Syntheses of pyridin-4-ylium chirons: Applications in a synthesis of (+)-coniine

Article abstract of DOI:10.1016/j.tetasy.2004.01.017

The compounds (3R,5S)-(+)-5-methyl-3-phenyl-2,3,5,6,7,8-hexahydro- oxazolo[3,2-a]pyridin-4-ylium iodide 4 and (3R,5S)-(+)-5-n-propyl-3-phenyl-2,3, 5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 5 were synthesized in two steps starting from the bicyclic thiolactam trans (3R,2aS)-(-)-5-thio-3- phenyl-2,3,6,7,8,2a-hexahydro-oxazolo[3,2-a]pyridine 1. In addition, starting from 5 an enantiospecific synthesis of (+)-coniine 7 was achieved.

Full text of DOI:10.1016/j.tetasy.2004.01.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 847–850
Syntheses of pyridin-4-ylium chirons: applications
in a synthesis of (+)-coniine
*
ꢀ
Luis F. Roa, Dino Gnecco, Alberto Galindo, Joel L. Teran and Sylvain Bernes
ꢁ
Centro de Quꢀımica del Instituto de Ciencias. BUAP. 14 Sur 6303. C.P. 72570. Ciudad Universitaria Puebla, Pue, Mexico
Received 4 December 2003; accepted 5 January 2004
Abstract—The compounds (3R,5S)-(+)-5-methyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide
4 and
(3R,5S)-(+)-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 5 were synthesized in two steps starting
from the bicyclic thiolactam trans (3R,2aS)-())-5-thio-3-phenyl-2,3,6,7,8,2a-hexahydro-oxazolo[3,2-a]pyridine 1. In addition,
starting from 5 an enantiospecific synthesis of (+)-coniine 7 was achieved.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
only 2 h to give the corresponding diastereoisomeric
mixture 6-methyl-piperidin-2-thiones 2a and 2b and 6-n-
propyl-piperidin-2-thiones 3a and 3b, in 95% and 90%
yield, respectively. The diastereoisomeric mixtures were
subjected to column chromatography furnishing the
diastereoisomers 2a and 3a in 80% yield, respectively
(Table 1).
Bicyclic lactams such as A and B permit the stereocon-
trolled introduction of a substituent at the a position
and have been used as effective starting material in the
asymmetric synthesis of alkaloids (Scheme 1).1–3
Previously, we described a preparation of the thiolactam
trans-(3R,2aS)-())-5-thio-3-phenyl-2,3,6,7,8,2a-hexahy-
dro-oxazolo[3,2-a]pyridine 1.4 Herein we report the
reactions of this thiolactam with Grignard reagents to
generate 6-alkylpiperidin-2-thiones and the reactivity of
the reaction products with methyl iodide.
Table 1
Ph
Ph
Ph
OH
R
6R
OH
R
6S
O
N
S
S
N
S
N
RMgBr
+
2aS
a
b
1
2. Results and discussion
Entry RMgBr
Products
R
Yield a:b ratioa
(%)
Firstly, we investigated the reaction of the thiolactam
trans-(3R,2aS)-())-5-thio-3-phenyl-2,3,6,7,8,2a-hexahy-
dro-oxazolo[3,2-a]pyridine 1 with MeMgCl and n-pro-
pylMgCl in anhydrous THF at )20 ꢁC, which required
1
2
CH3MgCl 2a+2b
n-PrMgCl 3a+3b
CH3 95
CH2CH2CH3 90
97:3
95:5
a Determined by 1H NMR.
Ph
Ph
Ph
Ph
OH
R
OH
R
O
O
N
N
O
O
O
N
O
N
RMgBr
RMgBr
α
α
A
B
Scheme 1.
