–1.20 (m,
1H, H8ax), 1.23 (s, 3H, CH3ax–C4), 1.45–1.50 (m, 1H, H7), 1.50–1.60

2456
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
(C8H16NO+, 26), 100 (C6H14N+, 39), 99 (M+ꢀC6H14N, 46), 86.1
(M+ꢀC5H12N, 100), 58.1 (C2H2O+, 36).
4.2.1.8. (ꢀ)-(2S,7R,9R,10S)-3-(Benzyl)-2-(20-furyl)-4,4,7-trimeth-
yloctahydro-2H-1,3-benzoxazine 2f. See typical condensation
procedure A. 2f (1.144 g, 88%) was obtained as a yellow oil from
1 (1.000 g) and 2-furaldehyde (1.104 g); Rf = 0.42 (65:35 petrol–
4.2.1.6. (2E)-N,N-Diisopropyl-4-oxobut-2-enamide (precursor
to 2e). To
a
(2E)-4-(diisopropylamino)-4-oxobut-2-enoic acid
CH2Cl2); ½a 2D3
ꢂ
¼ ꢀ24:6 (c 0.74, CH2Cl2); IR (film)
m
3061, 3021,
;
(0.300 g, 1.5 mmol, 1 equiv) solution in CH2Cl2 (1 mL) was added,
all at once, thionyl chloride (0.231 g, 1.66 mmol, 0.141 mL,
1.3 equiv). After stirring for 2 h, the solvent was removed under re-
duced pressure and then the product was dried under vacuum for
45 min. The crude acid chloride was dissolved in THF (2 mL),
cooled to ꢀ78 °C and to this was added, all at once, LiAl(O–
C(CH3)3)3H (0.5 M in diglime, 3.0 mL, 0.381 g, 1.5 mmol, 1 equiv)
with stirring. The reaction mixture was slowly allowed to warm
to room temperature and was stirred for a further 24 h. The prod-
uct was hydrolyzed with water (10 mL) and acidified HCl (1 N,
1 mL). This mixture was extracted with CH2Cl2 (3 ꢃ 5 mL), washed
with water (5 mL), dried over Na2SO4, filtered, and the solvent was
removed under reduced pressure. The residue (containing the de-
sired aldehyde, the corresponding alcohol, and diglyme) was sepa-
rated by chromatography using a gradient: petrol–Et2O (1:1), then
Et2O (100%) followed by Et2O–MeOH (95:5), which gave 83 mg
(30% yield) of the title aldehyde as a colorless oil. Rf = 0.45 (pet-
2978, 2868, 1603, 1506, 1493, 1054, 733 and 696 cmꢀ1 1H NMR
(CDCl3, 300 MHz): d 1.00 (d, J = 6.7 Hz, 3H, CH3–C7), 1.04 (br d,
J = 10.3 Hz, 1H, H6ax), 1.06 (br d, J = 10.1 Hz, 1H, H5ax), 1.09 (s, 3H,
CH3eq–C4), 1.26 (q, J = 11.6 Hz, 1H, H8ax), 1.34 (s, 3H, CH3ax–C4),
1.48–1.60 (m, 1H, H7), 1.69–1.72 (m, 2H, H5eq + H10), 1.72–1.80
(m, 1H, H6eq), 2.05 (d app., J = 11.6 Hz, 1H, H8eq), 3.69 (AB-d,
J = 16.9 Hz, 1H, NCH2Ph), 3.67–3.70 (m, 1H, H9), 4.03 (AB-d,
J = 16.9 Hz, 1H, NCH2Ph), 5.78 (s, 1H, H2), 6.15 (dd, J = 3.0, 1.6 Hz,
0
0
1H, H4 ), 6.30 (dd, J = 3.0, 0.7 Hz, 1H, H3 ), 7.13 (t, J = 7.9 Hz, 1H,
0
H
p-Ph), 7.15 (dd, J = 1.6, 0.7 Hz, 1H, H5 ), 7.21 (t, J = 7.8 Hz, 2H, Hm-
Ph), 7.28 (d, J = 7.7 Hz, 2H, Ho-Ph); 13C NMR (CDCl3, 75 MHz): d
19.36 (CH3ax–C4), 22.22 (CH3–C7), 25.01 (CH2, C5), 27.39 (CH3eq
–
C4), 31.34 (CH, C7), 34.98 (CH2, C6), 41.28 (CH2, C8), 46.19 (CH,
C10), 47.89 (NCH2Ph), 57.21 (Cq, C4), 76.46 (CH, C9), 84.12 (CH,
0
0
C2), 107.90 (CH, H3 ), 109.85 (CH, H4 ), 125.42 (CH, Cp-Ph), 127.00
(2CH, Cm-Ph), 127.53 (2CH, Co-Ph), 141.57 (CH, C5‘), 143.18 (Cq,
+
0
CPh), 152.47 (Cq, C2 ); GC–MS (70 eV, m/z, %): 339.2 (M , 4.0), 228
rol–Et2O, 1:1); IR (film)
m
2971, 2939, 2876, 2827, 2737, 1695
(C16H22N+, 20), 186 (M+ꢀC12H12NO, 16), 148 (C10H14N+, 43), 91
(C7H7þ, 100); Anal. Calcd for C22H29NO2: C, 77.84; H, 8.61; N,
4.13. Found: C, 78.11; H, 8.63; N, 4.11.
(HC@O), 1642 (NC@O), 1372, 1207, 1154 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 1.27 (50%, d, J = 6.6 Hz, 6H, (CH3)2CH–N), 1.42 (50%,
d, J = 6.6 Hz, 6H, (CH3)2CH–N), 3.69 (50%, sept., J = 6.6 Hz, 1H, N–
CH–(CH3)2), 3.98 (50%, sept., J = 6.6 Hz, 1H, N–CH–(CH3)2), 6.73
(dd, J = 15.7, 7.4 Hz, 1H, H3), 7.19 (d, J = 15.7 Hz, 1H, H2), 9.70 (d,
J = 7.4 Hz, 1H, CHO); 13C NMR (CDCl3, 75 MHz): d 20.30 (50%,
(CH3)2CH–N), 21.23 (50%, (CH3)2CH–N), 46.22 (N–CH–(CH3)2),
49.40 (N–CH–(CH3)2), 136.40 (CH, C3), 143.87 (CH, C2), 164.11
(Cq, CON(iPr)2), 199.78 (Cq, COH); GC–MS (70 eV, m/z, %): 183.0
(M+, 0.5), 168.1 (M+ꢀCH3, 16), 126.1 (M+ꢀC3H7N, 33), 100.1
(C6H14N+, 95), 86.1 (M+ꢀC5H12N, 100), 58.1 (C2H2O+, 32).
