Oxadiazinones as chiral auxiliaries: Increased diastereoselectivities in the glycolate aldol reaction of oxadiazinones

Article abstract of DOI:10.1016/j.tetasy.2004.09.015

Glycolate aldol reactions were conducted using a (1R,2S)-norephedrine based N₄-isopropyloxadiazinone as a chiral template to afford aldol adducts 8a-h. The yields ranged from 57% to 99% while the diastereoselectivities ranged from 94:6 to 99:1.

Full text of DOI:10.1016/j.tetasy.2004.09.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3449–3455
Oxadiazinones as chiral auxiliaries: increased
diastereoselectivities in the glycolate aldol
reaction of oxadiazinonesq
Jeremy F. Vaughn and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 13 August 2004; accepted 7 September 2004
Available online 18 October 2004
Abstract—Glycolate aldol reactions were conducted using a (1R,2S)-norephedrine based N4-isopropyloxadiazinone as a chiral tem-
plate to afford aldol adducts 8a–h. The yields ranged from 57% to 99% while the diastereoselectivities ranged from 94:6 to 99:1.
Adduct 8a was hydrolyzed to afford the oxadiazinone auxiliary and b-hydroxyacid 9, which was converted to the known methyl
(2S,3R)-2,3-dihydroxy-3-phenylpropionate 12 with 95% ee as determined by chiral HPLC.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In our ongoing efforts to develop oxadiazinones as chi-
ral auxiliaries, we recently disclosed the synthesis and
application of a novel N4-isopropyloxadiazinone 2
derived from (1R,2S)-norephedrine.1a This auxiliary
yielded better diastereoselectivities than the ephedrine
based auxiliary in the aldol reaction involving either a
propionate or thiophenylpropionate side chain.1a The
enhanced diastereoselectivity was thought to originate
from the increased steric demand of the N4-substituent,
that is, N4–CH(CH3)2 versus N4–CH3.
The use of chiral, non-racemic oxadiazinones as chiral
auxiliaries in aldol reactions has recently been investi-
gated by our group.1 The first reported asymmetric aldol
applications of this class of auxiliary employed (1R,2S)-
ephedrine as the chiral template 1 (Fig. 1).1b,c The ste-
reochemical induction in the aldol addition reaction of
this oxadiazinone is attributed to the conformational
arrangement of the ring system and the positioning of
the methyl substituent of the stereogenic nitrogen, that
is the N4-methyl group. The diastereoselectivities of
the ephedrine based oxadiazinone mediated asymmetric
aldol reactions were fair to very good.1b,c
With a superior oxadiazinone auxiliary in hand, we
became interested in pursuing the asymmetric aldol
reaction of glycolate substrates. The utility of the asym-
metric glycolate reaction has been demonstrated in the
synthesis of a variety of natural products.2 An earlier
study was carried out to determine the viability of the
(1R,2S)-ephedrine based oxadiazinone 1 in the glycolate
aldol reaction.3 However, the chemical yields and ob-
served diastereoselectivities were not optimal. Further-
more, aliphatic aldehydes were problematic, for
example, low diastereoselectivity and incomplete reac-
tivity. Herein we report our efforts in developing the
(1R,2S)-norephedrine based N4-isopropyloxadiazinone
in the glycolate aldol reaction.
O
H
N
N
O
Ph
R
CH
3
1: R = -CH3
2: R = -CH(CH3)2
Figure 1. Ephedrine and norephedrine based oxadiazinones.
q This work has been presented in part at the 36th Central Regional
Meeting of the American Chemical Society, Indianapolis, IN, USA,
June 2–4, 2004.
2. Results and discussion
*
N4-isopropyloxadiazinone 2 was synthesized as de-
scribed before (Scheme 1).1a (1R,2S)-Norephedrine was
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438
5538; e-mail: hitchcock@ilstu.edu
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.015

3450
J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
OR
O
1. (CH3)2CO; NaBH4
2. NaNO2, HCl
O
O
OH
H
NH2
N
N
O
LiH, ROCH2COCl
CH2Cl2
N
N
O
Ph
3. LiAlH4, THF
4. (EtO)2CO, LiH
Ph
Ph
CH3
(1R,2S)-norephedrine
CH3
CH3
2
3: R = -CH2Ph
4: R = -p-C6H4OCH3
Scheme 1. Synthesis and acylation.
R
reductively alkylated with acetone and sodium borohy-
dride, N-nitrosated,4 reduced to the corresponding b-
hydrazinoalcohol, and cyclized using diethyl carbonate
and lithium hydride. Oxadiazinone 2 was subsequently
acylated with either benzyloxyacetyl chloride or p-meth-
oxyphenoxyacetyl chloride to afford N3-acylated deriva-
tives 3 and 4 in 83% and 92% yield, respectively.
MPO
OH
OMP
a. TiCl4, 25 o
b. TEA, 0 oC
c. RCHO
C
O
O
O
O
N
N
O
N
N
O
Ph
Ph
CH3
8a-h
CH3
4: MP = p-C6H4OCH3
These substrates were then used in the titanium medi-
ated asymmetric aldol addition reaction (Scheme 2).
