A simple stereoselective synthesis of enantiopure 2-substituted pyrrolidines and piperidines from chiral (R)-phenylglycinol-derived bicyclic 1,3-oxazolidines

Article abstract of DOI:10.1002/(SICI)1099-0690(200005)2000:9<1719::AID-EJOC1719>3.0.CO;2-R

Chiral, nonracemic 2-substituted pyrrolidines and piperidines were prepared in high ee and moderate to good chemical yields in three steps from (R)-phenylglycinol and γ- or δ-chloroketones. The key step of the synthesis was the stereo- selective reductive ring-opening of chiral bicyclic 1,3- oxazolidines prepared by condensation of (R)-phenylglycinol and the corresponding ketones.

Full text of DOI:10.1002/(SICI)1099-0690(200005)2000:9<1719::AID-EJOC1719>3.0.CO;2-R

FULL PAPER
A Simple Stereoselective Synthesis of Enantiopure 2-Substituted Pyrrolidines
and Piperidines from Chiral (R)-Phenylglycinol-Derived Bicyclic
1,3-Oxazolidines
[a]
[a]
[a]
[a]
´
´
´
´
Jose M. Andres, Ignacio Herraiz-Sierra, Rafael Pedrosa,* and Alfonso Perez-Encabo
Keywords: Asymmetric synthesis / Nitrogen heterocycles / Heterocycles / Pyrrolidines / Piperidines
Chiral, nonracemic 2-substituted pyrrolidines and piperid-
selective reductive ring-opening of chiral bicyclic 1,3-oxazol-
ines were prepared in high ee and moderate to good chem-
idines prepared by condensation of (R)-phenylglycinol and
ical yields in three steps from (R)-phenylglycinol and γ- or δ- the corresponding ketones.
chloroketones. The key step of the synthesis was the stereo-
Introduction
The pyrrolidine and piperidine ring systems are present
in many natural products and biologically important sub-
stances.[1] As a part of an ongoing project directed to this
type of heterocycle,[2] we describe now a short route to en-
antiopure 2-substituted pyrrolidines and piperidines from
the chiral perhydropyrrolo[2,1-b][1,3]oxazoles 3a؊f and
perhydropyrido [2,1-b][1,3]oxazoles 3g؊i (bicyclic oxazolid-
ines) derived from (R)-phenylglycinol. Both enantiomers of
phenylglycinol have been used as chiral auxiliaries in mono-
and bicyclic oxazolidine-mediated diastereoselective syn-
thesis.[3] Recently, the preparation of alkaloids,[4] amino ac-
ids,[5] piperidines,[6] and isoindoline derivatives[7] by using
oxazolidines derived from phenylglycinol has been re-
ported. In the same way, bicyclic oxazolidines prepared
from phenylglycinols and dialdehydes have been demon-
strated to be excellent starting materials in the synthesis of
Scheme 1. (a) Et3N, CHCl3, room temp., 24Ϫ96 h
enantiopure morpholines,[8] pyrrolidines,[9] piperidines[10] or
aminophosphonates;[11] chiral bicyclic lactams have also
been successfully used in the preparation of both pyrrolid- system in good diastereomeric excesses (84Ϫ92%). The only
ines[12] and piperidines.[13]
exception was the δ-chloroketone 2g, which gave 3g as an
The chiral bicyclic oxazolidines 3a؊i were prepared 80:20 mixture of diastereoisomers at C-8a. NOESY experi-
(Scheme 1) by condensation of (R)-(Ϫ)-phenylglycinol and ments allowed us to assign a cis relationship between the
the corresponding γ- or δ-chloroketones 2a؊i at room phenyl group and the substituent at the angular carbon for
temp. in chloroform or toluene and triethylamine as solv- all the bicyclic structures 3a؊i, showing that the condensa-
ents. It should be noted that it was necessary to work at tion of γ- and δ-chloroketones followed the same stereo-
high concentration (ca. 10 ) to ensure that the condensa- chemical outcome as that described for keto acids.[12]
tion finished in 24Ϫ120 h.[14] Chloroketone 2a was com-
The mixtures of diastereoisomers were used in the next
mercially available and 2b,[15] 2c,[16] 2d,[17] 2e,[15] 2f,[18] 2g,[19] stage because they could not be separated. The ring open-
2h[20] and 2i[21] were easily prepared from 4-chlorobutanoyl ing of bicyclic oxazolidines 3a؊i was first tested by hydro-
chloride or 5-chloropentanoyl chloride by reaction with or- genation. This method would allow the preparation of 2-
ganometallic reagents.[22]
substituted pyrrolidines and piperidines in one step. Unfor-
The condensation was diastereoselective, leading to a tunately, hydrogenation of 3a with palladium on carbon
mixture of epimers at the angular carbon of the bicyclic yielded 2-methylpyrrolidine in good yield but with very low
enantiomeric excess (7%). The preparation of pyrrolidine
[a]
and piperidine derivatives was envisaged in two steps by
reductive ring opening of the oxazolidine ring followed by
hydrogenolytic elimination of the phenylethanol append-
age (Scheme 2).
´
´
Departamento de Quımica Organica, Facultad de Ciencias,
Universidad de Valladolid,
Doctor Mergelina s/n, 47011 Valladolid, Spain
Fax: (internat.) ϩ 34-98/342-3013
E-mail: pedrosa@qo.uva.es
Eur. J. Org. Chem. 2000, 1719Ϫ1726
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0509Ϫ1719 $ 17.50ϩ.50/0
1719

