Peracid-induced ring opening of some hexahydro-2H-isoxazolo[2,3-a]pyridines to second-generation cyclic aldonitrones

Article abstract of DOI:10.1016/j.tet.2009.07.058

A study of the stereo- and face selectivity of the cycloaddition reactions of several mono- and disubstituted alkenes with 4-hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. The addition reactions have displayed a very high degree of

Full text of DOI:10.1016/j.tet.2009.07.058

Tetrahedron 65 (2009) 8231–8243
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Tetrahedron
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Peracid-induced ring opening of some hexahydro-2H-isoxazolo[2,3-a]pyridines
to second-generation cyclic aldonitrones
*
Basem A. Moosa, Shaikh A. Ali
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A study of the stereo- and face selectivity of the cycloaddition reactions of several mono- and di-
substituted alkenes with 4-hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. The
addition reactions have displayed a very high degree of face selectivity in the range 13-48:1. Use of
dimethyl methylenemalonate as a protective group in nitrone cycloaddition reactions has been demon-
strated. The invertomeric analysis revealed that the bicyclic cycloadducts remain predominantly as the
cis-fused isomer, which leads to the formation of synthetically important second-generation cyclic al-
donitrones via peracid oxidation. One interesting finding was that treatment of the cycloadducts with
two equivalents of peracid afforded the cyclic N-hydroxy lactams, presumably via further oxidation of the
aldonitrones. The piperidine ring has been elaborated by cycloaddition reaction of the second-generation
nitrones with several alkenes, which in most cases gave the cycloadducts in a stereoselective manner.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 20 April 2009
Received in revised form 28 June 2009
Accepted 23 July 2009
Available online 29 July 2009
Keywords:
Nitrone cycloddition
Stereoselectivity
Face selectiviy
Peracid oxidation
Conformational analysis
R1
R1
H
H
1. Introduction
R1
CI
NI
5
5
5
H
R2
N
O
1,3-Dipolar cycloaddition reaction of nitrones with alkenes has
become an important tool in the synthesis of natural products.1 The
efficacy of these additions lies on the remarkable selectivity in the
incorporation of multiple stereocenters in a single step.1,2 The cyclic
nitrones have been shown to exhibit greater stereoselectivity and
reactivity compared to their acyclic counterparts as a result of the
former existing in the E form.3,4 The pyrrolidine- and piperidine-
based alkaloids, which are widespread in nature, can be accessed
through the cycloaddition reaction of five- and six-membered cyclic
nitrones, respectively.1 Nitrones generated by peracid-induced ring
opening of the cycloaddition products derived from cyclic nitrones
marked the beginning of the utilization of the second-generation of
cyclic nitrones (Scheme 1).5 However, the proper utilization of these
second-generation nitrones has been hampered by the lack of se-
lectivity6 in the oxidation process in the 6/5-fused isoxazolidines 1
(R1¼H), where the major or sole trans invertomer leads to the
synthetically less important ketonitrone 3 either as the major or
sole product. Orientation of the nitrogen lone pair and the trans/cis
invertomer ratio dictate the regiochemical outcome of the oxida-
tion process. The higher activation barrier to nitrogen inversion
N
O
N
O
2
B
R2
A
R2
1-cis-invertomers
1: trans-invertomer
ArCO3H
ArCO3H
R1
R1
4
H
6
N
O
N
O
R2
R2
HO
HO
2: Aldonitrone
Isomer
3: Ketonitrone
Composition
1-cis/1-trans
2/3
x:y
~x:y
H
R
RCO3H
(D
G#, w70 kJ/mol)6b than the oxidation process does not permit the
N
O
N
OH
Curtin-Hammett principle7 to apply; as such the trans and cis
O
R
4-cis-invertomer
5: Aldonitrone
(Exclusive)
(Exclusive)
* Corresponding author. Tel.: þ966 3 860 3830; fax: þ966 3 860 4277.
E-mail address: shaikh@kfupm.edu.sa (S.A. Ali).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.058

8232
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
invertomers in a ratio of x:y afford the keto- and aldo-nitrones,
respectively, in a similar ratio. However, the corresponding 5/5-
fused isoxazolidines 4, which exist only as the cis invertomers, give
aldonitrones 5 exclusively (Scheme 1).8
diasteromers 10a and 12a was obtained in a w13:1 ratio. The
configuration of the major adduct 10a was based on the sterically
favorable exo approach (Scheme 2) of the Bu group from the less
hindered face (i.e.,
of the alkene afforded the adduct 12a. We are unable to detect the
formation of the stereoisomers 11a and 13a arising from the -endo
and -endo mode of approach, respectively, by the alkene. Likewise,
a face) of the nitrone, while the b-exo approach
Note that the 6/5-fused isoxazolidines 1 (R1¼H) remain in the
trans-form as the major or sole invertomer (Scheme 1). In our
continuing efforts to generate the synthetically important aldoni-
trones 2 in greater proportions, we realized that the proportion of
the cis invertomer has to be increased at the expense of its trans
counterpart. Attachment of an ester functionality (R1¼CO2R) via its
sp2 hybridized carbon at C(5) in 1 did bring about a moderate
change in the composition favoring the cis invertomer A as a result
of the equatorially oriented CO2R group.9 We anticipated that a C(5)
substituent attached through a sp3 hybridized carbon (having
a larger steric size than its sp2 counterpart) would motivate the ring
further in the direction of the cis invertomer A. Hence we report, for
the first time, the face- and stereoselectivity of cycloaddition of
a new cyclic nitrone 8 (Scheme 2) having a hydroxymethyl sub-
stituent at C(4) with various alkenes. The invertomer analysis and
peracid-induced ring opening of the resultant cycloadducts may
lead to the second-generation cyclic aldonitrones (Scheme 1) more
selectively. The study would give an opportunity to examine the face
selectivity associated with cycloaddition of the second-generation
nitrones 4,6-disubstitued-3,4,5,6-tetrahydropyridine 1-oxides 2.
a
b
the addition reaction with styrene (9b) led to the formation of the
cycloadducts 10b–13b in a ratio of 93:5:2:w0, thereby ascertaining
again the highly face selective (98:2) nature of the cycloadditions.
Such a high selectivity is surprising since the C(4)-CH2OH group
imparting the facial difference is positioned at the furthest point
from the nitrone functionality in 8. The face selectivitiy of the
nitrone 8 was found to be better than a nitrone containing C(4)-
CO2Bu group (attached to the ring through a sp2 carbon).9 In order
to confirm the stereochemistry of the cycloadducts, the compounds
14, 15a, and 15b having known configurations,9 were converted
into 10b, 12a, and 12b, respectively (Scheme 2).
The addition of disubstituted alkenes methyl crotonate (16) and
methyl methacrylate (21) to the nitrone 8 also demonstrated very
high face selectivity (97:3) in each case (Scheme 3). In both cases,
the major adducts (i.e., 17 and 22) were obtained via a-exo (Me)
approach. The stereochemistry is based on the precedent in the
lietrature9,11dthe major adducts were obtained via an endo-ori-
ented methoxycarbonyl group in the transition state as a result of
a favorable secondary orbital interaction.
OH
OH
OH
In order to study the effect of increasing the steric bulk of the
C(4) substituent in nitrone 8, the nitrone was first protected by
reacting with dimethyl methylenemalonate (26) to give a regioiso-
meric mixture of 27a and 28a, which upon silylation afforded 27b
and 28b (Scheme 4). Similar electronic controlled reversal in the
regioselections is known3d in the addition reaction of the highly
electron deficient alkene 26. The nitrone functionality is protected
in the sense that the cycloadducts derived from the highly electron
deficient alkene readily undergo cycloreversion to the starting
reactants.3d Thus upon thermolysis at 90 ꢀC, either 27b or 28b was
changed to a mixture of 27b and 28b in an equilibrium ratio of 3:1.
When the thermolysis was carried out in the presence of styrene,
the intervening nitrone 29 was trapped by undergoing stereo-
selctive cycloaddition to give a mixture of adducts 30–33 in a ratio
of 94:3:3:0. The exercise has thus demonstrated a suitable way to
protect a nitrone functionality and also paved the way to examine
the effect of changing the substituent C(4)-CH2OH in 8 to C(4)-
CH2OSitBuMe2 in 29 on the stereoselection and composition of
nitrogen invertomers of the cycloadducts (vide infra).
4
H2O2, SeO2
NaBH4
H
R
HgO
9
N
O
N
H
N
OH
7
(Racemic) 8
6
OH
OH
OH
OH
5
4
H
H
+
H
R
H
+
+
7
3a
2
N
N
N
N
3
2
2
2
O
O
O
O
R
R
R
α-exo
10
α-endo
11
Ratio
β -exo
12
%Yield
β -endo
13
10 / 11 / 12 / 13 10 + 11 +12 +13
a, R = Bu
93 :~0 : 7 : ~0
78%
85%
H
OH
b, R1= R = Ph 93 : 5 : 2 : ~0
β-exo
R
CO2Bu
CO2Bu
H
H
5
N
LiAlH4
LiAlH4
H
H
10b
12
O
The presence of –N–O– moiety in an organic molecule has
a distinctive place in conformational analysis;12–14 oxygen being
next to nitrogen raises the barrier to nitrogen inversion to such an
extent that the individual invertomers can be identified by NMR
spectroscopy.15 Orientation of the nitrogen lone pair with respect to
the bridgehead hydrogen and the trans-/cis-fused invertomer ratio
dictates the regiochemical outcome of the peracid oxidation
process leading to the second-generation nitrones (vide supra)
(Scheme 1). Therefore, the proper utilization of these second-gen-
eration nitrones requires prior information on the stereochemistry
of the ring fusion. We have examined the conformational aspects as
well as composition of the nitrogen invertomers by NMR spec-
troscopy. The 13C chemical shifts in CDCl3 were assigned on the
basis of DEPT experiment results, general chemical shifts argu-
ments, and consideration of substituent effects, and are given in
Table 1. At ambient temperature, the 1H and 13C NMR spectra of
these compounds show well separated signals for the two inver-
tomers in CDCl3. Integration of the relevant peaks gives the
population trends in these systems (Table 1, 3rd column).
N
N
a, R = Bu
b, R = Ph
H
2
O
14
O
15
Ph
R
R
α-exo
Scheme 2.
2. Results and discussion
The synthesis of nitrone 8 is outlined in Scheme 2. It was pre-
sumed at the outset that preparation of the nitrone by direct oxi-
dation of the secondary amine 9 will be a trivial matter. However,
we were unable to obtain the nitrone by the procedure of Mur-
ahashi et al.10 using hydrogen peroxide oxidation mediated by se-
lenium dioxide either in acetone or methanol. The oxidation
process gave a complicated mixture of products (presumably
a mixture of 7, 8, and other products), which upon treatment with
NaBH4 afforded the hydroxylamine 7. The required nitrone 8 was
then prepared by mercury(II) oxide oxidation of 7 (Scheme 2).
Next, we pursued the addition reaction of nitrone 8 with various
alkenes. The addition of monosubstituted alkene 1-hexene (9a) was
found to be stereo-, as well as highly faceselective; a mixture of
For the 6/5-fused carbocyclic compound 34, the
2.09 kJ/mol at 25 ꢀC favors the trans- over the cis-fused isomer
D
Gꢀ value of

