Oxadiazinones as chiral auxiliaries: Diastereoselective aldol addition reactions of N3-glycolyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2003.07.020

Asymmetric aldol reactions have been conducted with a series of N ₃-glycolyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones derived from (1R,2S)-ephedrine. These reactions afford the non-Evans syn-adducts in 43-97% yield and diastereoselectivities ranging from 62:38 to 99:1. Oxadiazinone substrates substituted with either the phenoxyacetyl or p-methoxyphenoxyacetyl groups gave the best results whereas the methoxyacetyl substituted oxadiazinone afforded diastereoselectivities that were modest.

Full text of DOI:10.1016/j.tetasy.2003.07.020

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3233–3241
Oxadiazinones as chiral auxiliaries: diastereoselective aldol
addition reactions of
N3-glycolyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-onesꢀ
Trisha R. Hoover and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 14 July 2003; accepted 25 July 2003
Abstract—Asymmetric aldol reactions have been conducted with a series of N3-glycolyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-
ones derived from (1R,2S)-ephedrine. These reactions afford the non-Evans syn-adducts in 43–97% yield and diastereoselectivities
ranging from 62:38 to 99:1. Oxadiazinone substrates substituted with either the phenoxyacetyl or p-methoxyphenoxyacetyl groups
gave the best results whereas the methoxyacetyl substituted oxadiazinone afforded diastereoselectivities that were modest.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
yields were good and the diastereoselectivities, directed
by the N4-methyl substituent, ranged from 3:1 to 99:1.
We became interested in investigating the potential of
the oxadiazinones as chiral auxiliaries for the related
glycolate aldol reaction. Crimmins,5 Davies,6 and
Evans7 have successfully applied N-glycolyloxazolidin-
2-ones and N-glycolyloxazolidine-2-thiones in asym-
metric aldol reactions to selectively afford either syn- or
anti-glycolate adducts. Andrus8 has employed N-gly-
colyldioxanones in the preparation of anti-glycolate
adducts with much success. Herein we report on our
efforts in employing N-glycolyl-oxadiazinones in the
asymmetric aldol reaction to afford syn-glycolate
adducts.
The development and utilization of chiral auxiliaries in
asymmetric reactions continues to evolve at an ever
increasing rate.1 Oxazolidinones have been among the
most successfully exploited auxiliaries2 and these com-
pounds have given inspiration to the synthesis and
application of a number of related auxiliaries.3 Our
efforts in this field led us to the development of 3,4,5,6-
tetrahydro-2H-1,3,4-oxadiazin-2-ones (oxadiazinones)
as potential candidates for asymmetric reactions
(Scheme 1).4a,b We recently demonstrated the usefulness
of N3-propionyloxadiazinones in titanium mediated
asymmetric aldol addition reactions.4a The chemical
Scheme 1. Asymmetric aldol reaction with a N3-propionyl oxadiazinones.
ꢀ Part of this work was presented at the 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23–27, Abstract
No. 445-CHED.
* Corresponding author. Tel.: +309-438-7854; fax: +309-438-5538; e-mail: hitchcock@xenon.che.ilstu.edu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.020

3234
T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
aldehyde, cooled to −78°C, treated with titanium tetra-
chloride, and finally reacted with triethylamine (Scheme
3). This process gave aldol adduct 8a, the cleaved
heterocycle 1, and hydroxyacid 9a in varying amounts
(5–25% in situ deacylation). This was surprising as this
phenomenon was not observed when these reaction
conditions were applied to the corresponding N3-propi-
onyloxadiazinone.4b A possible explanation for this
observation is associated with the fact that phenoxy-
acetyl group hydrolyzes nearly 50 times faster than the
acetyl group under basic conditions.10
Scheme 2. Acylation of oxadiazinone 1.
In order to improve the product distribution to favor
the aldol adduct, the reaction conditions were modified
to reflect our recent studies on improving the overall
reactivity of N3-propionyl-oxadiazinones in the asym-
metric aldol reaction.4a Oxadiazinone 4 was dissolved in
THF (0.33 M) and treated with titanium tetrachloride
at 25°C for 25 min. This reaction mixture was cooled to
−78°C, triethylamine was added, and the temperature
was allowed to come to 0°C. At this time, D2O was
added to confirm successful deprotonation (Scheme
4).11 The success of the deuteration experiment led us to
modify the asymmetric aldol reaction conditions to
allow for clean enolate formation (e.g. intermediate 11)
and subsequent carbonꢀcarbon bond formation with-
out significant concomitant product deacylation. Thus,
oxadiazinones 4–6 were treated with titanium tetra-
chloride at 25°C for a period of 25 min, cooled to
2. Results and discussion
The (1R,2S)-ephedrine based oxadiazinone 19 was
acylated with a variety of substituted acetyl chloride
derivatives (ROCH2COCl: R=-C6H5, -C6H4OCH3,
-CH3, and -CH2Ph) to afford N3-acylated oxadiazi-
nones 4–7 in 75–96% yield (Scheme 2). The method of
choice involved the addition of lithium hydride to a
mixture of 1 and the substituted acetyl chloride in
methylene chloride. The use of bases such as n-BuLi
and HMDS proved to be inefficient in the acylation
process.
Our initial efforts in applying the asymmetric aldol
reaction to the N3-glycolyloxadiazinones were not
promising. Oxadiazinone 4 was combined with benz-
Scheme 3. Initial attempt for asymmetric aldol reactions.
Scheme 4. Deuterium incorporation study of 4.

T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
3235
Scheme 5. Asymmetric aldol reaction of oxadiazinones 4–6.
