Synthesis, reactivity and conformational stability of an l-phenylalanine derived oxadiazinanone

Article abstract of DOI:10.1016/j.tetasy.2006.09.002

An l-phenylalanine derived oxadiazinanone bearing an isopropyl group at the N₄-position was prepared and acylated with either hydrocinnamoyl or propanoyl chloride. These oxadiazinanones were utilized in titanium-mediated asymmetric aldol reacti

Full text of DOI:10.1016/j.tetasy.2006.09.002

Tetrahedron: Asymmetry 17 (2006) 2386–2392
Synthesis, reactivity and conformational stability of an
L-phenylalanine derived oxadiazinanone
Delvis D. Dore, James R. Burgeson, Ryan A. Davis and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 7 August 2006; accepted 6 September 2006
Available online 26 September 2006
Abstract—An L-phenylalanine derived oxadiazinanone bearing an isopropyl group at the N4-position was prepared and acylated with
either hydrocinnamoyl or propanoyl chloride. These oxadiazinanones were utilized in titanium-mediated asymmetric aldol reactions with
aromatic and aliphatic aldehydes. The diastereoselectivities observed from these reactions ranged from fair to very good and suggested
that the N4-isopropyl-L-phenylalanine based oxadiazinanones are conformationally and configurationally stable at the N4-nitrogen.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
oxadiazinanones are considered to be conformation-
ally and, consequently, configurationally stable at the N4-
nitrogen.
3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones (oxadiazina-
nones) are structurally unique chiral auxiliaries that have
been employed in asymmetric aldol reactions.1–6 The
oxadiazinanones that have been synthesized have been
derived from the Ephedra alkaloids, namely (1R,2S)-
ephedrine,1–4 (1R,2S)-norephedrine,5,6 and (1S,2S)-pseudo-
ephedrine7 (Chart 1). We have demonstrated the utility of
(1R,2S)-ephedrine and (1R,2S)-norephedrine derived
oxadiazinanones as chiral auxiliaries in the asymmetric
aldol addition.1–6 Based on the observed diastereoselectivities
from these studies, as well as computational studies and 1H
NMR studies, the ephedrine and norephedrine derived
In contrast, the pseudoephedrine based oxadiazinanones
are conformationally flexible at the N4-nitrogen and have
not been used as chiral auxiliaries in the asymmetric aldol
reaction.7 The success of the (1R,2S)-ephedrine and
(1R,2S)-norephedrine based oxadiazinanone mediated
aldol reactions is believed to be dependent upon the
positional stability of the stereogenic N4-nitrogen. Our
previous studies of these systems have shown that the C5-
and C6-positions of these oxadiazinanones directly influ-
ence the stereochemical orientation of the N4 position by
means of an intramolecular chiral relay.8–10 The stereo-
chemical tandem of the C6–C5–N4-positions then
influences the approach of the aldehyde to the oxadiazina-
none enolate in asymmetric aldol additions.1–6 Based on
this argument, the stereochemical position of the C6-phenyl
ring is largely responsible for the conformational stability
of the N4-nitrogen because of its ‘anchoring’ position in
the relay tandem (cf. oxadiazinanones 1 and 2 in Chart
1). We became interested in determining the impact of
the absence of a substituent at the C6-position of the
oxadiazinanone ring system. a-Amino acids serve as excel-
lent chiral, non-racemic starting materials that can yield
oxadiazinanones that are unsubstituted at the C6-position.
Herein, we report on our use of L-phenylalanine to synthe-
size such an oxadiazinanone and we report on its applica-
tion in the aldol reaction. Finally, an argument is made
for the conformational and configurational stability of
O
O
O
H
H
1
H
O
N
N
O
N
N
O
N
N
5
CH3
CH3
Ph
CH3
4
Ph
6
Ph
CH3
CH3
CH3
CH3
chiral relay tandem
2001
2004
2001
Pseudoephedrine based
Ephedrine based
Norephedrine based
oxadiazinanone 2
oxadiazinanone 1
oxadiazinanone 3
Chart 1. Ephedra based oxadiazinanones.
*
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538;
e-mail: hitchcock@ilstu.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.002

D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
Table 1. Asymmetric aldol reactions of oxadiazinanone 8
2387
the L-phenylalanine derived oxadiazinanone as compared
to the Ephedra based oxadiazinanones.
O
1a. TiCl4, THF, 25 o
C
O
OH
1b. TEA, -78 o
C
O
N
N
R
8
CH2Ph
1c. RCHO
2. Results and discussion
Bn
L-Phenylalanine 4 was reduced to L-phenylalaninol by
reduction with sodium borohydride and iodine using a
method developed by Kanth and Periasamy11 and later
optimized for a-amino acids by Meyers et al. (Scheme
1).12 The resultant b-aminoalcohol was reductively alkyl-
ated13 with acetone and sodium borohydride to afford the
N-isopropyl derivative 5, which was converted to its corre-
sponding b-hydrazino-alcohol 6. The b-hydrazino alcohol
was then cyclized by treatment with lithium hydride and
diethyl carbonate to afford oxadiazinanone 7 in 58% yield
after column chromatography. The oxadiazinanone was
acylated with hydrocinnamoyl chloride to afford the N3-
hydrocinnamoyl derivative 8 in 79% isolated yield. This
particular side chain was selected as there was an interest
in employing 8 in the synthesis of a key intermediate of
the HIV protease inhibitor saquinavir.14 With oxadiazina-
none 8 in hand, we attempted the asymmetric aldol reac-
tion with a variety of aromatic and aliphatic aldehydes.
9a-e
Product % Yielda dr (crude)c
Entry RCHO
1
2
3
4
5
C6H5CHO
9a
9b
9c
9d
55
51
70
79
49b
P19:1d
19:1d
p-Cl-C6H4CHO
2-C10H7CHO
(CH3)3CCHO
P19:1d
7:1d
C6H5CH2OCH2CHO 9e
21:1e
a Purified yield after column chromatography.
b Purified yield after chromatography and recrystallization.
