Towards the development of oxadiazinanones as chiral auxiliaries: synthesis and application of N3-haloacetyloxadiazinanones

Article abstract of DOI:10.1016/j.tetasy.2006.06.036

Oxadiazinanones derived from (1R,2S)-ephedrine and (1R,2S)-norephedrine were employed in the asymmetric α-halo aldol reaction. The optimized yields and diastereoselectivities for the ephedrine based oxadiazinanone aldol reaction ranged from fair to good.

Full text of DOI:10.1016/j.tetasy.2006.06.036

Tetrahedron: Asymmetry 17 (2006) 1831–1841
Towards the development of oxadiazinanones
as chiral auxiliaries: synthesis and application
of N3-haloacetyloxadiazinanones
Trisha R. Hoover, Jonathan A. Groeper, Raleigh W. Parrott, II,
Seshanand P. Chandrashekar, Jennifer M. Finefield,
Alexandro Dominguez and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 16 May 2006; accepted 20 June 2006
Available online 25 July 2006
Abstract—Oxadiazinanones derived from (1R,2S)-ephedrine and (1R,2S)-norephedrine were employed in the asymmetric a-halo aldol
reaction. The optimized yields and diastereoselectivities for the ephedrine based oxadiazinanone aldol reaction ranged from fair to good.
The ephedrine based aldol adducts were hydrolyzed to afford the a-bromo-b-hydroxycarboxylic acids. The absolute stereochemistry and
enantiomeric purity of these products were determined by chiral HPLC and specific rotation measurements.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and Kim1a applied the a-chloroacetate ester of cis-1-tosyl-
amido-2-indanol in the synthesis of a-halo-b-hydroxy
esters.
There has been considerable interest in the synthesis of
enantiomerically enriched substrates, which contain the
a-halo-b-hydroxycarboxyl functional group.1 This is pri-
marily due to their utility as versatile intermediates (e.g.,
conversion to optically active a,b-epoxy carboxyl systems)2
in the synthesis of a wide variety of natural products.3–7 In
1984, Pridgen et al.1f,g,j conducted seminal studies in this
area by using N-haloacetyloxazolidinones as templates
for conducting asymmetric aldol reactions (Chart 1). Later
in 1999 and 2000, Yan et al. successfully employed a cam-
phor based oxazolidine-2-thione in a related bromination–
aldolization process.1b,d,e More recently in 2004, Ghosh
We previously demonstrated that (1R,2S)-ephedrine and
(1R,2S)-norephedrine based oxadiazinanones8 could be
employed as ‘chiral relay’ auxiliaries in the asymmetric
aldol addition reaction. It has been determined that stereo-
chemical induction in the oxadiazinanone mediated aldol
reaction is not the direct result of the asymmetry of the
Ephedra component. Rather, the asymmetric induction is
transmitted via an intramolecular ‘chiral relay’ from
the ephedrine based substituents at the C5 and C6 posi-
tions of the ring system to the stereogenic N4-nitrogen
Br
O
Br
O
NHSO2p-Tol
H
O
O
O
O
O
O
N
O
N
N
H
O
Cl
H3C
Ph
Evans2b
S
Prigden1f,g,j
Ghosh1a
Yan1b,d,e
Chart 1.
*
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538; e-mail: hitchcock@xenon.che.ilstu.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.036

1832
T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
O
X
X
O
O
O
1. NaNO2, HCl
2. LiAlH4, THF
1
O
3
2a = Cl
2b = Br
OH
X
H
O
N
N
N
NHCH3
Ph
N
4
3. (EtO)2CO, LiH
MH, (CH2Cl)2
M = Na+, Li+
Ph
CH3
Ph
CH3
CH3
(1R,2S)-ephedrine
CH3
CH3
Ref. 8
3: X = -Cl, 62%
4: X = -Br, 99%
1
Scheme 1. Synthesis of oxadiazinanones 3 and 4.
(Scheme 1).9 Based on this work, we became interested in
investigating the potential of oxadiazinanones in the
a-haloaldol addition reaction. Herein, we report on our
efforts to employ a-haloacetyl derivatives (chloro- and
bromo-) of an ephedrine based oxadiazinanone in the aldol
reaction.
mixture cooled to ꢁ78 ꢁC (Table 1). This mixture was then
treated with 2 equiv of titanium tetrachloride followed by
triethylamine. The reaction was quenched after 4 h and
the product mixtures then analyzed by H NMR spectro-
scopy and HPLC. The observed diastereoselectivities were
low and the purified yields ranged from low to fair (Table 1).
1
The major diastereomer was tentatively assigned as the syn-
stereoisomer based on our previous studies of the asym-
metric aldol reactions of oxadiazinanones, wherein the
absolute stereochemistry of the aldol fragment was unam-
biguously established by X-ray crystallography.8a,c In
addition, the measured coupling constants for the vicinal
protons of the aldol fragment were found to be 5.5 Hz.
These values suggested that the stereochemical relationship
between the two protons was syn as the values were in the
accepted range (Jsyn ꢂ 3–6 Hz) for syn-aldol products.10
2. Results and discussion
The (1R,2S)-ephedrine based oxadiazinanone 1 was pre-
pared as previously described by a process of N-nitrosa-
tion, reduction to the corresponding b-hydroxyhydrazine,
and cyclization with lithium hydride and diethylcarbonate
(Scheme 1).8b,d The oxadiazinanone was acylated with
either chloroacetyl chloride or bromoacetyl bromide to af-
ford oxadiazinanones 3 and 4 in 62% and 99% yield,
respectively. These substrates were then evaluated in the
asymmetric aldol reaction with a variety of aromatic and
aliphatic aldehydes.
Aromatic aldehydes were reactive in this process while
aliphatic aldehydes gave complex reaction mixtures that
included significant deacylation of the oxadiazinanone
auxiliary. The formation of a discrete enolate came into
question and so a deuterium incorporation test was per-
formed (Scheme 2).11 Oxadiazinanone 3 was dissolved in
THF and treated with TiCl4 at 0 ꢁC and allowed to stir
for 15 min (Scheme 2). Triethylamine was then added
and after 15 min D2O. Oxadiazinanone 7 was obtained in
92% yield after column chromatography and deuterium
incorporation (ca. 90%) at the a-position of the chloro-
We initiated our asymmetric aldol addition studies by first
conducting the reactions with N3-chloroacetyloxadiazina-
none 3. These reaction conditions involved the addition of
TiCl4 to a THF solution of oxadiazinanone (ꢀ0.33 M), fol-
lowed by cooling to ꢁ78 ꢁC and addition of triethylamine
along with the selected aldehyde. These conditions were
not satisfactory as the solution would freeze and there was
very little product formation and poor stereoselectivity.
The reaction conditions were changed so that 3 was dis-
solved in THF along with an aldehyde and the reaction
1
acetyl group was confirmed by both H and 13C NMR
spectroscopy.
Table 1. Asymmetric aldol reaction of oxadiazinanone 3
OH
1a. RCHO, -78 oC
1b. TiCl4; TEA
O
O
O
O
Cl
R
O
N
N
O
N
N
Cl
Ph
Ph
5a: R = -C6H5
CH3
CH3
5b: R = -p-C6H4Cl
5c: R = -2-C10H7
CH3
CH3
3
5a-c
Entry
RCHO
C6H5CHO
p-ClC6H4CHO
2-C10H7CHO
Adduct
Yield (%)a
drb
1
2
3
5a
5b
5c
54
49
26
62:38
74:26
59:41
a Purified yield after column chromatography.
All crude diastereomeric ratios were measured by HPLC using a Shimadzu SCL-10AVP system with a Dynamax Si-100 A column (3:2, hexanes–ethyl
b
˚
P
acetate, flow rate = 1.0 mL/min). Diastereoselectivities are represented as major diastereomer:
all other diastereomers.

T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
1833
Cln
O
O
Ti
O
O
Cl
1a. TiCl4,THF, 0 oC
1b. TEA
1c. D2O
O
N
N
Cl
3
O
N
N
D
Ph
CH3
H
Ph
CH3
CH3
CH3
7
6
Scheme 2. Deuterium incorporation of oxadiazinanone 3.
Unfortunately, the deuteration conditions were not opti-
mal for use of the aliphatic aldehydes in the aldol addition
reaction. The final optimized conditions involved dissolv-
ing oxadiazinanone 3 in THF, followed by the addition
of TiCl4 at 0 ꢁC, with a 15 min induction period. Triethyl-
amine was then added, and after 15 min the reaction mix-
ture was cooled to ꢁ78 ꢁC. After 10 min, the appropriate
aliphatic aldehyde was added. We were gratified to learn
that these reaction conditions led to the formation of aldol
adducts 8a and 8b in 34% and 82% yields, respectively
(Table 2). The superior yield of 8b [R = –C(CH3)3] can
be attributed to the absence of an a-proton in the aldehyde.
