Synthesis, X-ray crystallography and computational studies concerning an oxadiazinone derived from D-camphor: A structural limitation of oxadiazinones as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2005.01.020

A camphor-based oxadiazinone was prepared by reaction of the N-nitroimine of d-camphor with (1R,2S)-norephedrine; the reduction of the resultant imine; N-nitrosation of the amine; reduction to the corresponding hydrazine and cyclization. The conformationa

Full text of DOI:10.1016/j.tetasy.2005.01.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1047–1053
Synthesis, X-ray crystallography and computational
studies concerning an oxadiazinone derived from D-camphor:
a structural limitation of oxadiazinones as chiral auxiliaries
Michael D. Squire, Ryan A. Davis, Karah A. Chianakas, Gregory M. Ferrence,*
Jean M. Standard* and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 10 December 2004; accepted 5 January 2005
Abstract—A camphor-based oxadiazinone was prepared by reaction of the N-nitroimine of D-camphor with (1R,2S)-norephedrine;
the reduction of the resultant imine; N-nitrosation of the amine; reduction to the corresponding hydrazine and cyclization. The con-
formational behaviour of oxadiazinone 7 was modeled in the gas and solution phases using the semiempirical AM1 method and
density functional theory. Application of the oxadiazinone in the titanium mediated asymmetric aldol reaction provided the highly
diastereoselective formation of the expected syn-adducts 8a–d as evidenced by single crystal X-ray diffraction analysis. Attempts to
remove the oxadiazinone auxiliary using acidic or basic conditions failed to yield the expected b-hydroxyacid in significant yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The major difference between these two heterocycle fami-
lies is the transmission of stereochemical information.
Oxazolidinones transmit chirality by way of direct intra
ligand asymmetric induction; oxadiazinones transmit
their chirality by way of intra ligand asymmetric induc-
tion via intramolecular chiral relay.1a,7 The relay is made
possible by the stereogenic N4-nitrogen substituent of
the heterocycle. In effect, the transmission of informa-
tion relies on the conformational stability of the C6-
phenyl and C5-methyl in influencing the N4-nitrogen
substituent. This N4-nitrogen substituent can be intro-
duced into the heterocycle by the use of reductive alkyl-
ation of substrates, such as (1R,2S)-norephedrine.1a In
conjunction with our ongoing programme focused on
the development of oxadiazinones, we have been en-
gaged in a study of the impact of changing the nature
of the N4-substituent. In the process of developing sub-
stituents,1e we opted to pursue the use of D-camphor as
a candidate for constructing a unique bornyl substitu-
ent. The chirality of the bornyl group derived from cam-
phor is not expected to play a role in the asymmetric
induction; it is, however, expected to only provide a ste-
rically demanding environment at the N4-position of the
oxadiazinone core.
3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones 1 (oxadi-
azinones) have recently been introduced as viable chiral
auxiliaries for the asymmetric aldol reaction.1 Oxadiazi-
nones such as 1a were first prepared by Trepanier et al.
in the late 1960s for use as central nervous system stimu-
lants.2 Since these initial investigations, oxadiazinones
have re-emerged as reagents for asymmetric synthesis.1,3
The application of these compounds was, in part, in-
spired by the success of the related oxazolidinones 2 in
a myriad of reactions (Figure 1).4–6
O
O
H
O
N
N
H
N
O
Ph
R
Ph
CH3
CH3
1a: R = -CH3
1b: R = -CH(CH3)2
2
Figure 1. Oxadiazinones 1 and oxazolidinones 2.
*
Corresponding authors. Tel.: +1 309 438 7854; fax: +1 309 438 5538.