Surprisingly, N3-benzyloxyacetyloxadiazinone 3 failed
to generate the desired aldol adduct in significant
amounts (<10%). This same phenomenon was observed
in the ephedrine based oxadiazinone 5.3 The reason for
the failure of these two substrates to undergo the aldol
addition is unknown at this time, but could be attributed
to the interaction of the titanium tetrachloride (TiCl4)
with the N3-side chain. In fact, when 3 was treated with
a large excess of TiCl4 (5equiv), triethylamine (1equiv),
and benzaldehyde (5equiv), aldol adduct 6 was obtained
in 40% yield and 95:5 diastereoselectivity as determined
by 400MHz 1H NMR spectroscopy. These unusual con-
ditions were not satisfactory in terms of obtaining the
product and so the benzyloxyacetyl substrates were
abandoned.
8a: R = -C6H5
8b: R = -p-C6H4Cl
8c: R = -p-C6H4NO2
8d: R = -2-C10H7
8e: R = -CH(CH3)2
8f: R = -C(CH3)3
8g: R = -CH2OCH2C6H5
8h: R = -(E)-CH=CHC6H5
Scheme 3. Asymmetric aldol reaction.
Table 1. Diastereoselectivity in the oxadiazinone mediated glycolate
aldol reaction
Entry
Aldehyde
Adduct
Dra
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5CHO
8a
8b
8c
8d
8e
8f
97:3
98:2
94:6
98:2
98:2
98:2
99:1
99:1
97
82
66
80
57
98
87
62
p-ClC6H4CHO
p-NO2C6H4CHO
2-C10H7CHO
The N3-p-methoxyphenoxyacetyl side chain appended
to the N4-isopropyloxadiazinone proved to be more
promising (Scheme 3). The optimized method for the
aldol addition using oxadiazinone 4 involved treatment
with TiCl4 (2equiv) at 25°C, followed by reaction with
triethylamine (1.05equiv) at 0°C, and treatment with a
selected aldehyde (2equiv). The yields ranged from fair
to excellent and the observed diastereoselectivities
ranged from 94:6 to greater than 99:1 as measured by
HPLC (Table 1).
(CH3)2CHCHO
(CH3)3CCHO
C6H5CH2OCH2CHO
(E)-C6H5CHCHCHO
8g
8h
a All crude diastereomeric ratios were measured by HPLC using a
˚
Shimadzu SCL-10AVP system with a Dynamax Si-100A column
(7:3, hexanes/ethyl acetate, flow rate = 1.5mL/min). Diastereoselec-
all other
P
tivities are represented as major diastereomer:
diastereomers.
b Purified yields after column chromatography.
In addition, the glycolate aldol reactions for the nore-
phedrine based auxiliary were successful for aliphatic
aldehydes. These results were significantly improved
over the results obtained with the ephedrine based oxa-
diazinone auxiliary.3 This can be directly attributed to
a. TiCl4, 25 o
b. TEA, 0 oC
C
O
O
R
O
O
R
OH
Ph
OCH2Ph
OCH2Ph
N
N
O
N
N
O
c. PhCHO
Ph
Ph
CH3
CH3
6: R = -CH(CH3)2
7: R = -CH3
3: R = -CH(CH3)2
5: R = -CH3
Scheme 2.

J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
3451
OH
Ph
OMP
10
OH
Ph
O
OH
Ph
OMP
O
TMSCHN2
CH3OH
1
M NaOH
HO
CH O
3
8a
+
2
9
OBz
O
O
BzCl,TEA
DMAP
1. Ce(NH4)2(NO3)6
2. K2CO3, MeOH
CH O
3
Ph
CH O
3
OMP
11
OH
12
Scheme 4. Synthesis of the a,b-dihydroxyester 12.
the introduction of the isopropyl group at the N4-posi-
tion via the primary amine of norephedrine. Based on
earlier studies with the N4-isopropyloxadiazinone, the
stereochemistry of aldol adducts 8a–h was tentatively
assigned the (2S,3R)-configuration.1a,3
a chelated chair like Zimmerman–Traxler transition
state (Fig. 2).
Cl
Cl
Cl
O
Ti
In order to confirm this assignment, we sought to
hydrolyze adduct 8a and convert the resultant b-
hydroxyacid to the known methyl 2,3-dihydroxy-3-phen-
ylpropionate and evaluate its enantiomeric purity
(Scheme 4).5 Thus, oxadiazinone 8a was hydrolyzed to
the b-hydroxyacid 9 (88%) and the N4-isopropyloxadi-
azinone 2 (52%) by treatment with an aqueous solution
of NaOH (1M). The b-hydroxyacid 9 was esterified with
trimethylsilyldiazomethane6 in methanol to afford the
b-hydroxyester 10 in 67% yield after column chromato-
graphy. At this stage it was not possible to remove the
p-methoxyphenyl protecting group by reported
methods7 without significant decomposition, most likely
due to presence of the benzylic alcohol. Thus, the b-
hydroxy group was protected with benzoyl chloride to
afford the corresponding benzoate ester 11 in 68% yield
after chromatography.
O
O
O
R
O
N
N
H
H
CH
OCH
Ph
3
3
CH
3
CH
3
Figure 2. Proposed transition state.
3. Conclusion
In conclusion, we have demonstrated that the N4-iso-
propyloxadiazinone is a viable chiral auxiliary for the
glycolate aldol reaction. We have synthesized methyl
(2S,3R)-2,3-dihydroxy-3-phenylpropionate 12 in a dia-
stereomeric ratio of 19:1 favoring the syn-diastereomer
and in an enantiomeric purity greater than 95% by
means of an oxadiazinone mediated asymmetric aldol
reaction. A limitation to the use of p-methoxyphenyl
protecting group became evident as it could not be
cleanly removed without further protection of the
appendant b-hydroxy group. Studies directed toward
the synthesis of HIV protease inhibitors nelfinavir and
saquinavir are currently underway.