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
8233
OH
OH
OH
OH
MeO2C
5
4
H
+
H
+
H
H
+
Me
16
7
CO2Me
CO2Me
CO2Me
CO2Me
3a
2
N
N
N
N
2
2
2
O
O
O
O
Me
Me
Me
Me
α
-exo (Me)
-endo (Me)
-exo (Me)
β
-endo (Me)
α
β
17
18
19
20
Ratio
17 / 18 / 19 / 20 17 + 18 + 19 + 20
81 : 16 : 3 : ~0 85%
% Yield
8
OH
OH
OH
OH
H
CO2Me
Me
5
H
H
+
H
+
+
3a
N
N
N
N
3
2
2
2
2
21
O
O
O
O
CO2Me
CO2Me
Me
CO2Me
Me
Me
-endo (Me)
23
Me
CO2Me
α
α
β
-exo (Me)
-exo (Me)
22
-endo (Me)
β
24
25
Ratio
22 / 23 / 24/ 25 22 + 23 + 24 + 25
% Yield
92 : 5 : 3 : ~0
92%
Scheme 3.
the 5- position are also reported to favor, in most cases, the trans
invertomers.6c,15,16 The currently prepared major isoxazolidines,
90 o
C
OH
R
5
R
obtained by
a-mode of attack, can, in principle, exist in three
MeO2C
CO2Me
different chair conformations: the cis-fused pair A and B and the
trans isomer C (Scheme 5). While the cis pair is in rapid equi-
librium by chair inversion (CI), one of the cis conformers B is
converted into the trans invertomer C by a relatively slow nitro-
gen inversion process (NI). The NMR spectra, both 1H and 13C, for
some of the compounds show peaks due to two distinct isomers,
a major and a minor invertomer. With respect to the six-mem-
bered ring, both cis-fused A and trans-fused C have one axial
substituent at C(3a) and C(5), respectively, while cis-fused B has
two energetically destabilizing axial substituents at C(5) and N. As
5
+
4
H
H
7
26
CO2Me
CO2Me
3a
2
3a
N
N
O
N
2
O
O
CO2Me
CO2Me
(Racemic) 8
27
tBuMe2SiCl, imidazole
28
a, R = CH2OH
t
b, R = CH2OSiMe2 Bu
t
OSiMe2 Bu
such the major cycloadducts, obtained by an
expected to remain as A and/or C. For the reasons discussed
above, the minor isoxazolidines, obtained by -mode of attack,
a-mode of attack, are
90 °C
90 °C
26
28b
27b
+
N
O
b
should have an overwhelming preference for the trans-fused
invertomer F since it is free of any destabilizing axial group. The
conformer D having two axial substituents is anticipated to be the
least favored. Note that our objective is to have the isoxazolidines
exist as the cis-fused invertomer in order to get the desired sec-
ond-generation aldonitrones via peracid oxidation (vide supra).
While this may not be achieved in the case of the trans-fused
invertomer F, the overwhelmingly predominant cycloaddition
29
100 oC
H
Ph
9b
t
t
t
t
OSiMe2 Bu
OSiMe2 Bu
OSiMe2 Bu
OSiMe2 Bu
5
products (via an a-mode of attack), are, however, expected to be
in the desired cis-form A.
4
H
H
H
+
+
H
+
7
3a
N
N
N
N
3
Isoxazolidine 14 (Scheme 2) has been shown to exist in a cis-
A/trans-C ratio of 55:45 (Scheme 5).17 A comparison between
compound 14 and 10b (Scheme 2), both having a phenyl group at
C(2), may be helpful in identifying the stereochemistry of the
ring fusion in the latter. Since the axially disposed CH2OH sub-
stituent at C(5) of 10b, being larger in size than the ester sub-
stituent in 14, is expected to destabilize its trans 10-C as well as
cis 10-B conformers; the relative proportion of cis-10b-A is an-
ticipated to increase compared to that of compound 14 (Scheme
5). As evident from Table 1, this is indeed the case; the cis-A
isomer becomes the overwhelmingly major invertomer for all
2
2
2
2
O
O
O
O
Ph
Ph
Ph
Ph
α
α
-exo
-endo
-exo
β
-endo
β
30
31
Ratio
32
33
% Yield
30 + 31 + 32 + 33
30 / 31 / 32 / 33
94 : 3 : 3 : ~0
83%
Scheme 4.
(Scheme 5).16 Both 35 (the heterocyclic counterpart of 34) and its
the cycloadducts obtained via
a-mode of attack, except 27b
derivatives having substituents at the 2-, 3-, and an ester group at
(Scheme 4), which would be destabilized in cis-A as a result of

8234
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
Table 1
13C NMR chemical shifts of compounds studied in CDCl3 at þ25 ꢀ
C
Compound
% Invertomera
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
via -mode
a
10a
10b
11b
17
cis-A
trans-C
cis-A
trans-C
cis-A
trans-C
trans-C
cis-A
88
12
90
10
84
16
65
35
Solo
80
20
Solo
84
16
84
16
83
17
88
77.3
76.1
78.9
77.7
81.7
78.9
75.2
75.7
80.2
84.3
80.0
71.8
87.0
83.3
78.8
77.7
77.3
76.1
78.8
77.7
35.4
40.1
38.8
43.2
38.3
44.2
57.1
56.7
54.4
39.6
44.9
67.0
38.1
42.7
38.9
43.3
35.3
40.0
38.8
43.1
59.4
61.2
59.9
61.7
60.7
62.5
62.9
62.4
64.0
59.9
61.6
71.6
60.3
61.7
60.0
61.9
59.1
61.0
59.7
61.6
28.1
30.1
28.3
30.1
28.4
29.8
27.1
26.5
27.4
27.9
29.5
29.3
27.7
29.7
28.3
30.2
28.3
30.4
28.3
30.5
32.5
34.0
32.6
34.0
33.0
33.9
33.6
32.7
32.9
32.6
33.7
38.3
32.7
33.3
32.7
33.8
29.5
30.5
29.6
30.5
27.6
25.6
27.6
25.7
27.7
25.7
25.2
26.0
27.2
27.5
25.3
27.3
27.6
25.3
27.7
25.6
27.6
25.8
27.6
25.9
49.1
50.7
49.4
51.1
51.9
51.3
51.3
48.6
52.3
50.2
51.2
54.5
50.9
51.4
49.5
51.2
48.8
50.7
49.1
50.9
18
22
cis-A
cis-A
trans-C
trans-C
cis-A
trans-C
cis-A
trans-C
cis-A
trans-C
cis-A
27b
28b
30
36a
36b
trans-C
12
via
b
-mode
12a
12b
24
trans-F
trans-F
trans-F
Solo
Solo
Solo
76.6
78.2
80.5
39.8
42.8
44.6
65.7
66.2
66.1
32.1
32.1
31.6
38.7
38.6
38.4
27.9
27.9
27.5
53.9
54.0
54.1
a
Refers to invertomer A, C or F in Scheme 5.
3
5
2
N
O
Major Adducts
(via -mode of attack)
34
35
α
R5O
R5O
H
H
3a
R4
R5O
4
3
R4
R3
R1
R3
4
CI
NI
5
R1
H
5
N
O
R4
N
O
7
N
7
3a
6
2
O
2
R2
R3
R1
R2
R2
A (cis-fused)
Favoured
B (cis-fused)
C (trans-fused)
Minor Adducts
H
H
3a
R4
R2
(via
β
-mode of attack)
5
3
R5O
CI
R1
R5O
NI
R4
R3
4
R1
H
N
O
R4
N
O
7
N
6
2
R5O
R1
O
1 R3
R2
R2
R
D (cis-fused)
E (cis-fused)
F (trans-fused)
Favoured
Scheme 5.
placement of an axially oriented tertiary substituent (akin to a t-
butyl group) at C3a. The correctness of the assignment of the
configuration is based on the rationale detailed in the sub-
sequent discussion.
from table. In cis-A all the carbons appeared at lower frequency
except C-2 and C-6.
Where only one invertomer is observed as in the cases of 12a,
12b, 24, 27b (the minor products obtained via b-mode of attack),
The C(2)H of the cis invertomers of 6/5-fused isoxazolidines is
known to appear at higher frequency compared to its trans inver-
tomers.17,18 This is indeed found to be the case for the current
compounds in CDCl3; the C(2)H of the cis-A invertomers invariably
appeared at higher frequency compared to their trans-C isomers
(Scheme 5). The axially disposed C(3a)H of trans-C, as expected,
appeared at lower frequency in comparison to the corresponding
equatorially disposed proton of cis-A (See Experimental). The axial
the C(2), C(3), C(3a), and C(7) chemical shifts match those of the
trans-C invertomers, and we can therefore conclude that these
compounds exist almost exclusively in the trans-F conformation
(Scheme 5) (Table 1). The presence of 1,3-diaxial interaction ex-
cludes the participation of conformer cis-D in the equilibration
process (Scheme 5). In the absence of D#E equilibration, the sta-
bilization arising out of entropy gain will be lost, as such the all
equatorial trans invertomer F is expected to be overwhelmingly
favored over cis-E.
substituent at C(3a) of the cis conformer A will have g–gauche in-
teractions with C(5) and C(7) and as such these carbon signals are
To get an idea about the magnitude of nitrogen inversion bar-
riers in these compounds, 10b was selected as a representative
expected19 to be shielded in comparison to the trans-C as is evident

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
OAc OAc
8235
OAc
MCPBA
(1 Equiv)
4
5
4
4
H
H
2
Ac2O
7
2
6
6
+
10
3a
2
+ 20 °C
N
N
O
N
O
3
O
R
R
R
HO
HO
36
MCPBA
(2 Equiv)
- 40 °C
37
38
OAc
H
a, R = Bu
b, R = Ph
4
2
6
Invertomer
Composition Nitrone
Composition
38
+
O
N
36a-cis/36a-trans
36b-cis/36b-trans
83:17
88:12
37a/38a
37b/38b
80:20
82:18
OH
HO
R
39
OAc
OAc
OAc
B:
H
H
H
H
H
39
O
N
O
N
O
N
O
O
O
O
R
O
R
R
O
H
O
H
O
H
Ar
37
Scheme 6.
example. The nitrogen inversion barrier,
D
G#, was determined to be
and ketonitrone (38a) in a 80:20 ratio. For the corresponding ring
opening reaction of the isoxazolidine 36b, having the cis and trans
invertomers in a 88:12 ratio, a mixture of the aldo- (37b) and
ketonitrone (38b) in a ratio of 82:18 was obtained. It is indeed
gratifying to see the ratio in favor of the synthetically more useful
second-generation aldonitrones. One interesting finding was that
the treatment of the isoxazolidines 36 with two equivalents of
MCPBA at ꢁ40 ꢀC afforded the N-hydroxyamides 39, presumably
via further oxidation of the aldonitrones with peracid as shown in
Scheme 6. The formation of amide thus paves the way to obtain
acyclic compounds from the cyclic piperidine system via hydrolysis
of the amide functionality in 39.
Next, we explored the cycloaddition reaction of the second-
generation nitrones 37 and 38 with the alkenes 9. Under the re-
action conditions, the ketonitrones remained inactive while the
aldonitrones 37 afforded the cycloadducts 40 and 41 (Scheme 7).
While the aldonitrone 37a afforded 40a and 41a in a 2:1 ratio, the
71.3 kJ/mol for a major to minor inversion at 35 ꢀC in toluene-d8.
Simulations of exchange-affected proton spectra, corresponding to
two non-coupled sites exchange with unequal populations, were
carried out as described elsewhere.17 For 10b in toluene-d6, the
C(2)H signals at
d 5.42 (major, dd, J 1.7, 4.9 Hz) and 5.28 ppm (mi-
nor) in a 83:17 ratio at þ30 ꢀC were utilized. For such a high free
energy of activation barrier, the extremely fast peracid oxidation
process (presumably with a lower activation barrier) is not expec-
ted to follow the Curtin–Hammett principle;7 as such the trans and
cis invertomers in a ratio of x:y should afford the keto- and aldo-
nitrones, respectively, in a similar ratio. In order to ascertain the
correctness of the assignment of the configuration of the inver-
tomers, we carried out the peracid-induced ring opening of iso-
xazolidines 36a and 36b (Scheme 6). The isoxazolidine 36a, having
the cis and trans invertomers in a 83:17 ratio, on treatment with
m-chloroperbenzoic acid (MCPBA) gave a mixture of the aldo- (37a)
OAc
OAc
OH
OH
OAc
5
4
3a
N
4
H
H
H
H
H
H
H
H
7
OH -
H
+
R
6
N
N
N
+
38
+
3
N
9
O
HO
O
HO
O
HO
O
HO
R
R
Ph
Ph
Ph
R
R
Ph
O
HO
R
41
44
45
37
40
a, R = Bu
b, R = Ph
Zn/HOAc
OH
Zn/HOAc
OH
Zn/HOAc
OAc
Zn/HOAc
OAc
Me
CO2Me
OAc
21
5
4
4
H
H
H
H
H
H
H
H
2
6
H
H
3a
7
N
N
H
N
N
+
+
H
H
H
N
3
Bu
Bu
Ph
Ph
Bu
Bu
Ph
Ph
O O
H H
O O
O O
H H
O O
H H
O
Me
Bu
H H
HO
CO2Me
43
46
47
42
48
Scheme 7.