For X-ray crystallography contact G.M.F.; e-mail addresses:
gferren@ilstu.edu; hitchcock@ilstu.edu
Herein, we report on the synthesis, X-ray crystallogra-
phy, computational studies and asymmetric application
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.020

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M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
of the camphor-based oxadiazinone. We also report
on the difficulties encountered in attempts to hydro-
lyze the aldol adducts of the camphor-based oxadi-
azinone.
desired oxadiazinone 6 by reaction with 1,10-carbonyldi-
imidazole and p-toluenesulfonic acid in 55% yield from
the N-nitrosamine. In order to pursue test reactions with
the asymmetric aldol reaction, oxadiazinone 6 was acyl-
ated with propionyl chloride and lithium hydride in
methylene chloride to afford the N4-bornyl-N3-propion-
yloxadiazinone 7, the solid state structure of which was
confirmed by X-ray crystallography (Fig. 2).13
2. Results and discussion
The synthesis of the N4-bornyl heterocycle proved not to
be as straightforward as other syntheses of chiral oxadi-
azinones (Scheme 1).8 This difficulty was primarily due
to the fact that D-camphor does not readily form imines
with many amines.9 Morris and Ryder developed a
method for imine formation via the preparation of the
N-nitroimine of camphor.10 Using this method, we were
able to condense D-camphor with (1R,2S)-norephedrine
3 to yield the corresponding b-aminoalcohol 4.11 This
material was N-nitrosated12 and subsequently reduced
with LiAlH4 to the corresponding b-hydrazinoalcohol.
The crude b-hydrazinoalcohol was converted to the
The X-ray crystal structure revealed that oxadiazinone 7
adopts a twist boat conformation in which the N4-
bornyl substituent and the C5-methyl group have a
1,2-trans-diaxial relationship. As this conformation has
been observed for related oxadiazinones,1a,d we were
more concerned with the positioning of the bornyl
group. The X-ray crystal structure revealed that the bulk
of the N4-bornyl substituent is positioned directly under
the N3-propionyl substituent. It was thought that this
arrangement would be ideal for asymmetric induction
in the titanium mediated aldol addition reaction of the
H
N
HO
Ph
NO
HO
HO
Ph
NaNO2, HCl
N
NH2
CH3
Ph
CH3
CH3
H
H
3
5
4
O
O
H
O
N
N
1. LiAlH4, THF
2. CDI, p-TsOH
55%
CH3CH2COCl
O
N
N
O
Ph
LiH, CH2Cl2
Ph
CH3
88%
CH3
H
H
6
7
Scheme 1. Oxadiazinone synthesis.
Figure 2. Oxadiazinone acylation and RASTEP view of 7 showing the atom labelling scheme. Non-hydrogen atoms are represented by Gaussian
ellipsoids at the 50% probability level. Hydrogen atoms have been drawn arbitrarily small and are not labelled.

M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
1049
N4-bornyloxadiazinone provided that solid state con-
formation was a reflection of the solution conformation.
selected to model water. The geometries of two con-
formers, one with nearly parallel and one with nearly
anti-parallel carbonyl groups, were optimized at the
B3LYP/DZP level with the COSMO solvation model.
As would be expected in a polar solvent, the conformer
with the largest dipole moment exhibits the largest sol-
vation effect. The calculated gas phase dipole moment
was 7.42 Debye for the conformer with nearly parallel
carbonyl groups and 3.59 Debye for the conformer with
nearly anti-parallel carbonyl groups. The more favour-
able solvation energy of the conformer with parallel car-
bonyls lowers its energy relative to the conformer with
anti-parallel carbonyls. In the gas phase, the conformer
with parallel carbonyls is 4.4 kcal/mol higher in energy
than the conformer with anti-parallel carbonyls. In solu-
tion, this trend is reversed so that the conformer with
parallel carbonyls is now 0.1 kcal/mol lower in energy
than the conformer with anti-parallel carbonyls. This
computational evidence suggests that both the parallel
and anti-parallel orientations of the carbonyls are possi-
ble in the solution phase.
To address the conformational preferences of oxadiazi-
none 7 in the solution state, two different computational
approaches were employed, including the AM1 semiem-
pirical method and density functional theory (DFT).