The p-methoxyphenyl protecting group was then oxida-
tively removed by treatment of 11 with ceric ammonium
nitrate [Ce(NH4)2(NO3)6].8 The resultant a-hydroxy-
ester was not characterized as it was not possible to
completely remove the quinone by-product. Conse-
quently, the ester was directly treated with K2CO3 and
methanol to effect cleavage of the benzoate ester9 to
yield the desired a,b-dihydroxyester 12 in 37% yield
after chromatography for the two step process. This
was determined to be the (2S,3R)-enantiomer based on
25
D
the specific rotation: ½aꢀ ¼ ꢁ9:3 (c 0.175, CHCl3);
25
lit.5c = ½aꢀ ¼ ꢁ8:8 (c 1.0, CHCl3), 82% ee.
4. Experimental
4.1. General
D
Finally, chiral HPLC was used to accurately determine
the enantiomeric purity of the diol. The enantiomeric
purity of (2S,3R)-12 was determined to be 95% ee by
chiral HPLC analysis based on a comparison with the
racemic a,b-dihydroxy ester 12:10 [Chiralcel OD column,
6% isopropanol in hexanes: tR (2R,3S)-12 = 16.0min; tR
(2S,3R)-12 = 18.0min]. This work established the
relative and absolute configurations of the aldol side
chain of oxadiazinone 8a. By analogy, the stereochemis-
try of aldol adducts 8b–h were assigned to be in a
(2S,3R)-syn relationship. This would suggest that the
transition state of the aldol reaction closely resembles
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from a potassium/sodium alloy with benzophe-
none ketyl. Methylene chloride (CH2Cl2) was distilled
from phosphorus pentoxide. All reactions were run
under a nitrogen atmosphere. Unless otherwise noted,
1
all H and 13C NMR spectra were recorded at 25°C
on a Varian spectrometer in CDCl3 operating at 400
and 100MHz, respectively. Chemical shifts are reported
in parts per million (d scale), and coupling constants (J
values) are listed in hertz (Hz). Infrared spectra are

3452
J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
reported in reciprocal centimeters (cmꢁ1) and are mea-
sured either as a neat liquid or as a KBr window.
Melting points were recorded on a Mel-Temp apparatus
and are uncorrected.
7.26–7.28 (m, 3H), 7.32–7.43 (d, J = 8.0Hz, 2H). 13C
NMR: d 13.0, 20.4, 20.9, 51.5, 54.1, 55.6, 70.0, 79.0,
114.6, 116.2, 124.8, 128.3, 128.8, 135.6, 149.3, 152.1,
154.4, 170.3. IR (neat): 1728, 1204, 734cmꢁ1. EI-HRMS
calculated for C22H26N2O5 (M++Na+): 421.1743. found:
421.1739.
4.2. (5S,6R)-3-Benzyloxyacetyl-3,4,5,6-tetrahydro-4-iso-
propyl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 3
4.4. (20S,30R, 5S,6R)-3-(2-Benzyloxy-3-hydroxy-3-phen-
ylpropionyl)-3,4,5,6-tetrahydro-4-isopropyl-5-methyl-6-
phenyl-2H-1,3,4-oxadiazinan-2-one 6
In a flame-dried, nitrogen-purged 250mL round bottom
flask were placed N4-isopropyloxadiazinone 2 (3.00g,
12.8mmol) and CH2Cl2 (12.8mL). To this reaction mix-
ture was added benzyloxyacetyl chloride (15.4mmol)
and the reaction heated to a gentle reflux (ꢂ39°C). Lith-
ium hydride (13.4mmol) was then added to the reaction
mixture in one portion. The reaction was allowed to run
overnight and then quenched by the addition of satu-
rated aqueous solution of ammonium chloride (NH4Cl).
This solution was diluted with CH2Cl2 and the layers
separated, washed with brine, dried over MgSO4, and
the solvent removed via rotary evaporation. The result-
ing oil was purified via column chromatography using a
70/30 mixture of hexanes and ethyl acetate. The title
In a flame-dried, nitrogen-purged 100mL round bottom
flask were placed oxadiazinone 3 (0.589g, 1.54mmol)
and THF (4.5mL). To this reaction mixture was added
TiCl4 (0.85mL, 7.7mmol) at 25°C. This reaction mix-
ture was allowed to react for 30min. The reaction was
then cooled to 0°C and triethylamine (0.23mL,
1.6mmol) introduced and reacted for 1h. At this point,
the reaction was again cooled to 0°C, and benzaldehyde
added via syringe. After 4h the reaction was quenched
by the addition of a saturated solution of NH4Cl and
diethyl ether, separated, washed with brine, dried over
MgSO4, gravity filtered, and the solvent removed via
rotary evaporation. The resulting compound was purified
via column chromatography using a mixture of hexanes
and ethyl acetate and recovered. Isolated product was
compound was recovered in 92% yield (4.50g):
25
½aꢀ ¼ ꢁ40:7 (c 0.39, CHCl3); Rf = 0.31 (ethyl acetate/
