Hydrazide-catalyzed 1,3-dipolar nitrone cycloadditions

Article abstract of DOI:10.1016/j.tet.2007.08.110

The triflate salts of cyclic hydrazides function as asymmetric catalysts for the [3+2]cycloadditions of nitrones with α,β-unsaturated aldehydes. The camphor-derived hydrazides show a preference for the exo isomers during these reactions, providing a compliment to other organically catalyzed dipolar cycloadditions. Enantiomeric excesses as high as 93% were realized for the exo isomers, while some endo products were obtained in 94% ee.

Full text of DOI:10.1016/j.tet.2007.08.110

Tetrahedron 63 (2007) 11644–11655
Hydrazide-catalyzed 1,3-dipolar nitrone cycloadditions
*
Mathieu Lemay, John Trant and William W. Ogilvie
Department of Chemistry, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
Received 29 June 2007; revised 23 August 2007; accepted 30 August 2007
Available online 6 September 2007
Abstract—The triflate salts of cyclic hydrazides function as asymmetric catalysts for the [3+2]cycloadditions of nitrones with a,b-unsatu-
rated aldehydes. The camphor-derived hydrazides show a preference for the exo isomers during these reactions, providing a compliment to
other organically catalyzed dipolar cycloadditions. Enantiomeric excesses as high as 93% were realized for the exo isomers, while some endo
products were obtained in 94% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
1,3-dipolar cycloadditions between nitrones and a,b-unsatu-
rated aldehydes to provide isoxazolidines with high selec-
tivity.
Using small chiral organic molecules as catalysts, numerous
new technologies have recently been developed making
enantioselective organocatalysis a viable tool for asymmet-
Diels-Alder
1
ric synthesis. Several strategies have emerged, and among
these methods, the use of asymmetric secondary amines
has received considerable attention. An example of the ap-
plication of this can be found in the catalytic asymmetric
OHC
+
R
R
CHO
TfOH
NH
R
4
5
2
[
3+2]dipolar cycloaddition reaction, a powerful method
2
:1 endo:exo
up to 92% ee
for the enantioselective construction of heterocycles. Of
the heterocycles that have been prepared using this chemis-
try, isoxazolidines are implicated in the assembly of biolog-
ically relevant compounds such as amino acids, b-lactams,
O
N
N
H
Bn
O
N
1
TfO
Bn
3
Bn
Ph
Bn
Ph
R
O
O
O
N
N
O
N
2
+
R
R
3
Ph
Ph
amino carbohydrates, and alkaloids. Metal-catalyzed asym-
metric variations of these [3+2]cycloadditions have enjoyed
CHO
8 CHO
6
7
4
,5
considerable success, however, there have been few devel-
opments making use of chiral organocatalysts since the orig-
inal report from MacMillan.
[
3+2] Dipolar Cycloaddition
2
a
The catalytic effect of secondary amine salts has been de-
scribed as the result of a reversible activation of an a,b-un-
saturated aldehyde by iminium ion formation. The LUMO
of the alkene moiety is consequently lowered and its interac-
tion with the nitrone is facilitated, leading to increased reac-
2. Results and discussion
We sought to establish reaction conditions that would fur-
nish the isoxazolidine products in good yield by the reaction
with N-benzylidenebenzylamine-N-oxide (6) and E-croto-
naldehyde (9) in the presence of hydrazide catalyst 1. The
products were obtained as mixtures of exo and endo isomers,
6
tion rates. Recently, our laboratory has been involved in the
development of strategies for enantioselective catalysis us-
ing chiral hydrazides. In our studies, we have demonstrated
7
8
generally favoring the exo isomer. The choice of solvent
that the LUMO-lowering activation of a,b-unsaturated alde-
hydes by the reversible formation of hydrazonium ions from
hydrazides is an efficient platform for the development of
enantioselective Diels–Alder cycloadditions. Herein, we
demonstrate the efficacy of hydrazide-based catalysts in
was found to have a significant impact on the outcome of
the reaction, not only in terms of selectivity, but also with
respect to the yield of the process. This was in part a conse-
quence of the formation of an undesired side-product result-
ing from the hydrolysis of nitrone 6. During the reaction, the
initial nitrone could react with water to release a hydroxyl-
amine, which could then condense with the a,b-unsaturated
aldehyde 9 to afford a new nitrone. This new species then
*
Corresponding author. Tel.: +1 613 562 5800; fax: +1 613 562 5170;
e-mail: wogilvie@uottawa.ca
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.110

M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
11645
underwent a [3+2]cycloaddition to give the undesired prod-
uct 12. Although this type of nitrone exchange is not uncom-
Table 2. Effect of water content on the hydrazide-catalyzed cycloaddition
reaction between E-crotonaldehyde 9 and nitrone 6
2b,f
mon, we wished to minimize the production of 12, which
displayed no enantiomeric excess. Most of the solvents in-
9
O
Bn
Ph
Bn
Ph
vestigated gave mixtures that contained significant amounts
of this by-product (Table 1, entries 1, 4, and 8–10) making
further optimizations in these media impractical. The use
of benzene, CHCl , or CH CN resulted in the production
NH
O
O
9
N
N
O
N
+
+
TfOH
1
Bn
.1M CH3NO2
4 °C
O
N
CHO
10
11CHO
Ph
Ph
0
3
3
+
of modest amounts of this material (entries 2, 3, and 7)
whereas reactions run in CH Cl or CH NO afforded only
6
exo
endo
2
2
3
2
a
Entry Water (equiv) Yield % exo/endo
b
c
c
minor amounts of 12. In particular, the reaction run in
CH NO afforded a 68:32 mixture of exo and endo isomers
ee exo
ee endo
3
2
1
2
3
4
5
6
7.5
70 (6)
17 (0)
62 (12)
82 (0)
84 (0)
80 (0)
68:32
18:82
68:32
62:38
58:42
63:37
53
—
41
72
79
80
78
—
78
80
78
77
1
0
d
(
10 and 11) in 70% combined yield. The endo isomer was
formed in 78% enantiomeric excess while the formation of
2 was minimized (entry 6).
0
20
1
1
0.2
0.5
The effect of water on the outcome of the cycloaddition was
then investigated. When the solvent was dried by the pres-
ence of molecular sieves, the yield decreased to 17% consis-
tent with the requirement of water for catalyst turnover
a
Isolated combined yield of 10 and 11. Value in parentheses refers to the
yield of 12.
Determined by H NMR of the crude product.
Determined by HPLC after reduction to the corresponding alcohol.
Molecular sieves of 4 A˚ were added.
b
c
d
1
(
Table 2, entry 2). Unexpectedly, the anhydrous reaction
also showed a propensity to generate the endo isomer.
When excess water was added, the hydrolyzed product 12
became more prevalent and the enantiomeric excess of the
exo adduct was lowered (entry 3). Reducing the amount of
available water to 1 equiv gave not only improved product
yields, but also increased the enantioselectivity of both the
exo and endo isomers relative to that realized in entries 1
and 3. No by-product 12 was observed in this reaction, con-
sistent with the observed requirement for excess water dur-
ing the formation of 12 (entry 4). Further reducing the
amount of water available resulted in a slight improvement
in enantioselectivity for the exo isomer while providing no
clear advantage for the endo product (entries 5 and 6). The
impact of the presence of water on the enantioselectivity is
surprising, in that only the enantiomeric ratio of the exo iso-
mer was strongly affected. The reasons for this are not clear,
but a Brønsted acid-catalyzed background reaction may be
implicated for this isomer.
Dipolar cycloadditions catalyzed by organic molecules typ-
ically require the presence of a large excess of a,b-unsatu-
rated aldehyde (up to 15 equiv) to assure completion of
2
the reaction. Hydrazide catalysts such as 1 rapidly and
completely form iminium ions with the aldehyde compo-
7
,11
nents of these processes,
and so a consistent supply of
reactive iminium intermediate is available enabling the reac-
tions to be performed with as little as 5.5 equiv of dipolaro-
phile. Slow addition of the aldehyde component using
a syringe-pump did not result in better selectivity but instead
reduced the combined yield of the desired cycloadducts from
82% to 59%.
Table 1. Effect of solvent on the hydrazide-catalyzed 1,3-dipolar cycloaddition reaction between E-crotonaldehyde 9 and nitrone 6
NH
O
O
Bn
Ph
Bn
Ph
Bn
N
O
O
O
TfOH
N
N
N
9
1
+
Bn
+
+
O
N
0.1M Solvent
.5 equiv. H2O
4 °C
CHO
CHO
CHO
12
7
Ph
Ph
10
exo
11
endo
+
6
a
b
c
c
Entry
Solvent
Yield %
exo/endo
ee exo
ee endo
1
2
3
4
5
6
7
8
9
Dioxane
Benzene
14 (38)
67 (25)
67 (12)
5 (48)
54 (6)
70 (6)
46 (19)
17 (35)
14 (38)
20 (56)
58:42
48:52
50:50
62:38
58:42
68:32
33:67
38:62
28:72
48:52
23
20
13
9
21
53
29
33
25
32
40
51
55
46
75
78
70
62
2
CHCl
THF
3
CH
CH
CH
2
3
3
Cl
NO
CN
2
2
DMF
DMSO
10
H
2
O
50
a
b
c
Isolated combined yield of 10 and 11. Value in parentheses refers to the yield of 12.
Determined by H NMR of the crude product.
Determined by HPLC after reduction to the corresponding alcohol.
1

11646
M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
Table 3. Effect of temperature and concentration on the hydrazide-catalyzed
dipolar cycloaddition reaction between E-crotonaldehyde 9 and nitrone 6
product 12 (entries 3–5), together with reduced enantiomeric
excesses, primarily in the exo adduct.
Variations in the side chain of the hydrazide catalyst had pre-
viously produced significant improvements in reactivity and
enantioselectivity. Several hydrazides containing a variety of
side chains were therefore prepared and tested as catalysts in
the [3+2] process. Incorporating a bulky tert-butyl group at
this position dramatically reduced the yield of the process
and produced no enantiomeric excess (Table 5, entry 2), sug-
gesting that the aromatic residue found in catalyst 1 was
essential at this position. We have previously found that
O
Bn
Ph
Bn
Ph
NH
O
O
9
N
N
+
O
N
+
TfOH
O
N
Bn
CHO
CHO
Ph
Ph
1 equiv. H O
10
11
2
CH3NO2
exo
endo
6
a
Entry Concentration Temperature Yield % exo/endo ee exo ee endo
b
c
c
ꢁ
(
M)
( C)
1
2
3
4
0.1
0.1
1.0
1.0
+4
ꢀ20
ꢀ20
+4
82 (0)
81 (0)
55 (4)
62:38
74:26
79:21
72
63
28
26
80
82
75
71
Table 5. Effect of the side chain of the hydrazide catalyst on the dipolar
cycloaddition reaction between E-crotonaldehyde 9 and nitrone 6
55 (11) 72:28
a
Isolated combined yield of 10 and 11. Value in parentheses refers to the
yield of 12.
