Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2713
lar ring closure of 7a was achieved by treatment with
TFA in CH2Cl2 to give the bicyclic compound 8a as an
inseparable diastereomeric mixture of the C-5 epimeric
product in a ratio of 42:58. The methyl-substituted
carbon C-9 of 8a , which should be the C-6 moiety of the
subsequent piperidine ring, shows an R configuration.
Moreover, the reaction of 8a with methylmagnesium
bromide gave a piperidine derivative with complete cis
configuration at its 2,6-dimethyl substituents.10 On the
basis of these results, we next inserted the propynyl
functionality into 8a by reacting it with propynylmag-
nesium bromide, which was prepared in situ from eth-
ylmagnesium bromide and propyne, to give the 2,6-
disubstituted piperidine 9a in 96% yield. Compound 9a
had the cis configuration exclusively, which was con-
firmed by further conversion to the title compound 1a .11
The propynyl functionality was transformed into the
desired (E)-propenyl side chain by subjecting 9a to a
specific reduction according to the Birch procedure. We
took advantage of this process which provided N-depro-
tection similar to Kibayashi’s method5a to give the volatile
1a . Treatment with ethanolic-HCl and recrystallization
from EtOH-ether gave (-)-pinidine hydrochloride
(1a ·HCl) as colorless crystals, mp 244-246 °C (lit.5a mp
244-246 °C); [R]20D -9.5 (c 1.01, EtOH) [lit.5a [R]24D -9.6
(c 0.25, EtOH)] in 70% yield.12
should also be applicable to the synthesis of other 2,6-
disubstituted piperidine compounds.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were measured with-
1
out correction. The H NMR and 13C NMR spectra were run in
CDCl3 unless otherwise noted. All chemical shifts are reported
as δ values (ppm) relative to TMS and residual CDCl3 as internal
standards on a 270 MHz spectrometer. Column chromatography
was performed on silica gel (45-75 mm, Wakogel C-300). The
THF was distilled over potassium metal, and CH2Cl2 was
distilled over phosphorus pentoxide. All other solvents and
reactants were of the best commercial grade available and used
without further purification unless noted.
(2R,6R,1′R)-N-(2′-Hydr oxy-1′-ph en yleth yl)-2-(1-pr opyn yl)-
6-m eth ylp ip er id in e (9a ). A stirred solution of ethylmagne-
sium bromide (2.93 mL, 8.8 mmol) in THF (20 mL), which was
cooled with ice water-NaCl, was bubbled with propyne gas for
3-5 min. To the resulting solution of propynylmagnesium
bromide was added dropwise a solution of the bicyclic compound
8a (prepared in three steps in 61% overall yield from 4)10 (0.48
g, 2.2 mmol) in THF (10 mL). After stirring at room temperature
under N2 for 18 h, the reaction mixture was quenched with
water, and the organic solution was decanted from the insoluble
solid. The residue was extracted with ether (2 × 20 mL), the
organic extracts were combined, dried over Na2SO4, and evapo-
rated under reduced pressure to give an oil. Column chroma-
tography on silica gel with CH2Cl2-MeOH (19:1) afforded the
2,6-disubstituted piperidine 9a as a pale yellow oil (0.55 g, 96%).
[R]20 +2.9 (c 1.12, CHCl3). 1H NMR δ 1.13 (d, 3 H, J ) 6.7
D
Next, the preparation of (S,S)-(+)-pinidine (1b) was
attempted starting from the oxazolidine 5b bearing a
propynyl moiety at C-2, as shown in Scheme 1. The
initial 5b was built up by the condensation of phenyl-
glycinol 4 with 2-butynal in CH2Cl2 by the addition of
dried MgSO4. The 1H NMR spectrum of the crude
product suggested an inseparable diastereomeric mixture
in a ratio of 69:31. The unstable mixture of 5b, without
purification, was treated with a Grignard reagent derived
from 2-(3-bromopropyl)-1,3-dioxolane 6 to give the dias-
tereomerically pure amino acetal 7b in 87% overall yield
from 4. The cyclization reaction of 7b gave the bicyclic
compound 8b in 74% yield as a single diastereomer. To
introduce a methyl moiety, the requisite intermediate 8b
was treated with methylmagnesium bromide to give the
2,6-disubstituted piperidine 9b in 92% yield with a
completely cis configuration, which was confirmed by
further conversion to the target compound 1b as follows.