The diastereoselectivities observed for these two reactions
were slightly improved as compared to the diastereo-
selectivities associated with aldol adducts 5a–c. Again,
the stereochemistry was tentatively assigned as the
syn-stereochemistry.
improvement in the diastereoselectivities. The origin of the
increased diastereoselectivity is unknown. Interestingly,
entry 11 had a very low diastereoselectivity. The syn-dia-
stereomer was presumed to be the major diastereomer;
however, the sum of the other diastereomers was greater.
This anomalous result was attributed to the steric environ-
ment of the aldehyde.
Table 3. Asymmetric aldol reactions of oxadiazinanone 4
O
O
OH
1a. RCHO, THF, -78oC
1b. TiCl4
1c. TEA, -78oC
O
N
N
R
4
Br
CH3
Ph
CH3
9a-h
Entry RCHO
TiCl4
(equiv)
Adduct Yield drb
(%)a
Table 2. Asymmetric aldol reaction of oxadiazinanone 3 with aliphatic
aldehydes
1
2
3
4
5
6
7
8
C6H5CHO
C6H5CHO
p-CH3OC6H4CHO
p-ClC6H4CHO
p-ClC6H4CHO
2-C10H7CHO
1
2
1
1
2
1
2
1
2
2
2
9a
9a
9b
9c
9c
9d
9d
9e
9f
44
72
49
72
83
36
36
30
85
90
28
86:14
91:9
O
O
OH
85:15
77:23
83:17
87:13
77:23
89:11
86:14
82:18
42:58
1a. TiCl4, THF, 0 oC
1b. TEA (15 min), -78 oC
O
N
N
R
3
Cl
CH3
1c. RCHO, -78 to 25 oC
Ph
2-C10H7CHO
CH3
m-CH3C6H4CHO
p-O2NC6H4CHO
p-NCC6H4CHO
p-C6H5CH2OC6H4CHO
8a: R = -CH(CH3)2
8b: R = -C(CH3)3
9
10
11
8a-b
9g
9h
Entry
RCHO
Adduct
Yield (%)a
drb
a Purified yield after column chromatography on silica gel or recrystal-
lization.
1
2
(CH3)2CHCHO
(CH3)3CCHO
8a
8b
34
82
83:17
82:18
b All crude diastereomeric ratios were measured by HPLC using a Shi-
a Purified yield after column chromatography.
b All crude diastereomeric ratios were measured by HPLC using a Shi-
madzu SCL-10AVP system with a Dynamax Si-100 A column (3:2,
hexanes–ethyl acetate, flow rate = 1.0 mL/min). Diastereoselectivities are
˚
madzu SCL-10AVP system with a Dynamax Si-100 A column (60:40,
hexanes–ethyl acetate, flow rate = 1.0 mL/min). Diastereoselectivities are
˚
P
represented as major diastereomer:
all other diastereomers.
P
represented as major diastereomer:
all other diastereomers.
Even though there was an improvement in the yield
and diastereoselectivity of the aldol addition reactions of
the N3-bromoacetyloxadiazinanone 4 with the aromatic
aldehydes when compared to the N3-chloroacetyloxadi-
azinanones 3, aliphatic aldehydes still gave little carbon–
carbon bond formation and poor diastereoselectivity. A
deuteration study was conducted to determine if the forma-
tion of a discrete enolate might lead to a superior result
(Scheme 3).8 The reaction conditions involved dissolving
oxadiazinanone 4 in THF and treating with TiCl4 at 0 ꢁC
for 15 min. The reaction mixture was then treated with
triethylamine and after 15 min, the reaction mixture was
cooled to ꢁ78 ꢁC. Finally, D2O was added and the solution
warmed to 25 ꢁC. Deuterium incorporation (ca. 90%) was
The asymmetric aldol reactions of the N3-chloroacetyloxa-
diazinanone 3 ultimately yielded results that were not sat-
isfactory for synthetic purposes. Thus, efforts were made
to investigate the usefulness of the N3-bromoacetyloxadiaz-
inanone 4. The acylated heterocycle was combined with an
aromatic aldehyde in THF, cooled to ꢁ78 ꢁC, treated with
titanium tetrachloride (1.05 equiv) and after 15 min, was
finally treated with triethylamine. This process afforded
aldol adducts 9a–h (Table 3). The diastereomeric ratios
obtained for these aldol adducts were superior to those
for the a-chloroaldol reactions, but were still not optimal.
Increasing the number of equivalents of TiCl4 to 2 equiv
afforded significantly improved chemical yields and a slight

1834
T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
Cln
Ti
O
O
O
O
O
O
Br
H
Br
Br
1a. TiCl4, THF, 0 ºC
1b. TEA
O
N
N
1c. D2O
O
N
N
O
N
N
D
H
Ha Hb
CH3
Ph
Ph
Ph
CH3
CH3
CH3
11
CH3
CH3
10
4
O
O
OH
1a. TiCl4, THF, 0 ºC
1b. TEA (15 min), -78 oC
O
N
N
4
Br
CH3
1c. (CH3)2CHCHO
Ph
CH3
-78 to 25 ºC
12
Scheme 3. Deuteration and aliphatic aldol reaction of oxadiazinanone 4.
confirmed by NMR spectroscopy and the product was iso-
lated by chromatography in 82% yield.
enantiomeric purity once cleaved from the oxadiazinone
auxiliary. Oxadiazinanone aldol adduct 9a was used for
the determination of the stereochemical outcome of the
asymmetric aldol reaction and success of the subsequent
hydrolysis to obtain the aldol component. The enantiomer
of 9a (ent-9a) was also prepared for this study by using
(1S,2R)-ephedrine as the starting material and following
the synthetic pathway outlined in Scheme 1 and Table 1.
Following the conditions established for the deuterium
incorporation, a series of aldol addition reactions with var-
ious aliphatic aldehydes was conducted. The N4-bromo-
acetyloxadiazinanone 4 was dissolved in THF and treated
with TiCl4 at 0 ꢁC for 15 min. Triethylamine was then
added, and after 15 min, the reaction mixture was cooled
to ꢁ78 ꢁC. After 10 min, isobutyraldehyde was added. This
process led to the formation and isolation of aldol adduct
12 in 84% yield and a diastereoselectivity of 78:22 favoring
the presumed major diastereomer, tentatively assigned as
the syn-diastereomer.
The enantiomeric aldol adducts 9a and ent-9a were both
recrystallized to a diastereomeric purity of 19:1 as deter-
1
mined by H NMR spectroscopy. The adducts were then
hydrolyzed with 2 M H2SO4 and the resultant a-bromo-
b-hydroxyacids12a were subsequently esterified with tri-
methylsilyldiazomethane12b,c to afford the expected methyl
esters 13 and ent-13 in 45% and 63% overall yield, respec-
tively (Scheme 4). The corresponding oxadiazinanones, 1a
We became interested in determining the absolute stereo-
chemistry of the aldol fragment and its corresponding
+1a
+ ent-1a
O
OH
O
OH
1. 2M H2SO4, 50 oC
MeO
MeO
or
9a/ent-9a
2. (CH3)3SiCHN2
Br
13 (45%)
Br
ent-13 (63%)
K2CO3, MeOH
63%
K2CO3, MeOH
96%
O
O
MeO
O
MeO
O
14
[α]D = +10.9 (c 0.25, CHCl3)
ent-14
[α]D = -10.0 (c 3.22, CHCl3)
(2R,3R)-Epoxide
lit.10a = [α]D = +15 (c 1.52, CHCl3)
lit.10b = [α]D = +14 (c 1.6, CHCl3)
lit.10c = [α]D = +11 (c 4.4, CHCl3)
Scheme 4. Stereospecific formation of epoxides 14 and ent-14.

T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
1835
Cln
O
Cln
O
H
Br
O
O
H
Ti
N
R
Ti
N
R
O
O
TiCl4, RCHO
TEA
Br
H
H
4
N
N
+
H3C
O
H3C
O
N4-methyl substituent
directs approach
H3C
Ph
H3C
Ph
E(O)-Enolate (Si)-RCHO (Si)
Z(O)-Enolate (Re)-RCHO (Si)
16
16
O
O
OH
O
O
OH
O
N
N
R
O
N
N
R
Br
CH3
Br
CH3
Ph
Ph
CH3
syn-9a
CH3
anti-9a
Scheme 5. Proposed transition states for the aldol addition reaction of 4.
and ent-1a could be recovered in ca. 80% crude yield but
were not reused. Chiral stationary phase (CSP) HPLC
analysis revealed that methyl ester 13 was obtained in
P98% ee and ent-13 was obtained in P98% ee.13 Methyl
ester 13 had a specific rotation of [a]D = ꢁ27.7 (c 082,
CHCl3) while methyl ester ent-13 had a specific rotation
of [a]D = +29.1 (c 0.42, CHCl3).14 Methyl esters 13 and
ent-13 were converted into the corresponding epoxides 14
and ent-14 by treatment with potassium carbonate in meth-
anol. Each of the epoxides 14 and ent-14 were determined
to be present in greater than 98% ee by CSP HPLC analy-
sis. Correlation with known literature values15,16 for the
specific rotation of (+)-methyl (2R,3R)-phenylglycidate
confirmed the earlier tentative assignment of aldol adducts
9a–h.
mer.1d,e Thus, efforts are currently underway to improve
the diastereoselectivity of the a-haloaldol reaction of
oxadiazinanones by conducting investigations directed
toward the stereoelectronic tuning of the oxadiazinanone
chiral auxiliary.