P
c Diastereoselectivities are represented as major diastereomer: all other
diastereomers.
d Crude diastereomeric ratios were determined from 400 MHz 1H NMR
spectroscopy.
e Crude diastereomeric ratio was determined by HPLC using a Shimadzu
˚
SCL-10AVP system with a Dynamax Si-100 A column (7:3, hexanes/
EtOAc, flow rate = 1.0 mL/min).
obtained in 63% isolated yield and was spectroscopically
identical with the reported literature data.14 There was no
reported specific rotation for the oxazolidinone and efforts
to evaluate the enantiomeric purity by chiral stationary
phase HPLC were not pursued.
The aldol reactions were conducted by dissolving oxadiaz-
inanone 8 in THF followed by the addition of 2 equiv of
titanium tetrachloride at 25 ꢁC for 25 min (Table 1). The
solution was cooled to ꢀ78 ꢁC and 2 equiv of triethylamine
was added. The solution was allowed to warm up to 0 ꢁC
over 45 min, then re-cooled to ꢀ78 ꢁC, and the appropriate
aldehyde was added. The aldol adducts were obtained in
49–79% isolated yield with diastereoselectivities ranging
The determination of the absolute stereochemistry of the
aldol addition reaction with L-phenylalanine derived
oxadiazinanone was carried out by using an alternate sub-
strate. Thus, oxadiazinanone 7 was acylated with propa-
noyl chloride and lithium hydride to yield 12 in 30%
yield (Scheme 3). This material was dissolved in THF
and treated with titanium tetrachloride, triethylamaine at
ꢀ78 ꢁC, and benzaldehyde. This process gave aldol adduct
13 in 47% yield in greater than 19:1 diastereomeric ratio
favoring the proposed syn-diastereomer, as determined by
1H NMR spectroscopy. This adduct was hydrolyzed with
6 M H2SO4 and the resultant b-hydroxycarboxylic acid
13 was esterified with trimethylsilyldiazomethane to
1
from 7:1 to greater than 19:1, as determined by either H
NMR spectroscopy or HPLC. The stereochemistry of the
aldol side chain in adducts 9a–e was tentatively assigned
as the non-Evans syn-stereochemistry based on earlier
studies concerning N4-isopropyloxadiazinanones.5 In order
to determine the relative stereochemistry of the aldol
adducts (i.e., syn- vs anti-), oxadiazinone 9e was hydrolyzed
with 6 M H2SO4 (Scheme 2). This process afforded the
expected b-hydroxycarboxylic acid 10 in 68% yield.15 The
carboxylic acid was treated with diphenylphosphoryl azide
and triethylamine to effect the Curtius rearrangement14,16
in toluene to yield the known syn-oxazolidinone 11, an
intermediate in the synthesis of a key fragment of saquina-
vir developed by Ghosh et al. The oxazolidinone was
afford ester 14 in 59% yield after chromatography. The
29
specific rotation was determined to be ½aꢁD ¼ ꢀ11:6 (c 0.74,
CHCl3) and the literature value17a for the (2R,3R)-ester
25
was reported as ½aꢁD ¼ þ23:5 (c 3.23, CHCl3). The abso-
OH
OH
NH2
N
H
N
1. NaBH4, I2, THF
1. NaNO2, HCl
2. LiAlH4, THF
NH3
O2C
2. (CH3)2CO; NaBH4
Bn
Bn
Bn
6
5
4
CH2Ph
O
O
H
PhCH2CH2COCl, LiH
CH2Cl2
(EtO)2C=O
O
N
N
O
O
N
N
6
LiH, hexanes
Bn
Bn
8
7
Scheme 1. Synthesis of L-phenylalanine derived oxadiazine 8.

2388
D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
O
O
OH
6M H2SO4
(PhO)2PON3
TEA
H
N
O
9e
7
+
HO
CH2OBn
PhCH2
CH2OBn
11
CH2Ph
10
Scheme 2. Synthesis of oxazolidinone 11.
O
O
OH
O
O
1a. TiCl4, THF
1b. TEA, -78 oC
1c. PhCHO
CH3CH2COCl, LiH
CH2Cl2
O
N
N
Ph
O
N
N
7
CH3
Bn
Bn
12
13
O
OH
1. 6M H2SO4
13
CH3O
Ph
2. (CH3)3SiCHN2
CH3
14
Scheme 3. The formation of b-hydroxyester 14.
lute stereochemistry of the recovered ester was assigned as
the (2S,3S)-enantiomer. We were uncertain of the enantio-
meric purity and so used chiral stationary phase HPLC
to determine that the enantiomeric ratio was 96:4 (92%
e.e.) [Chiralcel OD column, hexanes/i-PrOH, 95:5, 1 mL/
min: tR (2R,3R)-ester17b = 8.58 min; tR (2S,3S)-ester =
10.0 min].
acid derived system. Interestingly, Rodrigues et al.19,20
have also prepared an a-amino acid derived oxadiazina-
none 15 derived from (R)-phenylglycine and noted that
they observed two conformers in the unit cell of the X-
ray crystal structure (Fig. 2). The reason for this conforma-
tional flexibility in their oxadiazinanones is most likely
attributed to the relative sizes of the N4-methyl and C5-
phenyl substituents. In contrast, the stereochemical orien-
tation of the N4-isopropyl and C5-benzyl substituents of
the L-phenylalanine oxadiazinanone 7 is probably more
rigid and retains a dominant conformation and configura-
tion at the stereocontrol element, the N4-position.