D
hexanes, 3:7). 1H NMR: d 0.79 (d, J = 6.8Hz, 3H),
1.17 (d, J = 6.4Hz, 3H), 1.37 (d, J = 6.0Hz, 3H), 3.38
(septet, J = 6.0Hz, 1H), 3.79 (septet, J = 7.2Hz, 1H),
4.64 (s, 2H), 4.71 (AB quartet, J = 18.0Hz, 2H), 5.94
(d, J = 5.2Hz, 1H), 7.22–7.43 (m, 10H). 13C NMR (the
urethane carbonyl was not observed): 12.9, 20.3, 20.9,
51.4, 54.0, 70.9, 73.3, 78.8, 124.8, 127.9, 128.2, 128.4,
128.7, 135.6, 137.3, 149.0, 171.9. IR (neat): 1782, 1728,
collected in 40% yield as a yellow oil contaminated with
25
5% of an unidentified impurity. ½aꢀ ¼ ꢁ79:1 (c 0.172 in
D
CHCl3); Rf = 0.26 (ethyl acetate/hexanes, 2:3). 1H
NMR: d 0.73 (d, J = 6.4Hz, 3H), 1.23 (d, J = 6.4Hz,
3H), 1.39 (d, J = 5.6Hz, 3H), 3.00–3.19 (br s, 1H),
3.35–3.50 (m, 1H), 3.83 (septet, J = 6.4Hz, 1H), 4.23
(d, J = 11.6Hz, 1H), 4.44 (d, J = 11.6Hz, 1H), 5.21 (s,
1H), 5.40 (s, 1H), 5.98 (d, J = 4.8Hz, 1H), 6.99 (d,
J = 2.0Hz, 2H), 7.15–7.45 (m, 11H), 7.56 (d,
J = 7.6Hz, 2H). 13C NMR: 12.7, 20.4, 20.7, 51.3, 54.3,
72.8, 73.4, 79.1, 82.7, 124.7, 125.9, 127.3, 127.8, 128.0,
128.1, 128.2, 128.3, 128.8, 135.6, 136.8, 141.3, 149.4,
171.6. IR (neat): 3478, 1725, 1245. EI-HRMS calculated
for C29H32N2O5: 488.2303, found: 488.2311.
1206cmꢁ1
. EI-HRMS calculated for C22H26N2O4:
382.1893, found: 382.1893.
4.3. (5S,6R)-3,4,5,6-Tetrahydro-4-isopropyl-3-[2-(p-meth-
oxyphenoxy)acetyl]-5-methyl-6-phenyl-2H-1,3,4-oxadia-
zin-2-one 4
In a flame-dried, nitrogen-purged 500mL round bottom
flask were added p-methoxyphenoxyacetic acid
(43.1mmol) and CH2Cl2 (103mL). To this reaction mix-
ture was added oxalyl chloride (51.7mmol) and the solu-
tion then gently heated to reflux (ꢂ39°C) for 2h. At this
time, 50% of the reaction solvent was distilled away.
After removing the excess CH2Cl2, the N4-isopropyloxa-
diazinone 2 (10.0g, 34.5mmol) was added in one por-
tion. To this mixture was added lithium hydride
(48.3mmol) and the reaction allowed to run overnight.
The reaction was quenched by the addition of an aque-
ous solution of NH4Cl and diluted by the addition of
CH2Cl2, separated, washed with brine, dried over
MgSO4, and the solvent removed via rotary evapora-
tion. The resulting oil was purified via column chroma-
tography using a 65/35 mixture of hexanes and ethyl
4.5. General procedure for the synthesis of aldol adducts
8a–h
Method A 8a and 8b: In a flame-dried, nitrogen-purged
100mL round bottom flask were placed N4-isopropyloxa-
diazinone 2 (0.4–0.6g) and THF (0.33M). To this 25°C
solution was added TiCl4 (1equiv) via syringe. After
30min, the reaction was cooled to 0°C and 1.05equiv
of triethylamine introduced and reacted for 1h. At this
time, the reaction was again cooled to 0°C, and the de-
sired aldehyde (1.10equiv) added via syringe. The reac-
tion was allowed to stir for 4h and then quenched by
the addition of a saturated solution of NH4Cl and di-
luted with diethyl ether. The layers were separated and
the organic layer was washed with brine, dried over
MgSO4, and the solvent removed via rotary evapora-
tion. The resulting compounds were purified via column
chromatography using a mixture of hexanes and ethyl
acetate and then recovered. Method B 8c–h: In this pro-
cedure, 2equiv of TiCl4 and 2equiv of the desired alde-
hyde were employed. Diastereomeric ratios were
determined by HPLC using a Shimadzu SCL-10AVP
acetate. The isolated product was collected in 83%
25
D
0.19, CHCl3); Rf = 0.319 (ethyl acetate/hexanes, 2:3).
(11.4g) yield as an amber-colored oil. ½aꢀ ¼ ꢁ31:6 (c
1H NMR:
d 0.82 (d, J = 6.8Hz, 3H), 1.18 (d,
J = 6.0Hz, 3H), 1.37 (d, J = 6.4Hz, 3H), 3.41 (septet,
J = 6.0Hz, 1H), 3.76 (s, 3H), 3.80 (dq, J = 4.0, 2.0Hz,
1H), 5.18 (AB quartet, J = 19.2Hz, 2H), 5.98 (d,
J = 4.8Hz, 1H), 6.79–6.84 (m, 2H), 6.88–6.92 (m, 2H),

J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
3453
˚
system with a Dynamax Si-100A column (7:3, hexanes/
ethyl acetate, flow rate = 1.5mL/min). Diastereoselectiv-
ities are represented as the observed major diastereomer
versus the minor diastereomers. The chromatographic
peaks that were assigned as the minor diastereomers
have not been rigorously established, but the diastereo-
selectivities were determined so that they would not
overstate the success of the formation of the major
diastereomer.
