A chiral 1,4-oxazin-2-one: Asymmetric synthesis versus resolution, structure, conformation and VCD absolute configuration

Article abstract of DOI:10.1016/S0957-4166(01)00478-5

1,4-Oxazin-2-one 3 is obtained from 2-pinanone in 4 steps and 78% overall yield. Enantiopure (e.e. >99%) (R)-(+)-3 and (S)-(-)-3 were obtained through chiral supercritical fluid chromatography (using a semi preparative Chiralpak AS column) with almost quantitative recovery of material. The structure and the boat-conformation of the lactone ring have been determined by NMR and the absolute configuration determined by VCD.

Full text of DOI:10.1016/S0957-4166(01)00478-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2703–2707
A chiral 1,4-oxazin-2-one: asymmetric synthesis versus
resolution, structure, conformation and VCD absolute
configuration
A. Solladie´-Cavallo,a,* O. Sedy,a,b M. Salisova,b,† M. Biba,c C. J. Welch,c,‡ L. Nafie´d,§ and
T. Freedmand,¶
aECPM/Universite` Louis Pasteur, 67087 Strasbourg, France
bDepartment of Organic Chemistry, Comenius University, 842 15 Bratislava, Slovakia
cMerck & Co., Inc., Rahway, NJ 07065, USA
dDepartment of Chemistry, Syracuse University, Syracuse, New York, NY 13244-4100, USA
Received 14 September 2001; accepted 24 October 2001
Abstract—1,4-Oxazin-2-one 3 is obtained from 2-pinanone in 4 steps and 78% overall yield. Enantiopure (e.e. >99%) (R)-(+)-3 and
(S)-(−)-3 were obtained through chiral supercritical fluid chromatography (using a semi preparative Chiralpak AS column) with
almost quantitative recovery of material. The structure and the boat-conformation of the lactone ring have been determined by
NMR and the absolute configuration determined by VCD. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The chiral 1,4-oxazinone 1, derived from hydroxy-
pinanone was synthesized by Viallefont et al. in 19881,2
and has been shown to give dialkylation reactions as
well as dehydrated aldol products.3 The structurally
similar, but less constrained oxazinone 2 was proposed
in 2000 by Najera et al.4 and the propensity of 2 to give
dehydrated aldol products was also studied.
2.1. Synthesis
It is well known that methylation of 1-tetralone
through the lithium enolate generated with LDA leads
to low yields (ꢀ45%).5 However, by using a ‘naked’
enolate generated with t-BuP4,6 1-tetralone was quanti-
tatively methylated with MeI. The phosphazene base
(t-BuP4) can be recovered by isolation (through precip-
itation with hexane) of the hydro-iodide salt formed.
Asymmetric hydroxylation of 4 using Davis’ reagent,7
We present herein the synthesis, the structure and con-
formation determination by NMR, resolution using
supercritical fluid technique and VCD determination of
the absolute configuration of the chiral oxazinone 3.
(1S)-(+)-(8,8-dichlorocamphorsulfonyl)-oxaziridine
5
was tried; but, although the yield in 6 (83%) was
satisfying, only 90/10 e.r. was obtained. Therefore,
racemic oxazinone 3 was prepared8 and then resolved.
It is worth noting that formation of 3 occurs sponta-
neously upon reaction of 6 with methyl glycinate in
benzene at reflux in the presence of traces of BF3·OEt2.
The conversion is quantitative and pure 3 was isolated
in 96% yield (Scheme 1).
O
N
O
N
N
O
O
O
Me
O
Ph
Me
3
2
1
2.2. Structure and conformation of 3
2.2.1. NMR. No signal was observed which would
correspond to an ester–MeO but only one singlet corre-
sponding to the expected MeꢀC (1.55 ppm). The CH2
of the lactone ring exhibits a non-equivalence of 0.5
ppm in CDCl3 (d at 4.35 ppm and d at 4.85 ppm) and
* Corresponding author. E-mail: ascava@ecpm.u-strasbg.fr
† salisova@fns.uniba.sk
‡ christopher welch@merck.com
–
§ lnafie@syr.edu
¶ tbfreedm@syr.edu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00478-5

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2703–2707
9
O
O
O
N
O
Me
OH
8
5
O
7
6
2
Me
i
4
4
3
3
_
_
(+)-3, 96%
iv
ii (+)-6, 88%
4, 92%
iii 6, 83%, e.r. = 90/10 iv 3, 96%, e.r. = 91/9
Cl
N
= (+)-5
S
O2
O
Cl
Scheme 1. (i) t-BuP4 1 M in hexane, MeI, −78°C, THF; (ii) TMSCl/Et3N/NaI, MeCN/pentane, 25°C; m-CPBA/NaHCO3,
CH2Cl2, HCl, 25°C; (iii) NHMDS 1 M in THF, −78°C, 5, THF; (iv) H2NCH2CO2Me, trace BF3·OEt2, benzene, reflux.