4. Experimental
4.1. General remarks
Tetrahydrofuran (THF) was distilled from a potassium/
sodium alloy with benzophenone ketyl. Methylene chloride
and 1,2-dichloroethane were distilled from calcium hy-
dride. All reactions were run under a nitrogen atmosphere.
Unless otherwise noted, all 1H and 13C {1H} NMR spectra
were recorded in CDCl3 using an NMR spectrometer oper-
ating at 400 and 100 MHz, respectively. Chemical shifts are
reported in parts per million (d scale), and coupling con-
stants (J values) are listed in hertz (Hz). Tetramethylsilane
(TMS) was used as the internal standard (d = 0 ppm).
Infrared spectra are reported in reciprocal centimeters
(cmꢁ1) and are measured as either a neat liquid or as a
KBr window. Melting points were recorded on a Mel-
Temp apparatus and are uncorrected.
With regard to the observed diastereoselectivity, a Zimmer-
man–Traxler transition state involving a chair like interme-
diate (Scheme 5) was proposed.8a,b,17,18 The presence of the
two enolates would lead to the formation of both syn- and
anti-aldol adducts that are observed.
3. Conclusion
In conclusion, we have demonstrated that N3-haloacetyl-
N4-methyloxadiazinanones may be employed in the asym-
metric a-haloaldol reaction, although to limited effect.
The stereochemistry of the aldol fragment was unambigu-
ously determined and it was established that the major
product was the syn-diastereomer. The low to fair diastere-
oselectivities that were observed were primarily attributed
to the formation of Z(O)- and E(O)-enolates of the acyl-
ated oxadiazinanones. These results observed were not as
successful as those generated by Yan et al. whose camphor
based oxazolidine-2-thione (Chart 1) gave reported diaste-
reoselectivities greater than 99:1 favoring the syn-diastereo-
4.2. General procedure for the preparation of acylated
oxadiazinanones 3 and 4
In a flame-dried, nitrogen purged 250 mL round-bottomed
flask equipped with a condenser were placed the (1R,2S)-
ephedrine based oxadiazinanone (7.0 g, 34 mmol), freshly
distilled dichloroethane (34 mL), and the appropriate acyl
halide (41 mmol; chloroacetyl chloride for 3 and bromo-
acetyl bromide for 4). The reaction mixture was heated at
reflux and lithium hydride (0.28 g, 36 mmol) was added.
The reaction was allowed to stir overnight and then cooled

1836
T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
to 0 ꢁC and quenched by the addition of a saturated solu-
tion of ammonium chloride (75 mL). The solution was
extracted with EtOAc (2 · 75 mL), washed with a brine
solution, dried over MgSO4, and the solvent was removed
via rotary evaporation.
128.2, 128.3, 128.7, 135.0, 138.4, 147.0, 169.0. IR (neat):
3450, 3016, 1774, 1728, 1214, 1009, 746, 699 cmꢁ1. FAB-
HRMS calcd for C20H21N2O4NaCl (M++H): 411.1088.
Found: 411.1092.
4.3.2. (20S,30R,4R,5S,6R)-3-[2-Chloro-3-(4-chlorophenyl)-3-
hydroxypropanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadia-
zinan-2-one 5b. The yellow oil was purified by column
chromatography on silica gel (50:50, hexanes–EtOAc,
Rf = 0.20) to yield 5b in 49% yield as a yellow oil.
½aꢃD ¼ ꢁ17:2 (c 0.31, CHCl3). H NMR (CDCl3): d 0.75
(d, 3H, J = 7.0 Hz), 2.94 (s, 3H), 3.27 (br s, 1H), 3.37–
3.43 (m, 1H), 5.34 (d, 1H, J = 4.8 Hz), 5.80 (d, 1H,
J = 4.8 Hz), 6.05 (d, 1H, J = 4.8 Hz), 7.33–7.44 (m, 9H).
13C NMR (CDCl3): d 12.0, 43.3, 56.8, 61.5, 72.6, 78.3,
124.7, 128.27, 128.3, 128.4, 128.6, 134.0, 134.8, 137.1,
147.2, 168.9. IR (CCl4): 3436, 2980, 1738, 1723, 1214,
1015, 792, 760 cmꢁ1. FAB-HRMS calcd for C20H21-
N2O4Cl2 (M++1): 423.0878. Found: 423.0880.
4.2.1. (4R,5S,6R)-3-(2-Chloroacetyl)-4,5-dimethyl-6-phenyl-
2H-1,3,4-oxadiazinan-2-one 3. The isolated product was
purified by column chromatography (hexanes–EtOAc,
60:40, Rf = 0.28) to yield 3 (62%) as a yellow oil
½aꢃD ¼ ꢁ28:3 (c 0.53, CHCl3). H NMR (CDCl3): d 0.89
(d, 3H, J = 7.0 Hz), 3.00 (s, 3H), 3.41–3.47 (m, 1H), 4.79
(d, 2H, J = 1.8 Hz), 6.07 (d, 1H, J = 4.4 Hz), 7.29–7.44
(m, 5H). 13C NMR (CDCl3): d 12.2, 43.1, 46.0, 56.8,
77.9, 124.7, 128.3, 128.7, 134.9, 148.2, 166.7. IR (neat):
2978, 1783, 1731, 738, 700 cmꢁ1. HRMS calcd for
C13H15ClN2O3: 282.0771. Found: 282.0772.
25
1
25
1
4.2.2. (4R,5S,6R)-3-(2-Bromoacetyl)-4,5-dimethyl-6-phenyl-
2H-1,3,4-oxadiazinan-2-one 4. The isolated product was
purified by column chromatography (hexanes–EtOAc,
60:40, Rf = 0.28) to yield 4 (99%) as a yellow oil
4.3.3. (20S,30R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-3-naph-
thalen-2-yl-propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxa-
diazinan-2-one 5c. The white powder was purified by
recrystallization from ethyl acetate and hexanes to yield
25
1
½aꢃD ¼ ꢁ19:6 (c 0.58, CHCl3). H NMR (CDCl3): d 0.90
(d, 3H, J = 7.0 Hz), 3.00 (s, 3H), 3.41–3.48 (m, 1H), 4.51
(d, 1H, J = 12.8 Hz), 4.71 (d, 1H, J = 12.5 Hz), 6.08 (d,
1H, J = 4.39 Hz), 7.29–7.44 (m, 5H). 13C NMR (CDCl3):
d 12.2, 31.9, 42.9, 56.7, 77.9, 124.6, 128.1, 128.5, 134.9,
5c in 26% yield as a white powder (hexanes–EtOAc,
25
60:40, Rf = 0.23). Mp = 174–176 ꢁC. ½aꢃD ¼ ꢁ30:0 (c
0.33, CHCl3). 1H NMR (CDCl3): d 0.68 (d, 3H,
J = 7.0 Hz), 2.85 (s, 3H), 3.32–3.38 (m, 2H), 5.52 (d, 1H,
J = 5.5 Hz), 5.99 (d, 1H, J = 4.8 Hz), 5.99 (d, 1H,
J = 3.3 Hz), 7.21–7.96 (m, 12H). 13C NMR (CDCl3):
12.2, 43.3, 57.2, 61.9, 73.6, 78.4, 124.3, 124.8, 126.27,
126.3, 126.4, 127.6, 128.2, 128.3, 128.4, 128.8, 133.0,
133.2, 135.0, 135.8, 147.3, 169.3. IR (CCl4): 3489, 3035,
1766, 1690, 1283, 1226, 770 cmꢁ1. FAB-HRMS calcd for
C24H23N2O4NaCl: 461.1244. Found: 461.1246.
147.7, 166.3. IR (neat): 2978, 1779, 1728, 738, 700 cmꢁ1
.
HRMS calcd for C13H15BrN2O3: 326.0266. Found:
326.0262.
