New methodology for the synthesis of enantiopure (3R,2aR)-(-)-3-phenyl-hexahydro-oxazolo[3,2-a]-pyridin-5-one: A synthesis of (S)-(+)-coniine

Article abstract of DOI:10.1016/S0957-4166(01)00063-5

A new and efficient methodology for the enantiopure synthesis of (3R,2aR)-(-)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one 3 starting from (1′R)-(-)-1-(2′-hydroxy-1′-phenyl-ethyl)-(1H)-pyridin-2-one 1 is described. In addition, the enantiospecific synthesis of (S)-(+)-coniine hydrochloride 6 in good yield from 3 is reported.

Full text of DOI:10.1016/S0957-4166(01)00063-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 357–360
New methodology for the synthesis of enantiopure
(3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]-pyridin-5-one:
a synthesis of (S)-(+)-coniine
J. L. Tera´n,a D. Gnecco,a,* A. Galindo,a J. Jua´rez,a S. Berne`sa and R. G. Enr´ıquezb
aCentro de Qu´ımica del Instituto de Ciencias, BUAP, 14 Sur 6303, C.P. 72570, Ciudad Universitaria Puebla, Pue., Mexico
bInstituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, D.F. Mexico
Received 12 December 2000; accepted 22 January 2001
Abstract—A new and efficient methodology for the enantiopure synthesis of (3R,2aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-
a]pyridin-5-one 3 starting from (1%R)-(−)-1-(2%-hydroxy-1%-phenyl-ethyl)-(1H)-pyridin-2-one 1 is described. In addition, the
enantiospecific synthesis of (S)-(+)-coniine hydrochloride 6 in good yield from 3 is reported. © 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
zolo[3,2-a]pyridin-5-one in a 15% yield was observed. It
is well known that CDCl3 normally contain traces of
DCl and it was thought that this could explain the
observed transformation.
Chiral hexahydro-oxazolo[3,2-a]pyridin-5-ones are
widely used in the formation of CꢀC bonds a- to
nitrogen. The preparation, reactivity and application of
these compounds in the asymmetric synthesis of alka-
loids and piperidine derivatives1–3 have been thoroughly
studied. We have previously reported4 the synthesis of
enantiopure (1H)-pyridin-2-ones from chiral non-
racemic pyridinium salts. Considering the ease with
which these compounds are obtained, we decided to
explore the utility of (1%R)-(−)-1-(2%-hydroxy-1%-phenyl-
ethyl)-1H-pyridin-2-one 1 in the preparation of 3-
phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one. For this
purpose, we carried out three different reductions5 of 1,
Suitable crystals of 2 were obtained from an ether/n-
hexane mixture and X-ray diffraction analysis was per-
formed. Atom C-(4) is disordered over two sites (A and
B); nevertheless, bond lengths C-(3)ꢀC-(4A) and C-
(3)ꢀC-(4B), at 1.446 (16) and 1.380 (15), respectively,
were consistent with a single bond, while the C-(5)ꢀC-
(6) distance of 1.298 (5) has double bond character. The
C-(2)ꢀO-(1) bond length of 1.232 (4) is characteristic of
a carbonyl group8 (Fig. 1).
using L-selectride™, PtO2/H2 and LiAlH4.
In order to explore this transformation, we prepared a
solution of 2 in CHCl3 containing a catalytic amount of
The most efficient reduction of (1%R)-(−)-1-(2%-hydroxy-
1%-phenyl-ethyl)-(1H)-pyridin-2-one 1 was seen with
L
-
selectride™ (3 equivalents) in THF solvent (Scheme 1).
The reaction took 4 hours at room temperature.6 Using
these conditions and after purification by column chro-
matography over silica (dichloromethane/ethylacetate)
the
(1%R)-(−)-1-(2%-hydroxy-1%-phenyl-ethyl)-3,4-dihy-
dro-(1H)-pyridin-2-one 2 was obtained in 85% yield.