* Corresponding author. E-mail: dgnecco@siu.buap.mx
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.017

848
L. F. Roa et al. / Tetrahedron: Asymmetry 15 (2004) 847–850
Fortunately, 2a can be crystallized from chloroform and
its X-ray diffraction analysis was performed. The abso-
lute configuration of the new stereogenic center C-6 of
the major diastereoisomer 2a was determined as (S),
based on the auxiliary stereocenter, which is C-(10R);
[source of chirality: (R)-())-2-phenylglycinol]. There-
fore, we concluded that the absolute configuration of
C-6 of the main product 3a was (S) (Fig. 1).
In the second part of this work, we studied the reaction
of the thione function of 2a and 3a with iodomethane,
without a previous protection of the hydroxyl group.6
For this purpose, a solution of these compounds in THF
were treated with a large excess of iodomethane at room
temperature.7 After 4 h of stirring, the solvent and
unreacted iodomethane were removed in vacuo, giving 4
and 5 in quantitative yield, respectively. The structures
of these compounds were determined by 1H and 13C
NMR (Scheme 2).
Ph
I
Ph
HO
O
N
R
N
R
S
CH3I, THF
2a: R = Me
3a: R = n-propyl
4
5
Scheme 2.
This result could be explained by the nucleophilic attack
of the hydroxyl group on the C-2 of the methylsulfanyl
intermediate I to give the sulfonium II, which by elimi-
nation of the methanethiol group furnishes the 5-alkyl-
hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 4 or 5
(Scheme 3).
Figure 1. Crystal structure of 2a with thermal ellipsoids at 30%
probability level (non-H atoms). Minor disordered positions for the
hydroxyl group has been omitted for clarity.
The high stereoselectivity observed in this process can be
explained if the magnesium coordinate with the oxygen
of the oxazilidine causing the alkyl group to attack from
the same face the C–O bond.5 (Fig. 2).
Finally, to corroborate the absolute configuration
assigned as (C-6S) for compound 3a, we synthesized the
coniine, using as starting material the enantiopure
compound 5. For this purpose, this compound was
refluxed in THF in presence of LiAlH4 to produce 68 as
a single isomer in quantitative yield. Finally, the 2-
phenylethanol auxiliary of 6 was removed by catalytic
hydrogenation, furnishing (S)-(+)-coniine 7 HCl9 in
quantitative yield (Scheme 4).
Cl
Mg
6S
2aS
In conclusion, starting from 1 we have described an easy
access to compounds 2a and 3a in high yields and with a
remarkable diastereoselectivity. In addition, we have
found that these compounds can be easily converted
into the corresponding pyridin-4-ylium iodide.
Figure 2.
Ph
I
Ph
Ph
Ph
HO
HO
O
O
N
R
I N
R
N
R
N
R
S
H3CS
- CH3SH
THF
CH3I
H3CS
I
H
4 or 5
I
II
Scheme 3.
Ph
Ph
HO
H
N
I
O
N
N
LiAlH4
THF
MeOH, HCl
Pd/C, H2
5
6
7HCl
Scheme 4.

L. F. Roa et al. / Tetrahedron: Asymmetry 15 (2004) 847–850
849
We are currently continuing our exploration of the
synthetic potential of these useful building blocks
towards asymmetric synthesis.
for absorption and 2062 independent reflections
(Rint ¼ 2.71%) were used for the refinement of 165
parameters, without neither restraints nor constraints
(SHELXTL 5.10 package). The hydroxyl group is dis-
ordered over two positions, O1 and O10, with site
occupation factors 0.331(6) and 0.669(6), respectively.
Disordered H atoms for this hydroxyl group were found
on difference maps, while remaining H atoms were
placed on idealized positions. All H atoms were refined
using a riding model. Final R indices: R1 ¼ 4.10% for
1522 reflections with I > 2rðIÞ and wR2 ¼ 10.34% for all
data. The correctness of the absolute configuration was
checked on the basis of a refined Flack parameter:
x ¼ ꢁ0:11ð13Þ. A CIF file has been deposited with the
CCDC (Deposition number 223087) and structure fac-
tors are available on request.