Calculations were performed in the gas phase and in
solution phase through the use of continuum solvent
techniques. Semiempirical calculations were performed
using the Spartan 5.1 and Spartan 02 software packages
running on SGI O2 workstations.14 DFT calculations
were performed with the PQS 3.1 software package run-
ning on a Linux workstation.15 The optimized structures
obtained were verified as local minima by determination
of vibrational frequencies. A conformation search was
carried out in the gas phase using the AM1 semiempiri-
cal method to determine low-energy conformations of
oxadiazinone 7.16 In the AM1 search, 18 conformers
were found to exist within 5 kcal/mol of the lowest
energy conformer. About half of the low-energy conform-
ers had carbonyl orientations that were either nearly
parallel or anti-parallel. Several of the lowest energy
gas phase conformers from the AM1 conformation
search were then optimized with the B3LYP/DZP den-
sity functional method. The lowest energy structure
obtained using density functional theory (DFT) had a
dihedral angle between the carbonyl groups of 174ꢁ, a
nearly anti-parallel alignment (Fig. 3a). The DFT
conformer most closely resembling the one found in
the X-ray crystal structure had a gas phase energy
1.1 kcal/mol above the lowest energy conformer and a
carbonyl dihedral angle of 160ꢁ (Fig. 3b); this result
compares favourably to the X-ray crystal structure car-
bonyl dihedral angle of 167.0 (3)ꢁ. The only significant
difference between the lowest energy conformer and
the one resembling the X-ray crystal structure is the ori-
entation of the ethyl side chain attached to C8 (see Fig.
2).
With the N3-acylated heterocycle in hand, we pursued
the asymmetric aldol reaction. Oxadiazinone 7 was first
reacted with titanium tetrachloride (TiCl4) at 25 ꢁC in
tetrahydrofuran and then reacted with triethylamine at
ꢀ78 ꢁC over a 1 h period to ensure the complete forma-
tion of the enolate (Table 1).18 The aldehyde was then
added at 0 ꢁC and the reaction allowed to warm to room
temperature. The products of the asymmetric aldol
reactions were obtained in good yield and in high
diastereoselectivity. Aliphatic aldehydes bearing a-pro-
tons were problematic in terms of incomplete reactivity
and were not pursued. Surprisingly, these results were
not clearly superior to those observed for the norephe-
drine based N4-isopropyl based oxadiazinone,1a except
in the case of the formation of the aldol adduct 8d. This
was counter-intuitive as the diastereomeric ratio was
expected to be greater for the N4-bornyl system versus
the N4-isopropyl system due to the greater steric require-
ment. It is speculated that the aldol reactions of oxadi-
azinone 7 may involve alternative transition states
other than the proposed chair-like Zimmerman–Traxler
transition state that has been invoked for other
The effect of solvation upon the structure and energies
of the conformers of oxadiazinone 7 was investigated
by performing DFT calculations with the COSMO
continuum solvent model17 and a dielectric constant
Figure 3. (a) Lowest energy gas phase structure of oxadiazinone 7 determined using the B3LYP/DZP method. (b) Gas phase conformer of
oxadiazinone 7 closest to the X-ray crystal structure determined using the B3LYP/DZP method.

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M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
Table 1. Asymmetric aldol reaction of the N4-bornyloxadiazinone
2). The most successful hydrolysis occurred when the
N4-substituent was small (9, R = –CH3).1c The hydroly-
sis of the N4-isopropyl oxadiazinone proved to be not as
straightforward.1a The dominant problem was the
hydrolysis of the cleaved oxadiazinone and hydrolysis
of the oxadiazinone ring prior to the cleavage of the al-
dol side chain. The least successful hydrolysis occurred
when the N4-substituent was large (8a, R = –C10H17).
R
O
O
OH
O
N
N
O
H
O
N
N
O
1a. TiCl4; TEA
1b. RCHO
Ph
Ph
CH3
CH3
a: R = -C6H5
b: R = -p-C6H4Cl
c: R = -2-C10H7
d: R = -C(CH3)3
H
The failure of oxadiazinones 8a–d to undergo clean
hydrolysis can be attributed to the steric environment
created by the presence of the N4-bornyl substituent.
The N3-carbonyl moiety must undergo a hybridization
change from a trigonal planar carbonyl to a tetrahedral
intermediate; may not be viable due to the proximity of
the N4-bornyl substituent (Scheme 2). This suggests that
the process of hydrolysis becomes increasingly difficult
as larger groups are introduced at the N4-nitrogen.
8a-d
Drb
7
Entry
Compound
RCHO
Yielda
1
2
3
4
8a
8b
8c
8d
C6H5CHO
80
67
88
68
P49:1
P49:1
P49:1
P49:1
p-ClC6H4CHO
2-C10H7CHO
(CH3)3CCHO
a Yield represent purification by column chromatography or
recrystallization.
b Diastereomeric ratio of crude reaction mixture (major diastereo-
mers:minor diastereomers). The individual minor diastereomers were
not characterized.