8236
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
trans-3a,7- invertomers
H
H
3a
5
5
3
R
R
AcO
AcO
5
Bu
H
NI
CI
O
7
N
R
N
O
N
7
7
2
3a
AcO
Bu
O
2
Bu
R = H; 12a-A
R = CH2CH(OH)Bu
40a-A (~0%)
(~0%)
12a-C (~100%)
40a-C (85%)
12a-B (~0%)
40a-B (15%)
cis-3a,7- invertomers
AcO
AcO
H
H
AcO
3
3a
5
5
NI
CI
H
5
Bu
N
O
N
N
7
7
7
3a
2
R
O
R
Bu
2
R
O
Bu
R = H; 10a-A
R = CH2CH(OH)Bu
41a-A (~0%)
(~88%)
10a-C (~12%)
41a-C (~100%)
10a-B (~0%)
41a-B (~0%)
Scheme 8.
corresponding ratio for 40b and 41b was found to be 1:1.5. For
the addition of 1-hexene (9a) the face selectivity is thus dictated by
the steric influence of the substituent at C(6) so as to force the al-
88:12 (vide supra), the presence of two axial groups in A and B
forces the 3a,7-cis substituted adduct 41a to remain exclusively in
the invertomeric form of 41a-C (Scheme 8). While the adduct 12a
remained exclusively in the invertomeric form of 12a-C (vide su-
pra), the 3a,7-cis substituted adduct 40a remained in the inverto-
kene to approach from the
b-face of the nitrone, while styrene (9b)
prefers to approach the nitrone from its
a
-face. The face selectivity
is modest in these additions; however, we are unable to rationalize
the difference in the face selectivity observed in the addition re-
actions of these two alkenes. The stereochemistry of these addition
reactions was confirmed by chemical conversion into the ring
opened products by cleaving the N–O bond of the cycloadducts
with zinc/acetic acid. The NMR spectra of the amine 43
(C20H39NO4), obtained from adduct 41a, confirmed its symmetric
nature; as expected the 13C NMR spectrum revealed the presence of
12 carbon signals, whereas the isomeric 2,6-trans substituted
amine 42, obtained from adduct 40a, displayed 18 different carbon
signals as a result of its unsymmetrical nature. (In the un-
meric forms of 40a-B and 40a-C in a ratio of 28:72 (See
Experimental). The presence of 40a-B in sizable proportion is jus-
tified even though it has two axial groups; the additional gauche
interaction between C(7)R and N–O in 40a-C is absent in the con-
former 40a-B, thereby encouraging its presence.
A systematic study of the stereochemistry associated with the
cycloaddition of
a C(4)-substituted and second-generation
C(4),(6)-disubstituted six-membered cyclic nitrones has been
carried out for the first time. The remarkable exo/endo- and face
selectivity observed in our study reflects the scope inherent in
these important cycloaddition reactions. The study suggests that
a bulkier tertiary substituent at C(4) may freeze the invertomer
exclusively in the cis-fused form and thus would lead to the ex-
clusive formation of the synthetically important second-genera-
tion aldonitrones via peracid-induced ring opening of the
cycloadducts.
symmetrical amine the signals at
d 14.1 and 22.8 ppm belonged to
two carbons in each case). The nonseparable mixture of adducts
40b and 41b upon hydrolysis was converted into a separable
mixture of compounds 44 and 45. The N–O bond cleavage of 45
afforded the symmetrical cis amine 47, while 44 led to the
unsymmetricl trans amine 46.
Finally, we explored the face selectivity in the cycloaddition of
the aldonitrone 37a with 1,1-disubstituted alkene, methyl meth-
acrylate (21). To our surprise, the addition was found to be highly
face selective; adduct 48 and a nonseparable mixture of three mi-
nor adducts were obtained in a ratio of 88:12. The stereochemistry
of the adduct was based on the approach of the alkene from the
3. Experimental
3.1. General
Elemental analysis was carried out on a Perkin Elmer Elemental
Analyzer Series 11 Model 2400. IR spectra were recorded on a Per-
kin Elmer 16F PC FTI.R spectrometer. 1H and 13C NMR spectra were
measured in CDCl3 using TMS as internal standard on a JEOL LA
500 MHz spectrometer. Mass spectra were recorded on a GC–MS
system (Agilent Technologies, 6890 N). Silica gel chromatographic
separations were performed with Silica gel 100 from Fluka Chemie
AG (Buchs, Switzerland). Piperidine 4-carboxylic acid, 1-hexene,
styrene, methyl methacrylate, methyl crotonate, m-chloro-
perbenzoic acid, from Fluka Chemie AG (Buchs, Switzerland) were
used as received. All solvents were of reagent grade. Dichloro-
methane was passed through alumina before use. All reactions
were carried out under N2. 4-Piperidinemethanol (6) was prepared
from methyl ester of piperidine 4-carboxylic acid as described.9
b-face of the nitrone to give 2,6-trans substituted adduct 48. The
assignment of stereochemistry was based on the observed stereo-
chemistry of the addition reaction of the second-generation
nitrones 37 to 1-hexene and styrene. In both cases the 3a,7-trans
substituted adducts 40a and 44 were found to have two inver-
tomers, whereas the 3a,7-cis substituted adducts 41a and 45 gave
sharp NMR signals and revealed the presence of a single invertomer
in each case. The major adduct 48 in the nitrone 37a-methyl
methacrylate addition reaction was also found to have a single
invertomer and as such was assigned the 3a,7-trans configuration.
The conformational analysis revealed that while the adduct 10a
remained as a mixture of two invertomers A and C in a ratio of

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
8237
Dimethyl methylenemalonate was prepared using the literature
2954, 2925, 2858, 1455, 1379, 1260, 1100, 1037, 963, and 765 cmꢁ1
The major and minor invertomers at 25 ꢀC were found to be in
.
procedure.10
a ratio of 88:12 as determined by integration of the C(2)H at
(major) and 4.02 (minor) ppm.
d 4.38
3.2. N-Hydroxy-4-piperidinemethanol (7)
To a stirring solution of amine 6 (15 g, 130 mmol) with methanol
(200 mL) in presence of selenium dioxide (0.7 g) at 0 ꢀC under N2
was added dropwise a 30% H2O2 solution (18.5 g, 163 mmol) in
15 min. The mixture was then stirred at 20 ꢀC for 8 h. Sodium bo-
rohydride (2 g, 54 mmol) was added to the above mixture and
stirring continued for 2 h. After removal of the solvent, the residual
mixture was taken up in saturated K2CO3 solution (40 mL) and
extracted with CH2Cl2/MeOH (9:1) (4ꢂ50 mL). The combined or-
ganic layers were dried (Na2SO4), concentrated and the residual
liquid was purified by chromatography over silica using 1:1 ether/
methanol mixture as eluant to give the hydroxylamine 7 as a white
solid (10.2 g, 60%). m/z 131 [Mþ]; mp 103–104 ꢀC (methanol/ether),
(Found: C, 54.8; H, 9.9; N, 10.6. C6H13NO2 requires C, 54.94; H, 9.99;
N, 10.68%.); nmax (KBr) 3226, 2963, 2911, 2856, 2830, 1656, 1480,
3.4.1.1. Major invertomer of 10a. dH (500 MHz, CDCl3, 25 ꢀC) 4.42–
4.34 (1H, m, C2-H), 3.66–3.58 (1H, m, C3a-H), 3.49–3.41 (2H, m,
CH2OH), 3.08 (1H, td, J 3.2, 10.4 Hz, C7-HaHe), 2.92 (1H, br, OH), 2.68
(1H, ddd, J 2.5,10.3,12.8 Hz, C7-HaHe), 2.35 (1H, dt, J 9.5,11.9 Hz, C3-
HaHb), 2.00–1.20 (12H, m, (CH2)3, C3-HaHb, C4-H2, C5-H, C6-H2),
0.90 (3H, t, J 6.8 Hz, Me); dC (500 MHz, CDCl3, 25 ꢀC) 77.3, 67.1, 59.4,
49.1, 35.4, 35.2, 32.5, 28.4, 28.1, 27.6, 22.7, 14.0.
3.4.1.2. Minor invertomer 10a. Minor invertomer has the following
non-overlapping signals: dH (500 MHz, CDCl3, 25 ꢀC) 4.07–3.97 (1H,
m, C2-H), 3.64–3.60 (2H, m, CH2OH), 3.33–3.27 (1H, m, C3a-H),
2.61–2.51 (1H, m, C7-HaHe), 2.04–1.94 (1H, m, C3-HaHb); dC
(500 MHz, CDCl3, 25 ꢀC) 76.1, 63.2, 61.2, 50.7, 40.1, 35.0, 34.0, 30.1,
28.0, 25.6, 22.7, 14.0.
1446, 1383, 1276, 1242, 1133, 1103, 1037, and 996 cmꢁ1
; dH
(500 MHz, 9:1 CDCl3/CD3OD, þ25 ꢀC) 3.42–3.28 (4H, m, C2-HaHe,
C6-HaHe, and CH2O), 2.50–2.44 (2H, m, C2-HaHe, C6-HaHe), 1.81–
1.31 (5H, m, C3-H2, C4-H, C5-H2); dC (500 MHz, 9:1 CDCl3/CD3OD,
þ25 ꢀC) 66.6 (2C), 58.1, 37.2, 28.2 (2C). The hydroxylamine was
partially soluble in CDCl3, but soluble in a CDCl3/CD3OD mixture.
3.4.2. Minor diastereomer 12a. The sharp proton and carbon sig-
nals at þ25 ꢀC or ꢁ30 ꢀC indicated the presence of a single inver-
tomer. Coluorless liquid (Found: C, 67.7; H, 10.9; N, 6.5. C12H23NO2
requires C, 67.57; H, 10.87; N, 6.57%.); nmax (neat) 3386, 2928, 2859,
1460,1379,1259,1099,1049,1017, 898, and 779 cmꢁ1
; dH (500 MHz,
CDCl3, þ25 ꢀC) 4.10–4.02 (1H, m, C2-H), 3.56–3.46 (2H, m, CH2O),
3.51–3.43 (1H, m, C3a-H), 2.56–2.46 (1H, m, C7-HaHe), 2.30–2.20
(1H, m, C7-HaHe), 2.02–1.20 (13H, m, (CH2)3, C3-H2, C4-H2, C5-H,
C6-HaHe, OH), 1.14 (1H, q, J 12.2 Hz, C6-HaHe), 0.90 (3H, t, J 6.8 Hz,
Me); dC (500 MHz, CDCl3, þ25 ꢀC) 76.6, 67.2, 65.7, 53.9, 39.8, 38.7,
35.0, 32.1, 28.0, 27.9, 22.7, 14.0.
3.3. 4-Hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide (8)
To a solution of the hydroxylamine (5.24 g, 40 mmol) in EtOH or
MeOH (50 mL) was added yellow HgO (18.0 g, 84 mmol) and the
mixture was stirred using a magnetic stir bar at 35 ꢀC for 2 h or until
the oxidation was complete (as indicated by TLC experiment in
ether). The mixture was then filtered through a bed of Celite and
MgSO4. The bed was washed with liberal excess of ethanol. The
formation of the nitrone was assumed quantitative for the percent
yield calculation in the subsequent cycloaddition reactions. dH
(500 MHz, CD3OD, þ25 ꢀC) 7.34–7.33 (1H, m), 3.87–3.72 (2H, m, C6-
H2), 3.57–3.45 (2H, m, CH2O), 2.66–2.56 (1H, m, C3-HaHe), 2.30–
2.20 (1H, m, C3-HaHe), 2.11–2.03 (1H, m, C5-HaHe), 1.97–1.87 (1H,
m, C4-H), 1.83–1.71 (1H, m, C5-HaHe); dC (500 MHz, CD3OD, þ25 ꢀC)
143.6, 65.6, 57.7, 32.3, 29.5, 26.2. The nitrone cannot be purified
further since upon concentration it undergoes dimerization and
other side reactions.
3.5. Reaction of nitrone 8 with styrene (9b)
A solution of nitrone 8 (10 mmol) in EtOH (40 mL) containing
styrene (4 mL) was heated at 90 ꢀC for 4 h under N2 in a closed
vessel. After removal of the solvent and excess alkene, the residual
crude mixture of cycloadducts was separated by chromatography
over silica using 95:5 ether/methanol as eluant to give 10b con-
taining minor amount of 12b. Continued elution gave a pure sample
of the major adduct 10b as white crystals. Finally, a fraction con-
taining 10b and 11b was obtained; repeated chromatography
enriched the fraction to a ratio of 4:96 for the isomers 10b/11b. The
combined yield of the cycloadducts was found to be 1.98 g, 85%. The
fraction containing the mixture of 10b and 12b was crystallized to
separate the major adduct 10b, while the mother liquor upon re-
peated chromatography gave the minor adduct 12b.
3.4. Reaction of nitrone 8 with 1-hexene (9a)
A solution of nitrone (10 mmol) in EtOH (40 mL) containing 1-
hexene (9a) (6 mL) was heated at 90 ꢀC for 24 h under N2 in a closed
vessel. After removal of the solvent and excess alkene, the residual
crude mixture of cycloadducts was separated by chromatography
over silica using 95:5 ether/methanol as eluant to give 10a con-
taining minor amount of 12a. Continued elution gave a pure sample
of the major adduct 10a as a colorless liquid. The minor di-
astereomer 12a was obtained in the pure form after repeated
chromatography of the fraction containing the mixture of 10a and
12a. The combined yield of the cycloadducts was found to be
(1.67 g, 78%).
A careful 1H NMR (CDCl3, ꢁ40 ꢀC) analysis of the crude reaction
mixture and the separated fractions revealed the presence of the
isomers 10b–12b in a ratio of 93:5:2:w0, respectively. The C(2) of
the major adduct 10b appeared at
5.02 ppm (minor invertomer). The corresponding proton for the
isomer 11b appeared at 5.23(1H, apparent t, J 8.5 Hz). The C(2)H
signal for the isomer 12b appeared as a dd (J 4.0, 9.8 Hz) at
5.05 ppm.
d 5.39 (major invertomer) and
d
d
3.5.1. Major diastereomer 10b. Mp 104–105 ꢀC (ether/dichloro-
methane); m/z 233.1 [Mþ]; (Found: C, 72.0; H, 8.1; N, 5.9. C14H19NO2
requires C, 72.07; H, 8.21; N, 6.00%.); nmax (KBr) 3406, 2925, 2844,
1450, 1380, 1308, 1253, 1090, 1052, 955, 768, 701, and 630 cmꢁ1. The
major and minor invertomers at 25 ꢀC were found to be in a ratio of
90:10 as determined by integration of the C(2)H. (The ratio be-
comes 93:7 at ꢁ40 ꢀC).
The C(2) of the major adduct 10a appeared at
d 4.38 (major
invertomer) and 4.02 ppm (minor invertomer). The overlapping
C(2)H signal for the isomer 12a appeared at
d 4.06 ppm. The com-
plete 1H NMR analysis of the C(2)H of crude and the separated
fraction revealed the ratio of the isomers 10a–13a as 93:w0:7:w0,
respectively.
3.4.1. Major diastereomer 10a. (Found: C, 67.4; H, 10.7; N, 6.5.
C12H23NO2 requires C, 67.57; H, 10.87; N, 6.57%.); nmax (neat) 3352,
3.5.1.1. Major invertomer of 10b. dH (500 MHz, CDCl3, þ25 ꢀC) 7.44–
7.24 (5H, m, Ph), 5.39 (1H, dd, J 3.7, 9.8 Hz, C2-H), 3.88–3.80 (1H, m,