4.2.1.9. (ꢀ)-(10E)-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyl-2-20-
phenylethenyloctahydro-2H-1,3-benzoxazine 2g. Using general
condensation procedure A: To 1, (2.000 g; 7.66 mmol; 1 equiv) in
toluene (10 mL) was added cinnamaldehyde (2.025 g; 1.93 mL;
15.31 mmol; 2 equiv). The compound, 2g, was isolated by chroma-
tography using petrol–Et2O (9:1) and gave 2.760 g (96% yield) as a
white solid. Crystallization from CH2Cl2–hexane (1:1) gave 2g as
colorless crystals. Mp. 118 °C; Rf = 0.53 (petrol–CCl4–Et2O,
96:20:4); ½a 2D3
ꢂ
¼ ꢀ63:5 (c 0.66, CH2Cl2); IR (KBr)
m 3080, 3063,
4.2.1.7. (ꢀ)-(2E)-3-(2S,7R,9R,10S)-3-(Benzyl)-4,4,7-trimethyloc-
tahydro-2H-1,3-benzoxazin-2-yl-N,N-diisopropylprop-2-ena-
mide 2e. Using general condensation procedure A: 1, (114 mg,
0.437 mmol, 1 equiv) was dissolved in toluene (5 mL) and (2E)-
3021, 2982, 2946, 2877, 1495, 1452, 972, 956, 726, 692,
641 cmꢀ1 1H NMR (CDCl3, 500 MHz): d. 0.97 (d, J = 5.9 Hz, 3H,
;
CH3–C7), 0.98–1.03 (m, 2H, H5ax + H6ax), 1.09 (s, 3H, CH3-eq–C4),
1.20 (q, J = 12.0 Hz, 1H, H8ax), 1.27 (s, 3H, CH3ax–C4), 1.44–1.50
(m, 1H, H7), 1.48–1.58 (m, 1H, H10), 1.65–1.71 (m, 1H, H6eq),
1.71–1.78 (m, 1H, H5eq), 2.01 (d app., J = 12.0 Hz, 1H, H8eq), 3.61
(td, J = 10.2, 3.8 Hz, 1H, H9), 3.70 (AB-d, J = 17.2 Hz, 1H, NCH2Ph),
4.08 (AB-d, J = 17.2 Hz, 1H, NCH2Ph), 5.27 (d, J = 5.1 Hz, 1H, H2),
N,N-diisopropyl-4-oxobut-2-enamide
(80 mg;
0,437 mmol;
1 equiv) was added. The crude reaction mixture was purified by
chromatography, using petrol–Et2O (4:1), giving 137 mg (73%
yield) of 2e as a white solid. mp: 98 °C; Rf = 0.50 (petrol–Et2O,
1:1); ½a 2D3
ꢂ
¼ ꢀ65:1 (c 0.45, CH2Cl2); IR (KBr)
m 3090, 3056, 3022,
2973, 2860, 1615 (C@O), 1663, 1493, 1208, 1184, 939, 733, 696,
5.91 (dd, J = 16.0, 5.1 Hz, 1H, H1 ), 6.67 (d, J = 16.0 Hz, 1H, H2 ),
7.05 (d, J = 7.2 Hz, 2H, @C–Ho-Ph), 7.14 (tapp, J = 7.3 Hz, 2H, Hp-Ph),
7.18 (t, J = 7.2 Hz, 2H, @C–Hm-Ph), 7.24 (t, J = 7.4 Hz, 2H, NC–Hm-
Ph), 7.35 (d, J = 7.4 Hz, 2H, NC–Ho-Ph); 13C NMR (CDCl3, 75 MHz): d
0
0
648 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 0.97 (s, 3H, CH3eq–C4),
;
1.00 (d, J = 6.8 Hz, 3H, CH3–C7), 1.00–1.05 (m, 2H, H5ax+6ax), 1.02–
1.16 (m, 6H, N–CH–(CH3)2), 1.22 (q, J = 11.4 Hz, 1H, H8ax), 1.32 (s,
3H, CH3ax–C4), 1.28–1.40 (m, 6H, N–CH–(CH3)2), 1.51–1.59 (m,
19.00 (CH3ax–C4), 22.28 (CH3–C7), 25.10 (CH2, C6), 27.29 (CH3eq
–
C4), 31.39 (CH, C7), 35.02 (CH2, C5), 41.42 (CH2, C8), 46.82 (CH,
C10), 47.65 (NCH2Ph), 56.88 (Cq, C4), 75.76 (CH, C9), 87.79 (CH,
C2), 125.67 (CH, Cp-Ph), 126.55 (CH, Cp-Ph), 127.29 (2CH, Cm-Ph),
127.35 (2CH, Cm-Ph), 127.93 (2CH, Co-Ph), 128.19 (2CH, Co-Ph),
1H, H7), 1.62–1.77 (m, H5eq
, 3H, H6eq + H10), 2.01 (d app.,
J = 11.9 Hz, 1H, H8eq), 3.61 (td, J = 10.5, 3.5 Hz, 1H, H9), 3.68–3.52
(m, 1H, N–CH–(CH3)2), 3.89 (AB-d, J = 17.4 Hz, 1H, NCH2Ph),
3.85–3.95 (m, 1H, N–CH–(CH3)2), 4.02 (AB-d, J = 17.4 Hz, 1H,
0
0
129.51 (CH, C2 ), 131.83 (CH, C1 ), 136.72 (Cq, CPh), 143.98 (Cq,
CPh); GC–MS (70 eV, m/z, %): 375 (M+, 7); 284 (M+ꢀC7H7, 2); 272
(M+ꢀHC@CH–Ph, 12); 91 (C7H7þ, 100); Anal. Calcd for C26H33NO:
C, 83.15; H, 8.86; N, 3.73. Found: C, 82.86; H, 8.82; N, 3.74.
Crystallographic studies for 2g. Single crystals of 2g were ob-
tained by slow recrystallization in a 1:1 mixture of pentane and
dichloromethane. The crystal belonged to the chiral orthorhombic
P212121 space group, but the crystallographic results did not per-
mit determination of the absolute configuration. Nevertheless,
since the stereochemistry of the C1, C2, and C5 stereocenters of
the precursor (ꢀ)-8-benzylaminomenthol, 1 are known and the
structure of compound 5 has already been determined, the correct
enantiomer could be chosen and the stereochemistry at C7, C9, and
C10 in compound 2g was easily determined. Figure 1 shows the
0
0
NCH2Ph), 5.42 (s, 1H, H2), 6.52 (s, 2H, H2 +3 ), 7.17 (t, J = 7.1 Hz,
1H, Hp-Ph), 7.29 (t, J = 7.3 Hz, 2H, Hm-Ph), 7.40 (d, J = 7.4 Hz, 2H,
H
o-Ph); 13C NMR (CDCl3, 75 MHz): d 20.53 (50%, (CH3)2CH–N),
21.15 (50%, (CH3)2CH–N), 21.78 (CH3ax–C4), 22.30 (CH3–C7), 24.96
(CH2, C5), 26.97 (CH3eq–C4), 31.45 (CH, C7), 35.18 (CH2, C6), 41.39
(CH2, C8), 44.83 (CH, C10), 45.55 (N–CH–(CH3)2), 47.85 (NCH2Ph),
48.14 (N–CH–(CH3)2), 56.98 (Cq, C4), 76.33 (CH, C9), 86.08 (CH,
0
C2), 125.25 (CH, C2 ), 125.83 (CH, Cp-Ph), 126.82 (2CH, Co-Ph),
127.99 (2CH, Cm-Ph), 140.89 (CH, C3‘), 143.97 (Cq, CPh), 165.92 (Cq,
C@O); GC–MS (70 eV, m/z, %): 426.2 (M+, 2), 411 (M+ꢀCH3, 4),
272.2 (M+ꢀC9H16NO, 37), 91 (C7H7þ, 100.0). Anal. Calcd for
C27H42N2O2: C, 76.01; H, 9.92; N, 6.57. Found: C, 76.31; H, 9.95;
N, 6.55.

C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
2457
structure and the labeling scheme of compound 2g. The bond dis-
H
C3 -o-Ph); 13C NMR (CDCl3, 75 MHz): d 22.25 (CH3ax–C4), 22.58
0
tances and angles are available in the CIF.
(CH3–C7), 25.05 (CH2, C5), 27.34 (CH3eq–C4), 31.42 (CH, C7), 35.12
0
(CH2, C6), 37.81 (CH2, C4 ), 41.20 (CH2, C8), 45.76 (CH, C10), 46.31
0
4.2.2. General 1,3-dipolar cycloaddition procedure for the
synthesis of 2-isoxazolines cycloadducts 6–9
(NCH2Ph), 57.57 (Cq, C4), 76.75 (CH, C9), 81.85 (CH, C5 ), 88.81
0
(CH, C2), 126.41 (CH, Cp-Ph), 126.57 (2CH, C3 -o-Ph), 127.53 (2CH,
Method A. N-Hydroxybenzenecarboimidoyl chloride as precur-
CNC-o-Ph), 128.24 (2CH, Cm-Ph), 128.53 (2CH, Cm-Ph), 129.52 (Cq,
0
sor to phenylacetonitrile oxide. trans-Perhydrobenzoxazine
2
CPh), 129.82 (CH, Cp-Ph), 142.76 (Cq, CPh), 156.18 (Cq, C3 ); Anal.
(1 equiv) and triethylamine (1–20 equiv) were dissolved in CH2Cl2
(2 mL) and N-hydroxybenzenecarboimidoyl chloride33 (1–5 equiv)
in CH2Cl2 (1 mL) was added over 8 h using a syringe pump. The
solution was stirred for a total of 24 h and then CH2Cl2 (5 mL)
and a saturated Na2CO3 solution (3 mL) were added. After stirring
for 20 min, the aqueous phase was extracted with CH2Cl2
(3 ꢃ 5 mL). The combined organic layers were washed with water
(5 mL), dried over Na2SO4, and then the solvent was removed un-
der reduced pressure and the crude product dried under vacuum
(2 h). The residue was purified by chromatography as described
for each cycloadduct, 6 through 9.
Calcd for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C, 77.69;
H, 8.17; N, 6.70.
4.2.2.2. (+)-(2S,3R,50S,7R,9R,10S)-3-(Benzyl)-2-30-methyl-4,5-
dihydroisoxazol-50-yl-4,4,7-trimethyloctahydro-2H-1,3-benzox-
azine 6b and (ꢀ)-(50R)-epimer 8b. Method B: To
a cooled
(ꢀ30 °C) solution of nitroethane (37.5 mg, 0.50 mmol, 2.2 equiv),
phenyl isocyanate (100
lL, 109.6 mg, 0.92 mmol, 4 equiv) and tri-
ethylamine (50 L, 36.3 mg, 0.36 mmol, 1.6 equiv) in CH2Cl2
l
(2 mL), was added dipolarophile 2a (68 mg, 0.227 mmol, 1 equiv)
in CH2Cl2 (2 mL). The solution was allowed to warm to room tem-
perature and stirred for 24 h. The reaction mixture was hydrolyzed
with saturated NH4Cl (5 mL). The aqueous phase was extracted
with CH2Cl2 (2 ꢃ 5 mL) and the combined organic phases were
washed with saturated NaCl (5 mL), dried over MgSO4, concen-
trated under reduced pressure. The residue was separated by chro-
matography using hexanes–CH2Cl2–EtOAc, (4:1:1) to give
recovered 2a (48 mg) plus the two cycloadducts (26.5% combined
yield), 6b and 8b, as major and minor fractions, respectively. The
isomeric ratio was determined by integration of the 13C NMR sig-
nals for CH3ax–C4 (15.25 and 17.03 ppm). The results are shown
in Table 2.