4.3. General procedure for the preparation of aldol adducts
5a–c
In a nitrogen purged 100 mL round-bottomed flask were
placed oxadiazinanone 3 (3.54 mmol), freshly distilled
THF (10.6 mL, 0.33 M), and the appropriate aldehyde
(7.08 mmol). The reaction mixture was then cooled to
ꢁ78 ꢁC. After stirring for 10 min, titanium tetrachloride
(0.86 mL, 7.79 mmol) was added. The titanium tetrachlo-
ride was allowed to coordinate for 15 min and then tri-
ethylamine (0.98 mL, 7.08 mmol) was added. The reaction
was allowed to run for 4 h and then quenched upon the
addition of a saturated solution of sodium bicarbonate.
The resulting mixture was then extracted with EtOAc
(3 · 50 mL), and the extract then washed with a saturated
solution of NaCl, dried over MgSO4, and the solvent was
removed via rotary evaporation.
4.4. (4R,5S,6R)-3-(2-Chloro-2-deuterioacetyl)-4,5-dimethyl-
6-phenyl-2H-1,3,4-oxadiazinan-2-one 7
In a 100 mL round-bottomed flask were placed oxadiazin-
anone 3 (3.54 mmol), THF (10.6 mL, 0.33 M), and tita-
nium tetrachloride (3.72 mmol) at 0 ꢁC and the mixture
was allowed to react for 15 min. Triethylamine (7.08 mmol)
was then added, and after 15 min the reaction mixture was
cooled to ꢁ78 ꢁC. The reaction mixture had cooled for
10 min, D2O was added. The reaction mixture was stirred
for 30 min and then quenched by the addition of a satu-
rated solution of sodium bicarbonate. The resulting mix-
ture was then extracted with EtOAc (3 · 50 mL), washed
with a saturated aqueous solution of NaCl, dried over
MgSO4, and the solvent removed via rotary evaporation.
The isolated product was purified by column chromatogra-
phy (hexanes–EtOAc, 60:40, Rf = 0.28) to yield 7 (92%) as
a yellow oil. 1H NMR (CDCl3): d 0.90 (d, 3H, J = 5.9 Hz),
3.02 (s, 3H), 3.45 (br s, 1H), 4.78 (d, 1H, J = 7.7 Hz), 6.08
(s, 1H), 7.30–7.44 (m, 5H). 13C NMR (CDCl3): d 12.3,
43.3, 45.9 (t, 1:1:1, 13C–2H, J = 80 Hz), 57.0, 78.0, 124.8,
128.4, 128.7, 135.0, 148.3, 166.8. IR (neat): 2979, 1785,
4.3.1. (20S,30R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-3-phenyl-
propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-
one 5a. The residual light brown oil was purified by col-
umn chromatography on silica gel (hexanes–EtOAc,
60:40, Rf = 0.22) to yield 5a in 54% yield as an oil. Analyt-
ical data are reported only for the major diastereomer.
25
1
½aꢃD ¼ ꢁ20:3 (c 0.48, CHCl3). H NMR (CDCl3): d 0.68
(d, 3H, J = 7.0 Hz), 2.88 (s, 3H), 3.34–3.38 (m, 1H), 5.34
(d, 1H, J = 5.5 Hz), 5.85 (d, 1H, J = 5.5 Hz), 6.02 (d, 1H,
J = 4.0 Hz), 7.20–7.48 (m, 10H). 13C NMR (CDCl3): d
12.0, 43.3, 56.8, 61.5, 73.5, 78.2, 124.7, 127.0, 127.1,
1728, 1261, 736, 700 cmꢁ1
C13H14DN2O3NaCl: 306.0732. Found: 306.0736.
. FAB-HRMS calcd for

T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
1837
4.5. General procedure for the preparation of aldol adducts
8a,b
4 h and then quenched upon the addition of a saturated
solution of sodium bicarbonate. The resulting mixture
was then extracted with EtOAc (3 · 50 mL), washed with
a saturated aqueous solution of NaCl, dried over MgSO4,
and the solvent was removed via rotary evaporation.
In a 100 mL round-bottomed flask were placed oxadiazin-
anone 3 (3.54 mmol), THF (10.6 mL, 0.33 M), and tita-
nium tetrachloride (3.72 mmol). The reaction mixture was
kept at 0 ꢁC for 15 min. Triethylamine (7.08 mmol) was
then added, and after 15 min, the reaction mixture was
cooled to ꢁ78 ꢁC. After the reaction mixture was cooled
for 10 min, after which the appropriate aliphatic aldehyde
(7.08 mmol) was added. The reaction was allowed to run
for 4 h and then quenched upon the addition of a saturated
solution of sodium bicarbonate. The resulting mixture was
then extracted with EtOAc (3 · 50 mL), washed with a
brine solution, dried over MgSO4, and the solvent was
removed via rotary evaporation.
4.6.1. (20S,30R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-phenyl-
propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-
one 9a. The residual off-white powder was purified by
recrystallization from ethyl acetate and hexanes (hex-
anes–EtOAc, 60:40, Rf = 0.29) to yield 9a in 72% yield as
25
an off-white powder. Mp = 152–154 ꢁC. ½aꢃD ¼ ꢁ22:7 (c
0.29, CH3OH). 1H NMR (CDCl3): d 0.68 (d, 3H,
J = 7.0 Hz), 2.88 (s, 3H), 3.34–3.38 (m, 1H), 3.41 (br s,
1H), 5.24 (d, 1H, J = 5.9 Hz), 5.92 (d, 1H, J = 5.9 Hz),
6.01 (d, 1H, J = 4.8 Hz), 7.22–7.47 (m, 10H). 13C NMR
(CDCl3): d 12.2, 43.2, 52.3, 57.1, 73.0, 78.4, 124.8, 127.0,
127.2, 128.3, 128.4, 128.7, 135.0, 138.5, 147.0, 170.0. IR
(CCl4): 3503, 3039, 1766, 1690, 1277, 1086, 768,
4.5.1. (20S,30R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-4-methyl-
pentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-one
8a. The yellow oil was purified by column chromato-
701 cmꢁ1
. FAB-HRMS calcd for C20H21N2O4NaBr:
455.0582. Found: 455.0588.
graphy on silica gel (hexanes–EtOAc, 55:45, Rf = 0.16) to
25
yield 8a in 34% yield as a yellow oil. ½aꢃD ¼ ꢁ31:9 (c
4.6.2. (20S,30R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-meth-
oxyphenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxa-
diazinan-2-one 9b. The yellow oil was purified by column
0.25, CHCl3). 1H NMR (CDCl3): d 0.91 (d, 3H,
J = 6.6 Hz), 1.00 (d, 3H, J = 6.6 Hz), 1.10 (d, 3H,
J = 6.6 Hz), 1.88–1.97 (m, 1H), 2.87 (br s, 1H), 3.02 (s,
3H), 3.44–3.48 (m, 1H), 3.79 (d, 1H, J = 7.3 Hz), 5.91 (d,
1H, J = 1.8 Hz), 6.10 (d, 1H, J = 3.3 Hz), 7.29–7.44 (m,
5H). 13C NMR (CDCl3): d 12.4, 18.5, 18.7, 31.2, 43.3,
56.9, 60.9, 76.2, 78.3, 124.8, 128.3, 128.7, 135.0, 147.8,
170.0. IR (neat): 3467, 2964, 1775, 1716, 1255,
1139 cmꢁ1. FAB-HRMS calcd for C17H23N2O4NaCl:
377.1244. Found: 377.1248.
chromatography on silica gel (hexanes–EtOAc, 50:50, Rf =
25
0.35) to yield 9b in 49% yield as a yellow oil. ½aꢃD ¼ ꢁ16:5
(c 0.53, CHCl3). 1H NMR (CDCl3): d 0.67 (d, 3H,
J = 7.0 Hz), 2.87 (s, 3H), 3.34–3.38 (m, 1H), 3.79 (s, 3H),
5.20 (d, 1H, J = 6.6 Hz), 5.89 (d, 1H, J = 6.2 Hz), 6.01
(d, 1H, J = 4.4 Hz), 6.86 (d, 4H, J = 8.8 Hz), 7.22–7.40
(m, 5H). 13C NMR (CDCl3): d 12.2, 43.2, 52.2, 55.2,
57.0, 72.8, 78.3, 113.7, 124.8, 128.3, 128.34, 128.7, 130.5,
135.0, 147.0, 159.6, 170.0. IR (neat): 3464, 2936, 1770,
1732, 1251 cmꢁ1. FAB-HRMS calcd for C21H23N2O5-
NaBr: 485.0688. Found: 485.0685.
4.5.2.