Table 1. Diastereoselective aldol additions with oxadiazinones 4–6
Entry
Substrate
R%CHO aldehyde
Dra
Pure
Yieldb [%]
Adduct
Crude
1
2
3
4
5
6
7
8
4
4
4
4
4
5
5
5
5
5
6
6
6
6
6
-C6H5
94:6
96:4
93:7
91:9
93:7
95:5
91:9
93:7
97:3
99:1
99:1
99:1
99:1
99:1
96:4
98:2
70
88
79
43
57
82
66
76
8a
8b
8c
8d
-p-C6H4Cl
-p-C6H4OCH3
-2-C10H7
-m-C6H4CH3
-C6H5
-p-C6H4Cl
-p-C6H4OCH3
-2-C10H7
-m-C6H4CH3
-C6H5
8e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
9
95:5
97:3
99:1
99:1
63
76
97
10
11
12
13
14
15
79:21c
83:17c
62:38c
86:14c
74:26c
85:15c
90:10c
90:10c
91:9c
89:11c
-p-C6H4Cl
-p-C6H4OCH3
-2-C10H7
92d
46d
99d
64d
-m-C6H4CH3
a Diastereomer ratios determined by HPLC.
b Chemical yield of the purified product after column chromatography.
c The ratio of diastereomers was determined by 1H NMR.
d These products were contaminated with ꢀ13% of oxadiazinone 1 which could not be removed by chromatography or resolved by HPLC; see
Section 4.
−78°C, reacted with triethylamine, and warmed to 0°C
over a span of 15 min. The reaction was then cooled to
−78°C and the desired aldehyde was added. These
conditions gave the aldol adducts 8a–e, 13a–e, and
14a–e12 in 43–97% chemical yield and good diastereose-
lectivity (Scheme 5, Table 1). Unfortunately, we were
not able to successfully employ aliphatic aldehydes
using this approach. The reactions gave mixtures of the
desired aldol adduct, deacylation, and elimination.
was retained under the hydrolytic conditions.
The relative stereochemistry of 9a15 was determined to
be the syn-configuration based on the observed vicinal
coupling constant between the benzylic methine proton
and the a-methine of the carboxyl group (Ja-b=4.0 Hz)
1
from the 400 MHz H NMR spectrum.15 The absolute
stereochemistry of 9a was determined by optical rota-
tion to have the (2S,3R)-geometry {[h]D −41.3 (ee:
91%), (c 1.73, ethanol); lit.15 (2R,3S)-isomer: [h]D+44.3
(ee=98%), (c 2.1, ethanol)}.15 This suggested that the
transition state for the formation of the ‘non-Evans’
syn-adduct is a closed Zimmerman–Traxler transition
state16 in which the si-face of the aldehyde is directed
by the stereogenic N4-methyl substituent to the re-face
of the enolate (Fig. 1).17
We were disappointed to learn that the N3-benzyloxy-
oxadiazinone 7 did not readily undergo the asymmetric
aldol reaction. A series of control experiments were
conducted in an effort to determine the source of the
failure of this substrate to react. These experiments
included variation of reaction temperature, stoichiome-
try, and molarity. Unfortunately, none of these condi-
tions led to significant incorporation of deuterium.
In order to determine the stereochemical outcome of
the asymmetric aldol addition reaction, aldol adduct 8a
was hydrolyzed to the corresponding b-hydroxyacid 9a
by treatment with 1 M NaOH in THF (Scheme 6). This
process afforded 9a (74%) and the heterocycle 1 was
recovered (96%).13,14 The crude 1H NMR spectrum
suggested that the diastereomeric purity of the adduct
Scheme 6. Hydrolysis oxadiazinone adduct 8a.

3236
T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
appropriate acyl halide (41 mmol). The reaction mix-
ture was heated to reflux, and lithium hydride (0.28 g,
36 mmol) was added. The reaction was allowed to stir
overnight and was then cooled to 0°C and quenched by
the addition of a saturated solution of ammonium
chloride (75 mL). The solution was extracted with
EtOAc (2×75 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation.
Figure 1. Proposed transition state for the syn-glycolate aldol
addition.
4.2.1. (4R,5S,6R)-3,4,5,6-Tetrahydro-4,5-dimethyl-3-(2-
phenoxyacetyl)-6-phenyl-2H-1,3,4-oxadiazin-2-one
4.
Isolated product recrystallized from EtOAc to yield 4
(96%) as
a
white powder. [h]2D5=−41.8 (c 1.14,
3. Conclusion
methanol). Rf=0.35 (50:50, hexanes:EtOAc). Mp: 124–
1
In summary, we have synthesized a series of N3-gly-
colyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones and
have employed them in the asymmetric aldol reaction
to afford non-Evans syn-glycolate adducts. The reac-
tions with the glycolyl substrates (O-phenyl, O-anisyl,
O-methyl) afforded glycolate aldol adducts in fair to
good chemical yield and good diastereoselectivities.
Research is underway to refine the asymmetric aldol
reaction of N3-glycolyl-oxadiazinones for extension of
this method to the use of aliphatic aldehydes.12 Studies
focused on the reactivity of N3-benzyloxy-oxadiazinone
7 are also underway.
126°C. H NMR (CDCl3): l 0.90 (d, 3H, J=6.9 Hz),
3.02 (s, 3H), 3.41–3.47 (m, 1H), 5.17 (d, 1H, J=17.6
Hz), 5.27 (d, 1H, J=17.6 Hz), 6.07 (d, 1H, J=4.03 Hz),
6.95–7.45 (m, 10H). 13C NMR (CDCl3): 12.3, 43.3,
56.9, 69.4, 77.7, 114.9, 121.6, 124.9, 128.4, 128.8, 129.5,
135.1, 148.6, 157.9, 169.0. IR (CCl4): 1782, 1366, 1245,
1211, 784, 755 cm−1. Anal. calcd for C19H20N2O4: C,
67.05; H, 5.92; N, 8.23. Found: C, 67.00; H, 5.80; N,
8.21. HRMS calcd for C19H21N2O4: 341.1501. Found:
341.1503.
4.2.2. (4R,5S,6R)-3,4,5,6-Tetrahydro-3-[2-(4-methoxy-
phenoxy)acetyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadi-
azin-2-one 5. Product isolated by column chromatogra-
phy (60:40, hexanes:EtOAc, Rf=0.20, column
dimensions=5.5×15 cm) to yield 5 (75%) as an oil.