From the collected spectroscopic data and optical activity
data, a chair like Zimmerman–Traxler transition state
was proposed (Fig. 1).18 This is in accordance with our
earlier work regarding
a norephedrine derived N4-
isopropyloxadiazinanone.5,6
Regarding the conformational stability of the L-phenylala-
nine derived oxadiazinanones in this work, the diastereo-
meric ratios obtained from the aldol reaction are most
likely a reflection of the conformational and configura-
tional stability of the N4-isopropyl substituents in oxadiaz-
inanones 8 and 12. Indeed, the presence of multiple
conformers would have given rise to diminished diastereo-
selectivities, but these values were comparable to those
obtained in prior work.1–6 These results seem to suggest
that the C6-position need not be substituted in order to ob-
tain high stereoselectivities in the aldol reaction. Rather, it
is the C5-position that is dominant in establishing the con-
formational behavior of the N4-nitrogen in this a-amino
3. Conclusion
An L-phenylalanine derived oxadiazinanone has been syn-
thesized and utilized in aldol addition reactions with fair to
very good diastereoselectivities being obtained. An inter-
mediate in the synthesis of a key fragment of saquinavir
was prepared using the Curtius rearrangement. The abso-
lute stereochemistry and enantiomeric purity of the aldol
adducts were determined by correlation with the specific
rotation and chiral stationary phase HPLC of the ester
derived from oxadiazinanone 13. The observed diastereo-
selectivities suggest that the C6-unsubstituted oxadiazina-
nones are configurationally stable at the N4-nitrogen.
However, the work of Rodrigues et al. offers a compelling
argument for selecting C5 and C6 substituents that are of a
CH2Ph
Cln
Ti
O
O
O
O
O
Ph
H
H
H
O
N
N
O
N
N
O
N
N
H
vs.
H
CH(CH3)2
CH3
CH3
N
O
N
Bn
Ph
Ph
O
7
trans-15
cis-15
Bn
Figure 1. Proposed transition state 15.
Figure 2. Conformational stability in oxadiazinanones 7 and 15.

D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
2389
proper steric size to stabilize the conformational dynamics
of the stereodirecting N4-position.
100% ethanol (200 mL) was added. To the stirred mixture
was slowly added sodium borohydride (18.3 g, 484 mmol).
The mixture was allowed to stir at room temperature for
18 h and then quenched with 1 M NaOH (300 mL). Once
the solvents were removed in vacuo, the mixture was ex-
tracted with EtOAc. The organic extracts were washed with
brine, dried with MgSO4, and solvents were removed in
vacuo. The crude material was recrystallized with ethyl
4. Experimental
4.1. General remarks
1
All H and 13C NMR spectra were recorded at 25 ꢁC on a
acetate and hexanes to yield 23.33 g (73%) of 5 as a white
25
Varian spectrometer in CDCl3 operating at 400 and
100 MHz, respectively. Chemical shifts are reported in
parts per million (d scale), and coupling constants (J val-
ues) are listed in hertz (Hz). Tetramethylsilane (TMS)
was used as an internal standard (d = 0.00 ppm). Infrared
spectra are reported in reciprocal centimeters (cmꢀ1) and
are measured either with carbon tetrachloride (CCl4)
or chloroform (CHCl3). Melting points were recorded
on a Mel-Temp apparatus and are uncorrected. High-reso-
lution mass spectra were obtained from the Mass Spec-
trometry Laboratory, School of Chemical Sciences,
University of Illinois, Urbana-Champaign. HPLC chro-
matographic data were collected using a Shimadzu HPLC
and dynamax column (silica, 10 l, 4.6 mm · 25 cm).
Elemental analyses were conducted by the Microanalytical
Laboratory, School of Chemical Sciences, University of
Illinois, Urbana-Champaign. Optical Rotation data were
collected at the University of Illinois, Urbana-Champaign
on a JASCO P-1010 digital polarimeter operating at
589 nm.
solid: Mp = 52–54 ꢁC; ½aꢁD ¼ þ6:6 (c 0.38, CHCl3);
Rf = 0.53 (hexanes/EtAOc, 1:1). 1H NMR (CDCl3): d,
0.98 (d, J = 6.2 Hz, 3H), 1.03 (d, J = 6.2 Hz, 3H), 2.14
(broad singlet, –OH), 2.68–2.81 (m, 2H), 2.87 (septet,
J = 6.2 Hz, 1H), 2.95–3.00 (m, 1H), 3.22–3.26 (m, 1H),
3.55 (dd, J = 4.0, 10.6 Hz, 1H), 7.16–7.33 (m, 5H). 13C
NMR (CDCl3): d, 23.3, 38.5, 45.8, 57.2, 62.9, 126.3,
128.5, 129.2, 138.4. IR (CCl4): 2964, 1479, 1039 cmꢀ1
.
Anal. Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.25.
Found: C, 73.88; H, 9.84; N, 7.50.
4.3. (S)-2-N-Isopropylhydrazino-3-phenyl-1-propanol 6
In a 1 L round-bottom flask equipped with a stirrer bar
were placed (S)-2-N-isopropylamino-3-phenyl-1-propanol
5 (17.2 g, 89.0 mmol) and THF (60 mL). An aqueous solu-
tion of HCl (70 mL, 2.74 M, 192 mmol) was then added
followed by the addition of sodium nitrite (6.76 g,
97.9 mmol) in small portions over a period of 10 min.