8238
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
C3a-H), 3.54–3.42 (2H, m, CH2OH), 3.26–3.18 (1H, td, J 3.3, 10.4 Hz,
C7-HaHe), 2.82 (1H, ddd, J 2.2, 10.6, 12.8 Hz, C7-HaHe), 2.70 (1H, q, J
11.2 Hz, C3-HaHb), 2.50 (1H, br, OH), 2.05–1.60 (5H, m, C3-HaHb, C4-
H2, C5-H, C6-HaHe), 1.38–1.24 (1H, m, C6-HaHe); dC (500 MHz,
CDCl3, þ25 ꢀC) 142.3, 128.4 (2C), 127.6, 126.4 (2C), 78.9, 67.1, 59.9,
49.4, 38.8, 32.6, 28.3, 27.6.
in every respect to that obtained by cycloaddition reaction as
mentioned in Section 3.5.1.
3.7. Lithium aluminum hydride reduction of ester
cycloadduct 15a–12a
A sample of adduct 15a9 was reduced with LiAlH4 using pro-
cedure as described in Section 3.6 to give 12a as a coluorless liquid
(93% yield), which is identical in every respect to that obtained by
cycloaddition reaction as mentioned in Section 3.4.2.
3.5.1.2. Minor invertomer of 10b. Minor invertomer has the fol-
lowing non-overlapping signals: dH (500 MHz, CDCl3, þ25 ꢀC)
d
5.06–4.98 (1H, m, C2-H; at ꢁ40 ꢀC the signal becomes a dd (J 4.2,
9.6 Hz)), 3.70–3.62 (2H, m, CH2OH), 3.39–3.31 (1H, m, C3a-H), 2.38–
2.26 (1H, m C3-HaHb); dC (500 MHz, CDCl3, þ25 ꢀC) 141.6, 128.3
(2C), 127.7, 126.7 (2C), 77.7, 63.2, 61.7, 51.1, 43.2, 34.0, 30.1, 25.7.
3.8. Lithium aluminum hydride reduction of ester
cycloadduct 15b–12b
3.5.2. Minor diastereomer 11b. We were unable to obtain the dis-
tereomer 11b in pure form even after repeated chromatography.
Finally, a fraction containing adduct 11b along with minor amount
(w4%) of the isomer 10b was analyzed. The proton and carbon
signals at 25 ꢀC or ꢁ40 ꢀC indicated the presence of two inver-
tomers for 11b in a 84:16 ratio as indicated by the C(2)H (CDCl3,
A sample of adduct 15b9 was reduced with LiAlH4 using pro-
cedure as described in Section 3.6 to give 12b as a colorless liquid
(90% yield), which is identical in every respect to that obtained by
cycloaddition reaction as mentioned in Section 3.5.3.
3.9. Reaction of nitrone 8 with methyl crotonate (16)
ꢁ40 ꢀC) at
d 5.28 (1H, t, J 8.5 Hz) and 5.10 (1H, t, J 8.4 Hz). The
invertomer ratio becomes 80:20 at þ25 ꢀC. Colorless liquid;
(Found: C, 71.9; H, 8.3; N, 6.1. C14H19NO2 requires C, 72.07; H, 8.21;
N, 6.00%.); nmax (neat) 3336, 2921, 2859, 1448, 1355, 1279, 1258,
A solution of nitrone 8 (5.0 mmol) in EtOH (20 mL) containing
methyl crotonate (16) (4 mL) was heated at 90 ꢀC for 10 h under N2
in a closed vessel. After removal of the solvent and excess alkene
the residual crude mixture of cycloadducts was purified by chro-
matography over silica using 95:5 ether/methanol as eluant to give
a nonseparable mixture of adducts 17–19 as a colorless liquid
(0.974 g, 85%). We were unable to separate the isomers even after
repeated chromatography. (Found: C, 57.5; H, 8.2; N, 6.0. C11H19NO4
requires C, 57.63; H, 8.35; N, 6.11%.); nmax (neat) 3380, 2929, 2855,
1730, 1439, 1392, 1379, 12.97, 1265, 1203, 1179, 1113, 1090, and
1094, 1034, 961, 756, 700, and 673 cmꢁ1
.
3.5.2.1. Major invertomer of 11b. dH (500 MHz, CDCl3, 25 ꢀC) 7.52–
7.20 (5H, m, Ph), 5.24 (1H, t, J 8.5 Hz, C2-H), 3.90–3.78 (1H, m, C3a-
H), 3.53–3.41 (2H, m, CH2OH), 3.27 (1H, td, J 3.7, 11.0 Hz, C7-HaHe),
2.73 (1H, t, J 12.2 Hz, C7-HaHe), 2.59–2.47 (1H, m, C3-HaHb), 2.38
(1H, q, J 12.2 Hz, C3-HaHb), 2.09 (1H, apparent d, J 14.6 Hz, C6-HaHe),
1.85–1.57 (4H, m, C4-H2, C5-H, OH), 1.31 (1H, apparent q, J 12.2 Hz,
C6-HaHe); dC (500 MHz, CDCl3, þ25 ꢀC) 143.2, 128.3 (2C), 127.1,
125.6 (2C), 81.7, 67.3, 60.7, 52.0, 38.3, 33.0, 28.4, 27.7.
1029 cmꢁ1
.
A careful 1H NMR (CDCl3, ꢁ40 ꢀC) analysis of the crude reaction
mixture and the separated fractions revealed the presence of the
isomers 17–19 in a respective ratio of 81:16:3. The C(2) of the major
3.5.2.2. Minor invertomer of 11b. dC (500 MHz, CDCl3, þ25 ꢀC)
143.2, 128.3 (2C), 127.1, 125.6 (2C), 78.9, 63.6, 62.5, 51.3, 44.2, 33.9,
29.8, 25.7.
adduct 17 appeared at d 4.50 (quint, J 5.8 Hz, major invertomer) and
5.01 ppm (quint, J 6.1 Hz, minor invertomer) in a 65:35 ratio. The
ratio becomes 60:40 at þ25 ꢀC. The corresponding proton of the
isomers 18 and 19 appeared at
d 4.41 (qd, J 6.5, 8.9 Hz, single
3.5.3. Minor diastereomer 12b. Colorless liquid; (Found: C, 71.8; H,
8.0; N, 5.8. C14H19NO2 requires C, 72.07; H, 8.21; N, 6.00%.). The
signals were sharp; the 1H spectrum revealed the presence of
a single invertomer. nmax(neat) 3356, 2921, 2849, 1449, 1364, 1324,
invertomer), and 4.29 (quint, J 6.1 Hz, single invertomer). The
CO2Me singlets of the 17 appeared at 3.75 (major invertomer), and
d
3.79 (minor invertomer) and that of 18 appeared at 3.77 ppm. The
C(2)Me (CDCl3, þ25 ꢀC) signal for the isomer 17, 18, and 19
1260, 1099, 1051, 1011, 948, 912, 760, 730, and 699 cmꢁ1
;
dH
appeared at d 1.33 (d, J 6.4 Hz), 1.50 (d, J 6.4 Hz), and 1.44 (d, J
(500 MHz, CDCl3, þ25 ꢀC) 7.47–7.23 (5H, m, Ph), 5.05 (1H, dd, J 4.9,
9.8 Hz, C2-H), 3.54 (3H, m, C3a-H, CH2OH), 2.68 (1H, apparent t, J
9.8 Hz, C7-HaHe), 2.60–2.50 (1H, m C7-HaHe), 2.37 (1H, q, J 11.0 Hz,
C3-HaHb), 2.23–2.15 (1H, m, C3-HaHb), 2.08 (1H, d, J 12.2 Hz, C4-
HaHe), 2.01–1.89 (2H, m, C4-HaHe, OH), 1.76–1.64 (1H, m, C5-H), 1.48
(1H, dq, J 3.7, 13.4 Hz, C6-HaHe), 1.21 (1H, q, J 12.2 Hz, C6-HaHe); dC
(500 MHz, CDCl3, þ25 ꢀC) 141.6, 128.4 (2C), 127.8, 126.7 (2C), 78.2,
66.9, 66.2, 54.0, 42.8, 38.6, 32.1, 27.9.
6.4 Hz), respectively.
3.9.1. Major invertomer of major diastereomer 17. dC (500 MHz,
CDCl3, þ25 ꢀC) 172.1, 75.2, 64.5, 62.9, 57.1, 52.3, 51.3, 33.6, 27.1, 25.2,
19.3.
3.9.2. Minor invertomer of major diastereomer 17. dC (500 MHz,
CDCl3, þ25 ꢀC) 173.6, 75.7, 66.6 (CH2O), 62.4, 56.7, 51.8 (OMe), 48.6,
32.7, 26.5, 26.0, 19.5.
3.6. Lithium aluminum hydride reduction of ester
cycloadduct 14–10b
3.9.3. Minor diastereomer 18. A single invertomer: dC (500 MHz,
CDCl3, þ25 ꢀC) 171.8, 80.2, 66.6 (CH2O), 64.0, 54.4, 52.8, 52.3, 33.0,
27.4, 27.2, 22.7.
To a stirred solution of ester adduct 14 of known configuration9
(100 mg, 0.33 mmol) in ether (15 mL) was added lithium aluminum
hydride (100 mg, 2.7 mmol) at room temperature. The reaction was
completed in 10 min as indicated by TLC experiment (silica, ether).
To the reaction mixture were added water (0.1 mL), 10% NaOH so-
lution (0.1 g), and water (0.4 mL). The mixture was stirred for 1 h
and was then decanted and the residue was washed with CH2Cl2.
The organic layer was dried (Na2SO4), concentrated, and purified by
silica gel chromatography using a 95:5 CH2Cl2/methanol as the
eluant to give 10b as a white solid (71 mg, 92%), which is identical
3.10. Reaction of nitrone 8 with methyl methacrylate (21)
A solution of nitrone 8 (5.0 mmol) in EtOH (20 mL) containing
methyl methacrylate (21) (4 mL) was heated at 50 ꢀC for 6 h under
N2 in a closed vessel. After removal of the solvent and excess alkene
the residual crude mixture of cycloadducts was separated by
chromatography over silica using 95:5 ether/methanol as eluant to
give 24 containing minor amount 22. Continued elution afforded 22