Birch reduction was carried out to simultaneously remove
the N-protective group and reduce the triple bond to an
(E)-alkene to produce (+)-pinidine (1b). Treatment with
ethanolic-HCl and recrystallization from EtOH-ether
provided (+)-pinidine hydrochloride (1b·HCl), mp 246-
247 °C (lit.5a mp 246-248 °C); [R]20D +9.5 (c 1.05, EtOH)
Hz), 1.33-1.67 (m, 3 H), 1.73-1.87 (3 H, m), 1.85 (d, 3 H, J )
2.4 Hz), 2.52 (br s, 1 H), 2.83 (m, 1 H), 3.76 (m, 1 H), 3.89 (dd,
1 H, J ) 5.5, 11.0 Hz), 3.93 (dd, 1 H, J ) 4.9, 11.0 Hz), 4.09 (dd,
1 H, J ) 4.9, 5.5 Hz), 7.24-7.36 (m, 3 H), 7.42 (dd, 2 H, J ) 1.8,
7.6 Hz). 13C NMR δ 3.6, 15.0, 17.0, 32.7, 32.9, 45.4, 50.2, 63.8,
64.7, 80.0, 80.9, 127.4, 128.3, 128.6, 140.0. EIMS m/z (relative
intensity): 257 [M]+ (3), 226 [M - CH2OH]+ (100). IR (CHCl3):
3400 (OH) cm-1. Anal. Calcd for C17H23NO: C, 79.33; H, 9.01;
N, 5.44. Found: C, 79.08; H, 9.19; N, 5.36.
Syn th esis of (-)-P in id in e Hyd r och lor id e (1a ·HCl). To
stirred liquid ammonia (50 mL) in a flask equipped with a dry
ice condenser was added a solution of N-substituted piperidine
9a (0.54 g, 2.1 mmol) in THF (5 mL). Sodium (1.0 g, 43.5 mmol)
was added portionwise to the reaction mixture solution. After
being stirred for 9 h, THF (10 mL) was added, the reaction vessel
was opened to the atmosphere, and its contents were allowed
to warm to room temperature over 16-18 h. The residue was
quenched by the addition of MeOH and water and extracted with
CH2Cl2 (3 × 10 mL). The organic phase was dried over Na2SO4
and carefully evaporated below 30 °C under reduced pressure.
The remaining oil was subjected to column chromatography on
silica gel with CH2Cl2-MeOH (5:1) to give (-)-pinidine as a
colorless oil (0.204 g, 70%). Treatment with ethanolic-HCl gave
(-)-pinidine hydrochloride (1a ·HCl), which was recrystallized
from EtOH-ether to afford colorless needles, mp 244-246 °C.
[R]20 -9.5 (c 1.01, EtOH). 1H NMR δ 1.43-1.96 (m, 6 H), 1.59
D
(d, 3 H, J ) 6.7 Hz), 1.68 (dd, 3 H, J ) 1.8, 6.7 Hz), 3.09 (m, 1
H), 3.45 (m, 1 H), 5.75 (dd, 1 H, J ) 7.3, 15.9 Hz), 5.91 (dq, 1 H,
J ) 6.7, 15.9 Hz), 9.20 (br s, 1 H), 9.50 (br s, 1 H). 13C NMR δ
17.8, 19.5, 22.8, 28.8, 30.2, 54.3, 59.9, 126.9, 132.4. EIMS m/z
(relative intensity): 139 [M]+ (34), 124 [M - CH3]+ (84).
(2R,4R)-N-(2,4,6-Tr im et h oxyb en zyl)-2-(1-p r op yn yl)-4-
p h en yl-1,3-oxa zolid in e (5b). To a solution of the phenylgly-
cinol 4 (7.0 g, 22.06 mmol) in CH2Cl2 (100 mL) was added
2-butynal (4.5 g, 66.18 mmol) and an equal amount of dried
MgSO4. The reaction mixture was stirred at room temperature
under N2 for 1 h and filtered over a pad of Celite. The reaction
flask was rinsed twice with CH2Cl2, and then the combined CH2-
Cl2 solution was evaporated under reduced pressure and dried
under vacuum to afford a diastereomeric mixture (69:31) of 5b
as a pale yellow oil, which was unstable and used without further
purification. 1H NMR δ major component: 1.89 (d, 3 H, J ) 1.8
Hz), 3.65 (s, 3 H), 3.68 (s, 6 H), 3.61-3.96 (m, 4 H), 4.05 (t, 1 H,
J ) 6.7 Hz), 4.95 (q, 1 H, J ) 1.8 Hz), 6.04 (s, 2 H), 7.19-7.36
(m, 3 H), 7.45 (dd, 2 H, J ) 1.8, 7.9); minor component: 1.97 (d,
[lit.5a [R]24 +9.5 (c 0.20, EtOH)] in 65% yield.12
D
In conclusion, we have described the enantioselective
synthesis of (-)-pinidine (1a ) in 41.1% overall yield in
five steps, and of (+)-pinidine (1b) in 38.5% overall yield
in five steps, using the diastereoselective reaction of
chiral 1,3-oxazolidine and Grignard reagent as the key
step, as well as the 1-aza-4-oxabicyclo[4.3.0]nonane
derivative as a pivotal intermediate. This procedure
(11) The cis configuration of compouds 9a and 9b was determined
indirectly by the comparison of optical rotation values of pinidine 1a
and 1b, respectively, with the reference’s values.
(12) The enantiomeric purities of both (-)- and (+)-pinidine (>99%
ee) were determined chromatographically, as their N-benzoyl deriva-
tives, by using chiral HPLC-column CHIRALCEL OD (4.6 mm i.d. ×
250 mm) with hexane-isopropyl alcohol (93:7).