The reaction mixture was stirred for 24 h, and the mixture
was then diluted with a saturated aqueous solution of
sodium bicarbonate (150 mL). The reaction mixture was
then extracted with EtOAc and the extract was washed
with brine. The resulting solution was dried over MgSO4
followed by the removal of the solvent in vacuo. The crude
product was isolated as a yellow oil containing a mixture of
isomers in 99% yield (16.07 g). A portion was saved and
purified by chromatography, which resulted in a purified
4.2. (S)-2-N-Isopropylamino-3-phenyl-1-propanol 5
In a flame-dried, nitrogen-purged 5 L three-neck round-
bottomed flask fitted with a condenser and an addition fun-
nel were placed sodium borohydride (27.5 g, 726 mmol),
THF (1 L), and L-phenylalanine 4 (50.0 g, 303 mmol). This
mixture was cooled to 0 ꢁC utilizing an ice bath. A solution
of iodine (76.8 g, 303 mmol dissolved in 250 mL of THF)
was poured into the addition funnel and added dropwise
over a period of 45 min resulting in a vigorous evolution
of hydrogen gas. Once the gas evolution had ceased, the
contents of the flask were heated at reflux for 18 h and then
cooled to room temperature, after which methanol
(200 mL) was added until the mixture became clear. After
stirring for 30 min, the solvent was removed in vacuo
leaving a white paste, which was dissolved with 3 M
KOH (500 mL). The mixture was extracted with methylene
chloride. The organic extracts were washed with a satu-
rated brine solution, dried with MgSO4, and the solvents
were removed in vacuo. The crude material was recrystal-
lized with ethyl acetate and hexanes to yield 27.37 g
(60%) of (S)-phenylalaninol as a white solid. Mp: 85–
mixture of isomers. The rest of the material was taken on
25
as a mixture of isomers into the reduction: ½aꢁD ¼ ꢀ29:8
(c 0.48, CHCl3); Rf = 0.38 (hexanes/EtOAc, 1:1). Isomer
1
1 (major): H NMR (CDCl3): d, 0.68 (d, J = 7.0 Hz, 3H),
1.08 (d, J = 7.0 Hz, 3H), 3.05 (d, J = 7.0 Hz, 2H), 3.15–
3.32 (m, 2H), 4.14–4.23 (m, 2H), 4.38 (broad singlet,
–OH), 7.14–7.31 (m, 5H). Isomer 2 (minor): 1H NMR
(CDCl3): d, 1.24 (d, J = 6.6 Hz, 3H), 1.35 (d, J = 6.6 Hz,
3H), 2.04 (broad singlet, –OH), 3.73–3.89 (m, 2H), 3.95–
4.04 (m, 3H), 4.96–5.03 (m, 1H), 7.14–7.31 (m, 5H). Isomer
1 (major): 13C NMR (CDCl3): d, 18.1, 19.0, 38.9, 62.1, 65.3,
128.6, 128.6, 129.3, 137.6. Isomer 2 (minor): 13C NMR
(CDCl3): d, 22.2, 33.4, 45.3, 55.4, 62.2, 126.8, 126.9,
128.9, 137.4. IR (CCl4): 3384, 2978, 1171, 732 cmꢀ1
.
HRMS calcd for C12H18N2O2: 222.1368. Found: 222.1371.
1
87 ꢁC. H NMR (CDCl3): d, 2.40–2.65 (m, 2H), 2.79 (dd,
J = 5.1, 5.5 Hz, 1H), 3.09–3.15 (m, 1H), 3.37–3.42 (m,
1H), 3.64 (dd, J = 3.7, 3.7 Hz, 1H), 7.18–7.33 (m, 5H).
13C NMR (CDCl3): d, 40.7, 54.2, 66.1, 126.4, 128.6,
129.2, 138.5. In a flame-dried, nitrogen-purged 2 L
round-bottomed flask were placed (S)-phenylalaninol
(25.0 g, 165 mmol) and 100% ethanol (200 mL). To this
stirred mixture were added 2 g of MgSO4 and the reagent
grade acetone (24.3 mL, 331 mmol). The resulting mixture
was allowed to stir at room temperature for 5 h and then
4.3.1. Reduction of the N-nitrosamine. In a flame-dried,
nitrogen-purged 5 L, three-neck round-bottomed flask fit-
ted with an addition funnel and a condenser were placed
lithium aluminum hydride (5.47 g, 143.9 mmol) and freshly
distilled THF (200 mL). The mixture was then heated at
reflux and nitrosamine (16.0 g, 72.0 mmol), dissolved in
freshly distilled THF (100 mL), was added slowly through
the addition funnel over a period of 60 min. Once the addi-
tion was completed, the reaction mixture was maintained

2390
D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
under reflux for an additional 2 h. The reaction mixture
was cooled to 0 ꢁC followed by the cautious addition of
NaOH (3 M) until the remaining lithium aluminum hy-
dride was consumed. The mixture was diluted with a satu-
rated aqueous solution of sodium potassium tartrate
(Rochelle’s salt) and stirred for 15 min. The THF was re-
moved in vacuo. The mixture was then extracted with
EtOAc and the extract washed with brine, dried over
MgSO4, and the solvent was removed in vacuo. This pro-
cess afforded a viscous yellow oil, which was recrystallized
were washed with brine and dried over MgSO4. The
solvents were removed in vacuo and the crude product
was purified via column chromatography.
4.5.1. (4R,5S)-5-Benzyl-4-isopropyl-3-(3-phenylpropanoyl)-
2H-1,3,4-oxadiazin-2-one 8. Hydrocinnamoyl chloride
(7.6 mL, 51 mmol) was reacted with oxadiazinanone 7
(8.0 g, 34 mmol). The purified product was isolated as faint
yellow crystals (9.90 g) and gave a yield of 79%.