4.2.2.1. (+)-(2S,50S,7R,9R,10S)-3-(Benzyl)-2-30-phenyl-4,5-dihy-
droisoxazol-50-yl-4,4,7-trimethyloctahydro-2H-1,3-benzoxazine
6a and (ꢀ)-(50R)-epimer 8a. Using general cycloaddition proce-
dure A: To a solution of trans-perhydrobenzoxazine 2a (71 mg,
0.24 mmol, 1 equiv) and triethylamine (0.48 g, 4.7 mmol, 20 equiv)
in CH2Cl2 (2 mL) was added N-hydroxybenzenecarboimidoyl chlo-
ride33 (0.19 g, 1.2 mmol, 5 equiv). The residue obtained was sepa-
rated by chromatography using petrol–Et2O (4:1) to give
together 69.5 mg (70% yield) of cycloadducts 6a and 8a. The iso-
meric ratio was determined by integration of the 13C NMR signals
0
for C5 (81.50 and 81.85 ppm) and C2 (87.64 and 88.81 ppm). The
Data for 6b. Yield = 16.1 mg (19.9%); Pale yellow oil, Rf = 0.45
results are shown in Table 2.
(hexanes–CH2Cl2–EtOAc; 4:1:1); ½a D22
¼ þ29:3 (c 0.161, MeOH);
ꢂ
Data for 6a. Yield = 53.6 mg (54%); Yellow oil, Rf = 0.21 (petrol–
IR (film) m 3060, 3028, 2924, 2868, 1599 (C@N), 1603, 1493,
Et2O, 90:10); ½a D23
ꢂ
¼ þ13:4 (c 0.264, CH2Cl2); IR (film)
m
3060, 3026,
1452, 1385, 1324, 1063, 942, 730, 698, 664 cmꢀ1 1H NMR (CDCl3,
;
2922, 2866, 1597 (C@N), 1639, 1492, 1451, 1384, 1054, 941, 715,
300 MHz): d 0.92–0.98 (m, 1H, H5ax), 0.94 (d, J = 6.5 Hz, 3H, CH3–
C7), 0.98–1.04 (m, 1H, H6ax), 1.02 (q, J = 11.0 Hz, 1H, H8ax), 1.13
(s, 3H, CH3eq–C4), 1.16 (s, 3H, CH3ax–C4), 1.40–1.55 (m, 2H, H10+7),
696, 671 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.92 (d, J = 6.1 Hz,
3H, CH3–C7), 0.90–1.04 (m, 3H, H8ax,5ax,6ax), 1.16 (s, 3H, CH3eq
–
0
C4), 1.19 (s, 3H, CH3ax–C4), 1.46 (t app., J = 9.4 Hz, 2H, H7+10),
1.67–1.74 (m., 2H, H5eq+6eq), 1.92 (d app., J = 11.8 Hz, 1H, H8eq),
1.63–1.78 (m, 2H, H6eq+5eq), 1.84 (s, 3H, CH3–C3 ), 1.94 (br d,
0
J = 12.1 Hz, 1H, H8eq), 2.17 (dd, J = 17.1, 10.9 Hz, 1H, H4 a), 3.05
0
0
2.65 (dd, J = 17.0, 11.0 Hz, 1H, H4 a), 3.50 (dd, J = 17.0, 7.7 Hz, 1H,
(dd, J = 17.1, 7.5 Hz, 1H, H4 b), 3.51 (td, J = 10.5, 3.9 Hz, 1H, H9),
0
H4 b), 3.51 (td, J = 10.4, 3.8 Hz, 1H, H9), 3.67 (AB-d, J = 17.6 Hz, 1H,
3.60 (AB-d, J = 17.3 Hz, 1H, NCH2Ph), 4.00 (AB-d, J = 17.3 Hz, 1H,
0
NCH2Ph), 4.08 (AB-d, J = 17.6 Hz, 1H, NCH2Ph), 4.62 (ddd, J = 11.0,
NCH2Ph), 4.41 (ddd, J = 10.9, 7.5, 3.3 Hz, 1H, H5 ), 4.60 (d,
0
7.7, 3.9 Hz, 1H, H5 ), 4.69 (d, 3.9 Hz, 1H, H2), 7.20 (t, J = 7.1 Hz,
J = 3.3 Hz, 1H, H2), 7.18 (t, J = 7.1 Hz, 1H, Hp-Ph), 7.29 (t, J = 7.3 Hz,
1H, Hp-Ph), 7.32 (t, J = 7.4 Hz, 2H, Hm-Ph), 7.36–7.38 (m, 3H, Hm, p-
2H, Hm-Ph), 7.36 (d, J = 7.4 Hz, 2H, H o-Ph); 13C NMR (CDCl3,
0
Ph), 7.48 (d, J = 7.4 Hz, 2H, HNC-o-Ph), 7.60 (dd, J = 6.6, 3.0 Hz, 2H,
75 MHz): d 12.85 (CH3–C3 ), 15.25 (CH3ax–C4), 22.22 (CH3–C7),
HC3 -o-Ph); 13C NMR (CDCl3, 75 MHz): d 17.27 (CH3ax–C4), 22.18
25.08 (CH2–C5), 26.93 (CH3eq–C4), 31.14 (CH, C7), 34.92 (CH2, C6),
0
0
(CH3–C7), 25.08 (CH2, C5), 26.91 (CH3eq–C4), 31.16 (CH, C7), 34.91
39.32 (CH2, C4 ), 41.22 (CH2, C8), 47.51 (NCH2Ph), 48.28 (CH, C10),
0
0
(CH2, C6), 35.75 (CH2, C4 ), 41.16 (CH2, C8), 47.47 (NCH2Ph), 48.12
57.24 (Cq, C4), 74.93 (CH, C9), 80.60 (CH, C5 ), 87.72 (CH, C2),
0
(CH, C10), 57.31 (Cq, C4), 75.26 (Cq, C9), 81.50 (CH, C5 ), 87.64 (CH,
126.22 (CH, Cp-Ph), 127.12 (2CH, Co-Ph), 128.11 (2CH, Cm-Ph),
0
0
C2), 126.32 (CH, Cp-Ph), 126.64 (2CH, C3 -o-Ph), 127.17 (2CH, CNC-o-
144.28 (Cq, CPh), 155.38 (Cq, C3 ); GC–MS (70 eV, m/z, %): 272
(M+ÅꢀC4H6NO, 100), 136 (C10H16
, 20) 91 (C7H7 , 100), 81
þꢁ
þꢁ
Ph), 128.16 (2CH, Cm-Ph), 128.46 (2CH, Cm-Ph), 129.65 (CH, Cp-Ph),
129.82 (Cq, CPh), 142.64 (Cq, CPh), 156.51 (Cq, C3 ); Anal. Calcd for
C27H34N2O2: C, 77.48; H, 8.19; N, 6.69 . Found: C, 77.72; H, 8.22;
N, 6.71.