R
O
R
OH
H
O
O
OH
H
O
O
N
N
O
N
N
H
O
oxadiazinones. The absolute stereochemistry of the al-
dol adduct N3-side chain of oxadiazinone 8c was deter-
mined by single crystal X-ray crystallography favouring
the syn-diastereomer (Fig. 4). By analogy, it is proposed
that 8a, 8b and 8d possess the same absolute stereochem-
istry as 8c.19
H2O
H
Ph
Ph
CH3
CH3
H
H
9
8
With the aldol adducts 8a–d in hand, hydrolysis of the
N3-side chain was pursued. Unfortunately, it was not
possible to hydrolyze the adducts under either acidic
or basic conditions as had been done with previous
oxadiazinone aldol adducts.1 All reaction attempts
afforded complex mixtures, which suggested that retro-
aldol and elimination reactions were dominant reaction
pathways. When comparing the ease of hydrolysis for
oxadiazinone based aldol adducts, a trend emerged that
was dependent on the size of the N4-substituent (Table
Scheme 2.
3. Conclusion
A structurally novel oxadiazinone 6 has been synthe-
sized from (1R,2S)-norephedrine and D-camphor. The
oxadiazinone auxiliary was acylated to afford the N4-
bornyl-N3-propionyloxadiazinone 7. The structure of
oxadiazinone 7 was studied in the solid state by X-ray
Figure 4. RASTEP view of 8c showing the atom labelling scheme. Non-hydrogen atoms are represented by Gaussian ellipsoids at the 50%
probability level. Hydrogen atoms have been drawn arbitrarily small and are not labelled.

M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
Table 2. Comparative hydrolyses of oxadiazinone aldol adducts
1051
O
O
OH
Ph
O
OH
Ph
O
H
O
N
N
H2SO4
O
N
N
+
HO
CH3
Ph
R
Ph
R
CH3
CH3
CH3
8a: R = -C10H17 (-bornyl)
9: R = -CH3
10: R = -CH(CH3)2
6: R = -C10H17 (-bornyl)
11: R = -CH3
12: R = -CH(CH3)2
Entry
N4-Substituent
b-Hydroxyacid (% yield)
Oxadiazinone (% yield)
1
2
3
–CH3
–CH(CH3)2
–C10H17 (–bornyl)
71a
56a
<5b
98
46c
nad
a Yield after recrystallization.
b The relative amount of b-hydroxyacid was estimated from the 400 MHz 1H NMR spectrum.
c The remainder was a mixture of hydrolyzed oxadiazinone, elimination products and retro-aldol products.
d Yield not determined.
crystallography and modeled in the gas and solution
phases with computational methods. Oxadiazinone 7
was employed in the asymmetric aldol addition reaction
with good yields and very good diastereoselectivities,
although not superior to the related N4-isopropyloxadi-
azinone.1a The absolute stereochemistry of the aldol
adduct 8c was determined by X-ray crystallographic
studies. Attempts at the hydrolysis of the oxadiazinone
adducts failed, presumably due to the steric environment
created by the N4-bornyl substituent. This result sug-
gests that the steric tuning of oxadiazinones may be lim-
ited; larger substituents at the N4-position may not
necessarily give superior diastereoselectivities and the
ability to hydrolyze the aldol adduct is compromised
by the larger substituent. A broader study involving a
systemic study of potential substituents is underway
and will be disclosed.
flask, hydrazine (7.84 g, 25.9 mmol) was dissolved in
THF (75 mL) and to this solution was added 1,10-car-
bonyldiimidazole (5.01 g, 31.1 mmol) and then p-tolu-
enesulfonic acid (4.93 g, 25.9 mmol). The solution was
heated to reflux and stirred under nitrogen overnight.