(20S,30R,4R,5S,6R)-3-(2-Chloro-3-hydroxy-4,4-di-
methylpentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-
2-one 8b. The yellow oil was purified by column chro-
matography on silica gel (hexanes–EtOAc, 50:50, Rf =
0.31) to yield 8b as a colorless oil in 82% yield as a mixture
of diastereomers and an unknown contaminant that could
4.6.3. (20S,30R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-chloro-
phenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiaz-
inan-2-one 9c. The yellow oil was purified by column
chromatography on silica gel (hexanes–EtOAc, 50:50,
not be resolved. Only experimental data for the major
25
diastereomer are reported. ½aꢃD ¼ ꢁ20:5 (c 0.48, CHCl3).
Rf = 0.28) to yield 9c in 83% yield as a white powder.
1H NMR (CDCl3): d 0.90 (d, 3H, J = 6.6 Hz), 1.05 (s,
9H), 3.04 (s, 3H), 3.43–3.50 (m, 1H), 3.78–3.84 (m, 1H),
3.89 (br s, 1H), 5.86 (d, 1H, J = 2.6 Hz), 5.98 (d, 1H,
J = 2.6 Hz), 7.28–7.42 (m, 5H). 13C NMR (CDCl3): d
12.5, 26.6, 35.7, 43.2, 56.9, 57.9, 76.4, 78.5, 124.7, 128.2,
128.6, 135.0, 147.6, 171.1. IR (neat): 3459, 2962, 1760,
1680, 1216, 753 cmꢁ1. FAB-HRMS calcd for C18H25N2O4-
NaCl: 391.1401. Found: 391.1397.
25
Mp = 141–143 ꢁC. ½aꢃD ¼ ꢁ27:4 (c 0.49, CHCl3). 1H
NMR (CDCl3): d 0.75 (d, 3H, J = 7.0 Hz), 2.93 (s, 3H),
3.37–3.43 (m, 1H), 3.57 (br s, 1H), 5.22 (d, 1H,
J = 5.1 Hz), 5.88 (d, 1H, J = 5.1 Hz), 6.04 (d, 1H,
J = 4.4 Hz), 7.23–7.42 (m, 9H). 13C NMR (CDCl3): d
12.4, 43.3, 52.3, 57.1, 72.2, 78.5, 124.8, 128.36, 128.4,
128.5, 128.8, 134.1, 134.9, 137.1, 147.1, 169.9. IR (CCl4):
3488, 3033, 1756, 1685, 1216, 1080, 762, 699 cmꢁ1. FAB-
HRMS calcd for C20H20N2O4NaBrCl: 489.0193. Found:
489.0196.
4.6. General procedure for the preparation of aldol adducts
9a–h
4.6.4. (20S,30R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-naphth-
alen-2-yl-propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxa-
diazinan-2-one 9d. The white powder was purified by
recrystallization from ethyl acetate and hexanes to yield
In a nitrogen purged 100 mL round-bottomed flask were
placed oxadiazinanone 4 (0.750 g, 2.31 mmol), freshly dis-
tilled THF (6.92 mL, 0.33 M), and the appropriate alde-
hyde (4.6 mmol). The reaction mixture was then cooled
to ꢁ78 ꢁC. After stirring for 10 min, titanium tetrachloride
(0.56 mL, 5.1 mmol) was added and the reaction mixture
stirred for 15 min before the addition of triethylamine
(0.64 mL, 4.6 mmol). The reaction was allowed to run for
the title compound in 36% yield as a white powder.
25
Mp = 176–177 ꢁC. ½aꢃD ¼ ꢁ27:4 (c 0.32, CHCl3). 1H
NMR (CDCl3): d 0.68 (d, 3H, J = 7.0 Hz), 2.85 (s, 3H),
3.32–3.38 (m, 1H), 3.53 (br s, 1H), 5.41 (d, 1H,
J = 5.5 Hz), 5.98 (d, 1H, J = 4.4 Hz), 6.06 (d, 1H,

1838
T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
J = 5.5 Hz), 7.20–7.96 (m, 12H). 13C NMR (CDCl3): d
12.3, 43.3, 52.5, 57.2, 73.1, 78.4, 124.3, 124.8, 126.2,
126.3, 126.5, 127.6, 128.2, 128.3, 128.4, 128.8, 133.1,
133.2, 135.0, 136.0, 147.2, 170.0. IR (CCl4): 3492, 3036,
1761, 1688, 1278, 1226, 861, 786 cmꢁ1. Anal. Calcd for
C24H23BrN2O4: C, 59.64; H, 4.80; N, 5.80. Found: C,
59.47; H, 4.75; N, 5.76. FAB-HRMS calcd for
C24H23N2O4NaBr: 505.0739. Found: 505.0740.
J = 7.0 Hz), 2.86 (s, 3H), 3.22 (br s, 1H), 3.32–3.39 (m,
1H), 5.05 (s, 2H), 5.20 (d, 1H, J = 6.2 Hz), 5.88 (d, 1H,
J = 6.6 Hz), 6.00 (d, 1H, J = 4.8 Hz), 6.92 (s, 2H), 6.95
(s, 2H), 7.23–7.42 (m, 10H). 13C NMR (CDCl3): d 12.3,
43.2, 52.3, 57.1, 69.9, 72.9, 78.4, 114.8, 124.8, 127.3,
127.9, 128.36, 128.45, 128.5, 128.8, 130.8, 135.2, 136.8,
147.0, 158.8, 169.6. IR (neat): 3517, 3047, 1768, 1694,
1277, 1218, 758, 702 cmꢁ1. Anal. Calcd for C27H27BrN2O5:
C, 60.12; H, 5.05; N, 5.19. Found: C, 59.73; H, 5.00; N,
5.10. FAB-HRMS calcd for C27H28N2O5Br (M++1):
539.1182. Found: 539.1171.
4.6.5. (20S,30R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-3-m-tolyl-
propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-
one 9e. The yellow oil was purified by column chromato-
graphy on silica gel (hexanes–EtOAc, 60:40, Rf = 0.28) to
4.7. (4R,5S,6R)-3-(2-Bromo-2-deuterioacetyl)-4,5-dimethyl-
6-phenyl-2H-1,3,4-oxadiazinan-2-one 11
25
yield 9e in 30% yield as a light yellow oil. ½aꢃD ¼ ꢁ19:6 (c
0.30, CHCl3). 1H NMR (CDCl3): d 0.70 (d, 3H,
J = 6.8 Hz), 2.34 (s, 3H), 2.90 (s, 3H), 3.35–3.39 (m, 2H),
5.21 (d, 1H, J = 5.9 Hz), 5.92 (d, 1H, J = 5.9 Hz), 6.02
(d, 1H, J = 4.8 Hz), 7.10–7.41 (m, 9H). 13C NMR (CDCl3):
d 12.3, 21.4, 43.3, 52.5, 57.2, 73.1, 78.4, 124.1, 124.8, 127.6,
128.36, 128.38, 128.8, 129.2, 133.1, 138.1, 138.4, 147.0,
In a nitrogen purged 100 mL round-bottomed flask were
placed oxadiazinanone 4 (3.07 mmol), THF (9.21 mL,
0.33 M), and titanium tetrachloride (3.22 mmol) and the
reaction mixture was kept at 0 ꢁC for 15 min. Triethyl-
amine (6.14 mmol) was then added, and after 15 min the
reaction mixture was cooled to ꢁ78 ꢁC. After the reaction
mixture had cooled for 10 min, D2O was added. The reac-
tion mixture was allowed to stir for 30 min and then a
saturated solution of sodium bicarbonate was added.
The resulting mixture was then extracted with EtOAc
(3 · 50 mL), washed with brine solution, dried over
MgSO4, and the solvent removed via rotary evaporation.
The isolated product was purified by column chromatogra-
phy (hexanes–EtOAc, 60:40, Rf = 0.28) to yield 11 (82%) as
a yellow oil. 1H NMR (CDCl3): d 0.90 (d, 3H, J = 7.0 Hz),
3.00 (s, 3H), 3.41–3.48 (m, 1H), 4.49 (br s, 1H), 4.69 (br s,
1H), 6.08 (d, 1H, J = 4.4 Hz), 7.29–7.44 (m, 5H). 13C NMR
(CDCl3): 12.4, 31.1 (t, 1:1:1, 13C–2H, J = 80 Hz), 31.3,
43.3, 57.1, 78.2, 124.9, 128.3, 128.7, 135.1, 148.1, 166.6.
IR (neat): 2982, 1782, 1724, 1256, 738, 700 cmꢁ1. FAB-
HRMS calcd for C13H14DN2O3NaBr: 350.0227. Found:
350.0226.
170.0. IR (CCl4): 3465, 2978, 1774, 1720, 742, 701 cmꢁ1
.
FAB-HRMS calcd for C21H23N2O4NaBr: 469.0739.
Found: 469.0744.