(C6H9þꢁ, 18); Anal. Calcd for C22H32N2O2: C, 74.12; H, 9.05; N,
7.86. Found: C, 74.35; H, 9.02; N, 7.88.
0
Data for 8b. Yield = 5.4 mg (6.6%); Pale yellow oil; Rf = 0.27 (hex-
Data for 8a. Yield = 15.9 mg (16%); Yellow oil, Rf = 0.18 (pet:E-
anes–CH2Cl2–EtOAc; 4:1:1); ½a D23
¼ ꢀ106:1 (c 0.022, MeOH); IR
ꢂ
t2O, 4:1); ½a 2D3
ꢂ
¼ ꢀ90:6 (c 0.145, CH2Cl2); IR (film)
m
3068, 3019,
(film) m 3060, 3026, 2922, 2866, 1597 (C@N), 1639, 1492, 1451,
2928, 2861, 1592 (C@N), 1499, 1445, 1380, 1062, 942, 715, 695,
1384, 1323, 1054, 941, 715, 696, 671 cmꢀ1 1H NMR (CDCl3,
;
676 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.96 (d J = 6.8 Hz, 3H,
300 MHz): d 0.94 (d, J = 6.5 Hz, 3H, CH3–C7), 0.88–1.02 (m, 2H,
H5ax, 6ax), 1.14 (q, J = 11.7 Hz, 1H, H8ax), 1.15 (s, 3H, CH3eq–C4),
1.31 (s, 3H, CH3ax–C4), 1.44–1.56 (m, 2H, H7, 10), 1.57–1.65 (m,
1H, H5eq), 1.66–1.77 (m, 1H, H6eq), 1.82 (s, 3H, CH3–C3 ), 1.98 (dd,
J = 10.6, 7.5 Hz, 1H, H4 b), 2.07 (br d, J = 11.8 Hz, 1H, H8eq), 2.64
CH3–C7), 0.95–0.99 (m, 2H, H5ax,6ax), 1.20 (q app, J = 12.0 Hz, 1H,
H8ax), 1.21 (s, 3H, CH3eq–C4), 1.31 (s, 3H, CH3ax–C4), 1.48–1.58 (m,
2H, H7+10), 1.63 (br d, J = 10.5 Hz, 1H, H5eq), 1.74 (b d, J = 7.0 Hz,
1H, H6eq), 2.09 (d app., J = 12.1 Hz, 1H, H8eq), 2.35 (dd, J = 17.3,
0
0
0
0
0
10.7 Hz, 1H, H4 a), 3.02 (dd, J = 17.3, 7.1 Hz, 1H, H4 b), 3.62 (td,
J = 10.9, 3.5 Hz, 1H, H9), 4.03 (AB-d, J = 17.7 Hz, 1H, NCH2Ph), 4.13
(dd, J = 18.0, 7.5 Hz, 1H, H4 ), 3.59 (td, 1H, J = 10.5, 3.9 Hz, H9),
a
3.95 (AB-d, J = 17.5 Hz, 1H, NCH2Ph), 4.05 (AB-d, J = 17.5 Hz, 1H,
0
0
(AB-d, J = 17.7 Hz, 1H, NCH2Ph), 4.60–4.68 (m, 1H, H5 ), 4.72 (d,
NCH2Ph), 4.45 (ddd, J = 18.0, 10.6, 8.2 Hz, 1H, H5 ), 4.65 (d,
J = 8.6 Hz, 1H, H2), 7.23 (t, J = 7.3 Hz, 1H, Hp-Ph), 7.33–7.36 (m, 5H,
Jvic = 8.2 Hz, 1H, H2), 7.19 (t, J = 7.1 Hz, 1Hp-Ph), 7.30 (t, J = 7.2 Hz,
Hm,p-Ph), 7.42 (d, J = 7.8 Hz, 2H, HNC-o-Ph), 7.49 (br d, J = 7.2 Hz, 2H,
2H, Hm-Ph), 7.34 (d, J = 7.2 Hz, 2H, H o-Ph); 13C NMR (CDCl3,

2458
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
0
0
75 MHz): d 12.93 (CH3–C3 ), 17.03 (CH3ax–C4), 22.30 (CH3–C7),
25.14 (CH2, C5), 26.99 (CH3eq–C4), 31.20 (CH, C7), 34.98 (CH2, C6),
48.13 (NCH2Ph), 55.33 (CH, C4 ), 57.77 (Cq, C4), 61.33 (CH2, O–
0
CH2–CH3), 75.22 (CH, C9), 79.61 (CH, C5 ), 85.03 (CH, C2), 126.39
0
0
39.38 (CH2, C4 ), 41.28 (CH2, C8), 47.58 (NCH2Ph), 48.33 (CH, C10),
(CH, CNC-p-Ph), 126.64 (2CH, CNC-o-Ph), 127.51 (2CH, C3 -o-Ph),
0
0
57.24 (Cq, C4), 74.98 (CH, C9), 80.65 (CH, C5 ), 87.76 (CH, C2),
128.47 (2CH, CNC-m-Ph), 128.61 (Cq, CPh), 128.73 (2CH, C3 -m-Ph),
0
0
126.29 (CH, Cp-Ph), 127.18 (2CH, Co-Ph), 128.18 (2CH, Cm-Ph),
129.98 (CH, C3 -p-Ph), 142.24 (Cq, CPh), 156.92 (Cq, C3 ), 168.86 (Cq,
C@O); Anal. Calcd for C30H38N2O4: C, 73.44; H, 7.81; N, 5.71. Found:
C, 73.41; H, 7.83; N, 5.74.
0
144.90 (Cq, CPh), 155.46 (Cq, C3 ); GC–MS (70 eV, m/z, %): 272
(M+ÅꢀC4H6NO, 44), 136 (C10H16þꢁ, 17), 91 C7H7þꢁ, 100), 81 (C6H9
,
þꢁ
17); Anal. Calcd for C22H32N2O2: C, 74.12; H, 9.05; N, 7.86. Found:
C, 74.30; H, 9.07; N, 7.90.
Data for 8d. Yield = 4.6 mg (7%); Yellow oil, Rf = 0.20 (80:20 pet-
rol–Et2O); ½a 2D3
ꢂ
¼ ꢀ89:3 (c 0.045, CH2Cl2); IR (film)
m 3061, 3028,
2979, 2924, 2869, 1737 (C@O), 1602, 1494 (C@N), 1097, 1256,
4.2.2.3. Ethyl (+)-(2S,40S,50S,7R,9R,10S)-5-3-(benzyl)-4,4,7-trim-
ethyloctahydro-2H-1,3-benzoxazin-2-yl-3-phenyl-4,5-dihydrois-
oxazole-4-carboxylate 6d its diastereoisomer (ꢀ)-(40R,50R)-8d
and regioisomers ethyl (+)-(2S,40S,50S,7R,9R,10S)-4-3-(benzyl)-
4,4,7-trimethyl-octahydro-2H-1,3-benzoxazin-2-yl-3-phenyl-4,5-
dihydroisoxazole-5-carboxylate 7d and (ꢀ)-(40R,50R)-9d. Using
general cycloaddition procedure A: to trans-benzoxazine 2d
(50 mg, 0.135 mmol, 1 equiv) and triethylamine (0.375 mL,
0.272 g, 2.7 mmol, 20 equiv) was added phenyloximoyl chloride
(105 mg, 0.674 mmol, 5 equiv). The crude products were purified
by chromatography using petrol–Et2O (90:10) and provided a total
of 39.0 mg (59% conversion yield). The isomeric ratio was deter-
909, 732, 693, 647 cmꢀ1
J = 6.8 Hz, 3H, O–CH2–CH3), 0.95 (d, J = 6.5 Hz, 3H, CH3–C7), 0.94–
1.02 (m, 2H, H5ax 6ax), 1.13 (s, 3H, CH3eq–C4), 1.18 (q, J = 12.1 Hz,
;
1H NMR (CDCl3, 500 MHz): d 0.89 (t,
,
1H, H8ax), 1.26 (s, 3H, CH3ax–C4), 1.44–1.53 (m, 1H, H7), 1.56 (t,
J = 10.5 Hz, 1H, H10), 1.62 (d app., J = 11.3 Hz, 1H, H5eq), 1.72 (d
app., J = 7.8 Hz, 1H, H6eq), 2.06 (br d, J = 12.3 Hz, 1H, H8eq), 3.54 –
3.62 (m, 2H, H9 + O–CH2–CH3), 3.70 (dq, J = 11.3, 6.8 Hz, 1H, O–
CH2–CH3), 4.00 (d, J = 18.0 Hz, 1H, NCH2Ph), 4.15 (d, J = 18.0 Hz,
0
1H, NCH2Ph), 4.43 (d, J = 3.3 Hz, 1H, H4 ), 4.63 (d, J = 7.8 Hz, 1H,
H2), 5.09 (dd, J = 7.8, 3.3 Hz, 1H, H5 ), 7.18 (t, J = 7.3 Hz, 1H, HNC-p-
0
0 -m,p-Ph,
Ph), 7.31 (t, J = 7.4 Hz, 2H, HNC-m-Ph), 7.37–7.44 (m, 5H, H3
NC-o-Ph), 7.77 (dd, J = 7.4, 2.2 Hz, 2H, H3 -o-Ph). 13C NMR (CDCl3,
125 MHz): d 13.46 (CH3, O–CH2–CH3), 22.13 (CH3ax–C4), 22.21
(CH3–C7), 24.97 (CH2, C5), 26.78 (CH3eq–C4), 31.37 (CH, C7), 35.06
(CH2, C6), 41.09 (CH2, C8), 45.50 (CH, C10), 46.67 (NCH2Ph), 55.28
0
mined by integration of the 13C NMR signals for C5 (85.57 (6d),
0
85.22 (8d), 79.61 (7d), and 81.32 ppm (9d)). The results are shown
in Table 2.
0
Data for 6d. Yield = 20.5 mg (31%); Yellow oil; Rf = 0.41 (CH2Cl2);
(CH, C4 ), 57.77 (Cq, C4), 61.48 (CH2, O–CH2–CH3), 76.75 (CH, C9),
½
a 2D3
ꢂ
¼ þ81:0 (c 0.09, CH2Cl2); IR (film)
2861, 1735 (C@O), 1610, 1560 (C@N), 1261, 913, 738, 689,
641 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 0.88 (d, J = 6.9 Hz, 3H,
CH3–C7), 0.94 (t, J = 7.1 Hz, 3H, O–CH2–CH3), 0.91–1.00 (m, 3H,
H5ax 8ax), 1.12 (s, 3H, CH3eq–C4), 1.16 (s, 3H, CH3ax–C4), 1.38–
m
3068, 3021, 2984, 2929,
85.22 (CH, C5 ), 87.19 (CH, C2), 126.14 (CH, CNC-p-Ph), 126.96 (2CH,
CNC-o-Ph), 127.52 (2CH, C3 -o-Ph), 128.22 (2CH, CNC-m-Ph), 128.38
(2CH, C3 -m-Ph), 128.40 (Cq, CPh), 130.03, (CH, C3 -p-Ph) 142.21 (Cq,
CPh), 153.90 (Cq, C3 ), 167.30 (Cq, C@O). Anal. Calcd for
C30H38N2O4: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.40; H, 7.78;
N, 5.72.