The reaction was quenched by the addition of a satu-
rated aqueous solution of sodium bicarbonate
(100 mL). The organic products were extracted from this
mixture by the use of ethyl acetate (2 · 100 mL). The
combined layers were treated with a saturated aqueous
solution of brine (100 mL), dried over MgSO4 and the
solvent removed by rotary evaporation to afford an
orange oil. The solvents were removed by rotary
evaporation and the crude product purified by
column chromatography (EtOAc/hexanes, 1:9): 6.30 g
(19.2 mmol) of the oxadiazinone were recovered (55%
yield from 5) as colourless crystals, mp 154–155 ꢁC;
25
½aꢁ ¼ ꢀ10:9 (c 0.47, MeOH). 1H NMR (CDCl3): d
D
0.85 (s, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.99 (s, 3H),
1.15 (s, 3H), 1.18–1.24 (m, 2H), 1.51–1.58 (m, 1H),
1.69 (dd, J = 11.9, 8.6 Hz, 1H), 1.72–1.78 (m, 2H),
1.78–1.83 (m, 1H), 3.11 (dd, J = 8.1, 5.9 Hz, 1H), 3.56
(dq, J = 3.7, 3.1 Hz, 1H), 5.71 (d, J = 3.3 Hz, 1H), 7.16
(s, 1H), 7.29–7.39 (m, 5H). 13C NMR (CDCl3): d 11.9,
14.8, 19.3, 20.4, 26.9, 34.4, 36.8, 44.7, 47.2, 49.7, 50.7,
73.8, 75.2, 125.0, 127.7, 128.3, 136.6, 152.2. IR (CCl4):
3251, 2951, 2877, 1703, 1124 cmꢀ1. Anal. Calcd for
C20H28N2O2: C, 73.14; H, 8.59; N, 8.53. Found: C,
72.85; H, 8.58; N, 8.59.
4. Experimental
4.1. (5S,6R,10R,20R,40R)-3,4,5,6-Tetrahydro-5-methyl-4-
(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-2H-
1,3,4-oxadiazin-2-one 6
In a flame-dried, nitrogen purged, three necked 1 L
round bottom flask fitted with a condenser and pressure
equalizing addition funnel was placed lithium alumin-
ium hydride (3.973 g, 104.7 mmol) in THF (200 mL).
The reaction was heated to mild reflux and N-nitros-
amine 5 (11.04 g, 34.90 mmol) in THF (100 mL) added
to the reaction mixture over a period of 40 min. The
reaction was allowed to stir overnight at reflux (70 ꢁC).
After 24 h, the reaction was cooled to 0 ꢁC and an aque-
ous solution of sodium hydroxide (6 M, 400 mL) added.
The white paste that formed was washed with EtOAc
(3 · 500 mL) and the combined organic layers succes-
sively treated with an aqueous solution of RochelleÕs salt
(200 mL) and brine solution (200 mL). This process
afforded the crude hydrazine, which was used immedi-
ately in the next reaction without purification. In a
flame-dried, nitrogen purged 500 mL round bottom
4.2. (5S,6R,10R,20R,40R)-3,4,5,6-Tetrahydro-5-methyl-4-
(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)6-phenyl-3-propion-
yl-2H-1,3,4-oxadiazin-2-one 7
In a flame-dried, nitrogen purged 10 mL round bottom
flask fitted with a reflux condenser, the oxadiazinone
(1.350 g, 4.11 mmol) was dissolved in dichloroethane
(10 mL) and to this solution was added propionyl chlo-
ride (0.536 mL, 6.17 mmol). The solution was brought
to reflux and then lithium hydride (0.041 g, 5.14 mmol)
added. The solution was heated to reflux and stirred
under nitrogen overnight. The reaction was quenched by

1052
M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
the addition of a saturated aqueous solution of sodium
bicarbonate (50 mL). The organic products were ex-
tracted from this mixture by the use of methylene chlo-
ride (2 · 50 mL). The combined organic layers were
treated with a saturated aqueous solution of brine
(50 mL), dried over MgSO4 and the solvent removed
by rotary evaporation to afford a yellow oil. The sol-
vents were removed by rotary evaporation and the crude
product was purified by column chromatography
d 10.4, 13.2, 13.4, 19.7, 20.6, 27.2, 35.7, 38.4, 44.9,
45.5, 47.4, 50.1, 51.6, 69.7, 72.4, 79.7, 124.7, 126.1,
127.1, 128.07, 128.09, 128.7, 136.0, 141.3, 149.7, 178.1.
IR (CCl4): 3541, 3038, 1704 (very broad) cmꢀ1. HRMS
(FAB) calcd for C30H39N2O4 (M+1): 491.2910. Found:
491.2915.