Determined by H NMR of the crude product.
b
c
1
O
Bn
Ph
Bn
Ph
Determined by HPLC after reduction to the corresponding alcohol.
9
NH
O
O
N
N
+
O
N
R
+
TfOH
O
N
Reactions were performed at lower temperature in an at-
tempt to increase the selectivity. Although the diastereomer-
ic ratio of exo to endo products was found to be slightly
higher at ꢀ20 C than at +4 C, there was no significant ad-
vantage in terms of the enantioselectivity obtained (Table 3,
entries 1 and 2). Reactions performed at a higher concentra-
CHO
CHO
Ph
Ph
0.1M CH3NO2
10
11
endo
0
.5 equiv H2O
exo
6
ꢁ
ꢁ
a
b
c
Yield % exo/endo ee exo ee endo
c
Entry
1
R
Ph
80
24
63:37
67:33
80
2
77
2
ꢁ
tion at ꢀ20 C (entry 3) reduced the overall yield of the re-
action as well as the enantiomeric excess of the exo isomer.
When a concentrated reaction was performed at +4 C, de-
2
3
ꢁ
crease in both yields and enantioselectivities was noted. In
addition, significant amounts of the unwanted by-product
1
72 (3)
83
34:66
68:32
37
86
90
85
Ph
2 were observed using these conditions (entry 4).
4
Previously it has been shown that counterion effects may
have significant impacts on processes catalyzed by organic
catalysts. The present reaction was found to be sensitive
1
to the nature of the Brønsted co-catalyst used. Both triflic
and perchloric acids were found to produce the best yields
and enantioselectivities (Table 4, entries 1 and 2). Weaker
acids provided significantly larger amounts of undesired
5
81
76
88
81
55
94
75
72
64:36
63:37
78:22
74:26
76:24
83:17
75:25
71:29
73
77
17
64
0
76
63
53
65
18
59
68
57
CF3
Ph
6
Ph
N
Table 4. Effect of Brønsted acid co-catalyst on the 1,3-dipolar cycloaddition
between E-crotonaldehyde 9 and nitrone 6
7
N
N
8
NH
O
Bn
Ph
Bn
Ph
O
N
O
O
9
acid
N
N
1
Bn
+
9
+
O
N
0.1M CH3NO2
equiv H2O
CHO
CHO
11
1
Ph
Ph
10
+
4 °C
exo
endo
10
50
45
36
6
N
O
a
Yield %
b
c
c
Entry
Acid
exo/endo
ee exo
ee endo
O
N
1
1
2
1
2
3
4
5
CF SO
3
3
H
82 (0)
86 (0)
29 (31)
39 (24)
40 (14)
62:38
66:34
70:30
71:29
74:26
72
76
29
32
31
80
77
75
79
75
HClO
HCl
4
CH
CF
3
SO
CO
3
H
H
1
N
3
2
O
a
a
Isolated combined yield of 10 and 11. Value in parentheses refers to the
yield of 12.
Determined by H NMR of the crude product.
Isolated combined yield of 10 and 11. Value in parentheses refers to the
yield of 12.
Determined by H NMR of the crude product.
b
c
1
b
c
1
Determined by HPLC after reduction to the corresponding alcohol.
Determined by HPLC after reduction to the corresponding alcohol.

M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
11647
the incorporation of a conformational controlling element
onto the benzylic position of the catalyst afforded superior
picolyl-substituted catalysts (entries 7–9) afforded slightly
higher diastereoselectivities, in favor of the exo isomer, than
the catalyst bearing a simple benzyl side chain, the enantio-
meric excesses of the products were found to be low, particu-
larly when the 4-picolyl-substituted catalyst was used. The
picolyl-N-oxide substituted catalysts (entries 10–12) offered
somewhat higher exo/endo ratios (83:17 for entry 10) but af-
forded lower enantioselectivities than those of catalyst 1.
7
c
selectivities. The use of this rigidified catalyst did increase
the enantioselectivity of the endo isomer but also resulted in
a poor ee for the exo product (entry 3). The diastereoselectiv-
ity was reversed when this catalyst was used, thus giving
a slight preference for the endo adduct. When an electron
withdrawing p-CF group was incorporated on the phenyl
3
ring no significant changes were observed suggesting that
electronic effects did not offer any advantageous effects rel-
ative to the unsubstituted benzyl catalyst. Replacement of
the side chain with a bulkier diphenylmethyl group did not
improve the enantioselectivity as shown in entry 6. Interest-
ingly, this modification was previously found to be highly
Experiments that outline the scope of the present process are
given in Table 6. Ortho substituted aryl residues were toler-
ated on the nitrone component, resulting in a 92% yield of
products. In this case, the enantioselectivity of the endo
product was found to be higher than the enantioselectivity
of the same product produced from catalyst 1, however,
a slightly lower ee was noted for the corresponding exo ma-
terial (entry 3). Avariety of substituents were tolerated at the
para position including electron donating and withdrawing
substituents (entries 4, 6, 7, and 9). The nitrone substituents
7
c
deleterious in the Diels–Alder reaction.
We were pleased to find that a 1-methylnaphthyl moiety did
offer a slight advantage relative to the benchmark catalyst 1,
providing better diastereomeric ratios and improved enan-
tioselectivities for both the exo and endo cycloadducts (entry
(R ) could also be varied to include smaller groups, giving
3
4
). These improvements were, however, dependent on the
high ee’s for both the exo and endo products (entries 11–
14). In general the use of the catalyst bearing a 1-naphthyl
side chain gave small improvements in the enantioselectiv-
ities of the exo isomers (entries 2, 5, 8, and 12).
nature of the dipole used, and did not translate to all sub-
strates.
The investigation of the effect of the hydrazide catalyst side
chain was expanded to include sites for possible hydrogen-
bonding. Of the many organic catalysts being used for asym-
metric transformations, several incorporate pendant groups
that bring the reaction components together in the transition
state, often resulting in an increase in selectivity. To inves-
tigate this possibility, catalysts bearing picolyl or picolyl-
N-oxide side chains were synthesized and tested in the
We were pleased to find that larger a,b-unsaturated alde-
hydes such as those bearing n-propyl and iso-propyl substit-
uents afforded good enantioselectivities and yields (entries
15 and 16). Larger a,b-unsaturated aldehydes such as these
are seldom used in nitrone cycloadditions, particularly when
1
3
catalyzed by Lewis acid. On the other hand, when smaller
substrates such as acrolein were employed as the dipolaro-
phile, inseparable mixtures of regioisomers, together with
endo and exo cycloadducts, were obtained.
[3+2]cycloaddition reaction between N-benzylidenebenzyl-
amine-N-oxide 6 and E-crotonaldehyde 9. Although all the
Table 6. Hydrazide-catalyzed 1,3-dipolar cycloaddition reactions between various aldehydes and nitrones
NH
R2
O
O
R3
R4
R3
R4
N
R1
O
O
N
N
TfOH
+
R2
+
R2
CHO
endo
O
N
0.1M CH3NO2
.5 equiv H2O
4 °C
CHO
exo
0
R3
R4
+
a
Yield %
b
c
c
Entry
Catalyst (R
1
)
R
2
R
3
R
4
exo/endo
ee exo
ee endo
1
2
3
4
5
6
7
8
9
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Bn
Bn
Ph
Ph
82
83
92
87
87
88
85
89
67
94
71
80
61
38
86
68
62:38
68:32
33:67
48:52
48:52
57:43
64:36
66:34
55:45
45:55
52:48
52:48
57:43
50:50
60:40
57:43
72
86
59
79
76
84
85
90
61
60
92
93
80
69
84
66
80
85
94
87
92
80
76
76
73
81
80
79
89
88
74
77
CH
Bn
Bn
CH
Bn
Bn
CH
Bn
Bn
Bn
CH
Bn
Bn
Bn
Bn
2
2
2
-1-naphthyl
-1-naphthyl
-1-naphthyl
2-ClPh
4-OMePh
4-OMePh
4-MePh
i
4- PrPh
4- PrPh
i
3
4-CF Ph
10
11
12
13
14
15
16
2-Naphthyl
4-MePh
4-MePh
Ph
2-Furyl
Ph
Ph
2
-1-naphthyl
n-Propyl
Isopropyl
a
b
c
Isolated combined yield of endo and exo products.
Determined by H NMR of the crude product.
Determined by HPLC after reduction to the corresponding alcohol.
1

11648
M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
Based on calculations and X-ray structures of iminium ions
generated by hydrazide catalysts, a model for the facial
sensitive reagents. Reactions were monitored by thin layer
chromatography (TLC) using commercial aluminum-
backed silica gel sheets coated with silica gel 60 F254.
7
selectivity observed in the dipolar cycloaddition can be
proposed. The preferred cis-iminium intermediate leads to
the observed diastereoisomers 7 and 8 through bottom-face
approach of the nitrone as shown below. Stereochemical
bias is provided in this structure by the steric bulk of the
camphor bridgehead methyl groups that impair top-side ap-
proach of the nitrone. The low diastereoselectivity observed
is suggestive of a limited ability of the catalyst to discrimi-
nate between exo and endo pathways. Larger substituents
were introduced in place of the benzyl side chain of the cat-
alyst framework to test the effect of a potential increased ste-
ric requirement. Only small increases in diastereoselectivity
were observed (Table 6, entries 3, 4, and 6) suggesting that
other factors may be governing the diastereoisomer selection
in this catalytic system.
TLC spots were visualized under ultraviolet light or devel-
oped by heating after treatment with potassium permanga-
nate. Excess solvents were removed in vacuo at pressures
obtained by water or air aspirators connected to a rotary
evaporator. Trace solvents were removed on a vacuum
pump. Product purification by flash chromatography was
performed with Silica Gel 60 (230–400 mesh). Infrared
(IR) spectra were obtained as neat films on a sodium chloride
cell. Chemical shifts are reported downfield from tetrame-
thylsilane (d scale) in parts per million. Mass spectroscopy
(MS), using either electron impact (EI) or chemical ioniza-
tion (CI), was performed on a mass spectrometer with an
electron beam energy of 70 eV (for EI). Electrospray analy-
ses were run on a triple quad mass spectrometer VG QUAT-
TRO. High resolution mass spectroscopy (HRMS) was
performed on a mass spectrometer with an electron beam
of 70 eV, or a double focusing magnetic sector mass spec-
trometer. Melting points were measured using a Melt
Temp apparatus and are uncorrected.
Bn
O
N
N
N
N
Bn
O
N
O
O
N
4
1
2
.2. General procedure for the preparation of (S)-(D)-
0,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]dec-4-en-
-ones
1
,5
Bn
Bn
Ph
O
O
4.2.1. (S)-(D)-3-(2-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
cyclo[5.2.1.0 ]dec-4-en-2-one. Acetic acid (0.19 mL,
.38 mmol) was added dropwise to a solution of (S)-(+)-keto-
N
N
1
,5
Ph
3
CHO
exo
CHO
endo
1
2
13
pinic acid (3.08 g, 16.9 mmol) and 2-picolylhydrazine
2.50 g, 20.3 mmol) in anhydrous dichloromethane (150 ml)
(
at room temperature and the reaction mixture was stirred at
that temperature until judged complete by TLC analysis.