4. Experimental
4.1. General remarks
1
[h]2D5=−40.5 (c 1.66, methanol). H NMR (CDCl3): l
0.89 (d, 3H, J=6.9 Hz), 3.01 (s, 3H), 3.41–3.47 (m,
1H), 3.77 (s, 3H), 5.12 (d, 1H, J=17.6 Hz), 5.21 (d, 1H,
J=17.6 Hz), 6.07 (d, 1H, J=4.0 Hz), 6.82–6.94 (m,
4H), 7.30–7.44 (m, 5H). 13C NMR (CDCl3): 12.3, 43.3,
55.6, 56.8, 70.4, 77.7, 114.6, 116.3, 124.9, 128.4, 128.8,
135.1, 148.6, 152.1, 154.5, 169.3. IR (neat): 1786, 804,
747 cm−1. HRMS calcd for C20H23N2O5: 371.1607.
Found: 371.1607.
Tetrahydrofuran (THF) was distilled from a potassium/
sodium alloy with benzophenone ketyl. Methylene chlo-
ride (CH2Cl2) and ethylene chloride were distilled from
calcium hydride. All reactions were run under a nitro-
gen atmosphere. Flash chromatography was conducted
1
with silica gel (32–63 mesh). H and 13C NMR spectra
were recorded at 25°C on a Varian spectrometer in
CDCl3 operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (l
scale), and coupling constants (J values) are listed in
hertz (Hz). Tetramethylsilane (tms) was used as an
internal standard (l=0.00 ppm). Infrared spectra are
reported in reciprocal centimeters (cm−1) and are mea-
sured either as a neat solution of dissolved in CCl4.
Melting points were recorded on a Mel-Temp appara-
tus and are uncorrected. High-resolution mass spectra
were obtained from the Mass Spectrometry Labora-
tory, School of Chemical Sciences, University of Illi-
nois, Urbana-Champaign. Elemental analyses were
conducted by the Microanalytical Laboratory, School
of Chemical Sciences, University of Illinois, Urbana-
Champaign.
4.2.3. (4R,5S,6R)-3-(2-Methoxyacetyl)-4,5-dimethyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one 6. The product was
recrystallized from EtOAc to yield 6 (92%) as a white
powder. Rf=0.26 (20:80, hexanes:EtOAc). Mp: 100–
102°C. [h]2D5=−70.9 (c 1.86, methanol). 1H NMR
(CDCl3): l 0.87 (d, 3H, J=6.9 Hz), 3.00 (s, 3H),
3.40–3.46 (m, 1H), 3.51 (s, 3H), 4.56 (d, 1H, J=17.9
Hz), 4.68 (d, 1H, J=17.9 Hz), 6.05 (d, 1H, J=4.04 Hz),
7.29–7.43 (m, 5H). 13C NMR (CDCl3): 12.2, 43.3, 56.8,
59.3, 73.9, 77.6, 124.9, 128.3, 128.8, 135.2, 148.5, 170.6.
IR (CCl4): 1781, 1258, 1219, 793, 784, 766 cm−1. Anal.
calcd for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07.
Found: C, 60.08; H, 6.40; N, 9.97. HRMS calcd for
C14H18N2O4: 279.1345. Found: 279.1345.
4.2. General procedure for the preparation of com-
pounds 4–7
4.2.4.
(4R,5S,6R)-3-(2-Benzyloxyacetyl)-3,4,5,6-tetra-
hydro-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 7.
Yellow oil purified by column chromatography on silica
gel (50:50, hexanes:EtOAc, Rf=0.21, column dimen-
sions=5.5×15 cm) to yield 7 (92%) as a clear oil.
In a flame-dried, nitrogen purged, 250 mL round bot-
tomed flask equipped with a condenser was placed the
(1R,2S)-ephedrine heterocycle 1 (7.0 g, 34 mmol),
freshly distilled ethylene chloride (34 mL), and the
1
[h]2D5=−55.7 (c 2.15, methanol). H NMR (CDCl3): l

T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
3237
0.85 (d, 3H, J=6.9 Hz), 3.00 (s, 3H), 3.39–3.45 (m,
1H), 4.64 (d, 1H, J=17.9 Hz), 4.68 (d, 1H, J=2.2 Hz),
4.75 (d, 1H, J=17.9 Hz), 6.03 (d, 1H, J=4.0 Hz),
7.28–7.44 (m, 10H). 13C NMR (CDCl3): 12.3, 43.3,
56.8, 71.3, 73.3, 77.6, 124.9, 127.9, 128.2, 128.3, 128.4,
128.7, 135.2, 137.2, 148.4, 170.8. IR (neat): 1786, 1732,
1202, 1136, 738, 699 cm−1. HRMS calcd for
C20H23N2O4: 355.1658. Found: 355.1659.
(40:60, hexanes:EtOAc, Rf=0.27, column dimensions=
3×40 cm) to yield 8b (88%) as an oil. [h]2D5=−1.4 (c
2.22, methanol). 1H NMR (CDCl3): l 0.80 (d, 3H,
J=6.96 Hz), 2.96 (s, 3H), 3.40–3.46 (m, 1H), 5.41 (s,
1H), 6.01 (d, 1H, J=2.20 Hz), 6.08 (d, 1H, J=4.04
Hz), 6.74–7.55 (m, 14H). 13C NMR (CDCl3): 11.8, 42.8,
56.3, 72.9, 77.8, 81.8, 115.7, 122.1, 124.6, 127.6, 128.1,
128.2, 128.6, 129.3, 133.2, 134.9, 138.5, 148.9, 157.1,
169.2. IR (neat): 3438, 3064, 1700, 1598, 1134 cm−1.
HRMS calcd for C26H26N2O5Cl: 481.1530. Found:
481.1532.