Product 2 had satisfactory spectroscopic data.7
1
Unexpectedly, when the H NMR of 2 was recorded
after standing for 12 hours in CDCl3, its transforma-
tion to the corresponding 3-phenyl-hexahydro-oxa-
Scheme 1.
* Corresponding author. E-mail: dgnecco@siu.cen.buap.mx
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00063-5

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J. L. Tera´n et al. / Tetrahedron: Asymmetry 12 (2001) 357–360
Scheme 2.
was performed in three steps from 3 affording (S)-(+)-
coniine hydrochloride 6 exclusively in good yield.1–3
The first step was the reaction of 3 with 3 equivalents of
n-propylmagnesium chloride in THF;11 the reaction
was carried out at 0°C; and was complete after 6 hours.
After purification by column chromatography over sil-
ica (dichloromethane/ethylacetate), (1%R,6S)-(+)-1-(2%-
hydroxy-1%-phenyl-ethyl)-6-propyl-piperidin-2-one 412
was afforded in 85% yield. The 1H and 13C NMR
spectra of the crude reaction mixture of 4 showed that
only one product had formed. Assignments in 1H NMR
were confirmed by the extensive use of 13C–1H shift
correlation experiments (Scheme 2).
Figure 1. Crystal structure of 2. Thermal ellipsoids are at 30%
probability level. Disordered position for C-(4) was omitted
for clarity.
dry HCl gas. This solution was stirred for 6 hours at
25°C and a single product was formed with Rf=0.76
(Rf of 2 was 0.20 on SiO2 in the same CH2Cl2/MeOH,
19:1 eluent). The solution was dried over anhydrous
Na2SO4, filtered and the solvent removed in vacuo
affording 3 in quantitative yield.9 Both 1H and 13C
NMR data of the crude reaction showed only one
compound, in agreement with the single product
As shown in Scheme 3, the second step of the synthesis
was the lithium aluminium hydride reduction of 4
which was completed under reflux in 1 hour, and
afforded (2R,2%S)-(+)-2-phenyl-2-(2%-propyl-piperidin-
1%-yl)-ethanol 513 in 90% yield after purification by
column chromatography over silica (n-hexane/ethylac-
1
observed by TLC analysis. Assignments in H NMR
were confirmed by extensive use of 13C–1H shift correla-
tion experiments and the configuration of the new
stereogenic centre C-(2a) in 3 was assigned by 1H NMR
1D NOE and ROESY experiments, which showed that
H-(3) and H-(2a) had a cis relationship; these results
allowed us to assign the stereochemistry of 3 as cis-C-
(3R)/C-(2aR) as shown in Fig. 2. However, this com-
pound had identical spectral data with those reported
by Husson2c for the trans-(3R,2aS)-(−)-3-phenyl-
hexahydro-oxazolo[3,2-a]pyridin-5-one.10
1
etate). Assignments from the H NMR spectrum of 5
were again confirmed by use of 13C–1H shift correlation
experiments.
In the third step, 5 was subjected to hydrogenolysis in
ethanolic solution, in the presence of 10% Pd-C/HCl, at
30°C over 48 hours, affording (2S)-(+)-coniine hydro-
chloride 614 in a 90% yield.
This reaction sequence described for the synthesis of
coniine indicates that in the first step, the oxazolo
opening of 3 by n-propylmagnesium chloride proceeds
with complete inversion11 at C-(2aR) via an SN2 mech-
anism. Such an interpretation is in agreement with the
enantiomerically pure (S)-(+)-coniine 6 obtained.
These contradictions stimulated our interest and
prompted us to carry out the synthesis of a coniine
enantiomer, which is accepted as a standard for the
demonstration of chiral methodology. The synthesis
Figure 2. Selected NOE and ROESY of 3.

J. L. Tera´n et al. / Tetrahedron: Asymmetry 12 (2001) 357–360
359
Scheme 3.