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
8239
along with minor amounts of 23 and 24. The first fraction was
rechoramatographed to obtain 24 as a colorless liquid. Adduct 22
was obtained from the second fraction as white crystals by crys-
tallization. The mother liquor contained a mixture of 22–24. The
combined yield of the cycloadducts was found to be 1.05 g, 92%.
stirring at 0 ꢀC for 1 h, was allowed to warm to 20 ꢀC and stirring
continued for an additional 4 h. The mixture was taken up in ether
(50 ml) and washed with water (3ꢂ50 mL). The organic layer was
dried over MgSO4, concentrated and the residual liquid was chro-
matographed over silica gel using hexane/ether as the eluent to
give 27b as a white solid. Continued elution afforded a mixture of
27b and 28b, and finally, the isomer 28b as a coluorless liquid. The
approximate ratio of 27b and 28b was found to be 3:1. The overall
yield for the two steps was determined to be (3.18 g, 82%).
13
The C (CDCl3, ꢁ40 ꢀC) spectrum of the crude mixture revealed
the presence of C(2) of the major and minor invertomers of 22 at
d
84.2 and 79.8 ppm in a 80:20 ratio. The corresponding signal for
the isomer 24 appeared as a sole invertomer at 80.33, while the
signals at 84.8 and 80.6 in a respective ratio of 65:35 were assigned
d
to C(2) of the major and minor invertomers of 23. The ratio, as ap-
proximated, by analysis of 13C and 1H of the crude as well as the
separated fraction revealed the presence of 22, 23, and 24 in ratio of
92:5:3, respectively. We were unable to obtain a pure sample of the
minor isomer 23 even after repeated chromatography.
3.11.1. Major diastereomer 27b. Both the 1H and 13C NMR spectra in
CDCl3 revealed the presence of a single invertomer. Mp 45–46 ꢀC
(ether/hexane); (Found: C, 55.7; H, 8.5; N, 3.6. C18H33NO6Si requires
C, 55.79; H, 8.58; N, 3.61%.); nmax (KBr) 2953, 2927, 2855, 1741, 1460,
1435, 1257, 12.05, 1104, 1005, 836, and 776 cmꢁ1
; dH (500 MHz,
CDCl3, þ25 ꢀC) 4.56 (1H, d, J 8.8 Hz, C2-HaHb), 4.21 (1H, d, J 8.8 Hz,
C2-HaHb), 3.78 (3H, s, COMe), 3.77 (3H, s, COMe), 3.53–3.48 (1H, m,
C3a-H), 3.47–3.42 (2H, m, CH2OSi), 2.88 (1H, dd, J 2.4, 11.7 Hz, C7-
HaHe), 2.50 (1H, ddd, J 2.9, 9.5, 12.3 Hz, C7-HaHe), 2.12 (1H, apparent
d, J 13.1 Hz, C4-HaHb), 1.83 (1H, apparent d, J 14.0 Hz, C6-HaHe),
1.68–1.60 (1H, m, C5-H), 1.41 (1H, dq, J 4.0, 12.5 Hz, C4-HaHb), 1.03
(1H, q, J 11.9 Hz, C6-HaHe), 0.87 (9H, s, CMe3), 0.031 (6H, s, Me2); dC
(500 MHz, CDCl3, þ25 ꢀC) 170.2, 168.9, 71.8, 71.6, 67.0, 54.5, 53.3,
52.9, 52.8, 38.3, 29.3, 27.3, 25.9 (3C), 18.3, (-) 5.4 (2C).
3.10.1. Major diastereomer 22. The major and minor invertomers at
25 ꢀC were found to be in a ratio of 80:20 as determined by in-
tegration of several non-overlapping signals (the ratio remains the
same at ꢁ40 ꢀC). Mp 72–73 ꢀC (ether/dichloromethane); m/z 229
[Mþ]; (Found: C, 57.5; H, 8.3; N, 6.1. C11H19NO4 requires C, 57.62; H,
8.35; N, 6.11%); nmax (KBr) 3337, 3234, 2953, 2926, 2862, 1746, 1727,
1454, 1442, 1370, 1300, 1255, 1127, 1183, 1086, 1026, 980, 962, 770,
and 631 cmꢁ1
.
3.10.1.1. Major invertomer of 22. dH (500 MHz, CDCl3, þ25 ꢀC) 3.78
(3H, s, COMe), 3.69–3.61 (1H, m, C3a-H), 3.53–3.42 (2H, m, CH2OH),
3.16 (1H, d, J 7.5 Hz, C7-HaHe), 2.87 (1H, t, J 11.7 Hz, C7-HaHe), 2.68
(1H, t, J 10.0 Hz, C3-HaHb), 2.10–1.50 (6H, m, C3-HaHb, C4-H2, C5-H,
C6-HaHe, OH), 1.49 (3H, s, Me), 1.35–1.19 (1H, m, C6-HaHe); dC (CDCl3,
þ25 ꢀC) 175.5, 84.3, 67.1, 59.9, 52.7, 50.2, 39.6, 32.6, 27.9, 27.5, 25.7.
3.11.2. Minor diastereomer 28b. (Found: C, 55.6; H, 8.5; N, 3.5.
C18H33NO6Si requires C, 55.79; H, 8.58; N, 3.61%.). The 13C NMR
spectrum revealed the presence of two invertomers in a 84:16 ratio.
nmax (neat) 2954, 2928, 2855, 1766, 1754, 1746, 1738, 1731, 1470,
1462, 1454, 1434, 1251, 1203, 1135, 1108, 1083, 1044, 1005, 837, and
776 cmꢁ1
;
dH (500 MHz, CDCl3, þ25 ꢀC) 3.28–3.83 (10H, m, in-
cluding several CO2Me singlets), 2.30–2.90 (2H, m), 1.50–2.03 (5H,
m), 0.87 (9H, s, CMe3), 1.29–1.15 (1H, m, C6-HaHe), 0.034 (3H, s, Me),
0.031 (3H, s, Me).
3.10.1.2. Minor invertomer of 22. Minor invertomer has the fol-
lowing non-overlapping signals: dH (500 MHz, CDCl3, þ25 ꢀC):
d
3.39–3.30 (1H, m, C3a-H), 2.64–2.53 (1H, m, C7-HaHe), 2.50–2.35
(1H, m, C7-HaHe), 2.18–2.07 (1H, m, C3-HaHb); dC (CDCl3, þ25 ꢀC)
3.11.2.1. Major invertomer of 28b. dC (500 MHz, CDCl3, þ25 ꢀC)
170.3, 168.9, 87.0, 67.1, 60.3, 53.3 (2C), 50.9, 38.1, 32.7, 27.7, 27.6, 25.9
(3C), 18.3, (-) 5.4 (2C).
175.5, 80.0, 63.3, 61.6, 52.7, 51.2, 44.9, 33.7, 29.5, 25.3, 24.8.
3.10.2. Minor diastereomer 24. Colorless liquid. (Found: C, 57.4; H,
8.2; N, 5.9. C11H19NO4 requires C, 57.62; H, 8.35; N, 6.11%.). The 1H
spectrum revealed the presence of a single invertomer. nmax (neat)
3350, 2924, 2853, 1730, 1445, 1373, 1260, 1210, 1142, 1040, and
3.11.2.2. Minor invertomer of 28b. dC (500 MHz, CDCl3, þ25 ꢀC)
170.3, 168.9, 83.3, 63.5, 61.7, 53.3, 52.7, 51.4, 42.7, 33.3, 29.5, 25.9
(3C), 25.3, 18.3, (-) 5.4 (2C).
986 cmꢁ1
;
dH (500 MHz, CDCl3, þ25 ꢀC) 3.77 (3H, s, COMe), 3.58–
3.46 (3H, m, C3a-H, CH2OH), 2.58–2.48 (1H, m, C7-HaHe), 2.47–2.35
(2H, m, C7-HaHe, OH), 2.20–2.12 (1H, m, C3-HaHb), 2.07–1.97 (1H, m,
C3-HaHb), 1.92–1.82 (1H, m, C5-H), 1.73–1.60 (2H, m, C4-HaHe, C6-
HaHe), 1.50 (3H, s, Me), 1.48–1.40 (1H, m, C4-HaHe), 1.16 (1H, q, J
11.9 Hz, C6-HaHe); dC (500 MHz, CDCl3, þ25 ꢀC) 175.6, 80.5, 67.2,
66.1, 54.1, 52.6, 44.6, 38.4, 31.6, 27.5, 24.7.
3.12. Thermolysis of 27b in toluene-d6
A solution of the adduct 27b (20 mg) in toluene-d6 was ther-
molyzed at 90 ꢀC. After 30 min of heating the ratio of 27b and 28b
became 77:23, while the ratio became72:28 after 2 h at 90 ꢀC and
thereafter remained unchanged. The CO2Me of 27b appeared at
d
3.29 and 3.35 ppm, while that of 28b appeared at 3.32 and
3.11. Reaction of nitrone 8 with dimethyl methylenemalonate
(26) and conversion of cycloadducts 27a and 28a to silylated
ethers 27b and 28b
3.39 ppm. The C(3a) proton of the 28b appeared at 3.70, while the
C(2) Hs appeared at 4.83 (1H, d, J 8.6 Hz), 4.20 (1H, J 8.6 Hz).
d
3.13. Thermolysis of 27b in toluene in the presence of
styrene (9b)
A solution of nitrone 8 (10 mmol) in methanol (40 mL) was
reacted with dimethylmethylene malonate (26) (1.73 g, 12 mmol)
at 20 ꢀC for 1 h. After removal of the solvent by blowing a gentle
stream of N2, the residual liquid was dried under vacuum to
a constant weight (3 g). Extensive decomposition happened during
silica gel chromatography to separate and purify the cycloadducts
27a and 28a. As such, the crude products were silylated using the
following procedure. To a solution of the crude adducts 27a and 28a
(w10 mmol) in DMF (25 mL) was added imidazole (2.7 g,
40 mmol). A solution of tert-butyldimethylsilyl chloride (2.1 g,
14 mmol) in DMF (10 mL) was added dropwise to the above mix-
ture at 0 ꢀC over a period of 15 min the reaction mixture, after
A solution of 27b (400 mg, 1.03 mmol), styrene (1.5 mL) in tol-
uene (5 mL) was stirred under N2 at 100 ꢀC overnight. After removal
of the solvent and excess alkene, residual liquid was chromato-
graphed over silica gel using hexane/ether as the eluent to give 30
as a white solid. Continued elution afforded a mixture of 30–32. The
yield was found to be 83% (0.297 g). The crude mixture revealed the
presence of three adducts as revealed by the presence of C(2)H of
29 at d 5.40 (major invertomer) and 5.02 (minor invertomer), 31 at
5.23 (1H, t, J 8.7 Hz, major invertomer) and 5.10 (minor invertomer,
overlapping), and 32 at 5.10.