4.3. Procedure for the synthesis of (2%S,3%R,4R,5S,6R)-
3,4,5,6-tetrahydro-3-(3-hydroxy-2-phenoxy-3-phenylpro-
pionyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
8a
4.4.2.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-3-(4-methoxyphenyl)-2-phenoxypropionyl]-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-one 8c. Yellow oil
purified by column chromatography on silica gel (40
hexanes: 60 EtOAc, Rf=0.24, column dimensions=3×
40 cm) to yield 8c (79%) as an oil. [h]2D5=−20.8 (c 2.29,
In a nitrogen-purged, flame-dried 100 mL, round bot-
tomed flask was placed 4 (0.75 g, 2.20 mmol), freshly
distilled THF (6.60 mL), and titanium tetrachloride
(0.25 mL, 2.3 mmol). The solution was stirred for 25
min and was then cooled to −78°C for 15 min. Triethyl-
amine (0.61 mL, 4.4 mmol) was then added, and the
reaction was brought to 0°C over a period of 15 min.
The reaction mixture was again cooled to −78°C and
benzaldehyde (0.44 mL, 4.4 mmol) was added. The
reaction stirred for 4 h and was quenched by the
addition of a saturated solution of ammonium chloride
(50 mL). The resulting mixture was then extracted with
EtOAc (3×50 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation. This process afforded a yellow
oil purified by column chromatography on silica gel
(40:60, hexanes:EtOAc, Rf=0.27, column dimensions=
3×40 cm) to yield 8a (70%) as an oil. [h]2D5=−6.0 (c
2.46, methanol). 1H NMR (CDCl3): l 0.79 (d, 3H,
J=6.9 Hz), 2.91 (s, 3H), 3.38–3.44 (m, 1H), 5.41 (d,
1H, J=2.2 Hz), 6.05 (d, 1H, J=3.6 Hz), 6.10 (d, 1H,
J=2.6 Hz), 6.77–7.60 (m, 15H). 13C NMR (CDCl3):
11.9, 42.9, 56.5, 73.8, 77.8, 82.1, 115.9, 122.1, 124.7,
126.3, 127.8, 128.1, 128.2, 128.7, 129.3, 135.0, 139.7,
148.8, 157.3, 169.5. IR (neat): 3460, 3063, 1716, 1599,
1186, 732, 700 cm−1. HRMS calcd for C26H27N2O5:
447.1920. Found: 447.1922.
1
methanol). H NMR (CDCl3): l 0.74 (d, 3H, J=6.9
Hz), 2.74 (s, 3H), 3.31–3.37 (m, 1H), 3.49 (d, 1H,
J=7.3 Hz), 3.72 (s, 3H), 5.33 (d, 1H, J=4.0 Hz), 5.95
(d, 1H, J=4.03 Hz), 6.09 (d, 1H, J=2.9 Hz), 6.78–7.50
(m, 14H). 13C NMR (CDCl3): 11.7, 42.6, 54.9, 56.3,
73.5, 77.7, 81.9, 113.4, 115.7, 121.8, 124.6, 127.6, 128.1,
128.5, 129.2, 131.7, 135.0, 148.7, 157.3, 159.0, 169.4. IR
(neat): 3455, 2936, 1717, 1599, 740, 700 cm−1. HRMS
calcd for C27H29N2O5: 477.2026. Found: 477.2026.
4.4.3.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-3-naphthalen-2-yl-2-phenoxypropionyl)-4,5-di-
methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8d. Yellow
oil purified by column chromatography on silica gel
(50:50, hexanes:EtOAc, Rf=0.19, column dimensions=
3×40 cm) to yield 8d (43%) as an oil. [h]2D5 +10.3 (c 2.00,
1
methanol). H NMR (CDCl3): l 0.79 (d, 3H, J=6.6
Hz), 2.87 (s, 3H), 3.32 (d, 1H, J=6.6 Hz), 3.36–3.42 (m,
1H), 5.59 (s, 1H), 5.99 (d, 1H, J=3.7 Hz), 6.20 (d, 1H,
J=2.7 Hz), 6.76–8.01 (m, 17H). 13C NMR (CDCl3):
11.9, 42.8, 56.4, 73.8, 77.7, 82.0, 115.8, 122.0, 124.2,
124.7, 125.3, 125.8, 125.9, 127.5, 127.9, 128.0, 128.2,
128.6, 129.3, 132.8, 132.9, 135.0, 137.3, 148.9, 157.3,
169.5. IR (neat): 3446, 3013, 1716, 1600, 751 cm−1.
HRMS calcd for C30H29N2O5: 497.2076. Found:
497.2070.
4.4. General procedure for the preparation of 8b–e
In a nitrogen-purged, flame-dried 100 mL, round bot-
tomed flask was placed 4 (1.00 g, 2.93 mmol), freshly
distilled tetrahydrofuran (8.80 mL), and the appropri-
ate aldehyde (5.86 mmol). The solution was then cooled
to −78°C for 10 min. To this solution was added
titanium tetrachloride (0.34 mL, 3.1 mmol) and the
reaction stirred for 15 min. Triethylamine (0.81 mL,
5.86 mmol) was then added. The reaction was allowed
to run for 4 h and was quenched by the addition of a
saturated solution of sodium bicarbonate (50 mL) at
25°C. The resulting mixture was then extracted with
EtOAc (3×50 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation.
4.4.4.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-2-phenoxy-3-m-tolylpropionyl)-4,5-dimethyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one 8e. Yellow oil purified
by column chromatography on silica gel (40:60, hex-
anes:EtOAc, Rf=0.30, column dimensions=3×40 cm)
to yield 8e (57%) as an oil. [h]2D5=−6.0 (c 1.28,
1
methanol). H NMR (CDCl3): l 0.79 (d, 3H, J=6.9
Hz), 2.34 (s, 3H), 2.84 (s, 3H), 3.22 (d, 1H, J=7.7 Hz),
3.35–3.41 (m, 1H), 5.37 (d, 1H, J=5.5 Hz), 6.00 (d, 1H,
J=4.0 Hz), 6.10 (d, 1H, J=2.6 Hz), 6.77–7.43 (m,
14H). 13C NMR (CDCl3): 11.8, 21.3, 42.7, 56.4, 73.8,
77.7, 82.0, 115.8, 121.9, 123.3, 124.6, 127.0, 128.0,
128.1, 128.4, 128.6, 129.2, 135.0, 137.6, 139.5, 148.7,
157.3, 169.4. IR (neat): 3464, 2976, 1718, 1239, 788, 752
cm−1. HRMS calcd for C27H29N2O5: 461.2076. Found:
461.2074.