3. Experimental
3.1. General
1H NMR spectra of CDCl3 solutions were recorded with
a Varian Unity instrument at 400 MHz (internal tetra-
methylsilane as reference). IR spectra were obtained
with a Nicolet FT-IR Magna 750 spectrometer. Chro-
matography was carried out using SiO2. Optical rota-
tions were determined at room temperature with a
Perkin–Elmer 341 polarimeter, using a 1 dm cell with a
total volume of 1 mL and are referenced to the D-line of
sodium. Mass spectra were recorded with a JEOL JEM-
AX505HA instrument at a voltage of 70 eV. Melting
points were determined using a Fisher–Johns apparatus
and are uncorrected.
3.2.3. (10R,6S)-())-1-(20-Hydroxy-10-phenyl-ethyl)-6-n-
20
propyl-piperidine-2-thione 3a. Yellow oil. ½aꢀ ¼ )107.2
D
1
(c 3.9, CH2Cl2); IR (KBr, cmꢁ1) 3419, 2956, 1475. H
NMR (400 MHz, CDCl3): d (ppm, J Hz): 7.27–7.43 (m,
5H, 1H-10), 4.38 (dd, 6.0, 1H-20), 4,22 (dd, 10.4, 6.0, 1H-
20), 3.33 (m, 1H-3, 1H-6), 3.05 (m, 1H-3), 2.83 (OH),
1.83 (m, 1H-4), 1.72 (m, 1H-4, 2H-7, 1H-5), 1.26 (m, 2H-
8, 1H-5), 0.90 (t, 7.2, 3H-9). 13C NMR (CDCl3): 203.30
(C-2), 135.42 (1C), 128.65–127.45 (5C), 64.46 (C-10),
62.12 (C-20), 54.73 (C-6), 40.06 (C-3), 34.41 (C-4), 24.71
(C-7), 19.98 (C-5), 16.24 (C-8), 13.91 (C-9). HRMS
(FAB+): Calcd for C16H23NOS: 277.1500; found:
277.1488.
3.2. Reaction of thiolactam trans-1 with MeMgCl and
n-PrMgCl
3.2.1. General procedure. A solution of 1 (1 equiv) in
anhydrous THF (5 mL) was added to a solution of the
corresponding Grignard reagent (3 equiv) in THF at
)20 ꢁC. The reaction mixtures were stirred at this tem-
perature during 2 h. The reaction was quenched by
addition of saturated aqueous ammonium chloride, and
the mixture was extracted with AcOEt (3 · 20 mL). The
combined organic extracts were dried with anhydrous
Na2SO4, filtered, and concentrated in vacuo to give the
corresponding mayor products 2a and 3a in 80%,
respectively, after purification by column chromatogra-
phy (CH2Cl2/MeOH ¼ 95:5).
3.2.4. Synthesis of (3R,5S)-())-5-alkyl-3-phenyl-2,
3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide.
General procedure. To a solution of 2a or 3a in anhy-
drous THF at 5 ꢁC was added dropwise an excess of
CH3I in THF. The resulting mixture was stirred for 4 h
at room temperature, then the solvent was removed in
vacuo and the corresponding pyridin-4-ylium iodide 4
and 5 were obtained in quantitative yield, respectively.
3.2.2.
(10R,6S)-())-1-(20-Hydroxy-10-phenyl-ethyl)-6-
methyl-piperidine-2-thione 2a. White solid. Mp 107–
20
110 ꢁC ½aꢀ ¼ )172.2 (c 1.1, CH2Cl2); IR (KBr, cmꢁ1
)
D
3.2.5. (3R,5S)-())-5-methyl-3-phenyl-2,3,5,6,7,8-hexahy-
dro-oxazolo [3,2-a]pyridin-4-ylium iodide 4. Yellow oil.