25
Mp = 47.5–50.0 ꢁC; ½aꢁD ¼ ꢀ61:6 (c 0.30, CHCl3);
with diethyl ether and hexanes to yield 6 as a white solid
Rf = 0.34 (hexanes/EtOAc, 3:1). 1H NMR (CDCl3): d,
0.99–1.02 (m, 6H), 2.32–2.37 (m, 2H), 2.65–2.73 (m, 1H),
2.93–3.09 (m, 2H), 3.11–3.24 (m, 1H), 3.47–3.54 (m, 1H),
3.59–3.64 (m, 1H), 4.27–4.28 (m, 2H), 7.14–7.30 (m,
10H). 13C NMR (CDCl3): d, 19.5, 20.1, 30.8, 36.7, 38.8,
56.9, 57.4, 67.9, 126.1, 126.7, 128.4, 128.5, 129.1, 136.6,
140.6, 152.7, 173.0. IR (CHCl3): 2977, 1790, 1220,
754 cmꢀ1. HRMS calcd for C22H26N2O3: 366.1943. Found:
366.1941.
25
(8.6 g). Yield: 57%. Mp: 51–53 ꢁC; ½aꢁD ¼ þ7:5 (c 0.36,
1
CHCl3); Rf = 0.10 (100% EtOAc). H NMR (CDCl3): d,
1.14 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H), 2.72–
2.85 (m, 2H), 2.89–2.98 (septet, J = 6.2 Hz, 1H), 3.04–
3.10 (m, 1H), 3.53–3.59 (m, 2H), 7.17–7.31 (m, 5H). 13C
NMR (CDCl3): d, 19.8, 20.9, 29.7, 55.3, 62.4, 63.1, 126.0,
128.4, 129.2, 139.4. IR (CCl4): 3349, 2975, 796 cmꢀ1
.
HRMS calcd for C12H20N2O: 208.1576. Found: 208.1570.
4.4. (4R,5S)-5-Benzyl-4-isopropyl-2H-1,3,4-oxadiazinan-2-
one 7
4.5.2. (4R,5S)-5-Benzyl-4-isopropyl-3-propanoyl-2H-1,3,4-
oxadiazinan-2-one 12. Propanoyl chloride (1.46 mL,
16.8 mmol) was reacted with oxadiazinanone 7. The puri-
fied product was isolated by chromatography (hexanes/
In a flame-dried, nitrogen-purged 2 L round-bottomed
flask equipped with a condenser were placed hydrazine 6
(26.1 g, 126 mmol) and hexanes. To this solution was
added diethyl carbonate (38.0 mL, 314 mmol). After the
addition was completed the resulting mixture was heated
at reflux, upon which LiH (1.05 g, 132 mmol) was added.
The reaction mixture was cooled to room temperature after
18 h and an aqueous saturated solution of NH4Cl (250 mL)
was added. After the solvent was removed in vacuo, the
mixture was extracted with EtOAc and the extract was
washed with a saturated brine solution, dried (MgSO4),
and the solvent was removed in vacuo. This process yielded
a yellow oil that was purified by chromatography and
EtOAc, 1:1) to afford 12 as an oil (0.47 g). Yield: 30%.
29
½aꢁD ¼ ꢀ167:5 (c 5.5, CHCl3); Rf = 0.33 (hexanes/EtOAc,
1
1:1). H NMR (CDCl3): d, 1.06 (d, J = 6.2 Hz, 3H), 1.05
(d, J = 6.3 Hz, 3H), 1.20 (t, J = 7.4 Hz, 3H), 2.57–2.62
(dd, J = 5.9, 7.8 Hz, 1H), 2.65–2.74 (m, 1H), 2.87–2.97
(m, 2H), 3.04–3.11 (septet, J = 6.3, 1H), 3.57–3.64 (p,
J = 7.0 Hz, 1H), 3.88–3.93 (dd, J = 7.4, 4.3 Hz, 1H),
4.38–4.43 (dd, J = 6.6, 4.7 Hz, 1H), 7.23–7.34 (m, 5H).
13C NMR (CDCl3): d, 9.1, 19.8, 20.2, 28.9, 39.2, 56.9,
57.3, 68.0, 126.9, 128.7, 136.8, 152.8, 174.7; IR (CHCl3):
2977, 1790, 891, 806 cmꢀ1. HRMS calcd for C16H22N2O3:
290.1630. Found: 290.1631.
recrystallized to yield 7 as a white solid (17.1 g). Yield:
25
58%. Mp = 50–52 ꢁC; ½aꢁD ¼ þ24:7 (c 0.36, CHCl3);
4.6. General procedures for aldol adducts 9a–e
Rf = 0.27 (hexanes/EtOAc, 3:2). 1H NMR (CDCl3): d,
1.03 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 2.82–
2.89 (m, 1H), 2.93–3.07 (m, 2H), 3.30–3.49 (m, 1H),
4.05–4.15 (m, 1H), 4.46 (dd, J = 3.4, 11.7 Hz, 1H), 6.83
(broad singlet, –NH), 7.21–7.34 (m, 5H). 13C NMR
(CDCl3): d, 20.3, 20.4, 36.7, 53.0, 55.8, 64.1, 126.7, 128.6,
129.3, 137.8, 152.2. IR (CCl4): 3514, 1702, 1093,
754 cmꢀ1. HRMS calcd for C13H18N2O2: 234.1368. Found:
234.1372. Anal. Calcd for C13H18N2O2: C, 66.64; H, 7.74;
N, 11.96. Found: C, 66.34; H, 8.07; N, 11.39.
In a nitrogen-purged 100 mL round-bottomed flask was
placed oxadiazinanone 8 (1.0 g) and THF (ꢂ0.33 M). TiCl4
(2 equiv) was added to this stirred solution and allowed
to sit at room temperature for 25 min. After this time,
the solution was cooled to ꢀ78 ꢁC and after five min,
2 equiv of triethylamine were introduced to the flask via
a syringe. Over the course of 45 min, the solution was
allowed to warm up while the enolate formed. After the
45 min had elapsed, the solution was chilled to ꢀ78 ꢁC
again and the reaction allowed to run overnight after the
addition of the appropriate aldehyde (1.3–2 equiv). The
reaction was quenched by the addition of a saturated aque-
ous solution of NaHCO3 and extracted with EtOAc. The
combined extracts were washed with a saturated brine solu-
tion and dried (MgSO4). The solvents were removed in
vacuo and reaction diastereoselectivity of the crude reaction
mixture was determined by 1H NMR spectroscopy or
HPLC.