The solution was then passed through a short silica plug and
the solvent was removed in vacuo. The crude product was dis-
solved in mesitylene (120 mL) and the resulting solution was
refluxed while water was removed using a Dean–Stark appa-
ratus. Reflux was continued until consumption of the starting
material was complete as judged by TLC (46 h). The cooled
reaction mixture was directly loaded onto a flash column
that was eluted with hexanes followed by 40% EtOAc in hex-
3
. Conclusion
We have developed a highly enantioselective organocata-
lyzed [3+2]cycloaddition reaction using a range of nitrones
and a,b-unsaturated aldehydes. This new system nicely
complements other examples of organocatalyzed cycloaddi-
2
tions reactions reported to date. Although the diastereo-
selectivities observed were lower than some that have been
previously observed, the use of hydrazide catalysts allows
access to the exo cycloadduct, which is otherwise difficult
to obtain from acyclic dipolarophiles. Reaction optimization
studies suggest that rigorous control of the water content is
necessary for good yields in this process. Minimizing the
amount of water available prevents the hydrolysis of the
nitrone dipole, thus minimizing the amount of by-products
such as 12. The amount of water present also has an impact
on the enantioselectivity of the major exo isomer, and
suggests that a non-asymmetric background reaction may
be operative. Further investigations into the mechanism
and use of new organocatalysts for this reaction are under-
way and will be reported in due course.
anes to provide the desired compound as a white solid (3.10 g,
ꢁ
967, 1691, 1589 cm ; H NMR (500 MHz, CDCl ) d 8.57–
.53 (m, 1H), 7.65–7.61 (m, 1H), 7.20–7.14 (m, 2H), 5.00 (d,
6
2
8
8%). Mp 131–133 C; [a] +24.6 (c 1.11, CHCl ); IR (neat)
D
3
ꢀ1 1
3
J¼16.0 Hz, 1H), 4.97 (d, J¼16.0 Hz, 1H), 2.60 (ddd, J¼17.7,
3
.4, 3.4 Hz, 1H), 2.32 (ddd, J¼12.2, 4.4, 4.4 Hz, 1H), 2.26 (t,
J¼4.3 Hz, 1H), 2.19–2.10 (m, 2H), 1.73 (ddd, J¼13.3, 9.5,
13
4
.4 Hz, 1H), 1.51 (ddd, J¼13.2, 9.5, 4.4 Hz, 1H), 1.23 (s,
3
3H), 0.96 (s, 3H);
d 174.7 (C), 173.9 (C), 156.7 (C), 149.4 (CH), 136.7 (CH),
C NMR (125 MHz, CDCl )
1
4
1
22.3 (CH), 121.4 (CH), 63.6 (C), 49.9 (C), 49.7 (CH2),
9.3 (CH), 32.0 (CH ), 27.0 (CH ), 25.5 (CH ), 19.2 (CH ),
8.6 (CH ); MS (EI) 269.2 (M ); HRMS calcd for
3
2
2
2
3
+
C H N O 269.1528; found 269.1520.
16 19 3
4
. Experimental section
4
.2.2. (S)-(D)-3-(3-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
1
,5
4
.1. General
cyclo[5.2.1.0 ]dec-4-en-2-one. Prepared by a procedure
similar to that described above for (S)-(+)-3-(2-picolyl)-
10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]dec-4-en-2-
one from (S)-(+)-ketopinic acid (3.08 g, 16.9 mmol) and
3-picolylhydrazine(2.50 g, 20.3 mmol). Purificationbysilica
1
,5
All solvents were used as obtained from commercial sup-
pliers unless otherwise indicated. Standard inert atmosphere
techniques were employed in handling air and moisture

M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
11649
gel chromatography (hexanes then 50% EtOAc in hexanes)
provided the compound as a white solid (2.41 g, 53%). Mp
(CH), 136.8 (CH), 122.4 (CH), 122.1 (CH), 65.2 (CH),
58.4 (C), 51.2 (C), 49.1 (CH ), 46.8 (CH), 36.4 (CH ),
2
2
ꢁ
1
24–126 C; [a] +27.5 (c 1.21, CHCl ); IR (neat) 2971,
D
28.7 (CH ), 26.7 (CH ), 21.0 (CH ), 20.4 (CH ); MS (EI)
2 2 3 3
3
ꢀ1
1
+
1
688, 1634 cm ; H NMR (500 MHz, CDCl ) d 8.57–8.48
3
271.2 (M ); HRMS calcd for C H N O 271.1685; found
16 21 3
(
m, 2H), 7.62–7.59 (m, 1H), 7.25–7.21 (m, 1H), 4.83 (d,
271.1711.
J¼15.4 Hz, 1H), 4.79 (d, J¼15.4 Hz, 1H), 2.54 (ddd,
J¼17.6, 3.5, 3.4 Hz, 1H), 2.30–2.21 (m, 2H), 2.15–2.07 (m,
4.3.2. (S)-(D)-3-(3-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
1
,5
2
H), 1.64 (ddd, J¼13.3, 9.5, 4.3 Hz, 1H), 1.47 (ddd, J¼
cyclo[5.2.1.0 ]decan-2-one. Prepared by a procedure
similar to that described above for (S)-(+)-3-(2-picolyl)-
10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]decan-2-one
1
3
13.1, 9.4, 4.3 Hz, 1H), 1.19 (s, 3H), 0.86 (s, 3H); C NMR
125 MHz, CDCl ) d 174.9 (C), 173.7 (C), 149.3 (CH),
1
,5
(
3
1
5
2
48.9 (CH), 135.6 (CH), 132.7 (C), 123.4 (CH), 63.7 (C),
0.0 (C), 49.2 (CH), 45.4 (CH ), 31.9 (CH ), 26.9 (CH ),
from (S)-(+)-3-(3-picolyl)-10,10-dimethyl-3,4-diaza-tricy-
1
,5
clo[5.2.1.0 ]dec-4-en-2-one (200 mg, 0.74 mmol). Purifi-
cation by silica gel chromatography (EtOAc) provided the
title compound as a white solid (175 mg, 87%). Mp 76–
2
2
2
+
5.3 (CH ), 19.1 (CH ), 18.6 (CH ); MS (EI) 269.2 (M );
3
2
3
HRMS calcd for C H N O 269.1528; found 269.1529.
16 19 3
ꢁ
78 C; [a] +9.0 (c 1.01, CHCl ); IR (neat) 3229, 2957,
1660 cm ; H NMR (500 MHz, CDCl ) d 8.57–8.51 (m,
D
1 1
3
ꢀ
4
.2.3. (S)-(D)-3-(4-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
3
1
,5
cyclo[5.2.1.0 ]dec-4-en-2-one. Prepared by a procedure
similar to that described above for (S)-(+)-3-(2-picolyl)-
1
from (S)-(+)-ketopinic acid (2.47 g, 13.5 mmol) and 4-pico-
lylhydrazine (2.00 g, 16.2 mmol). Purification by silica gel
chromatography (hexanes then 50% EtOAc in hexanes) pro-
2H), 7.67–7.63 (m, 1H), 7.28–7.23 (m, 1H), 4.67 (d,
J¼14.5 Hz, 1H), 4.51 (d, J¼14.4 Hz, 1H), 3.57–3.50 (m,
1H), 2.21–2.13 (m, 1H), 2.04–1.97 (m, 1H), 1.94–1.86 (m,
2H), 1.71–1.64 (m, 1H), 1.33–1.16 (m, 2H), 1.07 (s, 3H),
1
,5
0,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]dec-4-en-2-one
1
3
1.06 (s, 3H); C NMR (125 MHz, CDCl ) d 171.4 (C),
3
149.8 (CH), 149.2 (CH), 136.2 (CH), 131.8 (C), 123.6
(CH), 65.6 (CH), 58.3 (C), 51.3 (C), 46.8 (CH), 45.7
(CH ), 36.3 (CH ), 28.6 (CH ), 26.6 (CH ), 20.9 (CH ),
vided the compound as a white solid (2.59 g, 71%). Mp 140–
ꢁ
1
1
2
42 C; [a] +25.6 (c 1.04, CHCl ); IR (neat) 2963, 1692,
D
600 cm ; H NMR (500 MHz, CDCl ) d 8.55–8.52 (m,
3
H), 7.19–7.16 (m, 2H), 4.83 (d, J¼15.9 Hz, 1H), 4.79 (d,
3
2
2
2
2
3
ꢀ
1
1
+
20.3 (CH ); MS (EI) 271.2 (M ); HRMS calcd for
3
C H N O 271.1685; found 271.1689.
16 21 3
J¼15.9 Hz, 1H), 2.57 (ddd, J¼17.7, 3.4, 3.3 Hz, 1H),
2
9
.33–2.24 (m, 2H), 2.17–2.09 (m, 2H), 1.68 (ddd, J¼13.4,
.5, 4.3 Hz, 1H), 1.50 (ddd, J¼13.1, 9.5, 4.3 Hz, 1H), 1.21
4.3.3. (S)-(D)-3-(4-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
1
,5
cyclo[5.2.1.0 ]decan-2-one. Prepared by a procedure
similar to that described above for (S)-(+)-3-(2-picolyl)-
10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]decan-2-one
1
3
(
(
s, 3H), 0.91 (s, 3H); C NMR (125 MHz, CDCl ) d 175.1
3
C), 173.8 (C), 150.0 (CH), 146.0 (C), 122.5 (CH), 63.2 (C),
1
,5
5
2
0.0 (C), 49.2 (CH), 46.9 (CH ), 31.9 (CH ), 27.0 (CH ),
2
from (S)-(+)-3-(4-picolyl)-10,10-dimethyl-3,4-diaza-tricy-
clo[5.2.1.0 ]dec-4-en-2-one (300 mg, 1.11 mmol). Purifi-
2
2
+
1,5
5.5 (CH ), 19.1 (CH ), 18.6 (CH ); MS (EI) 269.2 (M );
3
2
3
HRMS calcd for C H N O 269.1528; found 269.1549.