4.5.4. (20S,30R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-hydroxy-
2-(p-methoxyphenoxy)-3-naphthalen-2-yl-propionyl]-4-
isopropyl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
8d. Isolated product was collected in 80% yield as a
25
amber oil. ½aꢀ ¼ ꢁ18:4 (c 0.37, CHCl3); Rf = 0.24
D
(ethyl acetate/hexanes, 2:3). 1H NMR: d 0.67 (d,
J = 6.8Hz, 3H), 1.22 (d, J = 6.0Hz, 3H), 1.38 (d,
J = 6.4Hz, 3H), 1.58 (s, 1H), 3.43 (septet, J = 6.8Hz,
1H), 3.65 (s, 3H), 3.82 (septet, J = 6.8Hz, 1H), 5.70 (s,
1H), 5.97 (s, 1H), 6.01 (d, J = 4.8Hz, 1H), 6.63
(s, 4H), 7.20–7.52 (m, 6H), 7.78–7.92 (m, 5H), 8.07 (s,
1H). 13C NMR: d 12.6, 20.5, 20.7, 51.3, 54.3, 55.5,
73.7, 79.3, 83.9, 114.4, 118.2, 124.2, 124.7, 125.2,
125.8, 126.0, 127.6, 128.0, 128.2, 128.3, 128.8, 133.0,
133.2, 135.5, 138.1, 149.6, 151.6, 155.0, 170.7. IR (neat):
3466, 1724, 1244, 733cmꢁ1. EI-HRMS calculated for
C33H34N2O6: 554.2417, found: 554.2425.
4.5.1. (20S,30R,5S,6R)-3-[3-Hydroxy-2-(p-methoxyphen-
oxy)-3-phenylpropionyl]-4-isopropyl-5-methyl-6-phenyl-
2H-1,3,4-oxadiazin-2-one 8a. Isolated product was
collected in 99% yield as a yellow oil. ½aꢀ ¼ ꢁ31:6
25
D
(c 0.33, CHCl3); Rf = 0.34 (ethyl acetate/hexanes, 1:1).
1H NMR (the alcohol proton, ROH, was not observed):
d 0.66 (d, J = 7.2Hz, 3H), 1.21 (d, J = 6.0Hz, 3H), 1.38
(d, J = 5.6Hz, 3H), 3.42 (septet, J = 6.4Hz, 1H), 3.67 (s,
3H), 3.81 (dq, J = 7.2, 1.8Hz, 1H), 5.53 (s, 1H), 5.85 (s,
1H), 6.00 (d, J = 4.8Hz, 1H), 6.64 (dd, J = 7.2, 4.0Hz,
4H), 7.23–7.44 (m, 8H), 7.64 (d, J = 8.0Hz, 2H). 13C
NMR: d 12.6, 20.5, 20.6, 51.3, 54.3, 55.5, 73.6, 79.3,
84.0, 114.4, 118.2, 124.7, 126.1, 127.6, 128.26, 128.28,
128.7, 135.5, 140.6, 149.6, 151.7, 155.0, 170.7. IR (neat):
3412, 1723, 1243, 699cmꢁ1. EI-HRMS calculated for
C29H32N2O6 (M+): 504.2260, found: 504.2254.
4.5.5. (20S,30R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-hydroxy-
2-(p-methoxyphenoxy)-4-methylpentanoyl]-4-isopropyl-5-
methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8e. Isolated
product was collected in 57% yield as a yellow wax.
25
½aꢀ ¼ ꢁ16:2 (c 0.31, CHCl3); Rf = 0.38 (ethyl acetate/
D
hexanes, 1:1). 1H NMR (the alcohol proton, ROH,
was not observed): 0.69 (d, J = 6.8Hz, 3H), 1.06 (d,
J = 7.2Hz, 3H), 1.13 (d, J = 6.8Hz, 3H), 1.20 (d,
J = 6.4Hz, 3H), 1.34 (d, J = 6.0Hz, 3H), 2.09 (dq, J =
7.2, 2.0Hz, 1H), 3.38 (septet, J = 6.0Hz, 1H), 3.71 (s,
3H), 3.79 (dq, J = 7.2, 1.6Hz, 1H), 3.92 (d, J = 8.4Hz,
1H), 5.87 (d, 0.8Hz, 1H), 5.98 (d, J = 4.8Hz, 1H),
6.72–6.82 (m, 4H), 7.25–7.45 (m, 5H). 13C NMR: d
12.5, 19.0, 19.4, 20.5, 20.7, 32.4, 51.4, 54.3, 55.6, 79.1,
79.7, 114.5, 116.8, 124.7, 128.2, 128.8, 135.6, 149.5,
151.5, 154.6, 171.3. IR (neat): 3466, 1725, 1228,
4.5.2. (20S,30R,5S,6R)-3-[3-(p-Chlorophenyl)-3-hydroxy-
2-(p-methoxyphenoxy)propionyl]-3,4,5,6-tetrahydro-4-iso-
propyl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8b.