0
0
0
0
;
0
,
,
6ax
1.45 (m, 1H, H7), 1.47 (td, J = 11.0, 2.3 Hz, 1H, H10), 1.67–1.71 (m,
2H, H5eq + H6eq), 1.83 (d app., J = 12.2 Hz, 1H, H8eq), 3.44 (td,
J = 10.4, 4.1 Hz, 1H, H9), 3.48 (AB-d, J = 17.8 Hz, 1H, NCH2Ph), 3.76
(q, J = 7.1 Hz, 2H, O–CH2–CH3), 4.07 (AB-d, J = 17.8 Hz, 1H,
Data for 9d. Yield = 3.3 mg (5%); Yellow oil; Rf = 0.22 (80:20 pet-
rol–Et2O); ½a 2D3
ꢂ
¼ ꢀ128:1 (c 0.086, CH2Cl2); IR (film)
m 3052, 3040,
2971, 2896, 1731 (C@O), 1620, 1543 (C@N), 1260, 897, 732, 693,
0
NCH2Ph), 4.65 (d, J = 4.3 Hz, 1H, H4 ), 4.68 (d, J = 3.2 Hz, 1H, H2),
647 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.83 (d, J = 6.4 Hz, 3H,
6ax); 0.92 (q, J = 11.7 Hz, 1H,
0
4.95 (t app., J = 4.3 Hz, 1H, H5 ), 7.19 (t, J = 7.3 Hz, 1H, HNC-p-Ph),
CH3–C7), 0.87–0.94 (m, 2H, H5ax
,
0
7.30 (t, J = 7.7 Hz, 2H, HNC-m-Ph), 7.35–7.40 (m, 3H, H3 -m,p-Ph), 7.45
H8ax), 1.00 (t, J = 7.1 Hz, 3H, O–CH2–CH3), 1.12 (s, 3H, CH3eq–C4),
1.27–1.34 (m, 1H, H7), 1.33 (s, 3H, CH3ax–C4), 1.39 (d app., J
=13.3 Hz, 1H, H8eq), 1.49 (t app, J = 10.2 Hz, 1H, H10), 1.66 (d app,
J = 11.8 Hz, 1H, H5eq), 1.63 – 1.70 (m, 1H, H6eq), 3.32 (td, J = 10.7,
3.6 Hz, 1H, H9), 3.78 (q, J = 7.1 Hz, 2H, O–CH2–CH3), 4.03 (AB-d,
0
(d, J = 7.5 Hz, 2H, HNC-o-Ph), 7.75 (dd., J = 6.6, 3.3 Hz, 2H, H3 -o-Ph);
13C NMR (CDCl3, 125 MHz): d 13.61 (O–CH2–CH3), 17.01 (CH3ax
–
C4), 22.15 (CH3–C7), 25.02 (CH2, C5), 26.85 (CH3eq–C4), 31.10 (CH,
C7), 34.87 (CH2, C6), 40.97 (CH2, C8), 47.71 (NCH2Ph), 48.00 (CH,
0
0
C10), 54.81 (CH, C4 ), 57.38 (Cq, C4), 61.47 (CH2, O–CH2–CH3),
J = 18.1 Hz, 1H, NCH2Ph), 4.07 (dd, J = 10.2, 1.9 Hz, 1H, H4 ), 4.24
0
75.00 (CH, C9), 85.57 (CH, C5 ), 88.38 (CH, C2), 126.24 (CH, CNC-p-
(AB-d, J = 18.1 Hz, 1H, NCH2Ph), 4.79 (d, J = 10.2 Hz, 1H, H2), 5.13
0
0
Ph), 126.92 (2CH, CNC-o-Ph), 127.25 (2CH, C3 -o-Ph), 128.33 (2CH,
(br s, 1H, H5 ), 7.17 (t, J = 7.1 Hz, 1H, HNC-p-Ph), 7.28 (t, J = 7.6 Hz,
0
0
CNC-m-Ph), 128.42 (2CH, C3 -m-Ph), 128.55 (Cq, CPh), 129.86 (CH,
2H, HNC-m-Ph), 7.33–7.38 (m, 3H, H3 -m,p-Ph), 7.41 (d, J = 7.1 Hz, 2H,
HNC-o-Ph), 7.82 (dd, J = 7.6, 2.1 Hz, 2H, H3 -o-Ph); 13C NMR (CDCl3,
125 MHz): d 13.68 (O–CH2–CH3), 22.11 (CH3–C7), 22.49 (CH3ax
C4), 24.79 (CH2, C5), 27.10 (CH3eq–C4), 31.15 (CH, C7), 35.03 (CH2,
C6), 40.49 (CH2, C8), 44.99 (CH, C10), 46.05 (NCH2Ph), 53.30 (CH,
C4 ), 58.18 (Cq, C4), 61.40 (O–CH2–CH3), 76.75 (CH, C9), 81.32 (CH,
0
0
0
C3 -p-Ph), 142.30 (Cq, CPh), 154.22 (Cq, C3 ), 168.64 (Cq, C@O); Anal.
Calcd for C30H38N2O4: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.25;
H, 7.75; N, 5.73.
–
Data for 7d. Yield = 10.6 mg (16%); Yellow oil; Rf = 0.23 (80:20
petrol–Et2O); ½a D23
ꢂ
¼ þ223 (c 0.104, CH2Cl2); IR (film)
m
3061,
0
0
3027, 2980, 2925, 2869, 1737 (C@O), 1602, 1566 (C@N), 1265,
C5 ), 87.48 (CH, C2), 126.96 (CH, CNC-p-Ph), 127.70 (2CH, CNC-o-Ph),
128.27 (2CH, C3 -o-Ph), 128.43 (2CH, CNC-m-Ph), 128.70 (Cq, CPh),
909, 732, 693, 647 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.88–0.98
0
0
0
(m, 2H, H5ax 6ax), 0.91 (d, J = 6.3 Hz, 3H, CH3–C7), 1.02 (t,
,
128.91 (Cq, CPh), 129.47 (CH, C3 -p-Ph), 129.73 (2CH, C3 -m-Ph),
0
J = 7.2 Hz, 3H, O–CH2–CH3), 1.03 – 1.10 (m, 1H, H8ax), 1.07 (s, 3H,
159.92 (Cq, C3 ), 168.34 (Cq, C@O); Anal. Calcd for C30H38N2O4: C,
CH3ax–C4), 1.11 (s, 3H, CH3eq–C4), 1.32 – 1.43 (m, 1H, H7), 1.49 (t,
73.44; H, 7.81; N, 5.71. Found: C, 73.41; H, 7.83; N, 5.70.
J = 10.7 Hz, 1H, H10), 1.63–1.72 (m, 2H, H5eq, 6eq), 1.88 (br d,
J = 12.4 Hz, 1H, H8eq), 3.32 (td, J = 10.4, 3.7 Hz, 1H, H9), 3.68 (AB-
d, J = 17.9 Hz, 1H, NCH2Ph), 3.74–3.84 (m, 2H, O–CH2–CH3), 4.00
4.2.2.4. (+)-(2S,40S,50S,7R,9R,10S)-4-(3-(Benzyl)-4,4,7-trimethyl-
octahydro-2H-1,3-benzoxazin-2-yl-N,N-diisopropyl-3-phenyl-
4,5-dihydroisoxazole-5-carboxamide 7e, its diastereoioisomer
(ꢀ)-(40R,50R)-9e and the regioisomer (+)-(2S,40S,50S,7R,9R,10S)-5-
(3-(benzyl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazin-2-yl-
N,N-diisopropyl-3-phenyl-4,5-dihydroisoxazole-4-carboxamide
6e. Using general cycloaddition procedure A: trans- benzoxazine
2e (53 mg, 0,125 mmol, 1 equiv), triethylamine (252 mg, 2.5 mmol,
0.35 mL, 20 equiv) and phenyloximoyl chloride (0.095 g,
0
(dd, J = 3.3, 1.4 Hz, 1H, H4 ), 4.13 (AB-d, J = 17.9 Hz, 1H, NCH2Ph),
0
4.74 (d, J = 1.4 Hz, 1H, H2), 5.43 (d, J = 3.3 Hz, 1H, H5 ), 7.20 (t,
J = 7.3 Hz, 1H, HNC-p-Ph), 7.31 (t, J = 7.7 Hz, 2H, HNC-m-Ph), 7.42–
0
0
7.48 (m, 5H, HC3 -m,p-Ph, NC-o-Ph), 7.77 (dd, J = 8.2, 1.9 Hz, 2H, HC3 -o-
Ph); 13C NMR (CDCl3, 125 MHz): d 13.61 (O–CH2–CH3), 17.09
(CH3ax–C4), 22.11 (CH3–C7), 24.96 (CH2, C5), 27.04 (CH3eq–C4),
31.10 (CH, C7), 34.83 (CH2, C6), 40.96 (CH2, C8), 47.56 (CH, C10),

C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
2459
0.625 mmol, 5 equiv) at rt gave a crude oil. This was purified by
chromatography using Pet/Et2O (9:1) and the three cycloadducts
were isolated in pure form with an overall yield of 51%
(34.7 mg). The isomeric ratio was determined by integration of
651 cmꢀ1; 1H NMR (CDCl3, 500 MHz): d 0.82 (d, J = 6.3 Hz, 3H, CH3–
C7), 0.90 (50%, d, J = 6.4 Hz, 6H, (CH3)2CH–N), 0.85–0.96 (m, 3H,
H5ax
,
, 8ax), 1.05 (s, 3H, CH3eq–C4), 1.11 (50%, d, J = 6.6 Hz, 6H,
6ax
N–CH–(CH3)2), 1.14 (50%, d, J = 6.6 Hz, 6H, (CH3)2CH–N), 1.22
(50%, d, J = 6.4 Hz, 6H, (CH3)2CH–N), 1.24–1.38 (m, 2H, H7, 8eq),
1.31 (s, 3H, CH3ax–C4), 1.43 (bt, J = 10.3 Hz, 1H, H10), 1.50–1.59
(m, 1H, H6 eq), 1.60–1.67 (m, 1H, H5eq), 3.16 (sep., J = 6.6 Hz, 1H,
N–CH–(CH3)2), 3.25 (td, J = 10.5, 3.4 Hz, 1H, H9), 3.95 (AB-d,
J = 17.6 Hz, 1H, NCH2Ph), 4.13 (sep., J = 6.4 Hz, 1H, N–CH–(CH3)2),
4.24 (AB-d, J = 17.6 Hz, 1H, NCH2Ph), 4.70 (dd, J = 10.2, 2.2 Hz, 1H,
the 13C NMR signals for C5 (79.92 (7e), 82.12 (9e) and 84.58 ppm
0
(6e)) and C2 (85.12 (7e), 87.68 (9e) and 87.05 ppm (6e)). The re-
sults are shown in Table 2.