16 19 3
cation by silica gel chromatography (EtOAc) provided the
title compound as a white solid (236 mg, 78%). Mp 105–
ꢁ
1663 cm ; H NMR (500 MHz, CDCl ) d 8.59–8.53 (m,
4
.3. General procedure for the preparation of (S)-(D)-
-(picolyl)-10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]-
106 C; [a] +14.2 (c 1.07, CHCl ); IR (neat) 3233, 2957,
D
3
1
,5
ꢀ1
1
3
3
decan-2-ones
.3.1. (S)-(D)-3-(2-Picolyl)-10,10-dimethyl-3,4-diaza-tri-
cyclo[5.2.1.0 ]decan-2-one. To a solution of (S)-(+)-3-(2-
2H), 7.23–7.18 (m, 2H), 4.71 (d, J¼15.6 Hz, 1H), 4.44 (d,
J¼15.6 Hz, 1H), 3.60–3.54 (m, 1H), 2.23–2.14 (m, 1H),
2.05–1.98 (m, 1H), 1.96–1.87 (m, 2H), 1.73–1.66 (m, 1H),
4
1
,5
13
1.36–1.20 (m, 2H), 1.14 (s, 3H), 1.09 (s, 3H); C NMR
(125 MHz, CDCl ) d 171.8 (C), 150.2 (CH), 145.2 (C),
1
,5
picolyl)-10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]dec-4-
en-2-one (300 mg, 1.11 mmol) in a 1:2 mixture of acetic
acid and methanol (20 mL) was added sodium cyanoborohy-
dride (700 mg, 10.0 mmol) in small portions over 1 h. The
reaction mixture was then stirred at room temperature until
TLC indicated that the reaction was complete (29 h). Excess
borohydride was quenched by the addition of 10% HCl. The
products were extracted using CH Cl and the aqueous
3
123.0 (CH), 65.8 (CH), 58.2 (C), 51.3 (C), 47.3 (CH2),
46.8 (CH), 36.2 (CH ), 28.7 (CH ), 26.7 (CH ), 21.0
(CH ), 20.4 (CH ); MS (EI) 271.2 (M ); HRMS calcd for
2
2
2
+
3
3
C H N O 271.1685; found 271.1689.
16 21 3
4.4. General procedure for the preparation of (S)-(D)-
3-(picolyl-N-oxide)-10,10-dimethyl-3,4-diaza-tricyclo-
[5.2.1.0 ]decan-2-ones
2
2
1
,5
phase was made basic using sodium hydroxide pellets and
then further extracted with CH Cl . The organic extracts
2
2
were combined, washed with brine, and dried over sodium
sulfate. The solvent was removed in vacuo and the product
was purified by flash chromatography (50% EtOAc in hex-
4.4.1. (S)-(D)-3-(2-Picolyl-N-oxide)-10,10-dimethyl-3,4-
diaza-tricyclo[5.2.1.0 ]decan-2-one. A mixture of (S)-
1
,5
1,5
(+)-3-(2-picolyl)-10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]-
dec-4-en-2-one (400 mg, 1.49 mmol) and methyltrioxorhe-
nium (1.9 mg, 0.01 mmol) in CH Cl (8 mL) was cooled
anes) to afford the desired compound as a white solid
(
ꢁ
IR (neat) 3241, 2956, 1665 cm ; H NMR (500 MHz,
248 mg, 82%). Mp 80–83 C; [a] ꢀ4.0 (c 1.04, CHCl );
D
1
3
2
2
ꢀ
1
ꢁ
to 0 C and treated with a 30% solution of aqueous hydrogen
peroxide (0.17 mL, 1.78 mmol). The biphasic reaction mix-
ture was stirred until judged complete by TLC (94 h) and fil-
tered over a small pad of Celite using CH Cl . Removal of
CDCl ) d 8.52–8.49 (m, 1H), 7.67–7.61 (m, 1H), 7.28–
3
7
1
2
1
.24 (m, 1H), 7.19–7.15 (m, 1H), 4.87 (d, J¼15.7 Hz,
H), 4.60 (d, J¼15.6 Hz, 1H), 3.65–3.58 (m, 1H),
.19–2.05 (m, 2H), 1.94–1.86 (m, 2H), 1.73–1.66 (m,
2
2
the solvent in vacuo afforded crude N-oxide-pyrazolone,
which was dissolved in a 1:2 mixture of acetic acid and
methanol (30 mL). Sodium cyanoborohydride (875 mg,
1
3
H), 1.35–1.20 (m, 2H), 1.17 (s, 3H), 1.06 (s, 3H);
C
NMR (125 MHz, CDCl ) d 171.2 (C), 156.4 (C), 149.3
3

11650
M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
+
1
3.9 mmol) was added in small portions for over 1 h and the
20.9 (CH ), 20.4 (CH ); MS (EI) 287.2 (M ); HRMS calcd
3 3
reaction mixture was stirred at room temperature until TLC
indicated that the reaction was complete. Excess borohy-
dride was quenched by the addition of 10% HCl. The prod-
ucts were extracted using CH Cl and the aqueous phase was
for C H N O 287.1634; found 287.1628.
16 21 3 2
4.5. ((3R,4S,5S)-2-Benzyl-5-methyl-3-phenylisoxazoli-
din-4-yl)methanol and ((3S,4S,5S)-2-benzyl-5-methyl-
3-phenylisoxazolidin-4-yl)methanol
2
2
made basic using sodium hydroxide pellets then further ex-
tracted with CH Cl . The organic extracts were combined,
2
2
7
a
washed with brine, and dried over sodium sulfate. The sol-
vent was removed in vacuo and the product was purified
by flash chromatography (2% MeOH in CHCl ) to afford
Catalyst 1 (15 mg, 0.05 mmol) was dissolved in CH NO
3 2
(2.4 mL, 0.1 M), and the resulting solution was cooled to
0 C. Distilled water (2.1 mL, 0.12 mmol) was added fol-
ꢁ
lowed by CF SO H (4.2 mL, 0.05 mmol) and the solution
3
the desired compound as a white solid (277 mg, 65%). Mp
3
3
ꢁ
959, 1651 cm ; H NMR (500 MHz, CDCl ) d 8.16 (d,
1
2
44–145 C; [a] +9.8 (c 1.00, CHCl ); IR (neat) 3419,
D
was then stirred for 5 min. (Z)-N-Benzylidenebenzyl-
amine-N-oxide (50 mg, 0.24 mmol) was then introduced
3
ꢀ1
1
14
3
J¼6.2 Hz, 1H), 7.42 (dd, J¼7.6, 2.0 Hz, 1H), 7.25–7.15
followed by freshly distilled (E)-crotonaldehyde (59 mL,
ꢁ
(
m, 2H), 4.81 (d, J¼15.2 Hz, 1H), 4.56 (d, J¼15.2 Hz,
0.71 mmol). The reaction was stirred at +4 C for 48 h, after
1
1
1
H), 3.57 (dd, J¼8.3, 4.6 Hz, 1H), 2.08–2.00 (m, 2H),
which time additional (E)-crotonaldehyde (50 mL,
0.60 mmol) was added. After a total of 72 h, the reaction
mixture was passed through a plug of silica using CH Cl
.85–1.77 (m, 2H), 1.61 (dd, J¼12.9, 8.3 Hz, 1H), 1.24–
1
3
.13 (m, 2H), 1.10 (s, 3H), 0.96 (s, 3H); C NMR
2
2
(
125 MHz, CDCl ) d 170.9 (C), 146.6 (C), 139.3 (CH),
3
as an eluant. Purification by silica gel chromatography
(5% EtOAc in hexanes) provided a 68:32 mixture of exo
and endo isoxazolidine aldehydes as a colorless oil
(55 mg, 83%). A portion of the aldehyde was dissolved in
1
5
2
27.1 (CH), 126.4 (CH), 125.2 (CH), 64.9 (CH), 58.1 (C),
1.1 (C), 46.6 (CH), 44.4 (CH ), 36.3 (CH ), 28.5 (CH ),
2
2
2
+
6.6 (CH ), 20.7 (CH ), 20.1 (CH ); MS (EI) 287.2 (M );
2
3
3
HRMS calcd for C H N O 287.1634; found 287.1652.
16 21 3 2
EtOH (2 mL) and reduced to the primary alcohol using
NaBH at 0 C. After 2 h, the reaction was quenched with
ꢁ
4
4
4
.4.2. (S)-(D)-3-(3-Picolyl-N-oxide)-10,10-dimethyl-3,
-diaza-tricyclo[5.2.1.0 ]decan-2-one. Prepared by a pro-
satd NH Cl and stirred for 15 min. The mixture was diluted
4
1
,5
with brine and extracted twice with CH Cl . The organic
2
2
cedure similar to that described above for (S)-(+)-3-(2-pi-
colyl-N-oxide)-10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]-
decan-2-one from (S)-(+)-3-(3-picolyl)-10,10-dimethyl-3,4-
layer was dried with Na SO , filtered, and concentrated. Pu-
2 4
1
,5
rification by silica gel chromatography (15% EtOAc in hex-
anes) provided the title compound as a clear oil for the
determination of enantiomeric purity; endo 85%, exo 86%.
Enantiomeric ratios were determined by HPLC using a Chir-
alcel OD-H column. l¼220 nm (2% IPA/hexanes, 0.8 mL/
1,5
diaza-tricyclo[5.2.1.0 ]dec-4-en-2-one (300 mg, 1.11 mmol).
Purification by silica gel chromatography (5% MeOH in
CHCl ) provided the title compound as a white solid
3
ꢁ
(
CHCl ); IR (neat) 3427, 2958, 1661 cm
173 mg, 54%). Mp 146–148 C; [a]D +6.2 (c 1.01,
min flow rate); endo isomers t ¼34.6 min (major enantio-
R
ꢀ
1
1
;
500 MHz, CDCl ) d 8.29–8.11 (m, 2H), 7.34–7.21 (m,
H NMR
mer) and 32.5 min (minor enantiomer); exo isomers
t ¼20.6 min (major enantiomer) and 22.8 min (minor enan-
3
(
3
R
2
3
1
H), 4.68 (d, J¼15.1 Hz, 1H), 4.45 (d, J¼15.0 Hz, 1H),
tiomer). exo isomer [a] ꢀ118 (c 2.87, CHCl ); IR (neat)
D
3
ꢀ1 1
.64–3.56 (m, 1H), 2.20–2.04 (m, 2H), 1.96–1.87 (m, 2H),
.77–1.69 (m, 1H), 1.35–1.17 (m, 2H), 1.10 (s, 3H), 1.06
3408, 2925, 1602, 1495, 1453 cm ; H NMR (500 MHz,
CDCl ) d 7.45–7.41 (m, 2H), 7.38–7.32 (m, 4H), 7.32–7.27
3
1
3
(
(
s, 3H); C NMR (125 MHz, CDCl ) d 170.8 (C), 138.9
3
CH), 138.3 (CH), 136.1 (C), 126.2 (CH), 125.9 (CH),
5.6 (CH), 58.0 (C), 51.3 (C), 46.7 (CH), 45.0 (CH ), 36.2
(m, 3H), 7.25–7.21 (m, 1H), 4.04–3.97 (m, 3H), 3.69 (d,
J¼13.9 Hz, 1H), 3.45–3.35 (m, 2H), 2.47–2.39 (m, 1H),
1
3
6
1.35 (d, J 5.3 Hz, 3H); C NMR (125 MHz, CDCl )
3
2
(
CH ), 28.5 (CH ), 26.6 (CH ), 20.9 (CH ), 20.3 (CH );
2
d 137.3 (C), 136.3 (C), 128.8 (CH), 128.7 (CH), 128.2
(CH), 128.1 (CH), 127.9 (CH), 127.2 (CH), 76.8 (CH), 72.1
(CH), 62.3 (CH ), 59.9 (CH ), 55.8 (CH), 19.9 (CH ); MS
2
2
3
3
+
MS (EI) 287.2 (M ); HRMS calcd for C H N O
6 21 3 2
2
1
87.1634; found 287.1620.