4.3.2. (5S,6R,10R,20R,40R,200S,300S)-3-[3-(4-Chlorophen-
yl)-3-hydroxy-2-methylpropionyl]-3,4,5,6-tetrahydro-5-
methyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-
(EtOAc/hexanes, 1:9): 88% yield as colourless crystals,
25
D
mp 225–226 ꢁC; ½aꢁ ¼ ꢀ139 (c 1.02, MeOH). 1H
2H-1,3,4-oxadiazin-2-one (8b). Yield 76%; colour-
25
NMR (CDCl3): d 0.68 (d, J = 6.6 Hz, 3H), 0.84 (s,
3H), 0.91 (s, 3H), 1.10–1.25 (m, 1H), 1.61 (t,
J = 7.33 Hz, 3H), 1.20 (s, 3H), 1.47–1.53 (m, 1H),
1.72–1.81 (m, 2H), 1.97–2.02 (m, 2H), 2.80–2.98 (m,
3H), 3.21 (dd, J = 8.1, 5.9 Hz, 1H), 3.80 (quintet,
J = 6.61 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H), 7.19–7.39
(m, 5H). 13C NMR (CDCl3): d 8.98, 13.0, 13.4, 19.7,
20.5, 27.1, 30.7, 35.6, 38.4, 44.9, 47.3, 49.8, 51.3, 69.8,
79.1, 124.7, 127.9, 128.5, 136.3, 149.7, 175.0. IR
(CCl4): 2928, 2879, 1731(broad), 1132 cmꢀ1. Anal.
Calcd for C23H32N2O3: C, 71.84; H, 8.39; N, 7.29.
Found: C, 71.76; H, 8.41; N, 7.37.
less crystals, mp 134–135 ꢁC; ½aꢁ ¼ ꢀ113 (c 0.65,
D
MeOH). 1H NMR (CDCl3): d 0.69 (d, J = 7.0 Hz,
3H), 0.85 (s, 3H), 0.94 (s, 3H), 1.04 (d, J = 7.0 Hz,
3H), 1.12–1.28 (m, 2H), 1.22 (s, 3H), 1.74–1.84 (m,
3H), 1.96–2.06 (m, 2H), 3.24 (dd, J = 7.7, 5.5 Hz, 1H),
3.45 (br s, 1H), 3.84 (quintet, J = 6.7 Hz, 1H), 3.89
(dq, J = 2.2, 7.0 Hz, 1H), 5.25 (d, J = 2.2 Hz, 1H), 6.07
(d, J = 5.9 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.26 (s,
1H), 7.26–7.42 (m, 7H). 13C NMR (CDCl3): d 10.4,
13.1, 13.3, 19.7, 20.5, 27.1, 35.6, 38.4, 44.8, 45.4, 47.3,
50.0, 51.5, 69.6, 71.9, 79.6, 124.6, 127.6, 128.0, 128.1,
128.6, 132.7, 135.8, 139.9, 149.7, 177.6. IR (CCl4):
3500, 1706, 754 cmꢀ1
. HRMS (FAB) calcd for
C30H38ClN2O4 (M+1): 525.2520. Found: 525.2536.
4.3. General procedure for the formation of the aldol
adducts
4.3.3. (5S,6R,10R,20R,40R,200S,300S)-3,4,5,6-Tetrahydro-
3-(3-hydroxy-2-methyl-3-naphthalen-2-yl-propionyl)-5-
methyl-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-
In a flame-dried, nitrogen purged, 25 mL round bottom
flask, the N3-propionylated oxadiazinone (0.625 g,
1.63 mmol) was dissolved in THF (5.5 mL). To this
solution was added titanium tetrachloride (0.20 mL,
1.7 mmol) by syringe. The temperature of the solution
was lowered to ꢀ78 ꢁC after 1 h of induction time. Tri-
ethylamine (0.25 mL, 1.7 mmol) was added to the solu-
tion and the system allowed to warm to 0 ꢁC over
approximately 30 min. Once the solution had reached
0 ꢁC, the aldehyde (0.198 mL, 1.95 mmol) was added
to solution by syringe and the system was allowed to
warm to room temperature and run overnight. The reac-
tion was quenched by the addition of a saturated aque-
ous solution of ammonium chloride (25 mL). The
organic products were extracted from this mixture by
the use of ethyl acetate (2 · 25 mL). The combined
organic layers were treated with a saturated aqueous solu-
tion of brine (25 mL), dried over MgSO4 and the solvent
removed by rotary evaporation to afford a yellow oil.