4.6.6. (20S,30R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-nitro-
phenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiaz-
inan-2-one 9f. The yellow oil was purified by column
chromatography on silica gel (hexanes–EtOAc, 50:50,
Rf = 0.22) to yield 9f in 85% yield as a light yellow oil.
25
1
½aꢃD ¼ ꢁ23:2 (c 0.38, CHCl3). H NMR (CDCl3): d 0.79
(d, 3H, J = 7.0 Hz), 3.00 (s, 3H), 3.43–3.50 (m, 1H), 4.14
(br s, 1H), 5.37 (d, 1H, J = 4.4 Hz), 5.94 (d, 1H,
J = 4.4 Hz), 6.09 (d, 1H, J = 4.4 Hz), 7.24–7.40 (m, 5H),
7.66 (d, 2H, J = 8.8 Hz), 8.18 (d, 2H, J = 8.8 Hz). 13C
NMR (CDCl3): d 12.4, 43.2, 51.9, 57.0, 71.6, 78.6, 123.3,
124.7, 127.7, 128.3, 128.6, 134.7, 146.1, 147.2, 147.5,
169.9. IR (CCl4): 3479, 3026, 1738, 1732, 1216, 792,
698 cmꢁ1. FAB-HRMS calcd for C20H21N3O6Br (M++1):
478.0614. Found: 478.0623.
4.8. (20S,30R,4R,5S,6R)-3-(2-Bromo-3-hydroxy-4-methyl-
pentanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
12
4.6.7. (20S,30R,4R,5S,6R)-3-[2-Bromo-3-(4-cyanophenyl)-3-
hydroxypropanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadi-
azinan-2-one 9g. The yellow oil was purified by column
chromatography on silica gel (hexanes–EtOAc, 40:60,
Rf = 0.22) to yield 9g in 90% yield as a yellow oil.
In a nitrogen purged 100 mL round-bottomed flask were
placed oxadiazinanone 4 (3.07 mmol), THF (9.21 mL,
0.33 M), and titanium tetrachloride (3.22 mmol) at 0 ꢁC
for 15 min. Triethylamine (6.14 mmol) was then added,
and after 15 min the reaction mixture was cooled to
ꢁ78 ꢁC. After the reaction mixture had cooled for
10 min, isobutyraldehyde (6.14 mmol) was added. The
reaction was allowed to run for 4 h and then quenched
upon the addition of a saturated solution of sodium bicar-
bonate. The resulting mixture was then extracted with
EtOAc (3 · 50 mL), and the extract washed with a satu-
rated aqueous solution of NaCl, dried over MgSO4, and
the solvent removed via rotary evaporation. The residual
yellow oil was purified by column chromatography on sil-
25
1
½aꢃD ¼ ꢁ16:5 (c 0.40, CHCl3). H NMR (CDCl3): d 0.72
(d, 3H, J = 6.6 Hz), 3.00 (s, 3H), 3.43–3.45 (m, 1H), 4.17
(br s, 1H), 5.32 (d, 1H, J = 4.0 Hz), 5.90 (d, 1H,
J = 4.8 Hz), 6.07 (d, 1H, J = 6.4 Hz), 7.23–7.40 (m, 5H),
7.60 (s, 4H). 13C NMR (CDCl3): d 12.1, 43.1, 51.6, 56.7,
71.7, 78.4, 111.5, 118.4, 124.6, 127.5, 128.2, 128.5, 131.8,
134.6, 144.2, 147.0, 169.6. IR (neat): 3468, 3020, 1773,
1716, 1214, 754, 700 cmꢁ1
. FAB-HRMS calcd for
C21H21N3O4Br (M++1): 458.0715. Found: 458.0715.
4.6.8. (20S,30R,4R,5S,6R)-3-[2-Bromo-3-hydroxy-3-(4-benz-
yloxyphenyl)propanoyl]-4,5-dimethyl-6-phenyl-2H-1,3,4-oxa-
diazinan-2-one 9h. The white powder was purified by
recrystallization from ethyl acetate and hexanes (hex-
ica gel (hexanes–EtOAc, 60:40, Rf = 0.20) to yield the aldol
25
product in 84% yield as a yellow oil. ½aꢃD ¼ ꢁ25:6 (c 0.30,
1
CHCl3). H NMR (CDCl3): d 0.96 (d, 3H, J = 7.3 Hz),
anes–EtOAc, 50:50, Rf = 0.33) to yield 9h in 28% yield as
0.96 (d, 3H, J = 6.6 Hz), 1.56 (d, 3H, J = 6.6 Hz), 1.85–
1.94 (m, 1H), 3.00 (s, 3H), 3.46 (d, 1H, J = 3.3 Hz), 3.50–
3.55 (m, 1H), 5.98 (d, 1H, J = 2.2 Hz), 6.10 (d, 1H,
25
an off-white powder. Mp = 146–147 ꢁC; ½aꢃD ¼ ꢁ16:8 (c
0.27, CHCl3). 1H NMR (CDCl3): d 0.66 (d, 3H,

T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
1839
J = 4.4 Hz), 7.29–7.44 (m, 5H). 13C NMR (CDCl3): d 12.7,
18.4, 18.6, 31.4, 43.4, 50.8, 57.2, 75.4, 78.5, 124.8, 128.3,
128.7, 135.0, 147.6, 171.1. IR (neat): 3513, 2964, 1774,
14) = 7.7 min]; Ester 14 was determined to have P98% ee
as compared to the racemic mixture. [a]D = +10.0 (c 0.25,
CHCl3). H NMR (CDCl3): d 3.50 (s, 3H), 3.81 (d, 1H,
J = 4.8 Hz), 4.23 (d, 1H, J = 4.8 Hz), 7.27–7.34 (m, 3H),
7.39 (d, 1H, J = 1.6 Hz), 7.41 (d, 1H, J = 2.0 Hz). 13C
NMR (CDCl3): d 51.7, 55.6, 57.2, 126.3, 127.8, 128.2,
132.6, 166.7. IR (neat), 1755, 1211, 751, 699 cmꢁ1. HRMS
calcd for C10H10O3Na: 201.0527. Found: 201.0528.
1
1732, 1253, 1139 cmꢁ1
.
FAB-HRMS calcd for
C17H23N2O4NaBr: 421.0739. Found: 421.0738.
4.9. Methyl (2S,3R)-2-bromo-3-hydroxy-3-phenylpropano-
ate 13
In a 2 L, three-neck round-bottomed flask, the aldol
adduct (9.058 g, 20.90 mmol) was dissolved in THF
(217 mL). To this solution was added 6.12 M sulfuric acid
(6.2 equiv) and the reaction mixture stirred at 50 ꢁC for
22 h. After the time had elapsed, heating was stopped
and the reaction mixture was allowed to cool to room tem-
perature. The solution was basified with a saturated aque-
ous solution of sodium bicarbonate. The THF was
removed by rotary evaporation and the aqueous portion
was then treated with ethyl acetate (2 · 400 mL). The water
layer was then acidified with 3 M HCl to litmus. The
organic layer was then washed with saturated brine and
the solvent removed to give the desired a-bromo-b-hydr-
oxyacid (4.76 g).
4.11. Synthesis of oxadiazinanone ent-1a: procedure for
N-nitrosation of (1S,2R)-ephedrine
(1S,2R)-Ephedrine (50.30 g, 249.4 mmol), HCl (2.74 M,
109 mL), and THF (109 mL) were combined in 1 L flask.
Sodium nitrite (20.7 g, 299 mmol) was added in portions
and the solution was allowed to stir for 24 h. The solu-
tion was concentrated via rotary evaporation and the N-
nitrosamine was extracted with ethyl acetate (200 mL).
The combined organic layers were washed with brine
(100 mL), dried over MgSO4, and the excess solvent re-
moved via rotary evaporation to yield the N-nitrosamine
as a yellow-white solid and as a mixture of diastereomers
in quantitative yield. Rf = 0.47 (hexanes–EtOAc, 50:50).
Mp = 82–85 ꢁC. 1H NMR (CDCl3): d 1.46 (d, 3H,
J = 7.2 Hz), 2.95 (s, 1H), 3.73 (s, 3H), 4.69 (qd, 1H,
J = 8.0, 2.0 Hz), 5.04 (d, 1H, J = 4.8 Hz), 7.33 (m, 5H).