4.4.1.
(2%S,3%R,4R,5S,6R)-3-[3-(4-Chlorophenyl)-3-
hydroxy-2-phenoxypropionyl]-3,4,5,6-tetrahydro-4,5-di-
methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8b. Yellow
oil purified by column chromatography on silica gel

3238
T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
4.5.
(+)-(2S,3R)-3-Hydroxy-2-phenoxy-3-phenylpropi-
added. The reaction stirred for 4 h and was quenched
onic acid 9a
by the addition of a saturated solution of ammonium
chloride (50 mL). The resulting mixture was then
extracted with EtOAc (3×50 mL), washed with a satu-
rated solution of brine, dried over MgSO4, and the
solvent was removed via rotary evaporation.
In a 100 mL, round bottomed flask was placed 8a
(1.00g, 2.24 mmol), tetrahydrofuran (6.70 mL), and
NaOH (1 M, 6.72 mL). The resulting solution was
stirred overnight. A saturated solution of sodium bicar-
bonate (50 mL) was then added. The mixture was then
extracted with EtOAc (2×50 mL), washed with a satu-
rated solution of brine, dried over MgSO4, and the
solvent was removed via rotary evaporation. The
aqueous layer was acidified with 1 M HCl. This solu-
tion was extracted with EtOAc (2×50 mL), washed with
a saturated solution of brine, dried over MgSO4, and
the solvent was removed via rotary evaporation. This
process afforded 9a (79%) as an oil. Rf=0.13 (50:50,
hexanes:EtOAc). [h]D25=−41.3 (c 1.73, ethanol). 1H
NMR (CDCl3): l 3.63 (s, 1H), 4.81 (d, 1H, J=4.03
Hz), 5.27 (d, 1H, J=4.03 Hz), 6.82–7.49 (m, 10H). 13C
NMR (CDCl3): 74.3, 80.8, 115.5, 122.3, 126.6, 128.4,
129.5, 133.8, 138.7, 157.3, 173.8. IR (neat): 3408, 3064,
1732, 1599, 753, 700 cm−1. HRMS calcd for C15H15O4:
259.0970. Found: 259.0970.
4.7.1.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-2-(4-methoxyphenoxy)-3-phenylpropionyl]-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 13a. Yellow
oil purified by column chromatography on silica gel
(30:70, hexanes:EtOAc, Rf=0.24, column dimensions=
3×40 cm) to yield 13a (82%) as an oil. [h]2D5=−13.7 (c
2.10, methanol). 1H NMR (CDCl3): l 0.74 (d, 3H,
J=6.9 Hz), 2.91 (s, 3H), 3.37–3.43 (m, 1H), 3.39 (s,
3H), 5.38 (d, 1H, J=2.6 Hz), 5.95 (d, 1H, J=2.9 Hz),
6.03 (d, 1H, J=4.0 Hz), 6.69 (s, 4H), 7.25–7.60 (m,
10H). 13C NMR (CDCl3): 11.8, 42.8, 55.3, 56.3, 73.8,
77.7, 83.7, 114.3, 117.7, 124.6, 126.2, 127.6, 128.0,
128.1, 128.5, 135.0, 139.8, 148.6, 151.2, 154.7, 169.8. IR
(neat): 3458, 1720, 1258, 745, 700 cm−1. HRMS calcd
for C27H29N2O6: 477.2026. Found: 477.2025.
4.7.2.
(2%S,3%R,4R,5S,6R)-3-[3-(4-Chlorophenyl)-3-
4.6. (2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-4,5-
dimethyl-3-(2-deuterio-2-phenoxyacetyl)-6-phenyl-2H-
1,3,4-oxadiazin-2-one 12
hydroxy-2-(4-methoxyphenoxy)propionyl]-3,4,5,6-tetra-
hydro-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
13b. Yellow oil purified by column chromatography on
silica gel (30:70, hexanes:EtOAc, Rf=0.28, column
dimensions=3×40 cm) to yield 13b (66%) as an oil.
[h]2D5=−6.5 (c 2.20, methanol). 1H NMR (CDCl3): l
0.75 (d, 3H, J=6.9 Hz), 2.95 (s, 3H), 3.38–3.45 (m,
1H), 3.69 (s, 3H), 5.37 (d, 1H, J=1.8 Hz), 5.86 (d, 1H,
J=2.2 Hz), 6.05 (d, 1H, J=4.0 Hz), 6.69 (d, 4H, J=2.2
Hz), 7.28–7.55 (m, 9H). 13C NMR (CDCl3): 11.8, 42.8,
55.3, 56.3, 72.9, 77.7, 83.4, 114.3, 117.6, 124.6, 127.6,
128.1, 128.11, 128.5, 133.1, 134.9, 138.7, 148.7, 151.3,
154.7, 169.5. IR (neat): 3456, 1724, 757 cm−1. HRMS
calcd for C27H28N2O6Cl: 511.1636. Found: 511.1636.
In a nitrogen-purged, flame-dried 100 mL, round bot-
tomed flask was placed 4 (0.75 g, 2.2 mmol), freshly
distilled tetrahydrofuran (6.60 mL), and titanium tetra-
chloride (0.25 mL, 2.31 mmol). The solution was stirred
for 25 min and was then cooled to −78°C for 15 min.
Triethylamine (0.61 mL, 4.4 mmol) was then added,
and the reaction was brought to 0°C over a period of
15 min and D2O was added. Then, a saturated solution
of ammonium chloride (50 mL) was added. The result-
ing mixture was then extracted with EtOAc (3×50 mL),
washed with a saturated solution of brine, dried over
MgSO4, and the solvent was removed via rotary evapo-
ration. Isolated product recrystallized from EtOAc to
yield 12 (40%) as a white powder. Rf=0.36 (50 hex-
4.7.3.