4.5. General procedure for acylated oxadiazinanones 8
and 12
In a flame-dried, nitrogen-purged 250 mL round-bottomed
flask fitted with a Claisen adapter and a condenser was
placed oxadiazinanone 7, dissolved in methylene chloride.
To this stirred mixture was added the appropriate acyl
chloride via a syringe (1.1 equiv). This mixture was heated
at reflux after which LiH (1.1 equiv) was added. The con-
tents of the flask were reacted at reflux for a period of
18 h. After this time period, the mixture was cooled to
room temperature and quenched with NH4Cl and ex-
tracted with methylene chloride. The combined extracts
4.6.1.
(20S,30S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-
phenylpropanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-one
9a. Benzaldehyde (0.57 mL, 5.6 mmol) was reacted with
oxadiazinanone 8. The purified product was isolated by

D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
2391
chromatography to afford 9a as an oil (0.75 g). Yield: 55%.
representative of major isomer only): d, 0.85 (d,
J = 6.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.13 (s, 9H),
1.93–1.98 (dd, J = 7.4, 13.7 Hz, 1H), 2.13–2.18 (t,
J = 10.5 Hz, 1H), 2.34–2.39 (dd, J = 7.0, 13.7 Hz, 1H),
2.82–2.85 (m, 1H), 3.03–3.09 (t, J = 13.3 Hz, 1H), 3.15–
3.24 (m, 3H), 3.68 (singlet, –OH), 3.79–3.83 (dd, J = 7.0,
4.3 Hz, 1H), 4.13–4.17 (dd, J = 4.3, 7.8 Hz, 2H), 7.11–
7.34 (m, 10H). 13C NMR (CDCl3; values representative of
major isomer only): d, 19.4, 19.8, 27.4, 33.6, 39.4, 46.9,
57.8, 58.4, 67.9, 78.2, 126.9, 127.0, 128.7 129.2, 129.5,
129.6, 137.1, 139.7, 155.0, 176.5; IR (CHCl3): 3507, 2957,
1756, 1697, 1226, 754, 700 cmꢀ1. HRMS calcd for
C27H36N2O4: 453.2753. Found: 453.2746.
29
½aꢁD ¼ ꢀ130:9 (c 1.39, CHCl3); Rf = 0.15 (hexanes/EtOAc,
1
7:3). H NMR (CDCl3): d, 0.86 (d, J = 6.3 Hz, 3H), 0.80
(d, J = 5.9 Hz, 3H), 1.89–194 (dd, J = 7.0, 13.3 Hz, 1H),
2.28–2.33 (m, 2H), 2.75–2.83 (m, 2H), 3.03 (t,
J = 13.3 Hz, 1H), 3.20–3.28 (m, 1H), 3.52 (broad singlet,
–OH), 3.87–3.92 (dd, J = 7.0, 11.3 Hz, 1H), 4.09–4.14 (dt,
J = 12.1, 3.5 Hz, 1H), 5.27 (d, J = 3.1 Hz, 1H), 7.11–7.31
(m, 13H), 7.39 (t, J = 7.4, 1H), 7.58 (d, J = 7.4, 1H). 13C
NMR (CDCl3): d, 19.1, 20.0, 32.9, 39.1, 52.6, 57.6, 58.4,
68.0, 73.4, 126.4, 126.6, 127.6, 128.3, 128.4, 128.8, 129.3,
137.0, 139.3, 140.8, 155.2, 174.9; IR (CHCl3): 3461, 2976,
1756, 1711, 1219, 753, 701 cmꢀ1. HRMS calcd for
C29H32N2O4: 473.2440. Found: 473.2439.
4.6.5. (20S,30S,4R,5S)-5-Benzyl-3-(2-benzyl-4-benzyloxy-3-
hydroxybutanoyl)-4-isopropyl-2H-1,3,4-oxadiazinan-2-one
9e. Benzyloxyacetaldehyde (0.61 mL, 4.37 mmol) was re-
acted with oxadiazinanone 8. The purified product was iso-
lated by recrystallization with EtOAc and hexanes to afford
4.6.2. (20S,30S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-(4-
chlorophenyl)propanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-
2-one 9b. 4-Chlorobenzaldehyde (0.79 g, 5.6 mmol) was
reacted with oxadiazinanone 8. The purified product was
isolated by chromatography to afford the title compound
the target compound as a white solid (0.73 g). Yield: 49%.
29
25
as an oil (0.83 g). Yield: 51%. ½aꢁD ¼ ꢀ125:5 (c 0.58,
Mp = 106–108 ꢁC; ½aꢁD ¼ ꢀ103:5 (c 0.28, CHCl3);
CHCl3); Rf = 0.23 (hexanes/EtOAc, 7:3). 1H NMR
(CDCl3): d, 0.81 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.3 Hz,
3H), 1.88–1.93 (dd, J = 7.0, 6.3, 1H), 2.26–2.34 (m, 2H),
2.72–2.83 (m, 2H), 3.00 (t, J = 12.5 Hz, 1H), 3.21–3.29
(m, 1H), 3.60 (broad singlet, –OH), 3.89–3.94 (dd,
J = 3.1, 5.9 Hz, 1H), 4.03–4.07 (dt, J = 3.5, 12.1 Hz, 1H),
5.24 (d, J = 3.1 Hz, 1H), 7.10–7.38 (m, 12H), 7.52 (d,
J = 8.2, 2H); 13C NMR (CDCl3): d, 19.1, 20.0, 32.7, 39.1,
52.6, 57.6, 58.4, 68.1, 72.9, 126.7, 127.8, 128.4, 128.8,
129.3, 133.3, 137.0, 139.0, 139.3, 155.2, 174.6; IR (CHCl3):
3449, 2976, 1755, 1711, 1219, 754, 700 cmꢀ1. HRMS calcd
for C29H31N2O4Cl: 507.2051. Found: 507.2043.