Data for 6e. Yield = 4.1 mg (6%); Yellow oil; Rf = 0.15 (100%
CH2Cl2); ½a 2D3
ꢂ
¼ þ110:4 (c 0.064, CH2Cl2); IR (KBr)
m 3068, 3017,
2961, 2943, 2867, 1648 (NC@O), 1591, 1156, 1132, 766, 678,
655 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.82–0.95 (m, 2H, H5ax
,
H4 ), 4.80 (d, J = 10.2 Hz, 1H, H2), 5.30 (d, J = 2.2 Hz, 1H, H5 ), 7.11
0
0
6ax), 0.95 (d, J = 6.6 Hz, 3H, CH3–C7), 1.03 (s, 3H, CH3eq–C4), 1.09
(q, J = 11.8 Hz, 1H, H8ax), 1.17 (d, J = 6.6 Hz, 3H, (CH3)2CH–N), 1.20
(d, J = 6.6 Hz, 3H, (CH3)2CH–N), 1.22 (s, 3H, CH3ax–C4), 1.26 (d,
J = 6.6 Hz, 3H, (CH3)2CH–N), 1.28 (d, J = 6.6 Hz, 3H, (CH3)2CH–N),
1.40–1.53 (m, 1H, H7), 1.55 (bt, J = 11.1 Hz, 1H, H10), 1.62 (d app.,
J = 11.2 Hz, 1H, H5eq), 1.68–1.77 (m, 1H, H6eq), 1.85 (d app.,
J = 12.6 Hz, 1H, H8eq), 3.34 (sept. J = 6.9 Hz, 1H, N–CH–(CH3)2),
3.51 (td, J = 10.9, 4.1 Hz, 1H, H9), 3.98 (AB-d, J = 18.1 Hz, 1H,
NCH2Ph), 4.08 (AB-d, J = 18.1 Hz, 1H, NCH2Ph), 4.67–4.53 (m, 3H,
(t, J = 7.4 Hz, 1H, HNC-p-Ph), 7.23 (t, J = 7.4 Hz, 2H, HNC-m-Ph), 7.31–
0
0 -o-
7.39 (m, 5H, HNC-o-Ph
,
3 -m,p-P), 7.82 (dd., J = 7.1, 2.5 Hz, 2H, H3
Ph); 13C NMR (CDCl3, 125 MHz):
d 15.34 (CH3ax–C4), 19.77
((CH3)2CH–N), 20.08 ((CH3)2CH–N), 20.44 ((CH3)2CH–N), 20.79
((CH3)2CH–N), 22.10 (CH3–C7), 24.94 (CH2, C5), 27.35 (CH3eq–C4),
31.10 (CH, C7), 35.31 (CH2, C6), 41.24 (CH2, C8), 44.69 (CH,
C10 + NCH2Ph), 45.84 (N–CH–(CH3)2), 48.91 (N–CH–(CH3)2), 51.59
0
00
(CH, C4 ), 57.89 (Cq, C4), 76.82 (CH, C9), 82.12 (CH, C5 ), 87.68 (CH,
C2), 126.49 (CH, CNC-p-Ph), 127.57 (2CH, CPh), 128.22 (2CH, CNC-m-
0
0
0
0
H5 ,2 + N–CH–(CH3)2), 4.80 (d, J = 3.6 Hz, 1H, H4 ), 7.17 (t,
J = 6.9 Hz, 1H, HNC-p-Ph), 7.30 (t, J = 7.4 Hz, 2H, HNC-m-Ph), 7.33–
Ph), 128. (2CH, C3 -o-Ph), 129.45 (2CH, CPh), 129.64 (CH, C3 -p-Ph),
0
129.86 (Cq, CPh), 142.30 (Cq, CPh), 161.22 (Cq, C3 ), 165.34 (Cq,
0
7.37 (m, 3H, H3 -m,p-Ph), 7.51 (d, J = 7.4 Hz, 2H, HNC-o-Ph), 7.62 (dd,
C@O); Anal. Calcd for C34H47N3O3: C, 74.83; H, 8.68; N, 7.70. Found:
C, 74.79; H, 8.69; N, 7.71.
J = 6.6, 3.0 Hz, 2H, H3 -o-Ph); 13C NMR (CDCl3, 125 MHz): d 20.07
0
(CH3ax–C4), 20.32 (CH3, (CH3)2CH–N), 20.56 (CH3, (CH3)2CH–N),
20.67 (CH3, (CH3)2CH–N), 20.92 (CH3, (CH3)2CH–N), 22.29 (CH3–
C7), 24.85 (CH2, C5), 29.67 (CH3eq–C4), 31.25 (CH, C7), 34.97 (CH2,
C6), 41.20 (CH2, C8), 45.90 (CH, (N–CH–(CH3)2), 46.12 (NCH2Ph),
4.2.2.5. (ꢀ)-(2S,40R,50R,7R,9R,10S)-3-(Benzyl)-2-(30,50-diphenyl-
4,5-dihydroisoxazol-4-yl)-4,4,7-trimethyloctahydro-2H-1,3-ben-
zoxazine 9g, its diastereomer (+)-(400S,50S)-6g and regioisomers
(+)-(2S,7R,9R,10S)-3-(benzyl)-2-4S,5S-(30,50-diphenyl-4,5-dihydroi-
soxazol-4-yl)-4,4,7-trimethyloctahydro-2H-1,3-benzoxazine 7g
and (ꢀ)-(40R,50R)-8g. Using general cycloaddition procedure A:
0
46.35 (CH, C10), 48.30 (CH, N–CH–(CH3)2), 55.51 (CH, C4 ), 57.37
0
(Cq, C4), 76.74 (CH, C9), 84.58 (CH, C5 ), 87.05 (CH, C2), 126.82
(CH, CNC-p-Ph), 127.00 (2CH, CPh), 127.50 (2CH, CPh), 128.08 (2CH,
0
CPh), 128.55 (2CH, CPh), 129.78 (CH, C3 -p-Ph), 130.47 (Cq, CPh),
To a solution of trans-benzoxazine 2g (76.0 mg, 0.20 mmol,
0
142.94 (Cq, CPh), 156.00 (Cq, C3 ), 167.38 (Cq, C@O); Anal. Calcd
1 equiv) and triethylamine (0.563 mL, 0.410 g, 4.1 mmol, 20 equiv)
in CH2Cl2 (2 mL) was added phenyloximoyl chloride (0.155 g,
1.0 mmol, 5 equiv) and the mixture was brought to reflux. The
crude products were separated sequentially by chromatography;
that is, firstly, cycloadduct 8g was isolated using petrol–Et2O
(9:1); and then 9g was isolated as was some of 7g using petrol–
Et2O (7:3). The final fractions, that is, 7g and 6g were isolated using
petrol–CH2Cl2 (3:7). The isolated yield for all cycloadducts was
52.0 mg (52%). The isomeric ratio was determined by integration
for C34H47N3O3: C, 74.83; H, 8.68; N, 7.70. Found: C, 74.81; H,
8.67; N, 7.68.