(2%S,3%R,4S,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-2-(4-methoxyphenoxy)-3-(4-methoxyphenyl)pro-
pionyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
13c. Yellow oil purified by column chromatography on
silica gel (30:70, hexanes:EtOAc, Rf=0.20, column
dimensions=3×40 cm) to yield 13c (76%) as an oil.
1
anes:50 EtOAc). Mp: 125–126°C. H NMR (CDCl3): l
0.90 (d, 3H, J=6.9 Hz), 3.02 (s, 3H), 3.41–3.47 (m,
1H), 5.16 (s, 1H), 5.24 (s, 1H), 6.08 (d, 1H, J=4.0 Hz),
6.95–7.45 (m, 10H). 13C NMR (CDCl3): 12.3, 43.3,
56.9, 68.8, 69.1, 69.3, 77.7, 114.9, 121.6, 124.9, 128.4,
128.8, 129.5, 135.1, 148.6, 157.8, 169.0. IR (CCl4): 3011,
1770, 1210, 786, 760 cm−1. HRMS calcd for
C19H21DN2O4: 342.1564. Found: 342.1564.
1
[h]2D5=−14.5 (c 2.58, methanol). H NMR (CDCl3): l
0.73 (d, 3H, J=6.9 Hz), 2.88 (s, 3H), 3.36–3.42 (m,
1H), 3.70 (s, 3H), 3.81 (s, 3H), 5.32 (d, 1H, J=2.9 Hz),
5.95 (d, 1H, J=2.9 Hz), 6.01 (d, 1H, J=4.0 Hz),
6.69–6.75 (m, 4H), 6.91 (d, 4H, J=8.4 Hz), 7.29–7.51
(m, 5H). 13C NMR (CDCl3): 11.7, 42.7, 55.0, 55.3, 56.3,
73.5, 77.6, 83.6, 113.4, 114.3, 117.6, 124.6, 127.6, 128.1,
128.5, 131.8, 135.0, 148.6, 151.5, 154.6, 158.9, 169.8. IR
(neat): 3466, 3012, 1720, 1252, 750 cm−1. HRMS calcd
for C28H31N2O6: 507.2131. Found: 507.2131.
4.7. General procedure for the preparation of 13a–e
In a nitrogen-purged, flame-dried, 100 mL round bot-
tomed flask was placed 5 (1.00 g, 2.70 mmol), freshly
distilled tetrahydrofuran (8.10 mL), and titanium tetra-
chloride (0.31 mL, 2.8 mmol). The solution was stirred
for 25 min and was then cooled to −78°C for 15 min.
Triethylamine (0.75 mL, 5.4 mmol) was then added and
the reaction was brought to 0°C over a period of 15
min. The reaction mixture was again cooled to −78°C,
and the appropriate aldehyde (5.40 mmol) was then
4.7.4.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-2-(4-methoxyphenoxy)-3-naphthalen-2-yl-propi-
onyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
13d. Yellow oil purified by column chromatography on
silica gel (30:70, hexanes:EtOAc, Rf=0.28, column
dimensions=3×40 cm) to yield 13d (63%) as an oil.

T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
3239
[h]2D5=+2.2 (c 1.92, methanol). 1H NMR (CDCl3): l
0.74 (d, 3H, J=6.9 Hz), 2.89 (s, 3H), 3.36–3.42 (m,
1H), 3.66 (s, 3H), 5.56 (d, 1H, J=2.6 Hz), 6.00 (d, 1H,
J=4.0 Hz), 6.06 (d, 1H, J=2.6 Hz), 6.64–6.71 (m, 4H),
7.28–8.02 (m, 12H). 13C NMR (CDCl3): 11.6, 42.6,
55.2, 56.1, 73.7, 77.5, 83.6, 114.1, 117.5, 124.2, 124.5,
125.2, 125.6, 125.8, 127.3, 127.7, 127.8, 128.0, 128.4,
132.7, 132.8, 134.9, 137.5, 148.7, 151.5, 154.5, 169.7. IR
(neat): 3452, 3013, 1720, 750 cm−1. HRMS calcd for
C31H31N2O6: 527.2182. Found: 527.2180.
127.9, 128.4, 135.0, 140.3, 148.5, 170.7. IR (CCl4): 3450,
1728, 1720, 1258, 1134, 786, 762 cm−1. HRMS calcd for
C21H24N2O5: 385.1763. Found: 385.1762.
4.8.2.
(2%S,3%R,4R,5S,6R)-3-[3-(4-Chlorophenyl)-3-
hydroxy - 2 - methoxypropionyl] - 3,4,5,6 - tetrahydro - 4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 14b. Yellow
oil purified by column chromatography on silica gel
(20:80, EtOAc:hexanes Rf=0.22, column dimensions=
3×40 cm) to yield 14b (92%) as an oil. Crude product
contained 13.2% ephedrine heterocycle 1, and the
purified product contained 13.2% ephedrine heterocy-
cle. The contaminant could not be separated by column
chromatography or HPLC. [h]2D5=−44.1 (c 2.45,
4.7.5.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-2-(4-methoxyphenoxy)-3-m-tolylpropionyl]-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 13e. Yellow
oil purified by column chromatography on silica gel
(30:70, hexanes:EtOAc, Rf=0.22, column dimensions=
3×40 cm) to yield 13e (76%) as an oil. [h]2D5=−10.4 (c
2.71, methanol). 1H NMR (CDCl3): l 0.74 (d, 3H,
J=6.9 Hz), 2.37 (s, 3H), 2.89 (s,3H), 3.36–3.43 (m, 1H),
3.69 (s, 3H), 5.34 (d, 1H, J=2.6 Hz), 5.96 (d, 1H,
J=2.9 Hz), 6.02 (d, 1H, J=4.0 Hz), 6.70 (s, 4H),
7.10–7.43 (m, 9H). 13C NMR (CDCl3): 11.6, 21.2, 42.6,
55.2, 56.2, 73.7, 77.6, 83.6, 114.1, 117.5, 123.2, 124.5,
126.8, 127.8, 128.0, 128.2, 128.4, 134.9, 137.4, 139.6,
148.5, 151.5, 154.5, 169.8. IR (neat): 3458, 3008, 1720,
754 cm−1. HRMS calcd for C28H31N2O6: 491.2182.