Rf = 0.36 (hexanes/EtOAc, 7:3). 1H NMR (CDCl3): d,
0.79 (d, J = 6.2 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H), 1.92–
1.97 (m, 1H), 2.24–2.33 (m, 2H), 2.71–2.77 (m, 1H), 2.97
(dd, J = 12.1, 12.8 Hz, 1H), 3.15–3.26 (m, 2H), 3.68 (d,
J = 5.9 Hz, 2H), 3.85–3.96 (m, 2H), 4.26–4.30 (m, 1H),
4.56 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 7.12–
7.39 (m, 15H). The alcoholic proton was not observed.
13C NMR (CDCl3): d, 19.3, 20.0, 35.0, 39.0, 48.8, 57.7,
58.5, 67.9, 71.4, 71.8, 73.4, 126.7, 127.7, 127.8, 128.4,
128.9, 129.3, 137.1, 137.9, 139.4, 155.2, 173.6. IR (CCl4):
3438, 2914, 1756, 1687, 700 cmꢀ1. HRMS calcd for
C31H37N2O5: 517.2702. Found: 517.2694. Anal. Calcd for
C31H36N2O5: C, 72.07; H, 7.02; N, 5.42. Found: C, 72.07;
H, 7.10; N, 5.57.
4.6.3. (20S,30S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-(2-
naphthyl)propanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-
one 9c. 2-Naphthaldehyde (0.8 g, 5.5 mmol) was reacted
with oxadiazinanone 8. The purified product was isolated
4.6.6. (20S,30S,4R,5S)-5-Benzyl-3-(3-hydroxy-2-methyl-3-
phenylpropanoyl)-4-isopropyl-2H-1,3,4-oxadiazinan-2-one
13. Benzaldehyde (0.7 mL, 7.0 mmol) was reacted with
oxadiazinanone 12. The purified product was isolated via
by chromatography to afford the title compound as an
29
oil (1.06 g). Yield: 70%. ½aꢁD ¼ ꢀ81:9 (c 0.74, CHCl3);
Rf = 0.15 (hexanes/EtOAc, 7:3). 1H NMR (CDCl3): d,
0.78 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H), 1.89–
1.94 (dd, J = 7.0, 13.7 Hz, 1H), 2.29–2.35 (m, 2H), 2.77–
2.82 (m, 2H), 3.09 (t, J = 13.3 Hz, 1H), 3.22–3.26 (m,
1H), 3.71 (broad singlet, –OH), 3.87–3.92 (dd, J = 7.0,
11.3 Hz, 1H), 4.18–4.23 (dt, J = 4.0, 11.7 Hz, 1H), 5.44
(d, J = 2.73 Hz, 1H), 7.09–7.30 (m, 10H), 7.46–7.49 (m,
2H), 7.68–7.71 (d, 1H), 7.83–7.9 (m, 3H), 8.07 (s, 1H);
(CDCl3): d, 19.1, 19.9, 32.7, 39.1, 52.5, 57.6, 58.4, 68.1,
73.4, 124.3, 125.3, 125.8, 126.0, 126.6, 126.7, 127.6, 128.1,
128.2, 128.4, 128.8, 129.3, 133.0, 133.2, 137.0, 138.2,
139.2, 155.4, 175.1; IR (CHCl3): 3466, 2976, 1755, 1712,
1219, 754, 701 cmꢀ1. HRMS calcd for C33H34N2O4:
523.2597. Found: 523.2599.
recrystallization with hexanes and EtOAc to afford 13 as
29
a solid (0.65 g). Yield: 47%. Mp = 96–98.5 ꢁC. ½aꢁD
¼
ꢀ92:2 (c 1.39, CHCl3); Rf = 0.15 (hexanes/EtOAc, 7:3).
1H NMR (CDCl3): d 1.04 (t, J = 6.6 Hz, 6H), 1.10
(d, J = 7.0 Hz, 3H), 2.52–2.57 (dd, J = 7.8, 5.9 Hz, 1H),
2.83–2.88 (dd, J = 6.3, 7.42, 1H), 3.03–3.09 (m, 1H), 3.32
(broad singlet, –OH), 3.56–3.63 (pentet, J = 7.8 Hz, 1H),
3.76–3.88 (m, 2H), 4.36–4.40 (dd, J = 7.0, 4.3 Hz, 1H),
5.25 (d, J = 2.8 Hz, 1H), 7.21–7.37 (m, 8H), 7.45 (d,
J = 7.8, 2H). 13C NMR (CDCl3): d, 19.1, 20.0, 32.9, 39.1,
52.6, 57.6, 58.4, 68.0, 73.4, 126.4, 126.6, 127.6, 128.3,
128.4, 128.8, 129.3, 137.0, 139.3, 140.8, 155.2, 174.9; IR
(CHCl3): 3492, 2978, 1786, 1754, 1223, 760, 701 cmꢀ1
.
HRMS calcd for C23H28N2O4: 397.2127. Found:
397.2124. Anal. Calcd for C23H28N2O4: C, 69.67; H, 7.12;
N, 7.07. Found: C, 69.66; H, 6.94; N 7.10.