2
2
3
+
(EI) 283.2 (M ); HRMS calcd for C H NO 283.1572;
18 21 2
4
.4.3. (S)-(D)-3-(4-Picolyl-N-oxide)-10,10-dimethyl-3,4-
found 283.1556. endo isomer [a] ꢀ64.8 (c 1.29, CHCl );
D
3
1
,5
ꢀ1
1
diaza-tricyclo[5.2.1.0 ]decan-2-one. Prepared by a proce-
dure similar to that described above for (S)-(+)-3-(2-picolyl-
N-oxide)-10,10-dimethyl-3,4-diaza-tricyclo[5.2.1.0 ]de-
can-2-one from (S)-(+)-3-(4-picolyl)-10,10-dimethyl-3,4-di-
aza-tricyclo[5.2.1.0 ]dec-4-en-2-one (400 mg, 1.49 mmol).
Purification by silica gel chromatography (5% MeOH in
CHCl ) provided the title compound as a white solid
IR (neat) 3394, 2925, 1599, 1494, 1454 cm ; H NMR
(400 MHz, CDCl ) d 7.45–7.40 (m, 2H), 7.37–7.18 (m,
3
1
,5
8H), 4.28–4.27 (m, 1H), 3.98 (d, J¼14.1 Hz, 1H), 3.83–
13
3.63 (m, 4H), 2.43–2.33 (m, 1H), 1.43 (d, J¼6.1 Hz, 3H);
1
,5
C NMR (125 MHz, CDCl ) d 139.3 (C), 137.5 (C), 128.7
3
(CH), 128.5 (CH), 128.1 (CH), 127.9 (CH), 127.0 (CH),
76.3 (CH), 73.6 (CH), 62.3 (CH ), 61.8 (CH), 59.7 (CH ),
20.8 (CH ); MS (EI) 283.2 (M ); HRMS calcd for
3
2
2
ꢁ
+
(324 mg, 76%). Mp 186–188 C; [a]D +4.7 (c 1.01,
CHCl ); IR (neat) 3436, 2952, 1642 cm H NMR
3
ꢀ1
1
;
C H NO 283.1572; found 283.1575.
18 21
3
2
(
500 MHz, CDCl ) d 8.09 (d, J¼6.9 Hz, 2H), 7.20 (d,
3
J¼6.7 Hz, 2H), 4.59 (d, J¼15.4 Hz, 1H), 4.40 (d,
4.6. ((3R,4S,5S)-2-Benzyl-3-(2-chlorophenyl)-5-methyl-
isoxazolidin-4-yl)methanol and ((3S,4S,5S)-2-benzyl-3-
(2-chlorophenyl)-5-methylisoxazolidin-4-yl)methanol
J¼15.4 Hz, 1H), 3.54 (dd, J¼8.3, 4.6 Hz, 1H), 2.16–2.09
(
m, 1H), 2.03–1.97 (m, 1H), 1.92–1.84 (m, 2H), 1.68 (dd,
J¼13.1, 8.4 Hz, 1H), 1.30–1.13 (m, 2H), 1.07 (s, 3H), 1.03
1
3
(
s, 3H); C NMR (125 MHz, CDCl ) d 171.9 (C), 139.1
3
Prepared according to the general procedure from (E)-croto-
naldehyde (100 mL, 1.21 mmol), (Z)-N-2-chlorobenzylide-
nebenzylamine-N-oxide (50 mg, 0.20 mmol), 1 (11 mg,
(
CH), 135.4 (C), 125.8 (CH), 64.8 (CH), 58.1 (C), 51.3 (C),
6.8 (CH), 46.4 (CH ), 36.2 (CH ), 28.6 (CH ), 26.6 (CH ),
1
5
4
2
2
2
2

M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
11651
+
0.04 mmol), distilled water (3.7 mL, 0.20 mmol), and
CF SO H (3.6 mL, 0.04 mmol) in CH NO (2.0 mL,
MS (EI) 313.2 (M ); HRMS calcd for C H NO
19 23 3
313.1678; found 313.1670. endo isomer [a] ꢀ76.1 (c 1.30,
3
3
3
2
D
ꢀ
1 1
0
.1 M). Purification by silica gel chromatography (5% ethyl
CHCl ); IR (neat) 3423, 2928, 1611, 1512, 1248 cm ; H
3
acetate in hexanes) provided a 67:33 mixture of endo and exo
isomers as a colorless oil (59 mg, 92%). Reduction of the al-
dehydes to the primary alcohols followed by purification by
silica gel chromatography (15% EtOAc in hexanes) pro-
vided the title compounds as a clear oil for the determination
of enantiomeric purity; endo 94%, exo 59%. Enantiomeric
ratios were determined by HPLC using a Chiralcel OD-H
column. l¼220 nm (2% IPA/hexanes, 0.8 mL/min flow
NMR (300 MHz, CDCl ) d 7.42–7.20 (m, 7H), 6.93–6.88
3
(m, 2H), 4.20 (dq, J¼6.2, 6.1 Hz, 1H), 4.01–3.96 (d,
J¼14.6 Hz, 1H), 3.83 (s, 3H), 3.80–3.68 (m, 3H), 3.60 (d,
J¼8.5 Hz, 1H), 2.42–2.30 (m, 1H), 1.46 (d, J¼6.2 Hz, 3H);
1
3
C NMR (75 MHz, CDCl ) d 159.2 (C), 137.9 (C), 131.2
3
(C), 129.0 (CH), 128.4 (CH), 128.1 (CH), 126.8 (CH),
114.1 (CH), 76.1 (CH), 73.2 (CH), 62.5 (CH ), 61.7 (CH),
2
+
59.6 (CH ), 55.3 (CH ), 21.0 (CH ); MS (EI) 313.2 (M );
3
2
3
rate); endo isomers t ¼26.8 min (major enantiomer) and
HRMS calcd for C H NO 313.1678; found 313.1689.
19 23 3
R
2
3.5 min (minor enantiomer); exo isomers t ¼18.6 min
R
(major enantiomer) and 16.6 min (minor enantiomer). IR
(neat) 3389, 2929, 1572, 1441 cm . exo isomer H NMR
(
(
4.8. ((3R,4S,5S)-2-Benzyl-5-methyl-3-p-tolylisoxazoli-
din-4-yl)methanol and ((3S,4S,5S)-2-benzyl-5-methyl-
3-p-tolylisoxazolidin-4-yl)methanol
ꢀ
1
1
500 MHz, CDCl ) d 7.66 (d, J¼7.6 Hz, 1H), 7.42–7.13
3
m, 8H), 4.34–4.28 (m, 2H), 4.13–4.07 (m, 1H), 4.01 (d,
J¼13.3 Hz, 1H), 3.71 (d, J¼15.5 Hz, 1H), 3.35–3.26 (m,
Prepared according to the general procedure from (E)-croto-
naldehyde (106 mL, 1.27 mmol), (Z)-N-4-methylbenzylide-
nebenzylamine-N-oxide (50 mg, 0.22 mmol), 1 (12 mg,
2
H), 2.69–2.60 (m, 1H), 1.37 (d, J¼6.0 Hz, 3H). endo iso-
1
16
mer H NMR (500 MHz, CDCl ) d 7.79 (d, J¼7.6 Hz,
3
1
2
6
H), 7.41–7.11 (m, 8H), 4.36–4.33 (m, 1H), 3.98–3.91 (m,
H), 3.85 (dd, J¼10.9, 4.4 Hz, 1H), 3.78 (dd, J¼10.9,
.5 Hz, 1H), 2.32–2.25 (m, 1H), 2.31–2.25 (m, 1H), 1.40
0.04 mmol), distilled water (2.0 mL, 0.11 mmol), and
CF SO H (3.9 mL, 0.04 mmol) in CH NO (2.2 mL,
3
3
3
2
0.1 M). Purification by silica gel chromatography (5%
EtOAc in hexanes) provided the compound as a colorless
oil (58 mg, 88% 43:57 endo/exo). Reduction of the aldehyde
to the primary alcohol followed by purification by silica gel
chromatography (15% EtOAc in hexanes) provided the title
compound as a clear oil for the determination of enantiomer-
ic purity; endo 80%, exo 84%. Enantiomeric ratios were de-
termined by HPLC using a Chiralcel OD-H column.
l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow rate); endo
1
3
(
(
d, J¼6.2 Hz, 3H); C NMR (125 MHz, CDCl ) d 137.7
3
C), 137.2 (C), 135.0 (C), 134.6 (C), 133.7 (C), 133.0 (C),
1
(
1
29.6 (CH), 129.4 (CH), 129.3 (CH), 129.3 (CH), 129.1
CH), 129.0 (CH), 128.8 (CH), 128.7 (CH), 128.2 (CH),
28.1 (CH), 127.5 (CH), 127.2 (CH), 127.1 (CH), 127.0
(
(
CH), 77.4 (CH), 77.1 (CH), 68.7 (CH), 68.4 (CH), 62.6
CH ), 62.5 (CH), 61.7 (CH ), 60.3 (CH ), 60.1 (CH ),
3.2 (CH), 20.3 (CH ), 19.9 (CH ); MS (EI) 317.1 (M );
3 3
2
2
2
2
+
5
HRMS calcd for C H NO Cl 317.1183; found 317.1168.
isomers t ¼37.6 min (major enantiomer) and 24.4 min (mi-
1
8
20
2
R
nor enantiomer); exo isomers t ¼17.1 min (major enantio-
R
4
.7. ((3R,4S,5S)-2-Benzyl-3-(4-methoxyphenyl)-5-meth-
ylisoxazolidin-4-yl)methanol and ((3S,4S,5S)-2-benzyl-
-(4-methoxyphenyl)-5-methylisoxazolidin-4-yl)-
mer) and 18.4 min (minor enantiomer). exo isomer [a]D
ꢀ122 (c 2.07, CHCl ); IR (neat) 3397, 2924, 1602, 1511,
3
ꢀ1 1
3
1454 cm ; H NMR (300 MHz, CDCl ) d 7.40–7.19 (m,
3
methanol
9H), 4.09–3.96 (m, 3H), 3.69 (d, J¼14.5 Hz, 1H), 3.55–
3
.36 (m, 2H), 2.50–2.39 (m, 1H), 2.38 (s, 3H), 1.37 (d,
1
3
Prepared according to the general procedure from (E)-croto-
naldehyde (102 mL, 1.22 mmol), (Z)-N-4-methoxybenzylide-
J¼6.1 Hz, 3H); C NMR (75 MHz, CDCl ) d 137.7 (C),
3
137.7 (C), 133.3 (C), 129.5 (CH), 128.7 (CH), 128.1 (CH),
127.9 (CH), 127.0 (CH), 76.6 (CH), 72.0 (CH), 62.4
(CH ), 59.9 (CH ), 55.9 (CH), 21.1 (CH ), 19.9 (CH );
4
h
nebenzylamine-N-oxide (50 mg, 0.21 mmol), 1 (11 mg,
.04 mmol), distilled water (3.7 mL, 0.21 mmol), and
CF SO H (3.7 mL, 0.04 mmol) in CH NO (2.1 mL, 0.1 M).
