Controlled reduction of 5-alkyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2- a]pyridin-4-ylium iodide: Enantioselective synthesis of (-)-dihydropinidine and (+)-indolizidine 167B

Article abstract of DOI:10.1016/j.tetasy.2004.09.030

A controlled reduction of (+)-(3R,5S)-5-methyl- and (+)-(3R,5S)-5-n-propyl- 3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 1 and 2 to generate (3R,5S)-5-methyl- and (3R,5S)-5-n-propyl-3-phenyl-2,3,5,6,7,8- hexahydro-oxazolo[3,2-a]pyri

Full text of DOI:10.1016/j.tetasy.2004.09.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3393–3395
Controlled reduction of 5-alkyl-3-phenyl-
,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide:
enantioselective synthesis of (ꢀ)-dihydropinidine and
2
(
+)-indolizidine 167B
*
Luis F. Roa, Dino Gnecco, Alberto Galindo and Joel L. Ter a´ n
Centro de Qu ´ı mica del Instituto de Ciencias, BUAP, C.P. 72570, Ciudad Universitaria Puebla, Pue., Mexico
Received 13 July 2004; accepted 28 September 2004
Abstract—A controlled reduction of (+)-(3R,5S)-5-methyl- and (+)-(3R,5S)-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-
a]pyridin-4-ylium iodide 1 and 2 to generate (3R,5S)-5-methyl- and (3R,5S)-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-
a]pyridine 3 and 4, respectively, is reported. In addition, an enantioselective synthesis of (ꢀ)-(2R,6S)-dihydropinidine and
(
+)-(2S,6S)-indolizidine 167B starting from 3 and 4, respectively, was achieved.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
Herein, we report an efficient reduction of this function
2
with L-Selectride to generate the epimeric mixture
4
1
3
In a previous publication we described the synthesis
of 1 and 2. In addition, we reported that the iminium
function of these compounds in the presence of
of oxazilidines 3 and 4 in excellent yield and high
5
diastereoselectivity (Scheme 2).
NaBH or LiAlH4 gave the opening structure
4
0
0
0
(
2R,2 S)-2-(2 -methyl-piperidin-1 -yl)-2-phenyl-ethanol
0
Ph
I
Ph
0
0
I and (2R,2 S)-2-(2 -n-propyl-piperidin-1 -yl)-2-phenyl-
ethanol II, respectively (Scheme 1).
R
O
N
R
S
O
N
L-Selectride
5
1
2
, R = Me
, R = n-propyl
3
4
Ph
Ph
I
HO
O
N
R
N
R
Scheme 2.
5
S
1
2
, R = Me
I
Reduction of 1 and 2 with L-Selectride in anhydrous
THF at ꢀ10ꢁC furnished in 10min the epimeric mixture
, R = n-propyl
II
3
and 4 with overall yields of 95% and 93% and with an
:2 ratio, respectively. This ratio was determined by H
Scheme 1.
1
8
NMR from the crude reactions. Each epimeric mixture
was readily resolved by preparative flash chromatogra-
phy. However, the major epimer in the H NMR
2
. Results and discussion
1
showed diastereoisomeric contributions with a similar
ratio measured from the crude reactions. This situation
Enantiopure compounds 1 and 2 are synthetically useful
after a controlled reduction of the iminium function.
5a
can be explained as suggested by Amat et al. and
6
Husson et al.; ‘‘the solution of this bicyclic system is
in equilibrium with its iminium tautomeric form’’.
*
Corresponding author. E-mail: dgnecco@siu.buap.mx
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.030