4.6.4. (20S,30S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-4,4-
dimethylpentanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-one
9d. Pivaldehyde (0.57 mL, 5.6 mmol) was reacted with
oxadiazinanone 8. The purified product was isolated by
4.7. (4S,5S)-4-Benzyl-5-benzyloxymethyl-1,3-oxazolidin-2-
one 11
chromatography (hexanes/EtOAc, 70:30) to afford 9d as
29
an oil (0.99 g). Yield: 79%. ½aꢁD ¼ ꢀ180:1 (c 0.67, CHCl3);
In a 50 mL round-bottomed flask were placed aldol adduct
9e (0.180 g, 0.35 mmol), THF (8 mL), and 6 M H2SO4
1
Rf = 0.15 (hexanes/EtOAc, 7:3). H NMR (CDCl3; values

2392
D. D. Dore et al. / Tetrahedron: Asymmetry 17 (2006) 2386–2392
(6 mL). The mixture was heated at reflux and reacted for a
period of 48 h. The mixture was cooled to 0 ꢁC and made
basic by the addition of a saturated aqueous solution of
sodium bicarbonate. The solution was extracted with ethyl
acetate (2 · 25 mL) and the organic portion washed with
a saturated brine solution (50 mL), dried over MgSO4,
and the solvents were removed via rotary evaporation to
yield the oxadiazinanone and its corresponding b-hydr-
azino-alcohol. The aqueous layer was acidified to pH 1 with
ꢂ3 M HCl and extracted with ethyl acetate (2 · 25 mL).
The combined extracts were washed with a saturated brine
solution, dried over MgSO4 and concentrated under re-
duced pressure to afford 0.071 g of the b-hydroxycarboxy-
lic acid 10 as a white solid (68% recovery). The acid was
immediately taken on to the Curtius rearrangement. In a
flame-dried nitrogen-purged 5 mL round-bottomed flask
equipped with a condenser was placed 10 (0.135 g,
0.45 mmol) resourced from multiple hydrolysis reactions,
anhydrous toluene (1.0 mL) and diphenylphosphoryl azide
(0.12 mL, 0.54 mmol) followed by the addition of triethyl-
amine (0.08 mL, 0.59 mmol). The mixture was heated at re-
flux for a period of 4 h. The reaction mixture was cooled to
room temperature and quenched with a saturated solution
of sodium bicarbonate (50 mL). The organic portion was
extracted with ethyl acetate (2 · 25 mL), washed with a sat-
urated brine solution (50 mL), dried over MgSO4, and con-
centrated under reduced pressure. The residue was purified
by silica gel chromatography (EtOAc/hexanes, 3:2) to
afford 0.084 g as an oil representing an isolated yield of
63%. 1H NMR (CDCl3): d 2.70 (m, 1H), 2.99 (dd,
J = 13.2, 2.9 Hz, 1H), 3.81 (d, J = 5.9 Hz, 2H), 4.06–4.12
(m, 1H), 4.63 (AB spin system, benzyloxy –OCH2–,
Dm = 26.4 Hz, J = 2.6 Hz, 2H), 4.76 (s, 1H), 4.85 (q,
J = 6.8 Hz, 1H), 7.15–7.40 (m, 10H). 13C NMR (CDCl3):
36.0, 56.0, 67.2, 73.8, 77.2, 127.2, 127.9, 128.0, 128.6,
128.9, 129.1, 136.7, 137.2, 158.0. HRMS calcd for
C18H19NO3: 297.1365. Found: 297.1358. These data
matched the reported literature data from Ghosh et al.14
(CDCl3): d, 10.7, 46.3, 51.9, 73.6, 125.9, 127.5, 128.2,
141.4, 176.2; IR (CHCl3): 3477, 2949, 1732, 1198, 1172,
770, 702 cmꢀ1
.
Acknowledgments
We would like to thank Professor David Gin (University of
Illinois at Urbana-Champaign) for his help with polarime-
try measurements. The authors thank the donors of the
Petroleum Research Fund as administered by the Ameri-
can Chemical Society for support of this research. The
authors also thank the Department of Chemistry at Illinois
State University and the Dean’s Office of the College of
Arts and Sciences for summer support.
References
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15. It must be noted that this process was capricious and the
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17. (a) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am.
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Please see Ref. 4.
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4.8. (2S,3S)-Methyl 3-hydroxy-2-methyl-3-phenylprop-
anoate 14
In a 100 mL round-bottomed flask was placed oxadiazina-
none adduct 13 dissolved in 8.5 mL of THF and 6 mL of
6 M H2SO4. The mixture was heated at reflux for 48 h
and quenched with 5 M KOH. The aqueous layer was acid-
ified with HCl and extracted with EtOAc, washed with
brine, and dried over MgSO4. The solvent was evaporated
in vacuo, to afford 0.326 g of the carboxylic acid. The acid
was directly esterified. In a 50 mL round-bottomed flask
was placed the carboxylic acid (0.326 g, 1.8 mmol)
dissolved in 2 mL of THF and 2 mL of methanol. To this
stirred mixture was added trimethylsilyldiazomethane
(3.6 mL, 7.2 mmol). The reaction was allowed to stir over-
night and was then quenched with a saturated aqueous
solution of NaHCO3, extracted with EtOAc, dried over
MgSO4, and the solvent was removed in vacuo. The puri-
fied ester product was isolated by chromatography as an
29
oil (0.150 g). Yield: 59%. ½aꢁD ¼ ꢀ11:6 (c 0.74, CHCl3);
19. Rodrigues, A.; Olivato, P. R.; Zukerman-Schpector, J.;
Rittner, R. Z. Kristallogr. 2006, 221, 226–230.
20. Rodrigues, A.; Olivato, P. R.; Rittner, R. Synthesis 2005,
2578–2582.
Rf = 0.15 (hexanes/EtOAc, 7:3). 1H NMR (CDCl3): d,
1.13 (d, J = 7.0 Hz, 3H), 2.76–2.82 (m, 1H), 3.62 (s, 3H),
5.10 (d, J = 4.3 Hz 1H), 7.24–7.36 (m, 5H); 13C NMR