0
2
2
3
3
+
MS (EI) 297.2 (M ); HRMS calcd for C H NO
2
3
3
3
2
19 23
Purification by silica gel chromatography (3% EtOAc in hex-
anes) provided the compound as a colorless oil (57 mg, 87%,
297.1729; found 297.1712. endo isomer [a]D ꢀ127 (c
1.47, CHCl ); IR (neat) 3422, 2937, 1614, 1511,
3
ꢀ1
1
5
2:48 endo/exo). Reduction of the aldehyde to the primary al-
cohol followed by purification by silica gel chromatography
10% EtOAc in hexanes) provided the title compounds as
1248 cm ; H NMR (300 MHz, CDCl ) d 7.38–7.15 (m,
3
9H), 4.21 (dq, J¼6.1, 6.1 Hz, 1H), 3.99 (d, J¼14.5 Hz,
(
1H), 3.83–3.67 (m, 3H), 3.60 (d, J¼8.5 Hz, 1H), 2.42–
1
3
a clear oil for the determination of enantiomeric purity;
endo 87%, exo 79%. Enantiomeric ratios were determined
by HPLC using a Chiralcel AS-H column. l¼210 nm (2%
IPA/hexanes, 0.8 mL/min flow rate); endo isomers
2.32 (m, 1H), 2.37 (s, 3H), 1.46 (d, J¼6.2 Hz, 3H);
C
NMR (75 MHz, CDCl ) d 137.9 (C), 137.5 (C), 136.3 (C),
3
129.4 (CH), 128.4 (CH), 128.1 (CH), 127.8 (CH), 126.8
(CH), 76.1 (CH), 73.5 (CH), 62.5 (CH ), 61.8 (CH), 59.6
2
+
t ¼43.7 min (major enantiomer) and 70.3 min (minor enan-
(CH ), 21.1 (CH ), 21.0 (CH ); MS (EI) 297.2 (M );
2
R
3
3
tiomer); exo isomers t ¼37.9 min (major enantiomer) and
HRMS calcd for C H NO 297.1729; found 297.1725.
19 23 2
R
4
1
1
7
3
1
8.9 min (minor enantiomer). exo isomer [a]D ꢀ127 (c
.47, CHCl ); IR (neat) 3422, 2937, 1614, 1511,
3
4.9. ((3R,4S,5S)-2-Benzyl-3-(4-isopropylphenyl)-5-
methylisoxazolidin-4-yl)methanol and ((3S,4S,5S)-2-
benzyl-3-(4-isopropylphenyl)-5-methylisoxazolidin-
4-yl)methanol
ꢀ
1
1
248 cm ; H NMR (300 MHz, CDCl ) d 7.43–7.22 (m,
3
H), 6.97–6.91 (m, 2H), 4.07–3.95 (m, 3H), 3.84 (s, 3H),
.69 (d, J¼14.5 Hz, 1H), 3.54–3.37 (m, 2H), 2.48–2.36 (m,
1
3
H), 1.37 (d, J¼6.1 Hz, 3H); C NMR (75 MHz, CDCl )
3
d 159.2 (C), 137.6 (C), 131.5 (C), 129.2 (CH), 128.7 (CH),
Prepared according to the general procedure from (E)-croto-
naldehyde (100 mL, 1.20 mmol), (Z)-N-4-isopropylbenzyl-
idenebenzylamine-N-oxide (50 mg, 0.20 mmol), 1 (11 mg,
1
6
28.1 (CH), 127.1 (CH), 114.2 (CH), 76.7 (CH), 71.6 (CH),
2.4 (CH ), 59.8 (CH ), 55.8 (CH), 55.2 (CH ), 19.9 (CH );
2
2
3
3

11652
M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
0.04 mmol), distilled water (1.8 mL, 0.10 mmol), and
CF SO H (3.5 mL, 0.04 mmol) in nitromethane (2.0 mL,
7.51 (m, 4H), 7.32–7.20 (m, 5H), 4.09–4.00 (m, 2H), 3.95
(d, J¼14.3 Hz, 1H), 3.75 (d, J¼14.3 Hz, 1H), 3.38 (dd,
J¼10.9, 6.9 Hz, 1H), 3.30 (dd, J¼10.9, 6.4 Hz, 1H), 2.53–
3
3
0
.1 M). Purification by silica gel chromatography (2%
1
3
EtOAc in hexanes) provided the compound as a colorless
oil (55 mg, 85%, 36:64 endo/exo). Reduction of the alde-
hyde to the primary alcohol followed by purification by sil-
ica gel chromatography (10% EtOAc in hexanes) provided
the title compound as a clear oil for the determination of
enantiomeric purity; endo 76%, exo 85%. Enantiomeric ra-
tios were determined by HPLC using a Chiralcel AS-H col-
umn. l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow rate);
2.44 (m, 1H), 1.36 (d, J¼6.1 Hz, 3H);
C NMR
(100 MHz, CDCl ) d 141.1 (C), 137.0 (C), 129.8 (C),
3
128.8 (CH), 128.6 (CH), 128.2 (CH), 128.2 (CH), 127.3
(CH), 125.5 (q, CF , J ¼3.6 Hz) 77.3 (CH), 71.7 (CH),
3
CF
62.2 (CH ), 60.3 (CH ), 55.6 (CH), 19.9 (CH ); MS (EI)
2
2
3
+
351.1 (M ); HRMS calcd for C H NO F 351.1446; found
1
9
20
2 3
351.1445. endo isomer [a]D ꢀ62.6 (c 1.15, CHCl ); IR
3
ꢀ
1 1
(neat) 3446, 2925, 1621, 1325 cm ; H NMR (400 MHz,
CDCl ) d 7.59–7.50 (m, 4H), 7.31–7.17 (m, 5H), 4.23 (dq,
endo isomers t ¼19.2 min (major enantiomer) and
R
3
2
7.3 min (minor enantiomer); exo isomers t ¼14.3 min
J¼6.2, 6.1 Hz, 1H), 3.95 (d, J¼14.0 Hz, 1H), 3.89
R
(
major enantiomer) and 16.6 min (minor enantiomer). exo
(d, J¼14.1 Hz, 1H), 3.81–3.69 (m, 3H), 3.34–3.26 (m,
1
3
isomer [a] ꢀ98.8 (c 1.92, CHCl ); IR (neat) 3421, 2961,
1H), 1.41 (d, J¼6.13 Hz, 3H); C NMR (100 MHz,
D
3
ꢀ
1
1
1
7
4
611, 1454 cm ; H NMR (400 MHz, CDCl ) d 7.36–
3
CDCl ) d 144.5 (C), 137.2 (C), 129.7 (C), 128.6 (CH),
3
.32 (m, 4H), 7.31–7.26 (m, 2H), 7.25–7.19 (m, 3H),
.05–3.94 (m, 3H), 3.66 (d, J¼14.5 Hz, 1H), 3.50–3.36
128.2 (CH), 128.2 (CH), 128.0 (CH), 127.2 (CH),
125.6 (q, CF , J ¼3.8 Hz), 76.0 (CH), 72.8 (CH), 62.2
3
CF
(
2
m, 2H), 2.89 (sept, J¼6.9 Hz, 1H), 2.45–2.36 (m, 1H),
(CH), 62.0 (CH ), 60.3 (CH ), 20.4 (CH ); MS (EI) 351.1
2 2 3
1
3
+
.01 (d, J¼6.1 Hz, 3H), 1.23 (d, J¼6.9 Hz, 6H); C NMR
(M ); HRMS calcd for C H NO F 351.1446; found
19 20 2 3
(
100 MHz, CDCl ) d 148.6 (C), 137.7 (C), 133.6 (C),
3
351.1436.
1
(
28.6 (CH), 128.1 (CH), 128.0 (CH), 127.0 (CH), 126.9
CH), 76.6 (CH), 72.1 (CH), 62.4 (CH ), 60.0 (CH ), 56.0
4.11. ((3R,4S,5S)-2-Benzyl-5-methyl-3-(naphthalen-2-
yl)isoxazolidin-4-yl)methanol and ((3S,4S,5S)-2-benzyl-
5-methyl-3-(naphthalen-2-yl)isoxazolidin-4-yl)methanol
2
2
(
CH), 33.8 (CH), 23.9 (CH ), 19.9 (CH ); MS (EI) 325.2
3 3
+
(
M ); HRMS calcd for C H NO 325.2042; found
21 27 2
3
25.2034. endo isomer [a]D ꢀ75.3 (c 1.29, CHCl ); IR
3
ꢀ
1 1
(neat) 3416, 2925, 1602, 1455 cm ; H NMR (400 MHz,
CDCl ) d 7.37–7.29 (m, 4H), 7.28–7.23 (m, 2H), 7.22–
Prepared according to the general procedure from (E)-croto-
naldehyde (97 mL, 1.17 mmol), (Z)-N-2-naphthylbenzylide-
3
1
8
7
.25 (m, 3H), 4.17 (dq, J¼6.1, 6.1 Hz, 1H), 3.96 (d,
nebenzylamine-N-oxide (50 mg, 0.19 mmol), 1 (10 mg,
0.04 mmol), distilled water (1.7 mL, 0.10 mmol), and
CF SO H (3.4 mL, 0.04 mmol) in CH NO (1.9 mL,
J¼14.6 Hz, 1H), 3.79–3.65 (m, 3H), 3.56 (d, J¼8.4 Hz,
1
H), 2.88 (sept, J¼6.6 Hz, 1H), 2.39–2.30 (m, 1H), 1.42
3
3
3
2
1
3
(
(
d, J¼6.2 Hz, 3H), 1.23 (d, J¼6.9 Hz, 6H); C NMR
0.1 M). Purification by silica gel chromatography (5%
EtOAc in hexanes) provided the compound as a colorless
oil (59 mg, 94%, 55:45 endo/exo). Reduction of the alde-
hyde to the primary alcohol followed by purification by sil-
ica gel chromatography (15% EtOAc in hexanes) provided
the title compound as a clear oil for the determination of
enantiomeric purity. endo 81%, exo 60%. Enantiomeric ra-
tios were determined by HPLC using a Chiralcel OD-H col-
umn. l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow rate);
100 MHz, CDCl ) d 148.4 (C), 138.0 (C), 136.7 (C),
3
1
(
28.4 (CH), 128.1 (CH), 127.8 (CH), 126.8 (CH), 126.7
CH), 76.2 (CH), 73.6 (CH), 62.6 (CH ), 61.8 (CH), 59.7
2
(
CH ), 33.8 (CH), 24.0 (CH ), 21.0 (CH ); MS (EI) 325.2
3
2
3
+
(
M ); HRMS calcd for C H NO 325.2042; found
21 27 2
3
25.2044.