13C NMR (CDCl3): d 13.2, 31.2, 65.0, 76.5, 126.1, 128.2,
The a-bromo-b-hydroxyacid was then placed in a flame-
dried, 250 mL round-bottomed flask, and dissolved in
anhydrous THF (78 mL). To this were added methanol
(39 mL) and trimethylsilydiazomethane (2 M, 30 mL) via
syringe. The reaction mixture was allowed to stir for 24 h
and then quenched by the addition of a saturated aqueous
solution of sodium bicarbonate (75 mL). The THF was
removed by rotary evaporation and the water layer was
treated with ethyl acetate (3 · 75 mL). The organic layer
was washed with saturated brine and the solvent was
removed. The a-bromo-b-hydroxyester 13 was isolated in
45% yield after column chromatography (hexanes–EtOAc,
75:25, Rf = 0.29) as a yellow oil. Chiral Stationary Phase
HPLC: [Daicel Chiralcel AS column, 3% i-PrOH in hex-
anes: RT (ent-13) = 9.3 min; RT (13) = 11.2 min]; Ester 13
was determined to have P98% ee as compared to the race-
mic mixture. [a]D = ꢁ27.7 (c 0.082, CHCl3). 1H NMR
(CDCl3): d 3.07 (s, 1H), 3.67 (s, 3H), 4.45 (d, 1H,
J = 6.6 Hz), 5.09 (d, 1H, J = 6.6 Hz), 7.25–7.4 (m, 5H).
13C NMR (CDCl3): 52.6, 53.0, 73.7, 126.6, 128.6, 128.8,
138.2, 168.9. IR (neat): 3490, 1736, 1437, 1282. ESI-HRMS
calcd for C10H11BrO3: 280.9789. Found: 280.9793.
128.6, 140.7. IR (neat): 3368, 1450, 1376, 1041, 834 cmꢁ1
ESI-HRMS calcd for C10H14N2O2: 195.1134. Found:
195.1130.
.
4.11.1. Reduction of the N-nitrosamine. Lithium alumi-
num hydride (19.38 g, 510.8 mmol) and THF (1 L) were
combined in a 5 L round-bottomed flask fitted with a con-
denser and addition funnel and the reaction mixture was
heated. The N-nitrosamine (49.6 g, 255 mmol) was added
via drop-wise addition and the solution was allowed to un-
dergo a gentle reflux for 2 h. Warning: The addition of the
nitrosamine substrate into the lithium aluminum hydride/
THF must be done drop-wise near 50 ꢁC to prevent overheat-
ing the solution. After 2 h, the reaction mixture was cooled
to 0 ꢁC. Sodium hydroxide (1 M, 200 mL) was added via
drop-wise addition to quench the reaction and the solvent
THF was removed by rotary evaporation. The product
was extracted with ethyl acetate (3 · 200 mL) and Ro-
chelle’s salt (100 mL). The combined organic layers were
washed with brine (200 mL), dried over MgSO4, and excess
solvent removed via rotary evaporation. The b-hydroxy-
hydrazine was recrystallized with hexanes and diethyl
ether and the white crystals were collected in a 54% yield.
Mp = 40–42 ꢁC. 1H NMR (CDCl3): d 0.83 (d, 3H,
J = 6.4 Hz), 2.59 (s, 3H), 2.76 (qd, 1H J = 8.0, 2.0 Hz),
5.21 (s, 2H), 7.23 (m, 1H), 7.35 (m, 5H). 13C NMR
(CDCl3): d 2.9, 48.7, 64.9, 77.7, 125.9, 126.7, 127.9,
142.4. IR (neat): 3310, 1618, 1449, 1045, 699 cmꢁ1. ESI-
HRMS calcd for C10H16N2O: 181.1341. Found: 181.1340.
4.10. Methyl (2R,3R)-phenylglycidate 14
The a-bromo ester 13 (1.8 g, 6.9 mmol) was dissolved in
methanol (35 mL) and then potassium carbonate (1.93 g,
13.9 mmol) was added to the solution. The reaction was
monitored by TLC (hexanes–EtOAc, 80:20) for 2 h and
then it was quenched with a saturated aqueous solution
of sodium bicarbonate (50 mL). The methanol was re-
moved by rotary evaporation, the residue treated with ethyl
acetate (50 mL), washed with a brine solution (50 mL), and
then dried over MgSO4. The resulting yellow oil was puri-
fied by column chromatography (hexanes–EtOAc, 75:25,
Rf = 0.23) and the product was isolated with a yield of
63% as a clear oil. CSP HPLC: [Daicel Chiralcel AD col-
umn, 3% i-PrOH in hexanes: RT (14) = 6.6 min; RT (ent-
4.12. (5R,6S)-4,5-Dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-
2-one ent-1a
In a flame-dried, nitrogen purged, 2 L round-bottomed
flask equipped with a condenser were placed the (1S,2R)-

1840
T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
ephedrine hydrazine (14.3 g, 79.4 mmol), anhydrous
hexanes (398 mL), and diethyl carbonate (24.0 mL,
197 mmol). The reaction mixture was heated at reflux
and lithium hydride (0.67 g, 84 mmol) was added. The
reaction was allowed to stir overnight and was then cooled
to 0 ꢁC and quenched with a saturated solution of NH4Cl
(200 mL). The hexanes were removed via rotary evapora-
tion and the resultant mixture was extracted with EtOAc
(2 · 200 mL), washed with brine solution, dried (MgSO4),
and the solvent was removed via rotary evaporation. The
brine (100 mL), dried over MgSO4, and the solvent re-
moved via rotary evaporation. The aldol adduct was
recrystallized twice from ethyl acetate and hexanes to yield
a white solid in 39% yield. Rf = 0.36 (hexanes–EtOAc,
50:50). Mp = 154–156 ꢁC. 1H NMR (CDCl3): d 0.68
(d, 3H, J = 7.2 Hz), 2.88 (s, 3H), 3.36 (m, 1H), 5.24 (d,
1H, J = 6.0 Hz), 5.93 (d, 1H, J = 6.0 Hz), 6.01 (d, 1H,
J = 4.8 Hz), 7.25 (m, 5H), 7.35 (m, 5H), 7.46 (d, 1H,
J = 8.0 Hz). 13C NMR (CDCl3): d 12.3, 43.3, 52.4, 57.1,
73.1, 78.4, 124.8, 127.0, 128.3, 128.4, 128.7, 135.1, 138.5,
147.0, 169.8. IR (neat): 3503, 1764, 1690, 1277, 1223,
1085, 753, 701 cmꢁ1. ESI-HRMS calcd for C20H21N2O4Br:
433.0763. Found: 433.0768.
isolated product was recrystallized from Et2O and hexanes
25
to yield ent-1a (71%) as a white powder. ½aꢃD ¼ þ24 (c
0.58, CHCl3); Rf = 0.51 (EtOAc). Mp: 117–119 ꢁC. 1H
NMR (CDCl3): d 0.92 (d, 3H, J = 6.6 Hz), 2.87 (s, 3H),
3.07–3.13 (m, 1H), 5.79 (d, 1H, J = 2.94 Hz), 6.91 (br s,
1H), 7.30–7.42 (m, 5H). 13C NMR (CDCl3): 11.6, 46.5,
56.9, 74.1, 125.2, 127.9, 128.5, 136.3, 152.3. IR (CCl4):
4.15. Methyl (2R,3S)-2-bromo-3-hydroxy-3-phenylpropano-
ate ent-13
3224, 2943, 1688, 744, 698 cmꢁ1
.
Anal. Calcd for
The aldol adduct ent-9a (2.70 g, 6.24 mmol), THF (65 mL),
and H2SO4 (2 M, 65 mL) were combined in a round-bot-
tomed flask. The solution was heated to an internal temper-
ature of 50 ꢁC for 22 h. The reaction was quenched with
saturated sodium bicarbonate solution until the mixture
was slightly basic. The reaction solvent was removed via
rotary evaporation. The first organic layer was extracted
with ethyl acetate (200 mL). The water layer was then made
acidic with hydrochloric acid (3 M) and the carboxylic acid
extracted with ethyl acetate (150 mL · 3). The independent
organic layers were dried over MgSO4, and the solvent re-
moved via rotary evaporation. The recovered carboxylic
acid (1.66 g, 6.77 mmol) was placed into a 1 L round-bot-
tomed flask. Anhydrous tetrahydrofuran (20 mL), metha-
nol (20 mL), and trimethylsilyldiazomethane (10.2 mL,
20.3 mmol) were sequentially added via syringe. The reac-
tion was allowed to run for 20 h. Excess solvent was
removed via rotary evaporation. The ester was purified
via column chromatography on silica gel (hexanes–EtOAc,
80:20). The purified ester was a yellow oil and was collected
in 63% yield from the aldol adduct. Chiral Stationary
Phase HPLC: [Daicel Chiralcel AS column, 3% i-PrOH
in hexanes: RT (ent-13) = 9.3 min; RT (13) = 11.2 min];
Ester ent-13 was determined to have P98% ee as compared
to the racemic mixture. [a]D = +29.1 (c 0.42, CHCl3).