The solvents were removed by rotary evaporation and
the crude product was purified by column chromatogra-
phy (EtOAc/hexanes, 1:9).
4-2H-1,3,4-oxadiazin-2-one 8c. Yield 88%; colourless
25
crystals, mp 140–141 ꢁC; ½aꢁ ¼ ꢀ122 (c 1.33, MeOH).
D
1H NMR (CDCl3): d 0.71 (d, J = 7.0 Hz, 3H), 0.82 (s,
3H), 0.93 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.12–1.25
(m, 2H), 1.23 (s, 3H), 1.48–1.56 (m, 1H), 1.75–1.83 (m,
3H), 1.98–2.06 (m, 1H), 3.25 (dd, J = 8.1, 5.5 Hz, 1H),
3.60 (br s, 1H), 3.84 (quintet, J = 6.7 Hz, 1H), 4.12
(dq, J = 2.0, 7.2 Hz 1H), 5.45 (s, 1H), 6.10 (d,
J = 5.5 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.26–7.50
(m, 7H), 7.55 (d, J = 8.4 Hz, 1H), 7.83–7.89 (m, 2H),
7.96 (s, 1H). 13C NMR (CDCl3): d 10.5, 13.2, 13.4,
19.7, 20.4, 27.1, 35.7, 38.4, 44.9, 45.3, 47.3, 50.0, 51.6,
69.6, 72.5, 79.6, 124.3, 124.7, 125.0, 125.6, 125.8,
127.5, 127.7, 128.00, 128.03, 128.6, 132.7, 133.1, 135.9,
138.7, 149.7, 178.0. IR (CCl4): 3482, 1729, 1696 cmꢀ1
.
HRMS (ESI) calcd for C34H41N2O4 (M+1): 541.3066.
Found: 541.3066.
4.3.4. (5S,6R,10R,20R,40R,200S,300S)-3,4,5,6-Tetrahydro-
3-(3-hydroxy-2,4,4-trimethyl-pentanoyl)-5-methyl-6-phen-
yl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2H-1,3,4-
4.3.1. (5S,6R,10R,20R,40R,200S,300S)-3,4,5,6-Tetrahydro-
3-(3-hydroxy-2-methyl-3-phenylpropionyl)-5-methyl-6-
phenyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2H-1,3,4-
oxadiazin-2-one 8d. Yield 88%; colourless crystals, mp
25
D
149–150 ꢁC; ½aꢁ ¼ ꢀ135 (c 1.77, MeOH). 1H NMR
(CDCl3): d 0.69 (d, J = 7.2 Hz, 3H), 0.85 (s, 3H), 0.93
(s, 3H), 1.00 (s, 9H), 1.11–1.17 (m, 2H), 1.21 (d,
J = 7.0 Hz, 3H), 1.22 (s, 3H), 1.26–1.32 (m, 2H), 1.47–
1.54 (m, 1H), 1.73–1.82 (m, 2H), 1.96–2.04 (m, 1H),
3.21 (dd, J = 8, 6 Hz, 1H), 3.65 (s, 1H), 3.81 (quintet,
J = 6.8 Hz, 1H), 4.19 (q, J = 6.6 Hz, 1H), 6.05 (d,
J = 5.9 Hz, 1H), 7.19 (d, J = 7.3 Hz, 2H), 7.30–7.41
(m, 3H). 13C NMR (CDCl3): d 12.4, 13.3, 13.7, 14.1,
19.7, 20.6, 22.6, 27.1, 27.2, 31.6, 35.5, 35.7, 38.5, 39.9,
44.9, 47.4, 50.2, 51.6, 69.7, 79.7, 124.8, 128.1, 128.7,
136.1, 149.6, 179.7. IR (CCl4): 3450, 1722 cmꢀ1. HRMS
oxadiazin-2-one 8a. Yield 67%; colourless crystals,
25
D
mp 111–112 ꢁC; ½aꢁ ¼ ꢀ129 (c 0.47, MeOH). 1H
NMR (CDCl3): d 0.70 (d, J = 7.0 Hz, 3H), 0.85 (s,
3H), 0.94 (s, 3H), 1.07 (d, J = 7.0 Hz, 3H), 1.10–1.28
(m, 2H), 1.22 (s, 3H), 1.49–1.70 (m, 2H), 1.74–1.83 (m,
2H), 1.98–2.05 (m, 1H), 3.24 (dd, J = 5.9, 2.2 Hz, 1H),
3.44 (br s, 1H), 3.83 (quintet, J = 6.7 Hz, 1H), 4.00
(dq, J = 2.6, 7.0 Hz, 1H), 5.28 (d, J = 2.2 Hz, 1H), 6.07
(d, J = 5.9 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.20–7.40
(m, 8H), 7.49 (d, J = 7.7 Hz, 1H). 13C NMR (CDCl3):

M. D. Squire et al. / Tetrahedron: Asymmetry 16 (2005) 1047–1053
1053
boeuf, O.; Quaranta, L.; Renaud, P.; Liu, P.; Jasperse, C.