4
.10. ((3R,4S,5S)-2-Benzyl-5-methyl-3-(4-(trifluorome-
thyl)phenyl)isoxazolidin-4-yl)methanol and ((3S,4S,5S)-
-benzyl-5-methyl-3-(4-(trifluoromethyl)phenyl)isoxa-
zolidin-4-yl)methanol
endo isomers t ¼39.1 min (major enantiomer) and
R
2
46.3 min (minor enantiomer); exo isomers t ¼33.4 min
R
(major enantiomer) and 42.9 min (minor enantiomer). exo
isomer [a] ꢀ73.5 (c 1.93, CHCl ); IR (neat) 3408, 2925,
D
3
ꢀ1
1
Prepared according to the general procedure from (E)-croto-
naldehyde (103 mL, 1.21 mmol), (Z)-N-4-trifluoromethyl-
1599, 1447 cm ; H NMR (400 MHz, CDCl ) d 7.91–
3
7.80 (m, 4H), 7.57–7.52 (m, 1H), 7.52–7.45 (m, 2H),
7.37–7.33 (m, 2H), 7.32–7.26 (m, 2H), 7.25–7.20 (m, 1H),
4.17 (d, J¼8.2 Hz, 1H), 4.11–4.03 (m, 2H), 3.75 (d,
J¼14.5 Hz, 1H), 3.43 (d, J¼6.5 Hz, 2H), 2.56–2.47 (m,
1
7
benzylidenebenzylamine-N-oxide (50 mg, 0.18 mmol), 1
9.7 mg, 0.04 mmol), distilled water (1.6 mL, 0.09 mmol),
and CF SO H (3.2 mL, 0.04 mmol) in CH NO (1.8 mL,
(
3
3
3
2
1
3
0
.1 M). Purification by silica gel chromatography (5%
1H), 1.38 (d, J¼6.1 Hz, 3H); C NMR (100 MHz, CDCl )
3
EtOAc in hexanes) provided the compound as a colorless
oil (42 mg, 67%, 45:55 endo/exo). Reduction of the alde-
hyde to the primary alcohol followed by purification by sil-
ica gel chromatography (10% EtOAc in hexanes) provided
the title compound as a clear oil for the determination of
enantiomeric purity; endo 73%, exo 61%. Enantiomeric ra-
tios were determined by HPLC using a Chiralcel AS-H col-
umn. l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow rate);
d 137.5 (C), 134.1 (C), 133.2 (C), 133.0 (C), 128.8 (CH),
128.4 (CH), 128.2 (CH), 127.9 (CH), 127.7 (CH), 127.1
(CH), 127.0 (CH), 126.4 (CH), 126.2 (CH), 126.0 (CH),
77.1 (CH), 72.3 (CH), 62.4 (CH ), 60.1 (CH ), 56.0 (CH),
2
2
+
19.9 (CH ); MS (EI) 333.2 (M ); HRMS calcd for
3
C H NO 333.1729; found 333.1708. endo isomer [a]
D
2
2
23
2
ꢀ47.4 (c 2.57, CHCl ); IR (neat) 3420, 2924, 1599,
3
ꢀ
1 1
1454 cm ; H NMR (400 MHz, CDCl ) d 7.86–7.78 (m,
3
endo isomers t ¼19.4 min (major enantiomer) and
4H), 7.63 (dd, J¼8.4, 1.7 Hz, 1H), 7.50–7.43 (m, 2H),
7.36–7.30 (m, 2H), 7.28–7.16 (m, 3H), 4.25 (dq, J¼6.2,
5.9 Hz, 1H), 4.00 (d, J¼14.1 Hz, 1H), 3.86–3.70 (m, 4H),
R
2
3.5 min (minor enantiomer); exo isomers t ¼16.9 min
R
(
major enantiomer) and 18.0 min (minor enantiomer). exo
13
isomer [a] ꢀ76.8 (c 1.43, CHCl ); IR (neat) 3422, 2926,
2.48–2.40 (m, 1H), 1.46 (d, J¼5.8 Hz, 3H); C NMR
D
3
ꢀ
1
1
1
619, 1455 cm ; H NMR (400 MHz, CDCl ) d 7.62–
3
(100 MHz, CDCl ) d 137.8 (C), 137.1 (C), 133.3 (C),
3

M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
11653
1
1
33.1 (C), 128.6 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH),
27.7 (CH), 127.7 (CH), 127.0 (CH), 126.9 (CH), 126.2
were determined by HPLC using a Chiralcel OD-H column.
l¼220 nm (2% IPA/hexanes, 0.8 mL/min flow rate); endo
(
(
CH), 126.0 (CH), 125.4 (CH), 76.1 (CH), 73.8 (CH), 62.3
CH ), 61.9 (CH), 60.0 (CH ), 20.9 (CH ); MS (EI) 333.2
isomers t ¼29.4 min (major enantiomer) and 37.8 min
R
(minor enantiomer); exo isomers t ¼27.9 min (major
2
2
3
R
+
(
M ); HRMS calcd for C H NO 333.1729; found
2
enantiomer) and 33.8 min (minor enantiomer). IR (neat)
2
2
23
ꢀ
1
1
3
33.1715.
3392, 2933, 1656, 1500, 1458 cm . exo isomer
NMR (500 MHz, CDCl ) d 7.43–7.40 (m, 1H), 6.39–6.33
H
3
4.12. ((3R,4S,5S)-2,5-Dimethyl-3-phenylisoxazolidin-4-
yl)methanol and ((3S,4S,5S)-2,5-dimethyl-3-phenylisox-
azolidin-4-yl)methanol
(m, 2H), 4.13–4.04 (m, 1H), 3.87–3.77 (m, 1H), 3.53
(d, J¼6.0 Hz, 2H), 2.63 (s, 3H), 2.48–2.38 (m, 1H), 1.36
1
3
(d, J¼5.7 Hz, 3H); C NMR (125 MHz, CDCl ) d 150.0
3
(C), 142.6 (CH), 110.4 (CH), 108.8 (CH), 77.1 (CH),
74.9 (CH), 62.2 (CH ), 55.4 (CH), 43.7 (CH ), 19.4
Prepared according to the general procedure from (E)-croto-
naldehyde (142 mL, 1.7 mmol), (Z)-N-benzylidenemethyl-
amine-N-oxide (50 mg, 0.34 mmol), 1 (20 mg, 0.07 mmol),
2
3
1
(CH ). endo isomer H NMR (500 MHz, CDCl ) d 7.43–
3
3
7.35 (m, 1H), 6.36–6.26 (m, 2H), 4.19 (dq, J¼18.1,
distilled water (3.3 mL, 0.18 mmol), and HClO (6.2 mL,
4
5.9 Hz, 1H), 3.83–3.66 (m, 2H), 3.55–3.40 (m, 1H),
2.72–2.42 (m, 4H), 1.42 (d, J¼5.1 Hz, 3H); C NMR
1
3
0
.07 mmol) in CH NO (3.7 mL, 0.1 M). Purification by
3
2
silica gel chromatography (10% EtOAc in hexanes) pro-
vided the compound as a colorless oil (46 mg, 61%, 43:57
endo/exo). Reduction of the aldehyde to the primary alcohol
followed by purification by silica gel chromatography
(125 MHz, CDCl ) d 151.0 (C), 142.7 (CH), 110.3
3
(CH), 108.1 (CH), 77.5 (CH), 74.9 (CH), 62.2 (CH),
61.9 (CH ), 43.9 (CH ), 20.7 (CH ); MS (EI) 197.1
(M ); HRMS calcd for C H NO 197.1052; found
2
3
3
+
1
0
15
3
(
20% EtOAc in hexanes) provided the title compound as
197.1047.
a clear oil for the determination of enantiomeric purity;
endo 89%, exo 80%. Enantiomeric ratios were determined
by HPLC using a Chiralcel OD-H column. l¼210 nm
4.14. ((3R,4S,5S)-2,5-Dimethyl-3-p-tolylisoxazolidin-4-
yl)methanol and ((3S,4S,5S)-2,5-dimethyl-3-p-tolylisox-
azolidin-4-yl)methanol
(
2% IPA/hexanes, 0.8 mL/min flow rate); endo isomers
t ¼33.6 min (major enantiomer) and 27.0 min (minor
R
enantiomer); exo isomers t ¼18.7 min (major enantiomer)
Prepared according to the general procedure from (E)-croto-
naldehyde (134 mL, 1.6 mmol), (Z)-N-4-methylbenzylide-
nemethylamine-N-oxide (50 mg, 0.33 mmol), 1 (18 mg,
0.07 mmol), distilled water (3.0 mL, 0.17 mmol), and
CF SO H (5.9 mL, 0.07 mmol) in CH NO (3.4 mL,
R
and 20.3 min (minor enantiomer). exo isomer [a] ꢀ203
D
ꢀ
1
(
c 0.79, CHCl ); IR (neat) 3385, 2925, 1558, 1456 cm ;
H NMR (500 MHz, CDCl ) d 7.36–7.32 (m, 4H), 7.31–
3
1
3
7
.26 (m, 1H), 4.01 (dq, J¼6.1, 6.0 Hz, 1H), 3.74 (d,
3
3
3
2
J¼8.6 Hz, 1H), 3.42–3.32 (m, 2H), 2.61 (s, 3H), 3.47–3.40
0.1 M). Purification by silica gel chromatography (10%
EtOAc in hexanes) provided the compound as a colorless
oil (53 mg, 71%, 48:52 endo/exo). Reduction of the alde-
hyde to the primary alcohol followed by purification by sil-
ica gel chromatography (20% EtOAc in hexanes) provided
the title compound as a clear oil for the determination of
enantiomeric purity; endo 80%, exo 92%. Enantiomeric
ratios were determined by HPLC using a Chiralcel OD-H
column. l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow
1
3
(
CDCl ) d 136.2 (C), 128.8 (CH), 128.8 (CH), 127.9 (CH),
m, 1H), 1.38 (d, J¼6.2 Hz, 3H); C NMR (100 MHz,
3
7
1
6.9 (CH), 74.9 (CH), 62.4 (CH ), 55.4 (CH), 43.5 (CH ),
2 3
9.8 (CH ); MS (EI) 207.1 (M ); HRMS calcd for
3
+
C H NO 207.1259; found 207.1234. endo isomer [a]
D
1
2
17
2
ꢀ
100 (c 0.75, CHCl ); IR (neat) 3420, 2921, 1652,
3
455 cm ; H NMR (400 MHz, CDCl ) d 7.40–7.25 (m,
3
ꢀ
1 1
1
5
3
H), 4.21 (dq, J¼18.4, 6.3 Hz, 1H), 3.78–3.65 (m, 2H),
.40–3.25 (m, 1H), 2.56 (s, 3H), 2.42–2.32 (m, 1H), 1.44
rate); endo isomers t ¼14.9 min (major enantiomer) and
R
1
3
(
(
(
(
d, J¼6.4 Hz, 3H); C NMR (100 MHz, CDCl ) d 138.8
16.3 min (minor enantiomer); exo isomers t ¼34.7 min
3
R
C), 127.8 (CH), 128.1 (CH), 127.9 (CH), 76.2 (CH), 74.9
CH), 62.4 (CH), 62.2 (CH ), 43.5 (CH ), 21.4 (CH ); MS
EI) 207.1 (M ); HRMS calcd for C H NO 207.1259;
(major enantiomer) and 21.8 min (minor enantiomer). exo
isomer [a] ꢀ192 (c 1.42, CHCl ); IR (neat) 3416, 2925,
2
3
3
D
3
+
ꢀ1
1
1540, 1515 cm ; H NMR (400 MHz, CDCl ) d 7.22 (d,
3
1
2
17
2
found 207.1238.