a NOESY experiment shows that the methyl is corre-
lated with one H of the lactone ring CH2 (d at 4.35
ppm), as expected for a lactone ring in a boat-form and
with a methyl axial. Therefore, an axial position was
assigned to this proton at 4.35 ppm (d). Moreover, one
of the aromatic doublets (7.23 ppm) was correlated to
the CH2 multiplet at 3.05 ppm, which was thus assigned
to the benzylic protons. It is worth noting that the 22
Hz value observed for the geminal coupling constant on
the lactone CH2 is consistent with the boat conforma-
tion of this ring, as, in this conformation, the lactone–
carbonyl bisects the CH2 dihedral angle leading to a
maximum p-neighboring effect.9
AS column (2×25 cm, ChiralTechnologies, Exton, PA)
operating at a flow rate of 50 mL/min with a mobile
phase of 8% methanol in carbon dioxide (100 bar outlet
pressure). Detection was done by UV at 300 nm. Injec-
tion of 1 mL of ( )-3 as a 25 mg/mL solution in
methanol afforded the baseline resolution of both enan-
tiomer in less than 10 min. A total of 150 mg of ( )-3
was resolved with both enantiomers being obtained in
>99% e.e. with good recovery (93% for the first eluted
and 89% for the second).
Circular dichroism measurements (0.06 mg/mL in
methanol) indicated a negative CD signal at 300 nm for
the first eluted enantiomer ([h]2D0=−298, CHCl3) and a
positive signal at this wavelength for the second eluted
enantiomer.
The boat conformation of the lactone ring (origin of
the large non-equivalence of the CH2 protons) led us to
expect a very acidic compound with a strong p.s*-
hyperconjugative interaction between one of the CꢀH
bonds and the p-system of the carbonyl as well as good
stereodifferentiation because of an expected preferred
pseudo-equatorial substituent at this position.
2.4. Absolute configuration determination by VCD
The absolute configuration of 3 was determined by
comparing the measured VCD10–16 spectrum of a sam-
ple of (+)-3 having an e.r. of 91/9 and ꢀ100% chemical
purity with that of a DFT quantum calculation of the
VCD spectrum of the (R)-isomer. The sample was
dissolved in CDCl3 and placed in a 100 mm path length
cell with BaF2 windows. The VCD and IR spectra were
collected on a modified Chiralir VCD spectrometer
(ABB Bomem/Biotools) at 4 cm−1 resolution with the
instrument optimized for 1400 cm−1, with a 2 h collec-
tion for the VCD.17 Isomer (R)-3 was first constructed
with HyperChem (Hypercube, Inc.), and calculation of
the optimized geometry (Fig. 1), vibrational frequen-
cies, normal modes, IR and VCD intensities were car-
ried out at the DFT B3LYP/6-31G* level with
Gaussian 98.
The enantiomeric ratio of 3 (obtained from enriched 6)
was determined to be 91/9 by 1H NMR (400 MHz,
CDCl3) using Eu(hfc)3. A splitting of the methyl-singlet
(at 1.55 ppm) and of the doublet (at 4.85 ppm) of the
equatorial-H of the lactone ring–CH2 was rapidly
observed. In the major enantiomer, the methyl singlet is
shielded, while the H-equatorial doublet is deshielded
(compared to the minor isomer). An enantiomeric ratio
of 90/10 was found for the starting hydroxyketone 6
using 1H NMR (400 MHz, CDCl3) and the same
Eu(hfc)3 complex (splitting of the methyl singlet). It
thus appeared that the asymmetric induction during
hydroxylation was much lower than expected from
literature results.7
It is worth noting that the conformation found by
calculation corresponds to the conformation found by
NMR with a methyl axial and the iminolactone ring in
a boat shape.