P.; Sibi, M. P. Chem. Eur. J. 2003, 9, 28–35; (c) Quaranta,
L.; Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 39–
42.
(ESI) calcd for C28H43N2O4 (M+1): 471.3223. Found:
471.3217.
8. Hitchcock, S. R.; Casper, D. M.; Nora, G. P.; Blackburn,
J. R.; Bentley, J. T.; Taylor, D. C. J. Heterocycl. Chem.
2002, 39, 823–828.
Acknowledgements
We thank Dr. R. C. Freeman for helpful discussions.
We also thank Maria Teresa Navio of the Analytical
Research and Development Department of Pfizer Glo-
bal Research and Development in La Jolla, CA for opti-
cal activity measurements. Acknowledgments are also
made to the donors of the American Chemical Society
Petroleum Research Fund for support of this research.
We acknowledge Pfizer, Inc. for significant material sup-
port. We also acknowledge continued support from
Merck & Co, Inc.
9. (a) Baxter, E. W.; Reitz, A. B. Reductive Aminations of
Carbonyl Compounds with Borohydride and Borane
Reducing Agents. Org. React. 2002, 59, 3–714; (b) Bolton,
R.; Danks, T. N.; Paul, J. M. Tetrahedron Lett. 1994, 35,
3411–3412; (c) Danks and co-workers noted that sterically
hindered amines either require long reaction times to react
with camphor or fail to yield product in significant
amounts.
10. (a) Morris, D. G.; Ryder, K. S. Synthesis 1997, 620–622;
(b) Guziec, F. S., Jr.; Russo, J. M. Synthesis 1984, 479–
481.
11. Squire, M. D.; Burwell, A.; Ferrence, G. M.; Hitchcock, S.
R. Tetrahedron: Asymmetry 2002, 13, 1849–1854.
12. Caution. Many N-nitrosamines are potentially carcino-
genic and should be handled with great care. For more
information on N-nitrosamines, please see: Lawley, P. D.
In Chemical Carcinogens. ACS Monograph 182; Searle, C.
D., Ed.; American Chemical Society: Washington, DC,
1984.
13. Crystallographic data (excluding structure factors) for 7
has been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number CCDC
239755. Copies of this data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 IEZ, UK [fax: +44 (0)12233 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
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will be disclosed elsewhere.
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16. We have shown previously that the geometries of similar
heterocycles are described better with the AM1 semiem-
pirical method than with the PM3 semiempirical method.
See: Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire,
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18. Based on our previous studies, the enolate is believed to
possess the (Z)-configuration. See Ref. 1a.
19. (a) The relative stereochemistry of the N3-aldol adduct
side chain was determined by evaluating the coupling
constant of the aldol adduct. The coupling constant was
2 Hz or less in all examples, which suggests the syn-aldol
configuration. See: Evans, D. A.; Nelson, J. V.; Taber, T.
R. Top. Stereochem. 1982, 13, 1–115; (b) Crystallographic
data (excluding structure factors) for 8c has been
deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC
239756. Copies of this data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 IEZ, UK [fax: +44 (0)12233 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
7. (a) Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P.
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