Isolated product was collected in 82% yield as a
25
D
yellow wax. ½aꢀ ¼ ꢁ20:5 (c 0.34, CHCl3); Rf = 0.23
(ethyl acetate/hexanes, 2:3). 1H NMR: d 0.65 (d,
J = 7.2Hz, 3H), 1.20 (d, J = 5.6Hz, 3H), 1.37 (d,
J = 6.4Hz, 3H), 3.16 (br s, 1H), 3.41 (septet,
J = 6.4Hz, 1H), 3.67 (s, 3H), 3.81 (septet, J = 6.4Hz,
1H), 5.49 (br s, 1H), 5.78 (d, J = 2.0Hz, 1H), 6.00 (d,
J = 4.8Hz, 1H), 6.62–6.68 (m, 4H), 7.24 (d, J = 8.0Hz,
2H), 7.25–7.26 (m, 2H), 7.33–7.43 (m, 3H), 7.58 (d,
J = 7.2Hz, 2H). 13C NMR: d 12.6, 20.5, 20.6, 51.3,
54.3, 55.6, 73.1, 79.3, 83.6, 114.5, 118.2, 124.7, 127.6,
128.3, 128.4, 128.8, 133.4, 135.4, 139.3, 149.7, 151.4,
155.1, 170.4. IR (neat): 3433, 1723, 1243, 828,
732cmꢁ1. EI-HRMS calculated for C29H31ClN2O6:
538.1871 (M+), found: 538.1857.
730cmꢁ1
.
470.2417, found: 470.2413.
EI-HRMS calculated for C26H34N2O6:
4.5.6. (20S,30R,5S,6R)-3,4,5,6,-Tetrahydro-3-[3-hydroxy-
2-(p-methoxyphenoxy)-4,4-dimethylpentanoyl]-4-isoprop-
yl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8f. Iso-
lated product was collected in 98% yield as a yellow
25
D
wax. ½aꢀ ¼ ꢁ12:6 (c 0.38, CHCl3); Rf = 0.23 (ethyl
1
acetate/hexanes, 2:3). H NMR: d 0.69 (d, J = 6.4Hz,
3H), 1.12 (s, 9H), 1.20 (d, J = 6.4Hz, 3H), 1.35 (d,
J = 6.4Hz, 3H) 2.50 (d, J = 11.2Hz, 1H), 3.40 (septet,
J = 6.0Hz, 1H), 3.71 (s, 3H), 3.80 (septet, J = 4.8Hz,
1H), 3.96 (d, J = 10.8Hz, 1H), 5.99 (d, J = 4.4Hz,
1H), 6.02 (s, 1H), 6.74–6.79 (m, 4H), 7.25–7.45 (m,
5H). 13C NMR: d 12.5, 20.6, 20.7, 26.9, 36.3, 51.4,
54.4, 55.6, 78.0, 79.1, 114.6, 116.2, 124.7, 128.2, 128.8,
135.7, 149.4, 150.8, 154.5, 171.5. IR (neat): 1727, 1229,
4.5.3. (20S,30R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-hydroxy-
2-(p-methoxyphenoxy)-3-(p-nitrophenyl)propionyl]-4-iso-
propyl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8c.
Isolated product was collected in 66% yield as a
25
yellow wax. ½aꢀ ¼ ꢁ18:0 (c 0.22, CHCl3); Rf = 0.26
D
(ethyl acetate/hexanes, 1:1). 1H NMR: d 0.67 (d,
J = 6.8Hz, 3H), 1.23 (d, J = 6.4Hz, 3H), 1.38 (d,
J = 6.4Hz, 3H), 3.36 (d, J = 9.2Hz, 1H), 3.46 (septet,
J = 7.6Hz, 1H), 3.66 (s, 3H), 3.82 (septet, J = 6.8Hz,
1H), 5.62 (d, J = 8.4Hz, 1H), 5.81 (s, 1H) 6.02 (d,
J = 4.4, 1H), 6.58–6.67 (m, 4H), 7.24–7.44 (m, 5H),
7.83 (d, J = 8.8Hz, 2H), 8.25 (d, J = 8.8Hz, 2H). 13C
NMR: d 12.6, 20.5, 20.7, 51.3, 54.4, 55.5, 72.9, 79.4,
83.2, 114.5, 118.0, 123.5, 124.7, 127.0, 128.4, 128.8,
135.2, 147.4, 148.3, 149.8, 151.0, 155.2, 170.0. IR (neat):
3467, 1723, 1244, 833, 733cmꢁ1. EI-HRMS calculated
for C29H31N3O8: 549.2111, found: 549.2099.
732cmꢁ1
.
484.2573, found: 484.2577.
EI-HRMS calculated for C27H36N2O6:
4.5.7. (20S,30R,5S,6R)-3-[4-Benzyloxy-3-hydroxy-2-(p-
methoxyphenoxy)butyryl]-3,4,5,6-tetrahydro-4-isopropyl-
5-methyl-2H-1,3,4-oxadiazin-2-one 8g. Isolated prod-
uct was collected in 87% yield as a yellow wax.
25
½aꢀ ¼ ꢁ20:4 (c 0.29, CHCl3); Rf = 0.34 (ethyl acetate/
D
hexanes, 1:1). 1H NMR: d 0.66 (d, J = 7.2Hz, 3H),
1.19 (d, J = 6.4Hz, 3H), 1.34 (d, J = 6.0Hz, 3H), 2.57
(br s, 1H), 3.38 (septet, J = 6.8Hz, 1H), 3.72 (s, 3H),
3.77–3.80 (m, 3H), 4.57–4.70 (m, 3H), 5.85 (s, 1H),

3454
J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
5.97 (d, J = 4.4Hz, 1H), 6.73–6.85 (m, 4H), 7.24–7.43
(m, 10H). 13C NMR: d 0.0, 12.6, 20.5, 20.7, 51.4, 54.3,
55.6, 70.5, 71.0, 73.3, 74.4, 79.2, 79.5, 114.5, 117.5,
124.7, 127.6, 127.7, 128.3, 128.4, 128.8, 135.6, 138.0,
149.4, 151.5, 154.8, 170.7. IR (neat): 1725, 1229, 750,
700cmꢁ1. HRMS (EI) calculated for C31H36N2O7:
548.2523, found: 548.2520.
and extracted. The combined organic layers were
washed with brine, dried over MgSO4, gravity filtered,
and the solvent removed via rotary evaporation. The
resulting ester was purified via column chromatography
using a 70/30 mixture of hexanes and ethyl acetate and
recovered in a 67% yield (0.787g) as a yellow oil.