2.3. Resolution of ( )-3 via chiral HPLC
Resolution of ( )-3 was carried out by supercritical
fluid chromatography and a semi-preparative Chiralpak

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2703–2707
2705
The calculated IR and VCD spectra are compared to
experiment in Fig. 2. The excellent agreement between
experiment and calculation establishes the absolute
configuration of the sample studied as R, and also
indicates that the conformer calculated is the predomi-
nant one in solution in CDCl3.
3. Conclusion
In conclusion, the resolution which provides both enan-
tiomers of iminolactone 3 in high yield and high e.r. is
more efficient that the asymmetric synthesis which pro-
vides the desired compound in only 91/9 e.r. It has also
been determined by VCD that the second eluted enan-
tiomer (+, CHCl3)-3 has R configuration.
Figure 1. Optimized geometry of (R)-3.
Figure 2. Comparison of observed VCD and IR spectra of a sample of (+, CHCl3)-3 with calculated VCD and IR spectra of
geometry-optimized (R)-3. (red: observed; black: calculated).

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2703–2707
4. Experimental
4.3. 2-Hydroxy-2-methyl-1-tetralone (2-hydroxy-2-
methyl-3,4-dihydro-2H–naphthalen-1-one) 6
4.1. General remarks
To a stirred solution of 2-methyl-1-tetralone (0.913 g,
5.7 mmol, 1 equiv.) in anhydrous THF (10 mL) was
added dropwise a solution of NHMDS (sodium
bis(trimethylsilyl)amide) (1 M soln in THF, 6.84 mL,
6.84 mmol, 1.2 equiv.) at −78°C under argon. After
stirring for 0.5 h at −78°C, a precooled solution
(−78°C) of oxaziridine 5 (2.09 g, 6.84 mmol, 1.2 equiv.)
in anhydrous THF (10 mL) was added dropwise to the
reaction mixture at −78°C and stirring was maintained
for 1 h at the same temperature. The reaction was
quenched at −78°C by addition of saturated NH4Cl
solution (1 mL). The temperature was allowed to
increase to 20°C and solvents were evaporated under
vacuum. The crude product was dissolved in
dichloromethane (30 mL), NH4Cl was filtered off (frite
4), washed with access of CH2Cl2 and the solvent of the
combined organic phases was evaporated under vac-
uum. The residue was chromatographed on silica gel
(hexane/EtOAc, 9/1). Isolated yield: 828 mg (83%) col-
1H and 13C NMR spectra were recorded on a Bruker
AC 200 (200 MHz) and 2D-COSY on a Bruker Avance
(400 MHz) spectrometer with CDCl3 as solvent. Chem-
ical shifts (l) are given in ppm downfield from TMS
and coupling constants (J) in Hz.
The resolution was carried out using a semi preparative
SFC instrument from Berger Instrument, Newark, DE.
Circular dichroism measurements were performed on a
Jasco 810 instrument. TLC were performed on Merck’s
glass plates with silica gel 60 F254. Silica gel Si 60 (40–60
mm) from Merck was used for the chromatographic
purifications. a-Tetralone, sodium bis(trimethylsilyl)-
amide, 1m solution of t-BuP4 in hexane and (1S)-(+)-
(8,8-dichlorocamphorsulfonyl)-oxaziridine were pur-
chased from Aldrich, Aldrich, Fluka and Fluka,
respectively, and used without further purification.
Usual IR spectra and rotations were recorded/deter-
mined on a Perkin–Elmer Spectrum one and a Perkin–
Elmer 341, respectively.