2. Conclusion
7. Compound 2. Crystallised from ether/n-hexane. Rf=0.20
(SiO2, CH2Cl2/MeOH, 95/5); mp 76–78°C; [h]2D0 −49 (c
1
1.0, CH2Cl2). IR (KBr, cm−1): 3450–3300, 2960, 1658; H
A simplified method allowing the preparation of (1%R)-
(−)-1-(2%-hydroxy-1%-phenyl-ethyl)-3,4-dihydro-(1H)py-
ridin-2-one 2 in 85% yield from enantiopure (1H)-py-
ridin - 2 - one 1 has been developed. The structure of 2
was confirmed by X-ray crystal study. A new and facile
methodology for the synthesis of enantiopure (3R,2-
aR)-(−)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-
one 3 in quantitative yield from 2 is also presented.
NMR (400 MHz): l (ppm, CDCl3, J Hz): 7.35–7.26
(f-H, 5H, m); 6.02 (H-6, dt, 7.70, 1.47); 5.82 (H-1%, dd,
8.43, 5.13); 5.16 (H-5, dt, 8.08, 4.40); 4.17–3.99 (2H-2%,
AB system, 8.43, 5.13); 2.62 (2H-3, td, 8.10, 4.80); 2.32
(2H-4, m). 13C NMR: C-(2), 171.15; C-(7), 137.07; 2C-(8),
128.86; C-(10), 127.96; 2C-(9), 127.65; C-(6), 126.48; C-
(5), 107.24; C-(2%), 62.77; C-(1%), 57.38; C-(3), 31.79; C-(4),
19.98.
Finally, (S)-(+)-coniine was efficiently prepared in five
steps and 59% overall yield from 1. These results have
potential use in the total synthesis of this class of
alkaloid, and are currently under investigation in our
laboratory.
8. Crystal structure of 2. Colourless, irregular crystal, 0.34×
0.18×0.10 mm3, C13H15NO2, orthorhombic, P212121, a=
,
8.5603(8), b=10.7338(13), c=12.4368(16) A, Z=4.
Bruker P4 diffractometer using Mo Ka radiation, T=
298(2) K, 2827 reflections measured up to 2q=50°, 2013
independent data (Rint=3.56%) for 155 refined parame-
ters. The structure was refined on the basis of non-
absorption-corrected data, using standard methods15
without restraints or constraints. Final R indices: R1=
5.61% for 1246 data having F0>4| (F0) and wR2=14.18%
for all data.
Acknowledgements
D.G. and A.G. are grateful for financial support from
CONACyT-Me´xico (Project 28906N). T.J.L. thanks
CONACyT for a doctoral scholarship c112584.
9. Compound 3. Viscous oil (volatile in vacuo); Rf=0.76
(SiO2, CH2Cl2/MeOH, 95/5); [h]2D0 −92 (c 1.0, CH2Cl2),
[(lit.2c [h]2D0 −88 (c 0.6, CH2Cl2)]. IR (KBr, cm−1): 3450–
1
References
3400, 2954, 1660; H NMR (400 MHz): l (ppm, CDCl3,
J Hz): 7.33–7.25 (fH, 5H, m); 5.26 (H-3, dd, 8.07, 7.70);
5.00 (H-2a, dd, 4.77, 4.40); 4.48 (H-2, dd, 8.07,7.70); 3.74
(H-2, dd, 8.07, 7.70); 2.52 (H-6, dd, 18.33, 5.87); 2.37
(H-8, m); 2.31 (H-6, dd, 6.60, 5.13); 1.95 (H-8, m); 1.76
(H-7, m); 1.54 (H-7, m). 13C NMR: C-(5), 169.07; C-(9),
139.64; 2C-(11), 128.87; C-(12), 127.67; 2C-(10), 126.18;
C-(2a), 88.77; C-(2), 72.54; C-(3), 58.21; C-(6), 31.39;
C-(8), 28.53; C-(7), 17.21.
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See Ref. 3a,b. However, the authors obtained the (R)-(−)-
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allylic silanes in the presence of a Lewis acid.