J¼8.0 Hz, 2H), 7.15 (d, J¼8.0 Hz, 2H), 3.98 (dq, J¼18.4,
6
.2 Hz, 1H), 3.70 (d, J¼8.7 Hz, 1H), 3.45–3.31 (m, 2H),
4.13. ((3R,4S,5S)-3-(Furan-2-yl)-2,5-dimethylisoxazoli-
din-4-yl)methanol and ((3S,4S,5S)-3-(furan-2-yl)-2,5-
dimethylisoxazolidin-4-yl)methanol
2.59 (s, 3H), 2.44–2.35 (m, 1H), 2.32 (s, 3H), 1.37 (d,
J¼6.3 Hz, 3H); C NMR (100 MHz, CDCl ) d 137.6 (C),
1
3
3
133.1 (C), 129.5 (CH), 127.8 (CH), 76.7 (CH), 74.7 (CH),
62.4 (CH ), 56.5 (CH), 43.4 (CH ), 21.1 (CH ), 19.8
2 3 3
+
Prepared according to the general procedure from (E)-croto-
naldehyde (200 mL, 1.8 mmol), (Z)-N-fur-2-ylmethylidene-
(CH ); MS (EI) 221.1 (M ); HRMS calcd for C H NO
3 13 19 2
221.1416; found 221.1394. endo isomer [a]D ꢀ98.9 (c
1
9
ꢀ1
methylamine-N-oxide (50 mg, 0.40 mmol), 1 (22 mg,
.08 mmol), distilled water (3.6 mL, 0.20 mmol), and
HClO (6.7 mL, 0.08 mmol) in CH NO (4.0 mL, 0.1 M).
1.41, CHCl ); IR (neat) 3397, 2925, 1653, 1515 cm
3
;
1
0
H NMR (400 MHz, CDCl ) d 7.24 (d, J¼7.9 Hz, 2H),
3
7.13 (d, J¼8.0 Hz, 2H), 4.19 (dq, J¼18.1, 6.0 Hz, 1H),
4
3
2
Purification by silica gel chromatography (10% EtOAc in
hexanes) provided the compound as a colorless oil (29 mg,
3.75–3.63 (m, 2H), 3.34–3.19 (m, 1H), 2.54 (s, 3H), 2.39–
1
3
2.33 (m, 1H), 2.32 (s, 3H), 1.43 (d, J¼6.2 Hz, 3H);
C
NMR (100 MHz, CDCl ) d 137.8 (C), 135.5 (C), 129.4
3
8%, 50:50 endo/exo). Reduction of the aldehyde to the
3
primary alcohol followed by purification by silica gel
chromatography (20% EtOAc in hexanes) provided the title
compound as a clear oil for the determination of enan-
tiomeric purity; endo 88%, exo 69%. Enantiomeric ratios
(CH), 127.8 (CH), 76.1 (CH), 74.8 (CH), 62.4 (CH), 62.1
(CH ), 43.5 (CH ), 21.4 (CH ), 21.1 (CH ); MS (EI) 221.1
(M ); HRMS calcd for C H NO 221.1416; found
2
3
3
3
+
1
3
19
2
221.1390.

11654
M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
4
.15. ((3R,4S,5S)-2-Benzyl-3-phenyl-5-propylisoxazoli-
din-4-yl)methanol and ((3S,4S,5S)-2-benzyl-3-phenyl-
-propylisoxazolidin-4-yl)methanol
column. l¼220 nm (2% IPA/hexanes, 0.8 mL/min flow
rate); endo isomers t ¼24.7 min (major enantiomer) and
R
5
22.1 min (minor enantiomer); exo isomers t ¼13.0 min
R
(major enantiomer) and 15.0 min (minor enantiomer). exo
Prepared according to the general procedure from (E)-hex-2-
enal (93 mg, 0.95 mmol), (Z)-N-benzylidenebenzylamine-
N-oxide (50 mg, 0.24 mmol), 1 (13 mg, 0.05 mmol),
distilled water (1.4 mL, 0.11 mmol), and CF SO H
isomer [a] ꢀ134 (c 1.40, CHCl ); IR (neat) 3442, 2958,
D
3
ꢀ1
1
1652, 1454 cm ; H NMR (400 MHz, CDCl ) d 7.45–
3
7.21 (m, 10H), 4.05 (d, J¼14.4 Hz, 1H), 3.87 (d,
J¼7.6 Hz, 1H), 3.68–3.61 (m, 2H), 3.56 (dd, J¼11.5,
7.4 Hz, 1H), 3.36 (dd, J¼11.5, 4.1 Hz, 1H), 2.57–2.49 (m,
3
3
(
4.2 mL, 0.05 mmol) in CH NO (2.0 mL, 0.1 M). Purifica-
3 2
1
3
tion by silica gel chromatography (5% EtOAc in hexanes)
provided the compound as a colorless oil in 86% yield
1H), 1.89–1.77 (m, 1H), 0.96 (s, 3H), 0.95 (s, 3H);
C
NMR (100 MHz, CDCl ) d 137.2 (C), 136.2 (C), 129.2
3
(
63 mg, 86%, 40:60 endo/exo). Reduction of the aldehyde
(CH), 129.0 (CH), 128.1 (CH), 128.0 (CH), 127.2 (CH),
84.4 (CH), 72.2 (CH), 62.8 (CH ), 59.6 (CH ), 52.1 (CH),
18.5 (CH ), 18.4 (CH ); MS (EI) 311.2 (M ); HRMS calcd
to the primary alcohol followed by purification by silica
gel chromatography (15% EtOAc in hexanes) provided the
title compound as a clear oil for the determination of enan-
tiomeric purity; endo 74%, exo 84%. Enantiomeric ratios
were determined by HPLC using a Chiralcel OD-H column.
l¼210 nm (2% IPA/hexanes, 0.8 mL/min flow rate); endo
2
2
+
3
3
for C H NO 311.1885; found 311.1867. endo isomer
2
0
25
2
[a] ꢀ82.7 (c 1.01, CHCl ); IR (neat) 3461, 2921, 1652,
D
3
ꢀ
1
1
1454 cm
;
H NMR (400 MHz, CDCl ) d 7.46–7.41
3
(m, 2H), 7.36–7.30 (m, 4H), 7.30–7.23 (m, 3H), 7.22–7.16
(m, 1H), 3.92 (d, J¼14.7 Hz, 1H), 3.80–3.70 (m, 2H), 3.65
(d, J¼14.6 Hz, 1H), 3.60–3.56 (m, 2H), 2.57–2.48 (m,
1H), 2.16–2.03 (m, 1H), 0.94 (d, J¼6.6 Hz, 3H), 0.90 (d,
isomers t ¼26.1 min (major enantiomer) and 23.6 min (mi-
R
nor enantiomer); exo isomers t ¼15.3 min (major enantio-
R
mer) and 17.4 min (minor enantiomer). exo isomer [a]D
ꢀ
1
3
115 (c 2.40, CHCl ); IR (neat) 3420, 2930, 1599,
3
J¼6.8 Hz, 3H); C NMR (100 MHz, CDCl ) d 140.8 (C),
3
ꢀ1
1
1
454 cm
;
H NMR (400 MHz, CDCl ) d 7.44–7.20
3
138.2 (C), 128.7 (CH), 128.3 (CH), 128.3 (CH), 128.0
(CH), 127.8 (CH), 126.8 (CH), 85.2 (CH), 74.6 (CH), 63.7
(CH ), 59.4 (CH), 58.7 (CH ), 32.7 (CH), 19.1 (CH ), 18.5
(
8
m, 10H), 4.02 (d, J¼14.4 Hz, 1H), 3.96 (d, J¼
.1 Hz, 1H), 3.89 (dd, J¼12.2, 5.7 Hz, 1H), 3.68 (d,
2
2
3
+
J¼14.4 Hz, 1H), 3.47 (dd, J¼11.3, 6.7 Hz, 1H), 3.38 (dd,
(CH ); MS (EI) 311.2 (M ); HRMS calcd for C H NO
20 25
3
2
J¼11.3, 5.3 Hz, 1H), 2.51–2.43 (m, 1H), 1.70–1.56 (m,
311.1885; found 311.1888.
1
3
2
(
H), 1.52–1.35 (m, 2H), 0.93 (t, J¼7.3 Hz, 3H); C NMR
3
100 MHz, CDCl ) d 137.4 (C), 136.4 (C), 128.9 (CH),
1
(
28.8 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.1
CH), 80.0 (CH), 72.0 (CH), 62.5 (CH ), 59.9 (CH ), 55.5
Acknowledgements
2
2
(
CH), 37.1 (CH ), 19.2 (CH ), 14.2 (CH ); MS (EI) 311.2
3
M.L. is grateful for graduate scholarships from NSERC and
from the University of Ottawa. This research has been sup-
ported by NSERC, the Canadian Foundation for Innovation,
and by the University of Ottawa.
2
2
+
(
M ); HRMS calcd for C H NO 311.1885; found
20 25 2
3
11.1873. endo isomer [a]D ꢀ90.0 (c 1.38, CHCl ); IR
3
ꢀ
1 1
(
CDCl ) d 7.44–7.39 (m, 2H), 7.36–7.29 (m, 4H), 7.29–
neat) 3421, 2930, 1652, 1455 cm ; H NMR (400 MHz,
3
7
3
1
3
.23 (m, 3H), 7.22–7.16 (m, 1H), 4.01–3.90 (m, 2H),
.79–3.67 (m, 2H), 3.56 (d, J¼7.2 Hz, 1H), 2.43–2.35 (m,
H), 1.95–1.84 (m, 1H), 1.66–1.54 (m, 1H), 1.52–1.30 (m,
H), 0.92 (t, J¼7.4 Hz, 3H); C NMR (100 MHz, CDCl3)
Supplementary data
1
3
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.08.110.
d 139.6 (C), 138.0 (C), 128.7 (CH), 128.4 (CH), 128.0
CH), 127.9 (CH), 127.8 (CH), 126.8 (CH), 79.9 (CH),
(
7
3.8 (CH), 62.9 (CH ), 60.7 (CH), 59.5 (CH ), 37.7 (CH ),
2 2 2
+
1
for C H NO 311.1885; found 311.1858.
9.4 (CH ), 14.1 (CH ); MS (EI) 311.2 (M ); HRMS calcd
References and notes
2
3
2
0
25
2
1
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0
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M. Lemay et al. / Tetrahedron 63 (2007) 11644–11655
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6