Data for 7e. Yield = 20.4 mg (30%); Yellow oil; Rf = 0.41 (100%
CH2Cl2); ½a 2D3
ꢂ
¼ þ248:3 (c 0.202, CH2Cl2); IR (KBr)
m 3062, 3018,
2965, 2926, 2869, 1652 (NC@O), 1610 (C@N), 1168, 1127, 763,
687, 658 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.91 (d, J = 6.1 Hz,
), 0.95 (50%, d, J = 6.7 Hz,
3H, CH3–C7), 0.83–0.95 (m, 2H, H5ax 6ax
,
6H, (CH3)2CH–N), 1.00 (s, 3H, CH3eq–C4), 1.03 (s, 3H, CH3ax–C4),
1.05 (q, J = 12.1 Hz, 1H, H8ax), 1.16 (50%, d, J = 6.7 Hz, 6H,
(CH3)2CH–N), 1.22 (50%, d, J = 6.7 Hz, 6H, (CH3)2CH–N), 1.26 (50%,
d, J = 6.7 Hz, 6H, (CH3)2CH–N), 1.30–1.40 (m, 1H, H7), 1.49 (br t,
J = 11.1 Hz, 1H, H10), 1.64 (d app., 1H, J = 11.3 Hz, H5eq), 1.66 (d
app., 1H, J = 11.2 Hz, H6eq), 1.84 (d app., 1H, J = 12.4 Hz, H8eq),
3.17–3.28 (m, 2H, H9 + N–CH–(CH3)2), 3.80 (AB-d, J = 18.4 Hz, 1H,
NCH2Ph), 3.90 (AB-d, J = 18.4 Hz, 1H, NCH2Ph), 4.28 (sept.
J = 6.7 Hz, 1H, N–CH–(CH3)2), 4.74 (d, J = 2.0 Hz, 1H, H2), 4.81 (dd,
of the 13C NMR signals for C5 (84.93 (9g), 83.54 (7g), 90.75 (8g),
0
and 88.98 ppm (6g)). The results are shown in Table 2.
Data for 6g. Yield = 8.0 mg (8%); Yellow oil; Rf = 0.62 (CH2Cl2);
½
a 2D3
ꢂ
¼ þ170:3 (c 0.052, CH2Cl2); IR (film)
2919, 2861, 1594 (C@N), 1491, 1460, 1070, 931, 719, 690,
674 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 0.97 (d, J = 7.1 Hz, 3H,
CH3–C7), 0.96–1.02 (m, 2H, H5ax 6ax), 1.03 (s, 3H, CH3eq–C4), 1.13
m 3079, 3021, 2978,
;
,
(q, J = 11.7 Hz, 1H, H8ax), 1.26 (s, 3H, CH3ax–C4), 1.47–1.56 (m, 1H,
H7), 1.57 (t, J = 10.7 Hz, 1H, H10), 1.74 (d app., J = 11.0 Hz, 1H,
H5eq), 1.73 (d app., J = 8.2 Hz, 1H, H6eq), 1.98 (d app., J = 11.7 Hz,
1H, H8eq), 3.61 (td, J = 10.4, 3.9 Hz, 1H, H9), 3.84 (AB-d,
J = 18.0 Hz, 1H, NCH2Ph), 4.06 (AB-d, J = 18.0 Hz, 1H, NCH2Ph),
0
0
J = 4.0, 2.0 Hz, 1H, H4 ), 5.62 (d, J = 4.0 Hz, 1H, H5 ), 7.12 (t,
J = 7.1 Hz, 1H, HNC-p-Ph), 7.25 (t, J = 7.6 Hz, 2H, HNC-m-Ph), 7.36–
0
0 -o-
7.43 (m, 5H, HNC-o-Ph
,
3 -m,p-Ph), 7.73 (dd., J = 6.1, 3.3 Hz, 2H, H3
Ph); 13C NMR (CDCl3, 125 MHz): d 15.34 (CH3ax–C4), 19.81 (50%,
(CH3)2CH–N), 20.29 (50%, (CH3)2CH–N), 20.74 (50%, (CH3)2CH–N),
20.82 (50%, (CH3)2CH–N), 22.10 (CH3–C7), 24.94 (CH2, C5), 27.35
(CH3eq–C4), 31.06 (CH, C7), 34.31 (CH2, C6), 41.52 (CH2, C8), 45.91
(N–CH–(CH3)2), 47.68 (NCH2Ph), 48.72 (CH, C10), 48.84 (N–CH–
0
4.50 (dd, J = 7.3, 4.3 Hz, 1H, H5 ), 4.76 (d, J = 7.3 Hz, 1H, H2), 4.90
0
(d, J = 4.3 Hz, 1H, H4 ), 7.10 (t, J = 7.7 Hz, 1H, Hp-Ph), 7.13 (d,
0
J = 7.4 Hz, 2H, H4 -o-Ph), 7,16 (t, J = 7.7 Hz, 1H, Hp-Ph), 7.21 (t,
0
J = 7.0 Hz, 2H, HNC-m-Ph), 7.22 (t, J = 7.3 Hz, 2H, H3 -m-Ph), 7.27 (t,
0
0
(CH3)2), 53.19 (CH, C4 ), 57.95 (Cq, C4), 75.25 (CH, C9), 79.92 (CH,
0
J = 7.0 Hz, 2H, H4 -m-Ph), 7.30 (t, J = 7.4 Hz, 1H, + Hp-Ph) 7.43 (d,
J = 7.1 Hz, 2H, HNC-o-Ph), 7.59 (dd, J = 7.7, 2.2 Hz, 2H, HC3 -o-Ph), 13C
0
C5 ), 85.12 (CH, C2), 126.49 (CH, CNC-p-Ph), 127.40 (2CH, CPh),
0
127.50 (2CH, C3 -o-Ph), 128.16 (2CH, CPh), 128.61 (2CH, CPh),
NMR (CDCl3, 125 MHz): d 20.50 (CH3ax–C4), 22.29 (CH3–C7), 24.99
(CH2, C5), 27.03 (CH3eq–C4), 31.40 (CH, C7), 35.10 (CH2, C6), 41.27
0
129.66 (CH, C3 -p-Ph), 129.86 (Cq, CPh), 142.30 (Cq, CPh), 158.22 (Cq,
0
0
C3 ), 165.51 (Cq, C@O); Anal. Calcd for C34H47N3O3: C, 74.83; H,
(CH2, C8), 46.01 (CH, C10), 46.63 (NCH2Ph), 56.54 (CH, C4 ), 57.37
0
8.68; N, 7.70. Found: C, 74.77; H, 8.70; N, 7.70.
(Cq, C4), 76.70 (CH, C9), 87.69 (CH, C2), 88.98 (CH, C5 ), 125.88
Data for 9e. Yield = 10.3 mg (15%); Yellow oil; Rf = 0.23 (petrol–
(CH, Cp-Ph), 127.01 (2CH, CNC-o-Ph), 127.22 (CH, Cp-Ph), 127.35
Et2O, 4:1); ½a 2D3
ꢂ
¼ ꢀ212:7 (c 0.103, CH2Cl2); IR (KBr)
m
3059, 3021,
(2CH, C3 -o-Ph), 127.81 (2CH, C4 -o-Ph), 127.95 (2CH, CNC-m-Ph),
0
0
0
0
2969, 2938, 2874, 1658 (NC@O), 1598 (C@N), 1160, 1129, 760, 685,
128.45 (2CH, C4 -m-Ph), 128.95 (2CH, C3 -m-Ph), 129.03 (Cq, CPh),

2460
C. Poisson et al. / Tetrahedron: Asymmetry 20 (2009) 2447–2461
129.58 (CH, Cp-Ph), 139.28 (Cq, CPh), 143.12 (Cq, CPh), 158.11 (Cq,
H
6eq), 3.37 (td, J = 10.4, 3.8 Hz, 1H, H9), 3.74 (dd, J = 9.6, 1.4 Hz,
+
þ
0
0
C3 ); GC–MS (70 eV, m/z, %): 272 (M ꢀC15H12NO, 100), 91 (C7H7
,
1H, H4 ), 4.11 (AB d, J = 18.6 Hz, 1H, NCH2Ph), 4.27 (AB d,
J = 18.6 Hz, 1H, NCH2Ph), 4.96 (d, J = 9.6 Hz, 1H, H2), 5.69 (d,
J = 1.4 Hz, 1H, H5 ), 6.67 (d, J = 7.8 Hz, 2H, HC5 -o-Ph), 7.01 (t,
J = 7.6 Hz, 2H, H5 -m-Ph), 7.08 (t, J = 7.6 Hz, 1H, H5 -p-Ph), 7.16 (t,
J = 7.4 Hz, 1H, HNC-p-Ph), 7.28 (t, J = 7.6 Hz, 2H, HNC-m-Ph), 7.34–
85); FAB+ 495.2 (M+H+, 16), 272.1 (M+ꢀC15H12NO, 100), 91.1(8);
Anal. Calcd for C33H38N2O2: C, 80.13; H, 7.74; N, 5.66. Found: C,
80.13; H, 7.72; N, 5.66.