25
1
½aꢀ ¼ ꢁ25:0 (c 0.35, CHCl3). H NMR: d 2.98 (br s,
D
1H), 3.63 (s, 3H), 3.74 (s, 3H), 4.63 (d, J = 5.2Hz,
1H), 5.15 (s, 1H), 6.78 (s, 4H), 7.26–7.43 (m, 5H). 13C
NMR: d 52.3, 55.6, 74.8, 82.9, 114.7, 117.0, 126.6,
128.5, 138.5, 151.6, 155.0, 170.1. IR (neat): 3462, 1748,
1226, 701cmꢁ1. EI-HRMS calculated for C17H18O5:
302.1154, found: 302.1163.
4.5.8. (20S,30R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-hydroxy-
2-(p-methoxyphenoxy)-5-phenylpent-4-enoyl]-4-isoprop-
yl-5-methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8h. Iso-
lated product was collected in 62% yield as a yellow
25
wax. ½aꢀ ¼ ꢁ2:8 (c 0.29, CHCl3); Rf = 0.25 (ethyl ace-
D
tate/hexanes, 9:11). 1H NMR (the alcohol proton,
ROH, was not observed): d 0.62 (d, J = 6.8Hz, 3H),
1.18 (d, J = 6.4Hz, 3H), 1.34 (d, J = 6.4Hz, 3H), 3.37
(septet, J = 6.0Hz, 1H), 3.70 (s, 3H), 3.77 (septet,
J = 6.0Hz, 1H), 5.00 (br s, 1H), 5.81 (d, J = 2.4Hz,
1H), 5.97 (d, J = 4.8Hz, 1H), 6.50 (dd, J = 16.0,
6.0Hz, 1H), 6.73–6.88 (m, 5H), 7.20–7.45 (m, 10H).
13C NMR: 12.6, 20.5, 20.7, 51.3, 54.3, 55.6, 73.2, 79.3,
82.2, 114.5, 117.9, 124.7, 126.7, 127.8, 127.9, 128.3,
128.5, 128.8, 132.3, 135.5, 136.5, 149.6, 151.5, 155.0,
170.4. IR (neat): 1724, 1243, 732cmꢁ1. EI-HRMS
calculated for C31H34N2O6: 530.2417 (M+), found:
530.2421.
4.8. (2S,3R)-Methyl 3-benzoyl-2-(p-methoxyphenoxy)-3-
phenylpropionate 11
Methyl ester 10 (0.7785g, 1.92mmol) was placed in a
100mL round bottom flask and dissolved in CH2Cl2
(5.15mL). To this reaction mixture was added DMAP
(1.2mmol), followed by triethylamine (3.1mmol). The
reaction was cooled to 0°C and benzoyl chloride
(3.6mmol) was added. The reaction allowed to run over-
night, quenched by the addition of HCl (1M), extracted
via CH2Cl2, separated, washed with brine, dried over
MgSO4, and the solvent removed via rotary evapora-
tion. The resulting ester was purified via column chro-
matography using a 90/10 mixture of hexanes and
4.6. 3-Hydroxy-2-(p-methoxyphenoxy)-3-phenylpropionic
acid 9
ethyl acetate and recovered in a 68% yield (0.7151g) as
25
D
a yellow oil. ½aꢀ ¼ þ24:7 (c 0.25, CHCl3); Rf = 0.14
1
Aldol adduct 8a (5.01g, 10.1mmol) was placed in a
100mL round bottom flask and dissolved in THF
(50mL), and then reacted with NaOH (150mL, 1.0M).
The reaction was allowed to run for 20h, after which
point the reaction was diluted by the addition of diethyl
ether, washed with brine, dried over MgSO4, and the
solvent removed via rotary evaporation. This process
afforded the parent heterocycle 2 in 52% yield (1.21g).
The combined aqueous layers were then acidified using
HCl, diluted with diethyl ether, separated, washed with
brine, dried over MgSO4, and the solvent removed via
rotary evaporation. This process afforded the crude
carboxylic acid in 88% yield (2.52g) contaminated with
a small amount of benzaldehyde presumably arising
from a retro-aldol reaction. This material was not puri-
(ethyl acetate/hexanes, 1:9). H NMR: d 3.64 (s, 3H),
3.73 (s, 3H), 4.88 (d, J = 5.2Hz, 1H), 6.48 (d,
J = 4.8Hz, 1H), 6.72–6.78 (m, 4H), 7.32–7.58 (m, 8H),
8.10 (d, J = 7.2Hz, 1H). 13C NMR: d 52.5, 55.6, 75.9,
81.6, 114.6, 117.4, 127.2, 128.4, 128.5, 128.8, 129.6,
129.9, 133.3, 135.8, 152.2, 154.9, 165.3, 169.2. IR (neat):
1724, 1507, 1107, 1027, 743cmꢁ1. EI-HRMS calculated
for C24H22O6: 406.1416, found: 406.1416.