8240
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
In order to determine the structure and composition of 30–32,
98 ꢀC (hexane/ther); m/z 275 [Mþ]; (Found: C, 69.6; H, 7.6; N, 5.0.
C16H21NO3 requires C, 69.79; H, 7.69; N, 5.09%.); nmax (KBr) 3028,
2952, 2919, 2854, 1741, 1456, 1366, 1245, 1035, 946, 903, 765, 708,
670, and 644 cmꢁ1. The major and minor invertomers of 36b at
25 ꢀC were found to be in a ratio of 88:12 as determined by in-
tegration of the C(2)H.
a portion of the above crude adducts was hydrolyzed with 5:1
1
MeOH/HCl at 20 ꢀC (10 min) to 10b–13b. H NMR (CDCl3, ꢁ30 ꢀC)
analysis of the crude hydrolyzed products revealed the presence of
three isomers 10b–12b, hence 30–32, in a ratio of 94:3:3 as indicated
by integration of the C(2)H signals as described (Section 3.5).
3.13.1. Major adduct 30. Mp 80–81 ꢀC (ether/pentane); (Found: C,
68.9; H, 9.4; N, 3.9. C20H33NO2Si requires C, 69.11; H, 9.57; N,
4.03%.); nmax (KBr) 2928, 2888, 2855, 1459, 1386, 1361, 1253, 1115,
1077, 1044, 1006, 834, 763, 703 and 661 cmꢁ1. The major and minor
invertomers at 25 ꢀC were found to be in a ratio of 86:14 as de-
termined by integration of the C(2)H. (The ratio becomes 93:7 at
ꢁ40 ꢀC).
3.15.1. Major invertomer of 36b. dH (500 MHz, CDCl3, 25 ꢀC) 7.37–
7.25 (5H, m, Ph), 5.41 (1H, dd, J 3.7, 9.8 Hz, C2-H), 3.95 (2H, ABX, J 6.1,
6.4, 10.7 Hz, CH2OAc), 3.88–3.83 (1H, m, C3a-H), 3.24 (1H, td, J 3.4,
10.4 Hz, C7-HaHe), 2.84 (1H, ddd, J 2.5, 10.4, 12.8 Hz, C7-HaHe), 2.73
(1H, apparent q, J 11.6 Hz, C3-HaHb), 2.07 (3H, s, COMe), 1.75–2.15
(5H, m, C3-HaHb, C4-H2, C5-H, C6-HaHe), 1.40 (1H, dq, J 2.2, 12.2 Hz,
C6-HaHe); dC (500 MHz, CDCl3, þ25 ꢀC) 171.0,145.2,128.5 (2C),127.6,
126.4 (2C), 78.8, 68.2, 59.7, 49.1, 38.8, 29.6, 28.3,27.6, 20.9.
3.13.1.1. Major invertomer 30. dH (500 MHz, CDCl3, 25 ꢀC) 7.37–7.25
(5H, m, Ph), 5.40 (1H, dd, J 3.6, 9.8 Hz, C2-H), 3.85–3.75 (1H, m, C3a-
H), 3.51–3.41 (2H, m, CH2OSi), 3.26–3.20 (1H, m, C7-HaHe), 2.83 (1H,
ddd, J 2.6, 10.4, 13.1 Hz, C7-HaHe), 2.73 (1H, dt, J 10.0, 11.9 Hz, C3-
HaHb), 1.50–2.00 (5H, m, C3-HaHb, C4-H2, C5-H, C6-HaHe), 1.32–1.20
(1H, m, C6-HaHe), 0.89 (9H, s, CMe3), 0.03 (6H, s, Me2); dC (500 MHz,
CDCl3, 25 ꢀC) ꢁ5.4 (2C), 18.3, 25.9 (3C), 27.7, 28.3, 32.7, 38.9, 49.5,
60.0, 67.5, 78.8, 126.4 (2C), 127.5, 128.4 (2C), 142.5.
3.15.2. Minor invertomer of 36b. Minor invertomer has the follow-
ing non-overlapping signals: dH (500 MHz, CDCl3, 25 ꢀC) 5.02 (1H,
dd, J 3.9 and 8.8 Hz, C2-H), 4.14 (2H, d, J 7.9 Hz, CH2OAc), 3.42–3.37
(1H, m, C3a-H), 2.67–2.57 (1H, m), 2.33 (1H, apparent q, J 10.4 Hz),
1.74–1.65 (1H, m); dC (500 MHz, CDCl3, 25 ꢀC) 171.0, 141.5, 128.5 (2C),
127.9, 126.7 (2C), 77.7, 64.9, 61.6, 50.9, 43.1, 30.5 (2C), 25.9, 20.9.
3.16. MCPBA oxidation of adduct 36a to nitrones 37a and 38a.
Cycloaddition of 37a with 1-hexene (9a)
3.13.1.2. Minor invertomer 30. dH(500 MHz, CDCl3, 25 ꢀC). Minor
invertomer has the following non-overlapping signals:
d 5.02 (1H,
dd, J 4.3 and 9.0 Hz, C2-H, broad dd at 25 ꢀC became sharp at
ꢁ40 ꢀC), 3.58–3.52 (1H, m, C3a-H), 3.33–3.27 (2H, m); dC (500 MHz,
CDCl3, 25 ꢀC) 142.3, 128.4 (2C), 127.6, 126.8 (2C), 77.7, 63.8, 61.9,
51.2, 43.3, 33.8, 30.2, 25.6, 25.9 (3C), 15.0, ꢁ5.4 (2C).
To a stirred solution of the cycloadduct 36a (3.0 mmol) in
dichloromethane (30 mL) at 20 ꢀC was added MCPBA (3.0 mmol) in
one portion. After 30 m at 20 ꢀC the organic layer was washed with
5% NaHCO3 solution (3ꢂ10 mL). The combined aqueous layers were
re-extracted with CH2Cl2 (3ꢂ25 mL). The combined organic layers
were dried (Na2SO4), concentrated to give a mixture of the aldo-
nitrone 37a and ketonitrone 38a in a ratio of 80:20, respectively, as
a pale yellow liquid in almost quantitative yield. A small portion of
the solution was concentrated for 1H NMR analysis, which revealed
the aldonitrone 37a having the following characteristic signals at
3.14. Conversion 10a into its acetate 36a
The cycloadduct 10a (1.28 g, 6.0 mmol) in CH2Cl2 (10 mL) was
treated with acetic anhydride (3 mL) at 25 ꢀC for overnight. After
removal of the solvent and excess acetic anhydride the residual
liquid was purified by chraomatography over silica gel using ether
as eluant to give 36a as a colorless liquid (1.46 g, 95%). (Found: C,
65.9; H, 9.8; N, 5.4. C14H25NO3 requires C, 65.85; H, 9.87; N, 5.49%.);
nmax (neat) 2955, 2929, 2857,1742,1454, 1366, 1244, 1036, and
963 cmꢁ1. The 1H NMR spectrum revealed the presence of two
invertomers in a ratio of 83:17.
d
7.18 (1H, t, J 3.5 Hz, CH]N), 4.24 (1H, m, ]NCH), 2.08 (3H, s), 0.90
(3H, t, J 7.0 Hz). The ketonitrone 38a has the following non-over-
lapping signals at 3.00 (1H, dd, J 9.6, 13.1 Hz), 2.17 (3H, s).
d
After exchanging CH2Cl2 with toluene (15 mL), the above solu-
tion of nitrones was treated with 1-hexene (9a) (5 mL) at 75 ꢀC for
48 h. After removal of the solvent and excess alkene, the residual
mixture was separated by chraomatography over silica gel using
1:1 hexane/ether as eluant to give the minor cycloadduct 41a as
a colorless liquid (220 mg, 21%). Continued elution afforded the
major isomer 40a also as a colorless liquid (423 mg, 40%). Finally,
elution with 90:10 ether/methanol afforded the unreacted ketoni-
trone 38a as a colorless liquid.
3.14.1. Major invertomer of 36a. dH (500 MHz, CDCl3, þ25 ꢀC) 4.43–
4.37 (1H, m, C2-H), 3.92 (2H, ABX, J 6.4, 10.7 Hz, CH2OAc), 3.60 (1H,
apparent quint, J 5.8 Hz, C3a-H), 3.11 (1H, td, J 3.4, 10.4 Hz, C7-
HaHe), 2.69 (1H, ddd, J 2.6, 10.4, 12.9 Hz, C7-HaHe), 2.33 (1H, dt, J 9.4,
11.9 Hz, C3-HaHb), 2.06 (3H, s, COMe), 2.00–1.80 (2H, m, C3-HaHb,
C5-H), 1.78–1.68 (2H, m, C4-HaHe, C6-HaHe), 1.63–1.53 (1H, m, C4-
HaHe), 1.55–1.45 (1H, m, C6-HaHe), 1.43–1.23 (6H, m, (CH2)3Me),
0.90 (3H, t, J 7.0 Hz, Me); dC (500 MHz, CDCl3, þ25 ꢀC) 171.0, 77.3,
68.3, 59.1, 48.8, 35.3, 35.2, 29.5, 28.3, 28.1, 27.6, 22.7, 20.9, 14.0.
3.16.1. Major cycloadduct 40a. (Found: C, 67.3; H, 10.2; N, 3.8.
C20H37NO4 requires C, 67.57; H, 10.49; N, 3.94%.); nmax (neat) 3440,
2918, 2850, 1743, 1467, 1451, 1427, 1371, 1254, 1121, 1039, 901, 782,
and 732 cmꢁ1. The ratio of the invertomers by 13C was estimated to
be 85:15.
3.14.2. Minor invertomer of 36a. dH (CDCl3, þ25 ꢀC) non-over-
lapping signals at 4.13–4.09 (2H, m, CH2OAc), 4.06–4.01 (1H, m, C2-
H), 3.32–3.26 (1H, m, C3a-H), 2.62–2.54 (1H, m), 2.03 (3H, s, COMe);
dC (500 MHz, CDCl3, þ25 ꢀC) 173.8, 76.1, 65.0, 61.0, 50.7, 40.0, 34.9,
30.5, 30.4, 28.0, 25.8, 22.7, 21.1, 4.0.
3.16.1.1. Major invertomer of 40a. dH (500 MHz, CDCl3, ꢁ40 ꢀC) 5.48
(1H, br s, OH), 4.13–4.05 (1H, m, C2-H), 3.95–3.83 (2H, m, CH2OAc),
3.85–3.78 (1H, m, C3a-H), 3.74–3.66 (1H, m, C7-CH2CHO), 3.57–
3.49 (1H. m, C7-H), 2.10 (3H, s, COMe), 1.10–2.05 (21H, m), 0.91 (6H,
two overlapping t, J 7.0 Hz, CH2Me, CH2Me); dC (500 MHz, CDCl3,
ꢁ40 ꢀC) 171.7, 75.3, 70.0, 68.6, 54.2, 53.0, 40.9, 36.3, 35.9 (2C), 29.0,
28.6, 28.5, 28.1, 26.9, 22.8, 22.6, 21.2, 14.3, 14.2.
3.15. Conversion 10b into its acetate 36b
The cycloadduct 10b (1.40 g, 6.00 mmol) in toluene (10 mL) was
treated with acetic anhydride (1 mL) at 70 ꢀC for 3 h. After removal
of the solvent and excess acetic anhydride the residual liquid was
purified by chromatography over silica gel using 60:40 hexane/
ether as eluant to give 36b as white crystals (1.58 g, 96%). Mp 97–
3.16.1.2. Minor invertomer of 40a. Minor invertomer has the fol-
lowing non-overlapping signals: dC (500 MHz, CDCl3, ꢁ40 ꢀC) 76.2,
68.0, 54.5, 39.3, 36.8, 34.9, 33.5, 32.8, 32.5, 30.3, 30.0, 27.9, 22.7.