3387, 2945, 1480. 1H NMR (400 MHz, CDCl3): d (ppm,
J Hz): 7.28–7.42 (m, 5H, 1H-10), 4.38 (dd, 6.0, 1H-20),
4,26 (m, 1H-20), 3.57 (m, 1H-6), 3.31 (m, 1H-3), 3.11 (m,
1H-3), 1.98 (m, 1H-5, 1H-4), 1.70 (m, 1H-5), 1.53 (m,
1H-4), 1.30 (t, 6.8, 3H-7). 13C NMR (CDCl3): 203.04 (C-
2), 135.44 (1C), 128.62–127.38 (5C), 64.35 (C-10), 61.91
(C-20), 50.29 (C-6), 40.02 (C-3), 28.81 (C-5), 19.11 (C-4),
16.24 (C-7). HRMS (FAB+): Calcd for C14H19NOS:
249.1187; found: 249.1176.
20
½aꢀ ¼ +11.8 (c 1.0, MeOH); IR (KBr; cmꢁ1) 3445, 1645,
D
1480. 1H NMR (400 MHz, CDCl3): d (ppm, J Hz): 7.46–
7.53 (m, 5H), 5.87 (dd, 7.2, 6.8, 1H-3), 5.65 (dd, 9.2, 8.8,
1H-2), 4.65 (dd, 7.2, 1H-2), 4.37 (m, 5.6, 1H-5), 3.13 (m,
2H-8), 2.45 (m, 1H-7), 2.27 (m, 1H-7), 2.06 (m, 1H-6),
1.78 (m, 1H-6), 0.85 (t, 6.4, 3H-9). 13C NMR (CDCl3):
177.08 (C-2a), 135.95 (1C), 130.13–127.79 (5C), 78.77
(C-2), 66.99 (C-3), 55.00 (C-5), 29.36 (C-8), 25.37 (C-7),
19.74 (C-9), 15.30 (C-6). HRMS (FAB+): Calcd for
C14H18NO+: 216.1388; found: 216.1376.
3.2.2.1. Crystal structure of 2a. Colorless, irregular
crystal, 0.5 · 0.3 · 0.2 mm3, C19H14NOS. Orthorhombic,
P212121,
13:0296ð13Þ A, Z ¼ 4, qcalc ¼ 1:220 g cmꢁ3. A set 3318
a ¼ 9:8878ð12Þ,
b ¼ 10:5398ð10Þ,
c ¼
3.2.6. (3R,5S)-())-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexa-
hydro-oxazolo[3,2-a]pyridin-4-ylium iodide 5. Yellow
ꢂ
20
D
reflections was collected at T ¼ 296ð1Þ K using Mo-Ka
oil. ½aꢀ ¼ +9.2 (c 1.0, MeOH); IR (KBr, cmꢁ1) 3405,
1
ꢂ
radiation (k ¼ 0:71073 A, Bruker P4 diffractometer),
1648, 1460, 702. H NMR (400 MHz, CDCl3): d (ppm,
corresponding to 2hmax ¼ 50ꢁ. Raw data were corrected
J Hz): 7.47–7.61 (m, 5H), 5.90 (dd, 7.2, 1H-3), 5.66 (dd,

850
L. F. Roa et al. / Tetrahedron: Asymmetry 15 (2004) 847–850
1996, 26, 1605–1611; Teran, J. L.; Gnecco, D.; Galindo,
ꢀ
A.; Juarez, J.; Bernes, S.; Enrıquez, R. Tetrahedron:
10.0, 9.6, 1H-2), 4.80 (dd, 9.6, 7.4, 1H-2), 4.37 (m, 1H-5),
3.15 (m, 2H-8), 2.43 (m, 1H-7), 2.18 (m, 1H-7), 2.06 (m,
1H-6), 1.87 (m, 1H-6), 0.80–1.21 (m, 2H-9, 2H-10), 0.54
(t, 6.4, 3H-11). 13C NMR (CDCl3): 178 (C-2a), 134.97
(1C), 130.10–127.83 (5C), 78.41 (C-2), 67.25 (C-3), 58.82
(C-5), 33.73 (C-8), 29.51 (C-7), 24.82 (C-9), 18.67 (C-10),
15.30 (C-6), 13.28 (C-11). HRMS (FAB+): Calcd for
C16H22NO+: 244.1701; found: 244.1690.
ꢀ
Asymmetry 2001, 12, 357–360; Roa, L. F.; Gnecco, D.;
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