4.9. (2S,3R)-Methyl (2S,3R)-2,3-dihydroxy-3-phenyl-
propionate 12
Compound 11 (0.7780g, 1.9mmol) was placed in a
50mL round bottom flask and dissolved in acetonitrile
(4.8mL). To this reaction mixture was added ceric
ammonium nitrate (5.7mmol) dissolved in water
(4.8mL). The reaction was allowed to run for 2h, after
which point it was quenched using water and chloro-
form. The compound was then extracted into the chlo-
roform, washed with brine, dried (MgSO4), and the
solvent removed via rotary evaporation. This material
was then measured and placed in a 50mL round bottom
flask and dissolved in methanol (17.4mL), to which
1.00equiv (1.9mmol) of K2CO3 was added. The reaction
was allowed to run for 3h, quenched by the addition of
a saturated solution of NaHCO3, extracted via CHCl3,
separated, washed with brine, dried over MgSO4,
gravity filtered, and the solvent removed via rotary
evaporation. The resulting ester diol was purified via
column chromatography using a 60/40 mixture of
1
fied and was directly esterified: H NMR (CO2H not
observed): d 3.74 (s, 3H), 4.30–5.20 (br s, 1H), 4.71 (d,
J = 3.6Hz, 1H), 5.25 (d, J = 4.0Hz, 1H), 6.76 (s, 4H),
7.26–7.47 (m, 5H). 13C NMR: d 55.6, 74.4, 82.4, 114.7,
117.2, 126.5, 128.5, 128.6. IR (neat): 3062, 1733, 1225,
1031, 826, 700cmꢁ1
. HRMS (EI) calculated for
C16H16O5: 288.0998, found: 288.0996.
4.7. (2S,3R)-Methyl 3-hydroxy-2-(p-methoxyphenoxy)-3-
phenylpropionate 10
The crude carboxylic acid 9 (1.12g) was placed in a
100mL round bottom flask and dissolved in THF
(15.5mL) and CH3OH (7.8mL). To this reaction mix-
ture was added trimethylsilyldiazomethane (4equiv).
The reaction was allowed to run overnight, quenched
by the addition of a saturated solution of NH4Cl. The
reaction mixture was then diluted with diethyl ether
hexanes and ethyl acetate and recovered in 37% yield
25
D
(140.2mg). ½aꢀ ¼ ꢁ9:3 (c 0.46, CHCl3); Rf = 0.20 (ethyl
1
acetate/hexanes, 2:3). H NMR: d 3.81 (s, 3H), 4.37 (d,

J. F. Vaughn, S. R. Hitchcock / Tetrahedron: Asymmetry 15 (2004) 3449–3455
3455
3. Hitchcock, S. R.; Hoover, T. R. Tetrahedron: Asymmetry
2003, 14, 3233–3241.
J = 2.4Hz, 1H), 5.02 (d, J = 2.4Hz, 1H), 7.24–7.40 (m,
5H). 13C NMR: d 53.1, 74.4, 74.7, 126.2, 128.1, 128.5,
138.9, 173.1. IR (neat): 3449, 1737, 1212, 768cmꢁ1
.
4. (a) Linjinsky, W.; Reuber, M. D.; Saavedra, J. E.; Singer,
G. M. J. Natl. Cancer Inst. 1983, 70, 959; (b) Linjinsky,
W.; Saavedra, J. E.; Reuber, M. D.; Blackwell, B. N.
Cancer Lett. 1980, 10, 325; (c) Lawley, P. D. In Chemical
Carcinogens; Searle, C. D., Ed.; ACS Monograph 182;
American Chemical Society: Washington, DC, 1984; (d)
Linjinsky, W. Chemistry and Biology of N-nitroso
Compounds; Cambridge University Press: Cambridge,
UK, 1992; (e) Lunn, G.; Sansone, E. B.; Keefer, L. K.
Carcinogenesis 1983, 4, 315.
5. (a) Choudary, B. M.; Chowdari, N. S.; Madhi, S.;
Kantam, M. L. J. Org. Chem. 2003, 68, 1736–1746; (b)
Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem.
1994, 59, 5104–5105; (c) Denis, J.-N.; Correa, A.; Greene,
A. E. J. Org. Chem. 1990, 55, 1957–1959.
EI-HRMS calculated for C10H12O4: 196.0736, found:
196.0745.
Acknowledgements
J.F.V. would like to thank Ms. Trisha Hoover for refer-
ence samples of rac-12 and (2R,3S)-12. The authors
would also like to thank Professor Gin (University of
Illinois at Urbana-Champaign) for assistance with
polarimetric measurements. Thanks is also made to
the donors of the American Chemical Society Petroleum
Research Fund for support of this research. We thank
Merck & Co., Inc. for their continued generous support
of our research efforts. We also thank Pfizer, Inc. for
material support.
6. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm.
Bull. 1981, 29, 1475–1478.
7. (a) Dudding, T.; Hafez, A. M.; Taggi, A. E.; Wagerle, T.
R.; Lectka, T. Org. Lett. 2002, 4, 387–390; (b) Petitou, M.;
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8. Mechanistic studies on the oxidative removal of the p-
methoxyphenoxy group in the form of 1,4-benzoquinone
strongly suggest that there is retention of the stereochem-
istry of the carbon that bears the methoxyphenoxy
substituent. See Refs. 7b,c for mechanistic studies. See
Ref. 7a for an example of retention of stereochemistry of
the hydroxyl substituent.
9. Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936–7943.
10. Methyl trans-cinnamate was converted to the racemic syn-
diol 12 using the protocol described by Dore and co-
workers. Please see: Lu, M.; Fedoryak, O. D.; Moister, B.
R.; Dore, T. M. Org. Lett. 2003, 5, 2119–2122.
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