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
8241
3.16.2. Minor cycloadduct 41a. The 1H spectrum revealed the
presence of a single invertomer. (Found: C, 67.4; H, 10.3; N, 3.8.
C20H37NO4 requires C, 67.57; H, 10.49; N, 3.94%.); nmax (neat) 3430,
2954, 2927, 2858, 1742, 1466, 1451, 1433, 1370, 1237, 1036, 788, and
MCPBA (1.1 mmol) in one portion. The reaction mixture was then
stirred 10 min each at ꢁ40 ꢀC, ꢁ20 ꢀC, ꢁ0 ꢀC, and 20 min at 20 ꢀC.
The organic layer was then washed with 5% NaHCO3 solution
(3ꢂ10 mL). The combined aqueous layers were re-extracted with
CH2Cl2 (3ꢂ25 mL). The combined organic layers were dried
(Na2SO4), concentrated and the residual mixture was purified by
chromatography over silica gel using 90:10 ether/methanol as
eluant to give the lactam 39a as a liquid (110 mg, 77%). The crude
spectrum revealed the presence of ketonitrone 38a (w15%).
However, the ketonitrone 38a was not separated in this case.
39a: m/z 288 [Mþþ1]; (Found: C, 58.4; H, 8.6; N, 4.8. C14H25NO5
requires C, 58.52; H, 8.77; N, 4.87%.); nmax (KBr) 3380, 2954,
2930, 2870, 1743, 1642, 1632, 1468, 1454, 1416, 1371, 1315, 1246,
733 cmꢁ1 dH (500 MHz, CDCl3, 25 ꢀC) 3.80–4.15 (4H, m, C2-H,
;
CH2OAc, C3a-H), 2.98–2.90 (1H, m, C7-H), 2.48–2.36 (1H. m, C3-
HaHb), 2.05 (3H, s, COMe), 1.20–2.00 (21H, m), 0.90 (6H, two over-
lapping t, J 7.0 Hz, CH2Me, CH2Me); dC (500 MHz, CDCl3, þ25 ꢀC)
171.1, 75.9, 68.4, 65.2, 61.0, 58.4, 40.1, 39.8, 37.4, 34.8, 31.3, 31.2, 29.9,
27.9 (2C), 22.7, 22.6, 20.9, 14.1, 14.0.
3.16.3. Ketonitrone 38a. (Found: C, 61.7; H, 9.4; N, 5.2. C14H25NO4
requires C, 61.97; H, 9.29; N, 5.16%.); nmax (neat) 3366, 2955, 2929,
2858, 1738, 1446, 1367, 1245, 1193, 1150, and 1041 cmꢁ1
;
dH
1046, and 731 cmꢁ1
;
dH (500 MHz, CDCl3, þ25 ꢀC) 4.11–4.04 (1H,
(500 MHz, CDCl3, þ25 ꢀC) 6.13 (1H, Br OH), 4.05 (2H, apparent d, J
6.1 Hz, CH2OAc), 3.96 (1H, m, CHOH), 3.96–3.84 (2H, m, C6-H2), 3.04
(1H, dd, J 9.7, 12.9 Hz, C6-CHaHbCHOH), 2.73–2.57 (1H, m, C6-
CHaHbCHOH), 2.36 (1H, apparent d, J 11.9 Hz, C3-HaHb), 2.28–2.20
(1H, m, C3-HaHb), 2.09 (3H, s, COMe), 1.20–1.90 (9H, m), 0.91 (3H, t,
J 6.7 Hz, Me); dC (500 MHz, CDCl3, þ25 ꢀC) 170.8, 148.5, 71.8, 66.5,
57.0, 40.0, 38.4, 33.6, 30.0, 27.7, 25.7, 22.7, 20.8, 14.1.
m, C6-H), 4.03–3.94 (2H, m, CH2OAc), 3.92–3.84 (1H, m, C6-
CH2CHO), 2.57 (1H, dd, J 5.3, 17.2 Hz, C3-HaHe), 2.44–2.34 (1H, m,
C6-CHaHbCHO), 2.23 (1H, dd, J 10.2, 17.2 Hz, C3-HaHe), 2.07 (3H, s,
COMe), 1.99–1.90 (2H, m, C6-CHaHbCHO, C4-H), 1.89–1.78 (1H, m,
C5-HaHe), 1.75–1.65 (1H, m, C5-HaHe), 1.54–1.28 (6H, m, (CH2)3),
0.91 (3H, t, J 7.0 Hz, Me); dC (500 MHz, CDCl3, þ25 ꢀC) 170.8,
163.7, 69.2, 66.6, 55.6, 41.2, 37.4, 33.6, 31.3, 28.5, 27.7, 22.6,
20.7, 14.0.
3.17. MCPBA oxidation of adduct 36a to nitrones 37a and 38a.
Cycloaddition of 37a with methyl methacrylate (21)
3.19. MCPBA oxidation of adduct 36b to nitrones 37b and 38b.
Cycloaddition of 37b with styrene (9b) to cycloadducts 40b
and 41b
The mixture of nitrones 37a and 38a (prepared by MCPBA oxi-
dation of 36a (1.0 mmol) as described in Section 3.16) in CH2Cl2
(10 mL) was treated with methyl methacrylate (1.0 mL) and the
mixture was stirred at 20 ꢀC for overnight. The ketonitrone was
unreactive under these conditions. After removal of the solvent and
excess alkene, the residual liquid was separated by chromatography
over silica gel using 97:3 ether/methanol as eluant to give the first
fraction as a nonseparable mixture of three isomers as a colorless
liquid (48 mg, 8.7%). Continued elution gave the second fraction
containing the major adduct 48 as a colorless liquid (353 mg, 63%).
Analysis of the first fraction revealed the presence three isomers as
indicated by the 1H NMR spectrum, which displayed C(2) methyl
To a stirred solution of the cycloadduct 36b (3.0 mmol) was
oxidized with MCPBA using procedure as described in Section 3.16
to give in dichloromethane (30 mL) at 20 ꢀC was added MCPBA
(3.0 mmol) in one portion. After 30 min at 20 ꢀC the organic layer
was washed with 5% NaHCO3 solution (3ꢂ10 mL). The combined
aqueous layers were re-extracted with CH2Cl2 (3ꢂ25 mL). The
combined organic layers was dried (Na2SO4), concentrated to give
a mixture of the aldonitrone 37b and ketonitrone 38b in a ratio of
82:18, respectively, as determined by 1H NMR integration of several
proton signals. A small portion of the solution was concentrated for
1H NMR analysis, which revealed the aldonitrone 37b having the
singlets at
d 1.45, 1.46, and 1.49 ppm in an approximate ratio of
1.5:1:1. The acetyl singlets appeared at 2.01, 2.02, and 2.03 ppm and
the CO2Me singlets appeared at 3.71, 3.74, and 3.75 ppm. The ratio
of 48 and the combined minor isomers was thus found to be 88:12.
following characteristic signals at d 7.19 (1H, t, J 3.5 Hz, CH]N), 4.09
(1H, m, ]NCH), 2.06 (3H, s), 3.97 (2H, d, J 61 Hz, CH2O), 5.05 (1H,
dd, J 3.6, 7.4 Hz). The NMR spectra of the ketonitrone 38b are de-
scribed later.
3.17.1. Major adduct 48. (Found: C, 61.3; H, 8.9; N, 3.7. C19H33NO6
requires C, 61.43; H, 8.95; N, 3.77%.); nmax (neat) 3445, 2953, 2931,
2858,1742,1738,1732,1462,1454,1446,1434,1371,1242,1150,1121,
1038, and 982 cmꢁ1. The major and minor invertomers of 48 at
ꢁ40 ꢀC were found to be in a ratio of 72:28 as determined by in-
tegration of several proton signals.
After exchanging the solvent CH2Cl2 with toluene (15 mL), the
above solution of nitrones was treated with styrene (9b) (5 mL) at
60 ꢀC for 48 h. After removal of the solvent and excess alkene, the
residual mixture was analyzed by 1H NMR analysis, which revealed
the presence of two cycloadducts 40b and 41b as well as the
unreacted ketonitrone 38b. The 40b/41b was found to be in a ratio
of 40:60 as determined by integration of several proton signals at
3.17.1.1. Major invertomer of 48. dH (500 MHz, CDCl3, ꢁ40 ꢀC) 5.00 (1H,
Br OH), 3.82 (3H, s, CO2Me), 3.96–3.78 (4H, m, CH2OAc, C7-CH2CHO,
C3a-H), 3.65–3.55 (1H, m, C7-H), 2.11 (3H, s, COMe), 1.90–2.50 (5H, m),
1.50 (3H, s, C2-Me), 1.00–1.75 (10H, m), 0.91 (3H, t, J 6.7 Hz, CH2Me); dC
(500 MHz, CDCl3, ꢁ40 ꢀC) 173.8, 171.5, 80.5, 70.0, 68.3, 54.7, 53.1 (2C),
45.7, 36.6, 35.9, 32.1, 28.9, 28.4, 27.2, 25.9, 22.8, 21.2, 14.3.
d 3.16 (1H, m, major 41b), 4.15 (2H, AB, CH2O, major 41b), 3.90 (2H,
d, CH2O, minor 40b). The crude mixture of adducts were purified by
chromatography over silica gel using 3:2 hexane/ether as eluant to
give a nonseparable mixture of the cycloadducts 40b and 41b (in
a ratio of 40:60) as a colorless liquid (830 mg, 70%). TLC analysis in
several solvents revealed the nonseparability of the adducts by
silica gel chromatography. The adduct mixture was not analyzed
further, instead it was hydrolyzed by NaOH to a separable mixture
of isomers 44 and 45 (See Section 3.20). Finally, elution with 80:20
ether/methanol afforded the unreacted ketonitrone 38b as a white
solid (122 mg, 14%).
3.17.1.2. Minor invertomer of 48. The 1H NMR (500 MHz, CDCl3,
ꢁ40 ꢀC) revealed the following non-overlapping signals at: 3.79 (3H,
s, CO2Me), 2.89–2,82 (1H, m), 2.09 (3H, s, COMe),1.42 (3H, s, C2-Me);
dC (500 MHz, CDCl3, ꢁ40 ꢀC) 175.8, 171.5, 79.8, 71.2, 68.3, 56.2, 55.5,
53.1, 44.3, 37.8, 35.9, 31.2, 30.0, 28.4, 27.8, 24.7, 22.6, 21.2, 14.3.
3.19.1. Ketonitrone 38b. Mp 98–99 ꢀC (CH2Cl2/pentane), m/z 274
[MþꢁOH]; (Found: C, 65.8; H, 7.3; N, 4.7. C16H21NO4 requires C,
65.96; H, 7.27; N, 4.81%.); nmax (KBr) 3146, 2953, 2919, 2857, 1735,
1615, 1485, 1448, 1419, 1363, 1243, 1187, 1144, 1056, 1030, 990, 915,
3.18. MCPBA oxidation of adduct 36a to lactam 39a
To
a stirred solution of the cycloadduct 36a (128 mg,
0.5 mmol) in dichloromethane (10 mL) at ꢁ40 ꢀC was added
882, 834, 766, and 709 cmꢁ1
,
dH (500 MHz, CDCl3, þ25 ꢀC) 7.30

8242
B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
(6H, Ph, OH), 5.17 (1H, dd, J 3.1, 8.0 Hz, PhCHO), 3.92–3.82 (4H, m,
CH2OAc, C6-H2), 3.04 (1H, dd, J 2.2, 13.2 Hz, C2-CHaHbCHO), 2.94
(1H, dd, J 7.7, 13.2 Hz, C2-CHaHbCHO), 2.41 (1H, dd, J 5.5, 19.5 Hz,
C3-HaHb), 2.13–2.03 (1H, m, C3-HaHb), 2.05 (3H, s, COMe), 2.02–
1.90 (1H, m, C4-H), 1.70 (1H, dd, J 9.7, 19.5 Hz, C5-HaHb),1.67–1.55
(1H, m, C5-HaHb); dC (500 MHz, CDCl3, þ25 ꢀC) 170.6, 148.1, 144.3,
128.3 (2C), 127.3, 125.1 (2C), 73.7, 66.1, 56.7, 42.6, 33.9, 29.6, 25.3,
20.7.
(2C), 127.8, 127.0, 126.6 (2C), 125.7 (2C), 77.4, 71.3, 63.6, 61.8, 59.0,
43.0, 42.7, 34.6, 31.2, 29.6.
3.21. MCPBA oxidation of adduct 36b to lactam 39b
The cycloadduct 36b (0.5 mmol) was oxidized with MCPBA
(1.1 mmol) using procedure as described in Section 3.18. Similar work
up and chromatography afforded the lactam 39b as a white solid
(115 mg, 75%). 1H NMR revealed the presence of ketonitrone 38b
(w15%). Mp 96–97 ꢀC(ether); m/z307[Mþ];(Found:C,62.4;H, 6.7;N,
4.5. C16H21NO5 requires C, 62.53; H, 6.89; N, 4.56%.); nmax (KBr) 3136,
3025, 2942, 2922, 2883,1740,1622,1492,1454,1418,1365,1342,1243,
3.20. Conversion of 40b and 41b into 44 and 45 by hydrolysis
with NaOH
1225,1181, 1123, 1085,1045, 759, and 701 cmꢁ1
; dH (500 MHz, CDCl3,
A solution of 40b and 41b, in a ratio of 40:60 (800 mg,
2.02 mmol) in methanol (5 mL) containing NaOH (100 mg,
2.5 mmol) was stirred at 20 ꢀC for 10 min. The reaction was over
as indicated by TLC experiment (silica, ether). The reaction
mixture was diluted with water (10 mL) and extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers was dried
(Na2SO4) and concentrated and the residual liquid was separated
by chromatography over silica gel using ether as eluant to give
45 as a white solid (310 mg). Continued elution gave a mixture of
adducts 44 and 45 (132 mg) and finally the pure adduct 44
(200 mg). The total yield of the hydrolyzed adducts was found to
be 642 mg, 90%. The ratio of the hydrolyzed adducts 44 and 45
was found to be similar to the ratio of the starting acetylated
adducts 40b and 41b as revealed by the 1H NMR of the crude
mixture.
þ25 ꢀC) 7.40–7.26 (5H, m, Ph), 5.03 (1H, d, J 6.5 Hz, PhCHO), 4.12–4.00
(1H, m, C6-H), 3.95 (2H, d, J 6.1 Hz, CH2OAc), 2.56(1H, dd, J 5.0,17.1 Hz,
C3-HaHe), 2.38–2.24 (1H, m, C6-CHaHbCHO), 2.20 (1H, dd, J 10.4,
17.1 Hz, C3-HaHe), 2.20 (1H, overlapping m, C6-CHaHbCHO), 2.05 (3H,
s, COMe), 1.85–1.75 (2H, m, C4-H, C5-HaHe), 1.45–1.35 (1H, m, C5-
HaHe); dC (500 MHz, CDCl3, þ25 ꢀC) 170.8, 164.0, 144.2, 128.4 (2C),
127.4, 125.5 (2C), 71.51, 66.5, 55.8, 43.0, 33.6, 31.1, 28.2, 20.7.
3.22. Conversion of 40a to 42 by treatment with zinc
and acetic acid
To a vigorously stirred solution of the adduct 40a (0.3 mmol) in
acetic acid (2 mL) and water (2 mL) at 60 ꢀC was added Zn (0.85 g) in
two portions (ca. 5 min). The reaction mixture was stirred at 60 ꢀC for
a total 30 min. The reaction mixture was decanted and the residual
solid was washed with water (10 mL) and CH2Cl2 (20 mL). After ba-
sification (K2CO3), the aqueous layer was extracted with CH2Cl2
(3ꢂ20 mL). Theorganiclayerwasdried(Na2SO4), concentratedtogive
the amine 42 in almost quantitative yield as a solid. Mp 75–76 ꢀC
(ether); (Found: C, 66.9; H,10.8; N, 3.8. C20H39NO4 requires C, 67.19; H,
10.99; N, 3.92%.); nmax (neat) 3313, 2929, 2858,1742,1574,1433,1454,
3.20.1. Minor diasteromer 44. Colorless liquid; m/z 353 [Mþ];
(Found: C, 74.5; H, 7.5; N, 3.9. C22H27NO3 requires C, 74.76; H, 7.70;
N, 3.96%.); nmax (neat) 3354, 3062, 3030, 2919, 1603, 1493, 1452,
1367, 1307, 1043, 952, 911, 858, 788, 700 cmꢁ1. The major and minor
invertomers of 44 at ꢁ40ꢀꢀC were found to be in a ratio of 87:13 as
determined by integration of the benzylic proton signals.
1368, 1243, 1127, 1092, 1037, and 732 cmꢁ1
; dH (500 MHz, CDCl3,
þ25 ꢀC) 4.0–3.0 (3H, br, NH, OH, OH), 3.90 (1H, dd, BX of a ABX, J 6.1,
11.0 Hz, CHaHbOAc), 3.85 (1H, dd, AX of a ABX, J 6.4, 11.0 Hz,
CHaHbOAc), 3.82–3.80 (2H, m, CHOH, CHOH), 3.59–3.47 (1H, m, C2-H),
3.21–3.08 (1H, m, C6-H), 2.20–2.10 (1H, m, C4-H), 2.08 (3H, s, COMe),
1.20–1.70 (20H, m), 0.90 (6H, two overlapping triplets, J 7.0 Hz, Me,
Me); dC (500 MHz, CDCl3, þ25 ꢀC) 171.1, 69.8, 69.2, 68.2, 47.9, 45.6,
42.8,37.4,37.0,36.2, 35.1, 34.0, 30.9, 28.3, 28.1, 22.8(2C), 20.9,14.1(2C).
3.20.1.1. Major invertomer of 44. dH (500 MHz, CDCl3, ꢁ40 ꢀC) 7.37–
7.21 (10H, m, Ph, Ph), 6.75 (1H, br, OH), 5.12–5.06 (2H, m, C2-H,
PhCHOH), 3.75–3.65 (1H, m, C3a-H), 3.64–3.54 (1H, m, C7-H),
3.50–3.40 (2H, m, CH2OH), 2.56–2.40 (4H, m, C3-H2, C7-CHaHbCHO,
OH), 1.92–1.80 (1H, m, C5-H), 1.74 (1H, apparent d, J 14.0 Hz, C7-
CHaHbCHO), 1.63 (1H, apparent d, J 13.2 Hz, C4-HaHe), 1.55 (1H, dt, J
5.2, 13.2 Hz, C6-HaHe), 1.22 (1H, apparent q, J 12.2 Hz, C4-HaHe),
1.15 (1H, apparent d, J 12.2 Hz, C6-HaHe); dC (500 MHz, CDCl3,
-40 ꢀC) 144.0, 143.3, 128.5 (2C), 128.2 (2C), 127.4, 126.6, 125.4 (2C),
125.3 (2C), 76.3, 72.2, 67.4, 54.9, 53.3, 44.4, 38.7, 32.1, 28.6, 26.6.
3.23. Conversion of 41a to 43 by treatment with zinc
and acetic acid
Using procedure as described in Section 3.22, the adduct 41a
was converted into 43 as a solid in 95% yield. Mp 64–65 ꢀC (ether);
(Found: C, 66.9; H, 11.2; N, 4.0; C20H39NO4 requires C, 67.19; H,
10.99; N, 3.92%.) nmax (neat) 3351, 2928, 2858, 1742, 1645, 1632,
3.20.1.2. Minor invertomer of 44. Minor invertomer of 44 has the
following nonoverlaping signals: dH (500 MHz, CDCl3, ꢁ40 ꢀC)
4.90 (1H, m, C2-H), 4.88–4.80 (1H, m, PhCHOH), 3.92–3.84 (2H, m,
C3a-H, C7-H), 3.01–2.89 (2H, m, C3-H2), 2.46–2.38 (1H, m, C7-
CHaHbCHO), 2.30–2.20 (1H, m, C7-CHaHbCHO), 1.10–1.00 (1H, m,
C6-HaHe); dC (500 MHz, CDCl3, ꢁ40 ꢀC) 73.8, 66.5, 57.0, 42.4, 33.3,
33.0.
1573, 1555, 1452, 1370, 1246, 1128, and 1037 cmꢁ1
; dH (500 MHz,
CDCl3, þ25 ꢀC) 4.18 (2H,d, J 7.9 Hz, CH2OAc), 3.83–3.73 (2H, m,
CHOH, CHOH), 3.06–2.94 (2H, m, C2-H, C6-H), 2.20–2.10 (1H, m, C4-
H), 2.07 (3H, s, COMe), 1.20–1.60 (23H, m), 0.90 (6H, t, J 6.8 Hz, Me,
Me); dC (CDCl3, þ25 ꢀC) 171.2, 68.5 (2C), 65.3, 48.5 (2C), 42.8 (2C),
37.7 (2C), 32.5 (2C), 31.5, 28.0 (2C), 22.7 (2C), 21.0, 14.1 (2C).
3.20.2. Major diasteromer 45. m/z 353 [Mþ]; mp 125–126 ꢀC
(ether/pentane). (Found: C, 74.8; H, 7.8; N, 3.9. C22H27NO3 requires
C, 74.76; H, 7.70; N, 3.96%.) nmax (KBr) 3280, 3181, 3029, 2906, 1485,
1452, 1380, 1306, 1242, 1206, 1037, 910, 859, 799, 760, 699, 624, and
556 cmꢁ1. The 1H spectrum revealed the presence of a single
invertomer. dH (500 MHz, CDCl3, 25 ꢀC) 7.38–22 (10H, m, Ph, Ph),
5.11 (1H, dd, J 2.2, 10.2 Hz, C2-H), 5.07 (1H, dd, J 4.3, 9.5 Hz,
PhCHOH), 4.36 (1H, br s, OH), 3.66 (2H, d, J 7.3 Hz, CH2OH), 3.15–
3.05 (1H, m, C7-H), 2.79–2.63 (1H, m, C3-HaHb), 2.35 (1H, apparent
q, J 10.7 Hz, C3-HaHb), 1.70–2.30 (8H, m), 1.65 (1H, dt, J 5.1, 13.0 Hz,
C6-HaHe); dC (500 MHz, CDCl3, 25 ꢀC) 144.8, 141.4, 128.5 (2C), 128.2
3.24. Conversion of 44 to 46 by treatment with zinc
and acetic acid
Using procedure as described in Section 3.22, the adduct 44 was
converted into 46 as a solid in 95% yield. In the work up procedure,
the aqueous layer was extracted with hot CHCl3 instead of CH2Cl2 (as
a result of poor solubility of the product). Mp 146–148 ꢀC (ether);
(Found: C, 74.1; H, 8.1; N, 3.8. C22H29NO3 requires C, 74.33; H, 8.22;
N, 3.94%.); nmax (KBr) 3320, 3054, 3020, 2928, 2907, 2853, 1490,