11. Yamazaki, N.; Kibayashi, Ch. Tetrahedron Lett. 1997,
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12. Compound 4. Viscous oil; Rf=0.25 (Al2O3, CH2Cl2/
MeOH, 98/2); [h]D20 +21.0 (c 1.0, CH2Cl2). IR (KBr,
cm−1): 3550–3380, 2925, 1640; 1H NMR (400 MHz): l
(ppm, CDCl3, J Hz): 7.33–7.22 (f-H, 5H, m); 5.24 (H-1%,
dd, 7.70, 4.77); 4.21 (2H-2%, AB, 24.56, 4.77); 3.21 (H-6,
m); 2.56 (2H-3, dd, 8.43, 5.87); 1.85 (H-4, m); 1.74 (H-4,
m); 1.55 (2H-5, m); 1.52 (H-7, m); 1.28 (H-8, m); 1.25
(H-7, m); 1.10 (H-8, m); 0.83 (3H-9, t, 7.33). 13C NMR:
C-(2), 172.68; C-(10), 137.38; 2C-(11), 128.58; 2C-(12),
5. The reduction of 1 with, PtO2/H2 afforded quantitatively
the 1-(2-hydroxy-1-phenyl-ethyl)-piperidin-2-one, while
with LiAlH4 a complex mixture was obtained.
6. Mabic, S.; Castagnoli, Jr., N. J. Org. Chem. 1996, 61,
309–313.

360
J. L. Tera´n et al. / Tetrahedron: Asymmetry 12 (2001) 357–360
127.80; C-(13), 127.56; C-(2%), 64.0; C-(1%), 63.37; C-(6), C-(5%), 27.28; C-(7%), 25.42; C-(4%), 20.34; C-(8%), 20.33;
56.42; C-(3), 35.39; C-(4), 31.83; C-(7), 25.73; C-(8),
19.54; C-(5), 16.24; C-(9), 13.91.
C-(3%), 19.50; C-(9%), 14.38.
14. (S)-(+)-Coniine·6HCl. [h]2D0 +6.3 (c 1.0, EtOH), [(lit.11
[h]2D6 +6.2 (c 0.40 EtOH)]. Mp 212–214°C, [(lit.11 mp
219–221°C)]. IR (KBr, cm−1): 2950, 2848, 1587, 1454,
13. Compound 5. Viscous oil; Rf=0.63 (Al2O3, CH2Cl2/
MeOH, 98/2). [h]D20 +17 (c 1.0, CH2Cl2). IR (KBr, cm−1):
3650–3200, 2930, 1061; 1H NMR (400 MHz): l (ppm,
CDCl3, J Hz): 7.35–7.28 (f-H, 5H, m); 3.88 (H-2, dd,
6.23, 5.87); 3.77 (2H-1, AB, 30.08, 6.60); 2.95 (H-2%, m);
2.62 (2H-6%, AB, 44.76, 10.26); 1.85 (H-7%, m, 3.30); 1.68
(H-3%, m); 1.56–1.48 (H-7%, 2H-5%, 2H-4%, m); 1.42 (H-3%,
m); 1.25 (2H-8%, m); 0.86 (3H-9%, t, 7.33). 13C NMR:
C-(3), 135.20; C-(4), 128.81; C-(5), 128.50; C-(6), 127.73;
C-(2), 67.53; C-(1), 62.09; C-(2%), 57.58; C-(6%), 43.46;
1
1387; H NMR (400 MHz): l (ppm, CDCl3, J Hz): 3.45
(H-6, dd, 12.83, 3.30); 2.94 (H-2, m); 2.83 (H-6, td, 12.83,
3.30); 2.01–1.38 (2H-7, 2H-3, 2H-4, 2H-5, 2H-8, m); 0.95
(3H-9, t, 7.33). 13C NMR: C-(2), 57.18; C-(6), 44.79;
C-(7), 35.39; C-(3), 28.16; C-(5), 22.46; C-(4), 22.22;
C-(8), 18.61; C-(9), 13.78.
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.