C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C,
63.88; H, 6.87; N, 13.43. HRMS calcd for C11H14N2O2:
207.1133. Found: 207.1130.
4.13. (4S,5R,6S)-3-(2-Bromoacetyl)-4,5-dimethyl-6-phenyl-
2H-1,3,4-oxadiazinan-2-one ent-4
The oxadiazinanone (6.00 g, 29.2 mmol) and bromoacetyl
bromide (3.1 mL) were dissolved in CH2Cl2 (29 mL) in a
1 L round-bottomed flask. The solution was gently heated
and lithium hydride (0.371 g, 46.7 mmol) added. After
24 h, the solution was cooled to room temperature and
the reaction quenched with the addition of a saturated
aqueous solution of NH4Cl (100 mL). The reaction was ex-
tracted with dichloromethane (150 mL · 2). The combined
organic layers were washed with brine (100 mL), dried over
MgSO4, and the solvent removed via rotary evaporation.
The product was purified via column chromatography on
silica using a gradient: hexanes–EtOAc, 75:25 to 60:40.
This process yielded a yellow oil in 80% yield. Rf = 0.16
(hexanes–EtOAc, 70:30). 1H NMR (CDCl3): d 0.81 (d,
3H, J = 6.8 Hz), 2.94 (s, 3H), 3.46 (m, 1H), 4.46 (d, 1H,
J = 13.2 Hz), 4.64 (d, 1H, J = 13.2 Hz), 6.07 (d, 1H,
J = 4.0 Hz), 7.31 (m, 5H). 13C NMR (CDCl3): d 11.8,
30.9, 42.6, 56.1, 77.6, 124.4, 127.7, 128.1, 134.8, 147.2,
165.9. IR (neat): 1778, 1728, 1452, 1177, 1139, 1013, 754,
1
Rf = 0.31 (hexanes–EtOAc, 80:20). H NMR (CDCl3): d
3.30 (d, 1H, J = 3.6 Hz), 3.64 (s, 3H), 4.44 (d, 1H,
J = 6.8 Hz), 5.06 (dd, 1H, J = 6.4, 3.2 Hz), 7.34 (m, 5H).
13C NMR (CDCl3): d 52.4, 52.9, 73.7, 126.5, 128.5, 128.7,
700 cmꢁ1
.
ESI-HRMS calcd for C13H15N2O2Br:
327.0344. Found: 327.0352.
138.2, 168.8. IR (neat): 3490, 1743, 1282, 757, 700 cmꢁ1
.
4.14. (20R,30S,4S,5R,6S)-3-(2-Bromo-3-hydroxy-3-phenyl-
propanoyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazinan-2-
one ent-9a
ESI-HRMS calcd for C10H11O3Br: 280.9789. Found:
280.9801.
4.16. Methyl (2S,3S)-phenylglycidate ent-14
Oxadiazinanone ent-4a (7.98 g, 24.4 mmol), benzaldehyde
(4.4 mL, 43 mmol), and THF (75 mL) were combined in
a 500 mL round-bottomed flask and the solution then
cooled to ꢁ60 ꢁC. Titanium tetrachloride (5.92 mL,
53.70 mmol) was added via syringe and the solution was
left to stir at ꢁ60 ꢁC for 15 min. Triethylamine (6.80 mL,
48.8 mmol) was added via syringe and the solution left to
stir for 4 h while the solution gradually warmed to room
temperature. The reaction was quenched with a saturated
aqueous solution of NH4Cl (100 mL). The aldol adduct
was extracted with ethyl acetate (100 mL · 3), washed with
The ester (0.860 g, 3.32 mmol) was placed in a 100 mL
round-bottomed flask along with methanol (17 mL) and
potassium carbonate (0.92 g, 6.64 mmol). The reaction
was left to stir for 2 h. The epoxide was extracted with
saturated sodium bicarbonate solution (50 mL) and ethyl
acetate (100 mL · 2). The organic layers were combined,
dried (MgSO4), and the solvent was removed via rotary
evaporation. The resultant epoxide was purified via column
chromatography on silica (90:10, hexanes–EtOAc). The
process yielded a colorless oil in 96% yield. Rf = 0.45

T. R. Hoover et al. / Tetrahedron: Asymmetry 17 (2006) 1831–1841
1841
7. Green, R.; Cheeseman, M.; Duffill, S.; Merritt, A.; Bull, S. D.
Tetrahdron Lett. 2005, 46, 7931–7934, and references cited
therein.
(80:20, hexanes–EtOAc). CSP HPLC: [Daicel Chiralcel AD
column, 3% i-PrOH in hexanes: RT (14) = 6.6 min; RT (ent-
14) = 7.7 min]; Ester ent-14 was determined to have P98%
ee as compared to the racemic mixture. [a]D = ꢁ10.0 (c
8. (a) Hitchcock, S. R.; Casper, D. M.; Vaughn, J. F.; Finefield,
J. M.; Ferrence, G. M.; Esken, J. M. J. Org. Chem. 2004, 69,
714–718; (b) Casper, D. M.; Hitchcock, S. R. Tetrahedron:
Asymmetry 2003, 14, 517–521; (c) Casper, D. M.; Burgeson,
J. R.; Esken, J. M.; Ferrence, G. M.; Hitchcock, S. R. Org.
Lett. 2002, 4, 3739–3742; (d) Hitchcock, S. R.; Nora, G. P.;
Casper, D. M.; Squire, M. D.; Maroules, C. D.; Ferrence, G.
M.; Szczepura, L. F.; Standard, J. M. Tetrahedron 2001, 57,
9789–9798.
1
3.22, CHCl3). H NMR (CDCl3): d 3.50 (s, 3H), 3.81 (d,
1H, J = 4.8 Hz), 4.23 (d, 1H, J = 4.8 Hz), 7.34 (m, 5H).
13C NMR (CDCl3): d 51.7, 55.6, 57.2, 126.3, 127.8, 128.2,
132.6, 166.7. IR (neat): 1755, 1441, 1212, 747, 699 cmꢁ1
.
ESI-HRMS calcd for C10H10O3: 179.0708. Found:
179.0708.
9. (a) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.;
Jasperse, C. P.; Sibi, M. P. Chem. Eur. J. 2003, 9, 28–35; (b)
Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 2001, 123, 8444–8445; (c) Bull, S. D.; Davies, S.
G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R. Pure Appl.
Chem. 1998, 70, 1501–1506.
10. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1–115.
11. The stereochemistry [Z(O) vs E(O)] of the proposed enolate
was not determined.
Acknowledgments
We would like to thank Professor David Gin (University of
Illinois–Urbana) for help with polarimetry measurements.
We also thank Merck & Co., Inc. and Pfizer, Inc. for gener-
ous support. The authors thank the donors from the Amer-
ican Chemical Society-Petroleum Research Fund for
support of this research. We also acknowledge support for
R.W.P. from the Arnold and Mabel Beckman Foundation.
12. (a) The a-bromo-b-hydroxyacids proved to be difficult to
purify due to decomposition, for example, retro-aldol,
epoxide formation; (b) Murakami, N.; Tamura, S.; Wang,
W.; Takagi, T.; Kobayashi, M. Tetrahedron 2001, 57, 4323–
4336; (c) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem.
Pharm. Bull. 1981, 29, 1475–1478.
13. CSP HPLC analysis of the enantiomerically enriched methyl
esters was conducted in conjunction with CSP HPLC analysis
of the racemic mixture of the methyl esters [methyl (2S,3R)/
(2R,3S)-2-bromo-3-hydroxy-3-phenylpropanoate]. The race-
mic ester was prepared from racemic ephedrine using the
reaction pathway described in Scheme 1 and Table 1. The 1H
NMR spectra, 13C NMR spectra, and IR data all consistently
matched that of the enantiomerically pure materials.
14. Bromo-ester 13 has been previously synthesized in enantio-
merically pure form but no data regarding the optical activity
of the pure enantiomer could be found: (a) Wang, Y.-C.;
Yan, T.-H. Chem. Commun. 2000, 545–546; (b) Hoenig, H.;
Seufer-Wasserthal, P.; Weber, H. Tetrahedron 1990, 46, 3841–
3850.
15. (a) Wuts, P. G. M.; Gu, R. L.; Northius, J. M. Tetrahedron:
Asymmetry 2000, 11, 2117–2123; (b) Denis, J.-N.; Correa, A.;
Greene, A. E. J. Org. Chem. 1990, 55, 1957–1959; (c) Denis,
J.-N.; Greene, A. E.; Serra, A. A.; Luche, J.-J. J. Org. Chem.
1986, 51, 46–50.
16. The specific rotation measurements obtained for (2R,3R)-14
and (2S,3S)-14 were used only to establish the absolute
stereochemistry. The use of the CSP HPLC provided more
tangible evidence regarding the enantiomeric purities of the
individual isomers.
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