B.A. Moosa, S.A. Ali / Tetrahedron 65 (2009) 8231–8243
8243
1448, 1365, 1351, 1218, 1144, 1115, 1094, 1067, 1022, 914, 881, 853,
786, 760, 749, and 701 cmꢁ1 dH (500 MHz, 9:1 CDCl3/CD3OD, 25 ꢀC)
References and notes
;
1. (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, NY, 1984; Vol. 2, Chapter 9, pp 83–168; (b) Confalone,
P. N.; Huie, E. M. Org. React. 1988, 36, 1–173; (c) Iida, H.; Kibayashi, C. Yuki Gosei
Kagaku Kyokaishi 1983, 41, 652–666.
2. (a) For a review on asymmetric 1,3-dipolar cycloaddition reactions, see: Goe-
thelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863–909; (b) For a review on
enantiopure cyclic nitrones for asymmetric synthesis, see: Revuelta, J.; Cicchi,
S.; Goti, A.; Brandi, A. Synthesis 2007, 4, 485–504.
3. (a) Ali, S. A.; Wazeer, M. I. M. J. Chem. Soc., Perkin Trans. 1 1988, 597–604; (b) Ali,
S. A.; Wazeer, M. I. M. J. Chem. Soc., Perkin Trans. 2 1986, 1789–1792; (c) Ali, S. A.;
Wazeer, M. I. M. Tetrahedron 1988, 44, 187–193; (d) Ali, S. A.; Khan, J. H.;
Wazeer, M. I. M. Tetrahedron 1988, 44, 5911–5920.
4. For reviews on 1,3-dipolar cycloaddition reactions of cyclic nitrones, see: (a) De
March, P.; Figueredo, M.; Font, J. Heterocycles 1999, 50, 1213–1226; (b) Merino,
P. Sci. Synth. 2004, 27, 511–580; (c) Verboom, W.; Reinhoudt, D. N. Bull. Soc.
Chim. Fr. 1990, 704–713.
5. (a) LeBel, N. A.; Spurlock, L. A. J. Org. Chem. 1964, 29, 1337–1339; (b) Tufariello, J.
J.; Mullen, J. B.; Tribulski, E. J.; Wong, S. C.; Ali, S. A. J. Am. Chem. Soc. 1979, 101,
2435–2442; (c) LeBel, N. A.; Post, M. E.; Hwang, D. J. Org. Chem. 1979, 44,
1819–1823.
6. (a) Carruthers, W.; Coggins, P.; Weston, J. B. J. Chem. Soc., Perkin Trans. 1 1990,
2323–2327; (b) Ali, S. A.; Wazeer, M. I. M. Tetrahedron Lett. 1992, 33, 3219–
3222; (c) Perzanowski, H. P.; Al-Jaroudi, S. S.; Wazeer, M. I. M.; Ali, S. A. Tet-
rahedron 1997, 53, 11869–11880; (d) Ali, S. A. J. Chem. Res., Synop. 1994, 32–33;
(e) Ali, S. A. J. Chem. Res., Synop. 1994, 54–55; J. Chem. Res., Microprint 1994,
301–317.
7.37–7.24 (10H, m, Ph, Ph), 4.94 (1H, dd, J 3.4, 8.6 Hz, PhCHOH), 4.98
(1H, dd, J 4.3, 6.1 Hz, PhCHOH), 3.35 (3H, a two proton d, J 6.1 Hz,
CH2OH, and an overlapping 1H, m, C2-H), 3.19–3.11 (1H, m, C6-H),
2.71 (4H, br, OHs, NH), 2.37 (1H, ddd, J 4.2, 10.4, 14.6 Hz, C2-
CHaHbCHO), 1.90–1.75 (2H, m, C2-CHaHbCHO, C6-CHaHbCHO), 1.72–
1.65 (2H, m, C6-CHaHbCHO, C4-H), 1.59–1.53 (1H, m, C5-CHaHb),
1.51–1.47 (1H, m C5-CHaHb), 1.18 (1H, dt, J 5.5, 12.8 Hz, C3-CHaHb),
0.83 (1H, q, J 12.5 Hz, C3-HaHb); dC (500 MHz, 9:1 CDCl3/CD3OD,
25 ꢀC) 145.1, 144.9, 128.4 (2C), 128.4 (2C), 127.1, 127.1, 125.6 (2C),
125.6 (2C), 72.1, 70.5, 67.8, 48.2, 45.8, 45.3, 37.7, 36.2, 33.9 (2C).
3.25. Conversion of 45 to 47 by treatment with zinc
and acetic acid
Using procedure as described in Section 3.22, the adduct 45 was
converted into 47 as a solid in 90% yield. In the work up procedure,
the aqueous layer was extracted with hot CHCl3 instead of CH2Cl2
(as a result of poor solubility of the product). Mp 199–200 ꢀC
(ether); (Found: C, 74.2; H, 8.0; N, 3.9. C22H29NO3 requires C, 74.33;
H, 8.22; N, 3.94%.); nmax (KBr) 3311, 3171, 2931, 2884, 2718, 1450,
1388,1332,1262,1205,1119,1063,1037, 987, 914, 878, 827, 788, 759,
7. Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G. A. Conformational Analysis,
2nd ed.; Interscience: New York, NY, 1966; p 28.
and 702 cmꢁ1 dH (500 MHz, 9:1 CDCl3/CD3OD, 25 ꢀC) 7.38–7.32
;
8. Ali, S. A.; Wazeer, M. I. M. Tetrahedron 1993, 49, 4339–4354.
9. AlSbaiee, A.; Ali, S. A. Tetrahedron 2008, 64, 6635–6644.
10. Murahashi, S. I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383–2386.
11. Ali, S. A.; Khan, J. H.; Wazeer, M. I. M.; Perzanowski, H. P. Tetrahendron 1989, 45,
5979–5986.
(10H, m, Ph, Ph), 4.88 (2H, dd, J 4.3, 8.0 Hz, PhCHOH, PhCHOH), 4.00
(4H, br s, OHs, and NH), 3.55 (2H, d, J 7.6 Hz, CH2OH), 2.95–2.82 (2H,
m, C2-H, C6-H), 2.08–2.00 (1H, m, C4-H), 1.72–1.68 (4H, m, C3-
CH2CHO, C6-CH2CHO,), 1.64 (2H, apparent d, J 13.5 Hz, C3-HaHe, C5-
HaHe), 1.41 (2H, dt, J 5.2, 13.5 Hz, C3-HaHe, C5-HaHe); dC (500 MHz,
9:1 CDCl3/CD3OD, 25 ꢀC) 144.5 (2C), 128.1 (4C), 127.0 (2C), 125.4
(4C), 70.8 (2C), 62.7, 48.1 (2C), 44.7 (2C), 34.4, 32.6 (2C).
12. Riddel, F. G. Tetrahedron 1981, 37, 849–858.
13. Raban, M.; Cost, D. Tetrahedron 1984, 40, 3345–3381.
14. Raban, M.; Jones, F. B., Jr.; Carlson, E. H.; Bannuci, E.; LeBel, N. A. J. Org. Chem.
1970, 35, 1496 and references cited therein.
15. Wazeer, M. I. M.; Ali, S. A. Magn. Reson. Chem. 1993, 31, 12–16.
16. Finke, H. L.; McCullough, J. P.; Messerly, J. F.; Osborn, A.; Douslin, D. R. J. Chem.
Thermodyn. 1972, 4, 477–494.
17. Ali, S. A.; AlSbaiee, A.; Wazeer, M. I. M. Arkivoc 2008, 17, 96–106.
18. Hootele, C.; Ibebeke-Bomangwa, W.; Driessens, F.; Sabil, S. Bull. Soc. Chim. Belg.
1987, 96, 57–61.
19. Kalinowski, H.; Berger, S.; Braun, S. C-13 NMR Spectroscopy; Wiley: Chichester,
UK, 1988.
Acknowledgements
The facilities provided by the King Fahd University of Petroleum
and Minerals, Dhahran, are gratefully acknowledged.