0
0
0
0
Data for 7g. Yield = 20.0 mg (20%). Yellow oil; Rf = 0.58 (85:15
petrol–Et2O); ½a D23
ꢂ
¼ þ136:3 (c 0.45, CH2Cl2); IR (film)
m
3076,
7.40 (m, 3H, H3 -m,p-Ph), 7.48 (d, J = 7.5 Hz, 2H, HNC-o-Ph), 7.84 (dd,
0
J = 7.6, 2.0, 2H, H3 -o-Ph); 13C NMR (CDCl3, 125 MHz): d 22.14
0
3021, 2987, 2931, 2859, 1593 (C@N), 1491, 1450, 1076, 937, 719,
690, 667 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 0.95 (d, J = 6.7 Hz,
(CH3–C7), 22.60 (CH3ax–C4), 24.88 (CH2, C5), 27.08 (CH3eq–C4),
3H, CH3–C7), 0.88–1.05 (m, 2H, 5ax, 6ax), 1.09 (s, 3H, CH3eq–C4),
1.15 (s, 3H, CH3ax–C4), 1.16 (q, J = 12.0 Hz, 1H, H8ax), 1.44–1.48
(m, 1H, H7), 1.48 (t, J = 11.2 Hz, 1H, H10), 1.61 (br d, J = 12.2 Hz,
1H, H5eq), 1.71 (d app., J = 12.2 Hz, 1H, H6eq), 1.99 (br d,
J = 12.0 Hz, 1H, H8eq), 3.45 (td, J = 10.4, 4.5 Hz, 1H, H9), 3.73 (dd,
31.18 (CH, C7), 35.12 (CH2, C6), 40.60 (CH2, C8), 44.98 (CH, C10),
0
46.30 (NCH2Ph), 57.61 (Cq, C4), 58.04 (CH, C4 ), 77.00 (CH, C9),
0
0
84.93 (CH, C5 ), 88.10 (CH, C2), 125.39 (2CH, C5 -o-Ph), 126.32 (CH,
0
CNC-p-Ph), 127.06 (2CH, CNC-o-Ph), 127.39 (CH, C5 -p-Ph), 127.73
0
0
(2CH, C5 -m-Ph), 128.07 (2CH, CNC-m-Ph), 128.11 (2CH, C3 -o-Ph),
0
0
0
J = 6.8, 1.9 Hz, 1H, H4 ), 3.83 (AB-d, J = 18.4 Hz, 1H, NCH2Ph), 3.86
128.38 (2CH, C3 -m-Ph), 129.40 (CH, C3 -p-Ph), 130.57 (Cq, CPh),
0
(AB-d, J = 18.4 Hz, 1H, NCH2Ph), 4.96 (br s, 1H, H2), 6.05 (d,
139.37 (Cq, CPh), 142.62 (Cq, CPh), 159.50 (Cq, C3 ); GC–MS (70 eV,
m/z, %): 272 (M+ꢀC15H12NO, 32): 106 (C7H6O+, 13): 91 (C7H7
,
þ
0
J = 6.8 Hz, 1H, H5 ), 7.00 (t, J = 7.1 Hz, 1H, Hp-Ph), 7.05 – 7.17 (m,
0
5H, HPh), 7.07 (d, J = 7.1 Hz, 2H, H5 -o-Ph), 7.09 (d, J = 6.1 Hz, 2H,
80): 77 (C6H5+, 100). Anal. Calcd for C33H38N2O2: C, 80.13; H,
7.74; N, 5.66. Found: C, 80.07; H, 7.76; N, 5.66.
0
HNC-o-Ph), 7.41–7.47 (m, 3H, H3 -m,p-Ph), 7.82 (d, J = 7.5 Hz, 2H,
H3 -o-Ph); 13C NMR (CDCl3, 125 MHz): d 20.02 (CH3ax–C4), 22.22
Crystallographic studies for 9g. The crystal 9g was recrystallized
in a dichloromethane–diisopropylether mixture and it belongs to
the chiral monoclinic P21 space group. The crystallographic data
0
(CH3–C7), 24.96 (CH2, C5), 27.07 (CH3, Ceq–C4), 31.28 (CH, C7),
35.02 (CH2, C6), 41.12 (CH2, C8), 46.24 (CH, C10), 47.53 (NCH2Ph),
0
0
57.73 (Cq, C4), 58.22 (CH, C4 ), 76.25 (CH, C9), 83.54 (CH, C5 ),
85.62 (CH, C2), 126.03 (CH, Cp-Ph), 126.36 (2CH, Co-Ph), 126.55
were measured with Cu Ka radiation and the results permitted
the determination of the absolute structure. The crystal 9g con-
tains two independent molecules, which are very similar, except
for a few torsion angles between the five-membered ring and the
phenyl group located on C30. The H atoms were refined normally
with isotropic displacement parameters. All the bond distances
and angles are normal and are available in the CIF.
0
(2CH, C o-Ph), 127.46 (2CH, C3 -o-Ph), 127.81 (CH, Cp-Ph), 128.02
(2CH, Cmo-Ph), 128.43 (2CH, Cmo-Ph), 128.63 (2CH, C3 -m-Ph), 129.32
(CH, C3 -p-Ph), 129.72 (Cq, CPh), 140.51 (Cq, CPh), 142.03 (Cq, CPh),
0
0
+
0
157.16 (Cq, C3 ). GC–MS (70 eV, m/z, %): 272 (M ꢀC15H12NO, 92);
106 (C7H6O+, 8.1); 91 (C7H7þ, 100); 77 (C6H5þ, 34). Anal. Calcd
for C33H38N2O2: C, 80.13; H, 7.74; N, 5.66. Found: C, 80.09; H,
7.75; N, 5.67.
Acknowledgements
Data for 8g. Yield = 6.0 mg (6%); Yellow oil; Rf = 0.41 (CH2Cl2);
½
a 2D3
ꢂ
¼ ꢀ149:9 (c 0.187, CH2Cl2); IR (film)
2939, 2865, 1589 (C@N), 1490, 1454, 1070, 930, 710, 696,
686 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 0.95 (d, J = 6.0 Hz, 3H,
CH3–C7), 0.93–1.02 (m, 2H, 5ax, 6ax), 1.08 (s, 3H, CH3eq–C4), 1.15
(q, J = 11.7 Hz, 1H, H8ax), 1.29 (s, 3H, CH3ax–C4), 1.45–1.55 (m, 1H,
H7), 1.57 (t, J = 11.0 Hz, 1H, H10), 1.60–1.67 (m, 1H, H5eq), 1.73 (d
app., J = 6.8 Hz, 1H, H6eq), 2.05 (d app., J = 11.7 Hz, 1H, H8eq), 3.61
(td, J = 10.5, 3.4 Hz, 1H, H9), 3.98 (AB-d, J = 18.5 Hz, 1H, NCH2Ph),
4.04 (AB-d, J = 18.5 Hz, 1H, NCH2Ph), 4.59 (dd, J = 7.0, 2.7 Hz, 1H,
m 3091, 3029, 2980,
We gratefully acknowledge Dr. Hoa Lethanh for carrying out the
500 MHz NMR 1- and 2D analyses and to You Buoy Gov for assis-
tance with the preparation of starting materials. Several 500 MHz
spectra were recorded at the Québec/Eastern Canada High Field
NMR Facility, supported by the Canada Foundation for Innovation,
Natural Science and Engineering Research Council of Canada
(NSERC), Québec ministère de la recherche en science et technolo-
gie, and McGill University grants. Special thanks to K. Walsh for
copyediting the manuscript. The authors acknowledge financial
support from NSERC and from FCAR Funds (Québec). Financial sup-
port was also provided by the UQAM Foundation.
;
0
0
H5 ), 4.69 (d, J = 2.7 Hz, 1H, H4 ), 4.76 (d, J = 7.0 Hz, 1H, H2), 6.69
(d, J = 7.7 Hz, 2H, H4 -o-Ph), 7.01 (t, J = 7.4 Hz, 2H, H4 -m-Ph), 7.05 (t,
0
0
J = 6.6 Hz, 1H,
H
p-Ph), 7.24 (t, J = 7.2 Hz, 1H, Hp-Ph), 7.28 (t,
0
J = 6.6 Hz, 2H, H3 -m-Ph), 7.33 (t app., J = 7.3 Hz, 3H, Hm,p-Ph), 7.44
(d, J = 7.0 Hz, 2H, Ho-Ph), 7.58 (dd, J = 7.4, 1.7 Hz, 2H, Ho-Ph); 13C
References
NMR (CDCl3, 125 MHz):
24.95 (CH2, C5), 26.44 (CH3eq–C4), 31.36 (CH, C7), 35.12 (CH2, C6),
41.22 (CH2, C8), 44.96 (CH, C10), 47.04 (NCH2Ph), 57.72 (CH, C4 ),
57.75 (Cq, C4), 76.87 (CH, C9), 88.06 (CH, C2), 90.75 (CH, C5 ),
126.27 (CH, CPh), 127.07 (2CH, CPh), 127.10 (2CH, CPh), 127.13
(CH, CPh), 127.23 (2CH, CPh), 128.18 (2CH, CPh), 128.51 (2CH, CPh),
128.70 (2CH, CPh), 128.87 (CH, CPh), 129.71 (Cq, CPh), 138.25 (Cq,
d 22.15 (CH3–C7), 22.23 (CH3ax–C4),
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CPh), 142.82 (Cq, CPh), 159.58 (Cq, C3 ), GC–MS (70 eV, m/z, %): 272
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ꢂ
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