Found: 491.2184.
1
methanol). H NMR (CDCl3): l 0.88 (d, 3H, J=6.9
Hz), 3.00 (s, 3H), 3.29 (s, 3H), 3.43–3.49 (m, 1H), 5.11
(d, 1H, J=2.2 Hz), 5.17 (s, 1H), 6.07 (d, 1H, J=4.0
Hz), 7.29–7.49 (m, 9H). 13C NMR (CDCl3): 11.7, 42.6,
55.9, 58.3, 72.5, 77.4, 84.7, 124.4, 127.3, 127.7, 127.9,
128.3, 132.6, 134.8, 139.2, 148.5, 170.3. IR (neat): 3450,
2994, 1720, 750, 700 cm−1. HRMS calcd for
C21H24N2O5Cl: 419.1374. Found: 419.1375.
4.8.3.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-2-methoxy-3-(4-methoxyphenyl)propionyl]-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 14c. Yellow
oil purified by column chromatography on silica gel
(20:80, hexanes:EtOAc, Rf=0.18, column dimensions=
3×40 cm) to yield 14c (46%) as an oil. Crude product
contained 18% ephedrine heterocycle 1, and the purified
product contained 29.2% ephedrine heterocycle. The
contaminant could not be efficiently separated by
column chromatography or HPLC. [h]2D5=−41.8 (c
2.33, methanol). 1H NMR (CDCl3): l 0.87 (d, 3H,
J=6.9 Hz), 2.88 (s, 3H), 3.34 (s, 3H), 3.40–3.46 (m,
1H), 3.81 (s, 3H), 5.10 (d, 1H, J=2.6 Hz), 5.20 (d, 1H,
J=2.6 Hz), 6.02 (d, 1H, J=4.0 Hz), 6.90 (d, 4H, J=8.8
Hz), 7.29–7.45 (m, 5H). 13C NMR (CDCl3): 11.9, 42.8,
55.0, 56.3, 58.5, 73.3, 77.6, 85.1, 113.3, 124.6, 127.4,
128.1, 128.5, 132.4, 135.1, 148.6, 158.8, 171.0. IR (neat):
3310, 2938, 1720, 751, 700 cm−1. HRMS calcd for
C22H27N2O6: 415.1869. Found: 415.1867.
4.8. General procedure for the preparation of 14a–e
In a nitrogen-purged, flame-dried, 100 mL, round bot-
tomed flask was placed 6 (0.75 g, 2.70 mmol), freshly
distilled tetrahydrofuran (8.60 mL), and titanium tetra-
chloride (0.33 mL, 3.00 mmol). The solution was stirred
for 25 min, and was then cooled to −78°C for 15 min.
Triethylamine (0.79 mL, 5.70 mmol) was then added,
and the reaction was brought to 0°C over a period of 1
h. The reaction mixture was again cooled to −78°C, and
the appropriate aldehyde (5.70 mmol) was then added.
The reaction stirred for 4 h and was quenched by the
addition of a saturated solution of ammonium chloride
(50 mL). The resulting mixture was then extracted with
EtOAc (3×50 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation.
4.8.4.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-2-methoxy-3-naphthalen-2-yl-propionyl)-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 14d. Yellow
oil purified by column chromatography on silica gel
(20:80 hexanes:EtOAc, Rf=0.22, column dimensions=
3×40 cm) to yield 14d (99%) as a yellow powder. This
material was recrystallized from EtOAc to afford 14d
(31%). Mp: 150–152°C. Crude product contained 11.8%
ephedrine heterocycle, and the purified product con-
tained 15.9% ephedrine heterocycle. The contaminant
could not be efficiently separated by column chro-
matography or HPLC. [h]2D5=−56.9 (c 1.77, methanol).
1H NMR (CDCl3): l 0.88 (d, 3H, J=6.6 Hz), 2.91 (s,
3H), 3.29 (s, 3H), 3.41–3.47 (m, 1H), 5.31 (d, 1H,
J=2.6 Hz), 5.36 (s, 1H), 6.02 (d, 1H, J=4.0 Hz),
7.27–7.96 (m, 12H). 13C NMR (CDCl3): 11.7, 42.6,
56.0, 58.5, 73.4, 77.4, 85.0, 124.0, 124.5,
4.8.1.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-2-methoxy-3-phenylpropionyl)-4,5-dimethyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one 14a. Yellow oil
purified by column chromatography on silica gel (20:80,
hexanes:EtOAc, Rf=0.20, column dimensions=3×40
cm) to yield 14a (97%) as a white powder. A second
purification was carried out: white powder recrystal-
lized from CH2Cl2 to yield 14a (34%). Crude product
contained 6.5% ephedrine heterocycle 1. Mp: 148–
149°C. [h]2D5=−60.8 (c 1.98, methanol). 1H NMR
(CDCl3): l 0.87 (d, 3H, J=6.9 Hz), 2.91 (s, 3H), 3.31
(s, 3H), 3.40–3.46 (m, 1H), 5.17 (d, 1H, J=2.6 Hz),
5.22 (d, 1H, J=2.2 Hz), 6.04 (d, 1H, J=4.4 Hz),
7.29–7.54 (m, 10H). 13C NMR (CDCl3): 11.8, 42.7,
56.1, 58.4, 73.4, 77.4, 84.9, 124.5, 126.0, 127.2, 127.8,

3240
T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
124.8, 125.4, 125.6, 127.2, 127.5, 127.7, 127.9, 128.3,
132.5, 132.7, 134.9, 138.0, 148.6, 170.7. IR (CCl4): 3450,
1720, 754, 700 cm−1. HRMS calcd for C25H27N2O5:
435.1920. Found: 435.1921.
Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem.