1
orless oil. H NMR: (CDCl3) l 1.42 (3H, s, CH3), 2.24
2
3
3
(1H, ddd, J=13, J=11.5, J=5.5, CH3a), 2.29 (1H,
2
3
3
2
ddd, J=13, J=6, J=3, CH3e), 3.05 (1H, ddd, J=
18, 3J=5.5, 3J=3.5, CH4e), 3.13 (1H, ddd, 2J=18,
For VCD determination of absolute configuration,
infra red absorption and VCD spectrum were recorded
in a 100 mm pathlength BaF2 cell, at 4 cm−1 resolution,
using Chiralir Fourier transform VCD spectrometer
from ABB Bomem/BioTools (Quebec, Canada) opti-
mized for operation at 1400 cm−1. VCD spectrum was
recorded for 2 h by co-adding approximately 4800
interferometric scans. The sample was dissolved in
CDCl3 (80 mg/mL).
3J=12, J=6, CH4a), 3.86 (1H, bs, OH), 7.28 (1H, dd,
3
3J=7.5, 4J=1.5, H5), 7.37 (1H, dt, 3J=7.5, 7.5, 4J=1.5,
3
4
H7), 7.54 (1H, dt, J=7.5, 7.5, J=1.5, H6), 8.19 (1H,
dd, J=7.5, J=1.5, H8). 13C NMR: (CDCl3) l 24.0
(CH3), 26.9 (CH2), 36.0 (CH2), 73.7 (C-OH), 127.0
(CH), 128.1 (CH), 129.1 (CH), 134.2 (C), 134.2 (CH),
3
4
143.5 (C), 201.9 (CꢁO). IR: wCꢁO=1689 cm−1, wOH
=
3480 cm−1. Anal. for C11H12O2: C, 74.98; H, 6.86;
found C, 74.35; H, 6.94. [h]2D0=+10 (c=0.45, CHCl3),
e.r.=90/10, from asymmetric hydroxylation. ( )-6 has
been prepared through m-CPBA oxidation of the silyl
enol ether of ketone 4, followed by TBAF hydrolysis
(yield=88% from 4).8
4.2. 2-Methyl-1-tetralone (2-methyl-3,4-dihydro-2H–
naphthalen-1-one) 4
To a stirred solution of 1-tetralone (21 mg, 0.14 mmol,
1 equiv.) in anhydrous THF (2 mL) was added drop-
wise the phosphazene base t-BuP4 (0.14 mL of 1 M
soln in hexane, 0.14 mmol, 1 equiv.) at −78°C under
argon. After stirring for 20 min at the same tempera-
ture, iodomethane (36 mL, 0.57 mmol, 4 equiv.) was
added dropwise. Reaction mixture was then stirred at
−78°C for 0.5 h, while monitoring the by TLC (hexane/
ethyl acetate 4:1). When the reaction was complete, the
solvent was evaporated and the crude product was
chromatographed on silica gel (hexane/EtOAc, 50/1).
4.4. Iminolactone, 3
To a stirred solution of 2-hydroxy-2-methyl-3,4-dihyd-
ro-2H-naphthalen-1-one (47 mg, 0.27 mmol, 1 equiv.)
in dry benzene (2 mL) was added BF3–etherate (1 drop,
catalytic amount) at room temperature under argon.
After 10 min stirring at room temperature methyl glyci-
nate (2 equiv., 48 mg, 0.54 mmol) in dry benzene (2
mL) was added and the reaction mixture was stirred
under reflux for 2 h with a Dean–Stark trap. A second
portion of methylglycinate (2 equiv., 48 mg, 0.54 mmol)
in dry benzene (2 mL) was added and reflux continued
for 2 h; a third portion of methyl glycinate (1 equiv., 24
mg, 0.27 mmol) in dry benzene (1 mL) was added and
reflux continued for a further 12 h. The progress of the
reaction was monitored by TLC (hexane/ethyl acetate,
4/1). The temperature was allowed to decrease to room
temperature, solvent was evaporated and the crude
product was purified by chromatography (hexane/
EtOAc, 9/1). Isolated yield: 54 mg (96%), white crys-
1