3394
L. F. Roa et al. / Tetrahedron: Asymmetry 15 (2004) 3393–3395
Ph
HO
H
N
N
3
, R = Me
MeOH, HCl
Pd/C, H2
Ph
6
R
2S
6R
2S
5S
MgBr
R
S
5
O
N
6HCl
5
Ph
O
HO
N
N
4, R = n-propyl
MeOH, HCl
Pd/C, H2
O
2
S
6S
8aS
O
O
MgBr
7
8HCl
Scheme 3.
To synthesize the dihydropinidine and the indolizidine
reference). IR spectra were obtained with a Nicolet FT-
IR Magna 750 spectrometer. Optical rotations were
determined at room temperature with a Perkin–Elmer
341 polarimeter, using a 1dm cell with a total volume
of 1mL and are referenced to the D-line of sodium.
Mass spectra were recorded with a JEOL JEM-
AX505HA instrument at a voltage of 70eV.
1
2
67B, we decided to carry out the alkylation at the C-
5
a position of 3 and 4 with Grignard reagents. Firstly,
,7
epimeric mixture 3 reacted with n-propyl magnesium
bromide to give 5 in 90% yield as a single stereoisomer
after flash chromatography; [a] = ꢀ17.8 (c 1.5, EtOH),
D
7
a
{
lit. enantiomer [a] = +18.3 (c 1.16, EtOH)}.
D
Catalytic hydrogenation of 5 gave the hydrochloride
8
4.2. Reduction reaction of pyridin-4-ylium iodide 1 and 2
with L-Selectride
(
2S,6R)-dihydropinidine 6ÆHCl in quantitative yield,
7a
[
[
a] = ꢀ12.9 (c 1.0, EtOH). Enantiomer: {lit.
D
5
D D
b
a] = +11.9 (c 0.69, EtOH); lit. [a] = +12.5 (c 1.0,
4.2.1. General procedure. A solution of 1 or 2
(1.46mmol) in anhydrous THF (20mL) was cooled at
ꢀ10ꢁC and then a solution of L-Selectride in THF
EtOH)}. This result was enough to assign the configura-
tion at C-6 of 5 as (R).
(1.5mL,1.0equiv) slowly added. The resulting mixture
Finally, following the same procedure as described
above, epimeric mixture 4 was treated with the Grignard
reagent derived from 2-(2-bromoethyl)-1,3-dioxolane
to give 7 in 88% yield as a single stereoisomer after
flash chromatography. Catalytic hydrogenation of 7
furnished, the hydrochloride (+)-(5S,8aS)-indolizidine
was stirred for 10min and a brine solution (1.0mL)
was added. The reaction was then warmed to 0ꢁC and
an aqueous solution of H O (1.0mL, 30%) was added,
followed by 3M NaOH (1.0mL). Finally, to this mix-
ture was added AcOEt (20mL), dried, filtered, and the
solvent eliminated in vacuo. The epimeric mixture 3 or
4 was obtained in an overall yield 95% or 93% with an
approximate diastereoisomeric ratio of 8:2, respectively.
2
2
1
67B 8ÆHCl in quantitative yield, [a] = +107.4 (c 1.0,
D
9
CH Cl ); lit. [a] = +86.6 (c 1.3, CH Cl , 78% ee);
enantiomer lit. [a] = ꢀ109 (c 1.32, CH Cl ). This re-
2
2
D
2
2
5
a
D
2
2
sult was enough to assign the configuration at C-2 of 7
as (S) (Scheme 3).
4.2.2. (3R,5S)-5-Methyl-3-phenyl-2,3,5,6,7,8-hexahydro-
oxazolo[3,2-a]pyridine. Major epimer 3. Colorless oil.
IR (KBr, cm ): 3443, 2931, 908, 735. Determined
ꢀ
1
1
from the crude reactions: H NMR (400MHz, CDCl ),
3
3. Conclusion
d (ppm, J Hz): 7.15–7.45 (m, 5H), 4.34 (dd, 7.5, 1H-3),
4
.16 (AB, 7.2, 7.8, 1H-2), 3.74 (m, 2.4, 9.6, 1H-2a),
In conclusion, the transformations of 1 and 2 described
above provide a convenient and efficient method to syn-
thesize non-racemic chiral cis-2,6-disubstituted piperi-
dines with a high diastereoselectivity, which are
important for the synthesis of alkaloids.
3.62 (AB, 6.9, 7.8 1H-2), 2.40 (m, 1H-5), 2.00 (m, 1H-
8), 1.82 (m, 1H-8), 1.60 (m, 2H-6), 1.55 (m, 2H-7),
0.66 (d, 6.3, 3H-9). C NMR (CDCl ): 144.4 (1C),
126.4–128.4 (5C), 95.8 (C-2a), 74.5 (C-2), 66.1 (C-3),
57.5 (C-5), 34.7 (C-6), 30.1 (C-8), 22.3 (C-9), 18.4 (C-7).
1
3
3
Further applications of these versatile synthons to the
asymmetric synthesis of more complex alkaloid systems
are currently in progress.
4.2.3. (3R,5S)-3-Phenyl-5-n-propyl-2,3,5,6,7,8-hexahydro-
oxazolo[3,2-a]pyridine. Major epimer 4. Colorless oil.
IR (KBr, cm ): 3440, 2926, 900, 735. Determined
ꢀ
1
1
from the crude reactions: H NMR (400MHz, CDCl ),
3
d (ppm, J Hz): 7.18–7.42 (m, 5H), 4.40 (dd, 3.2, 3.6, 1H-
3), 4.33 (AB, 7.6, 1H-2), 3.71 (m, 2.4, 12.0, 1H-2-a), 3.64
4. Experimental
(AB, 7.6, 13.6 1H-2), 2.31 (m, 1H-5), 1.22–1.85 (m, 2H-
6, 2H-7, 2H-8, 2H-9, 2H-10), 0.52 (t, 7.2, 3H-11).
1
3
4
.1. General
C
NMR (CDCl ): 139.6 (1C), 126.6–128.3 (5C), 96.1
3
1
13
H NMR spectra were recorded at 400MHz, and C
NMR spectra at 100MHz (tetramethylsilane as internal
(C-2-a), 74.7 (C-2), 65.7 (C-3), 57.3 (C-5), 36.9, 31.0,
29.8, 22.6, 18.9, 14.5.