Soc. 1981, 103, 2127–2129.
3. (a) Davies, S. G.; Dixon, D. J. J. Chem. Soc., Perkin
Trans. 1 2002, 6, 1869–1876; (b) Mulzer, J.; Langer, O.;
Hiersemann, M.; Bats, J. W.; Bushmann, J.; Luger, P.
J. Org. Chem. 2000, 65, 6540–6546; (c) Yang, K.-S.;
Chen, K. Org. Lett. 2000, 2, 729–731; (d) Boeckman,
R. K., Jr.; Wrobleski, S. T. J. Org. Chem. 1996, 61,
7238–7239; (e) Ager, D. J.; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835–875; (f) Boeckman, R. K.,
Jr.; Nelson, G. G.; Gaul, M. D. J. Am. Chem. Soc.
1992, 114, 2258–2260; (g) Cardillo, G.; D’Amico, A.;
Orena, M.; Sandri, S. J. Org. Chem. 1988, 53, 2354–
2356.
4. (a) Casper, D. M.; Hitchcock, S. R. Tetrahdron: Asym-
metry 2003, 14, 517–521; (b) Casper, D. M.; Burgeson,
J. R.; Esken, J. M.; Ferrence, G. M.; Hitchcock, S. R.
Org. Lett. 2002, 4, 3739–3742.
5. (a) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003,
5, 591–594; (b) Crimmins, M. T.; Tabet, E. A. J. Am.
Chem. Soc. 2000, 122, 5473–5476; (c) Crimmins, M. T.;
King, B. W.; Zuercher, W. J.; Choy, A. L. J. Org.
Chem. 2000, 65, 8499–8509; (d) Crimmins, M. T.;
Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660;
(e) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997,
62, 7548–7549.
4.8.5.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-2-methoxy-3-m-tolylpropionyl)-4,5-dimethyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one 14e. Yellow oil
purified by column chromatography on silica gel (30:70,
hexanes:EtOAc, Rf=0.21, column dimensions=3×40
cm) to yield 14e (64%) as an oil. Crude product con-
tained 7.0% ephedrine heterocycle, and the purified
product contained 8.6% ephedrine heterocycle. The
contaminant could not be efficiently separated by
column chromatography or HPLC. [h]2D5=−28.6 (c
2.28, methanol). 1H NMR (CDCl3): l 0.87 (d, 3H,
J=6.9 Hz), 2.37 (s, 3H), 2.90 (s, 3H), 3.32 (s, 3H),
3.41–3.47 (m, 1H), 5.13 (d, 1H, J=2.6 Hz), 5.23 (d, 1H,
J=2.6 Hz), 6.03 (d, 1H, J=4.0 Hz), 7.10–7.44 (m,
10H). 13C NMR (CDCl3): 11.8, 21.2, 42.7, 56.2, 58.4,
73.5, 77.5, 84.9, 123.1, 124.5, 125.0, 126.7, 127.8, 128.0,
128.4, 135.0, 137.3, 140.2, 148.5, 170.8. IR (neat): 3466,
2938, 1728, 1720, 1260, 1132, 750, 700 cm−1. HRMS
calcd for C22H27N2O5: 399.1920. Found: 399.1921.
6. Davies, S. G.; Nicholson, R. L.; Smith, A. D. Synlett
2002, 10, 1637–1640.
Acknowledgements
7. (a) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am.
Chem. Soc. 1992, 114, 9434–9453; (b) Evans, D. A.;
Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961–1963; (c) Evans, D. A.; Kaldor, S. W.;
Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc.
1990, 112, 7001–7031; (d) Evans, D. A.; Bender, S. L.;
Morris, J. J. Am. Chem. Soc. 1988, 110, 2506–2526.
8. (a) Andrus, M. B.; Mendenhall, K. G.; Meredith, E.
L.; Soma Sekhar, B. B. V. Tetrahedron Lett. 2002, 43,
1789–1792; (b) Andrus, M. B.; Meredith, E. L.; Soma
Sekhar, B. B. V. Org. Lett. 2001, 3, 259–262; (c)
Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E.
L.; Dalley, N. K. Org. Lett. 2000, 2, 3035–3037.
9. Oxadiazinone 1 is prepared on multigram scale (10–75
g) in a three-step reaction sequence of N-nitrosation,
reduction, and cyclization. There is no need for chro-
matography as the products are all crystalline. See Ref.
4b.
We thank Mr. Jesse Wolfe and Mr. Yao Anim-Addo
for their technical assistance. We gratefully acknowl-
edge financial support for T. R. Hoover from Abbott
Laboratories for summer research. We also thank
Maria Teresa Navio of the Analytical Research and
Development Department of Pfizer Global Research
and Development in La Jolla, CA for optical activity
measurements. We also acknowledge continued support
from Merck & Co., Inc.
References
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11. The incorporation of deuterium was confirmed by 1H
and 13C NMR spectroscopy. The expected 1:1:1 triplet
signal was observed in the 75 MHz 13C NMR spectrum
at 68.5 ppm.
12. Successful reaction of oxadiazinone 6 required that the
enolate was formed over a period of 1 h rather than 15
min. The temperature was allowed to warm from −78
to 0°C. This process was optimal for complete enolate
formation. This is believed to be the source of the
lower diastereoselectivities, i.e. formation of (Z)- and
(E)-configured enolates.
13. Attempts to remove the auxiliary using lithium
hydroperoxide were not successful, possibly due to
competitive side reactions.

T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
3241
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14. Acid hydrolysis (6M H2SO4, THF) of adduct 8a under
reflux conditions afforded b-hydroxy acid 9a (74%) yield,
but the heterocycle was also hydrolyzed to the corre-
sponding b-hydroxyhydrazine. See: Vicario, J. L.; Baida,
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