Isolated yield: 21 mg, (92%) colorless oil. H NMR:
3
(CDCl3) l 1.28 (3H, d, J=6.5, CH3), 1.91 (1H, dddd,
2J=13, 3J=12, 3J=11, 3J=4.5, H3a), 2.23 (1H, dq,
2J=13, three times 3J=4.5, H3e), 2.62 (1H, ddq, 3J=12,
3J=4.5, three times 3J=6.5, H2), 3.00 (1H, dt, 2J=16.5,
twice 3J=4.5, H4e), 3.07 (1H, ddd, 2J=16.5, 3J=11,
3
3J=4.5, H4a), 7.25 (1H, d, J=7.5, H5), 7.32 (1H, t,
3
4
3J=7.5, H7), 7.46 (1H, dt, J=7.5, J=1.5, H6), 8.19
(1H, dd, J=7.5, J=1.5, H8). 13C NMR: (CDCl3) l
15.5 (CH3), 28.9 (CH2), 31.5 (CH2), 42.7 (CH), 126.6
(CH), 127.5 (CH), 128.8 (CH), 132.5 (C), 133.2 (CH),
144.3 (C), 200.9 (CꢁO); IR: wCꢁO=1684 cm−1. Anal. for
C11H12O: C, 82.46; H, 7.55; found C, 81.45; H, 7.55%
3
4
1
tals: mp 123–127°C. H NMR: (CDCl3) l 1.56 (3H, s,
CH3), 2.29 (2H, m, CH2 at C(3)), 3.05 (2H, m, CH2 at
C(4)), 4.35 (1H, d, J=22, OꢁC-CHaxial-Nꢁ), 4.85 (1H,
2

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2703–2707
2707
d, 2J=22, OꢁC-CHequat.-Nꢁ), 7.23 (1H, bd, 3J=7.5,
Diaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron:
Asymmetry 1992, 3, 567.
4. Chinchilla, R.; Falvello, L. R.; Galindo, N.; Najera, C. J.
Org. Chem. 2000, 65, 3034.
5. Goto, M.; Akimoto, K. I.; Aoki, K.; Shindo, M.; Koga,
K. Tetrahedron Lett. 1999, 40, 8129.
6. (a) Pietzonkan, T.; Seebach, D. Chem. Ber. 1991, 124,
1837; (b) Solladie´-Cavallo, A.; Csaky, A. G.; Gantz, I.;
Suffert, J. J. Org. Chem. 1994, 59, 5343.
7. Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55,
3715.
8. ( )-6 was prepared in two steps from 4. For m-CPBA
oxidation of silyl enol ether, cf. Vedejs, E.; Engler, D. A.;
Telschow, J. E. J. Org. Chem. 1978, 43, 188 and refer-
ences cited therein.
3
3
H5), 7.32 (1H, bt, J=7.5, H7), 7.42 (1H, dt, J=7.5,
4
3
4
7.5, J=1.5, H6), 8.19 (1H, dd, J=7.5, J=1.5, H8).
13C NMR: (CDCl3) l 21.4 (CH3), 26.7 (CH2), 35.1
(CH2), 50.5 (CH2N), 80.9 (C-O), 126.0 (CH), 127.2
(CH), 128.9 (CH), 130.3 (C), 131.6 (CH), 138.3 (C),
165.2 (CꢁO), 168.3 (CꢁN). IR: wCOlactone=1749 cm−1,
wCꢁN=1650 cm−1. Anal. for C13H13NO2: C, 72.54; H,
6.09; found C, 72.89; H, 6.15. [h]2D0=+240 (c=1,
CHCl3), e.r.=91.5/8.5 (through asymmetric hydroxyla-
tion). [h]2D0=−298 (c=1, CHCl3), e.r.=99.5/0.5
(through resolution).
Acknowledgements
9. Sternhell, S. Quart. Rev. 1969, 23, 236.
10. Nafie, L. A. Annu. Rev. Phys. Chem. 1997, 48, 357–386.
11. Nafie, L. A.; Freedman, T. B. Enantiomer 1998, 3, 283–
297.
12. Nafie, L. A.; Freedman, T. B. In Circular Dichroism,
Theory and Practice; Nakanishi, K.; Berova, N.; Woody,
W., Eds. Vibrational Optical Activity Theory; Wiley:
New York, 2000; pp. 97–131.
We are grateful to the ‘Ambassade de France a`
Bratislava-Service de Coope´ration et d’Action Cul-
turelle (M. B. Paqueteau)’ for encouragement and
financial support to O.S. and to M. Schmitt for assis-
tance with spectral.
13. Freedman, T. B.; Long, F.; Citra, M.; Nafie, L. A.
Enantiomer 1999, 4, 103–109.
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