L. F. Roa et al. / Tetrahedron: Asymmetry 15 (2004) 3393–3395
3395
1
(m, 1H, H-4). C NMR (CDCl ): 141.9 (1C), 127.5–
3
4.3. Reaction of epimeric mixture 3 and 4 with Grignard
reagents
3
128.6 (5C), 104.0 (C-2, dioxolane), 64.5 (2C-dioxolane,
0
0
C-1 ), 63.2 (C-2 ), 56.7 (C-2), 54.0 (C-6), 37.4 (C-3),
33.2 (C-7), 32.6 (C-9), 26.7 (C-8), 26.2 (C-10), 23.8 (C-
4), 19.9 (C-5), 14.6 (C-11). HRMS (FAB+): calcd for
C H NO : 347.4917; found: 347.4910.
4
1
.3.1. General procedure. To a solution of 3 (250mg,
.15mmol) in anhydrous THF (15mL) at ꢀ40ꢁC was
slowly added a solution of n-propyl magnesium bromide
in THF (2.0equiv) under nitrogen. The mixture was
kept at this temperature for 15h and then quenched
by adding water. The mixture was extracted with AcOEt
2
1
33
3
Acknowledgements
(
3 · 20mL) and the combined organic layers dried, fil-
tered, and concentrated in vacuo to give oil in yield
7%. The residue was purified by flash chromatography
SiO , CH Cl –MeOH 95:5) to give 5 in 90% yield. Fol-
D.G. and A.G. are grateful to CONACyT-M e´ xico
Project 28906N) for financial support. L.F.R. thanks
CONACyT for a doctoral Scholarship # 159389.
9
(
(
2
2
2
lowing the same procedure described, epimeric mixture 4
282mg, 1.15mmol) was treated with the Grignard
(
reagent derived from 2-(2-bromoethy)-1,3-dioxolane to
give 7 in 88% yield after flash chromatography (SiO2,
CH Cl –MeOH = 95:5).
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ꢀ1
1
KBr, cm ): 3422, 2930, 1100, 739. H NMR
(
(
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0
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4
2
1
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