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J. M. Andres, I. Herraiz-Sierra, R. Pedrosa, A. Perez-Encabo
FULL PAPER
syl chloride. The enantiomeric purity of the corresponding
pyrrolidines was measured by 19F NMR spectroscopy of
the MTPA derivatives and the configuration of the final
products was determined by comparison of the sign of the
optical rotation previously described.
In the same way, (ϩ)-pipecoline hydrochloride (5g),[13b]
(R)-2-ethylpiperidine hydrochloride (5h)[13b] and (Ϫ)-coni-
ine (5i)[29] were obtained from 4g؊i by hydrogenolysis over
Pd(OH)2 on carbon followed by treatment with hydrogen
chloride in anhydrous diethyl ether.
These results indicated that reductive ring opening of the
N,O-acetal moiety in bicyclic oxazolidines 3a؊i took place
with total retention of the configuration at the angular car-
bon and that the stereochemical outcome in the opening of
our compounds is similar to those described for related bi-
cyclic oxazolidines[11] or lactams.[12]
Scheme 2. (a) LiBHEt3, THF, 0 °C, 10 h; (b) i: H2, Pd(C) 10%,
EtOH; ii: TsCl, iPr2NEt; (c) i: LiAlH4, THF, 0 °C, 12 h; ii: Ac2O,
DMPA, room temp. 1.5 h; (d) H2, Pd(OH)2, HCl, Et2O
In order to broaden the scope of both the pyrrolidine
and piperidine routes, we tested the preparation of (Ϫ)-δ-
Treatment of 3a؊i with one equivalent of lithium alumi- coniceine 9 and (Ϫ)-anabasine 13. The proposed way to 9
nium hydride in THF at room temperature gave the desired was complementary to that described by Meyers,[13b] since
ring-opened compounds but with considerable epimeriz- in our case the six-membered ring was closed on the acetal-
ation. On the contrary, the reaction of 3a؊f with 1.5 containing 2-substituted pyrrolidine 8. To this end, the
equivalents of lithium triethylborohydride in THF at 0 °C ethylene acetal of 8-chloro-5-oxooctanal 6, prepared from
led to 4a؊f in good chemical yields and with complete dia- 4-chlorobutanoyl chloride and the copper derivative of 2-
stereoselectivity (Table 1) as demonstrated by 1H NMR (3-chloropropyl)-1,3-dioxolane, was condensed with (R)-
spectroscopy of the reaction mixture. At this stage the dia- phenylglycinol to give the angular substituted bicyclic ox-
stereomeric amino alcohols were separated by flash chroma- azolidine 7 in 78% yield and 90% de. Reductive ring open-
tography giving 4a؊f as enantiopure compounds. The per- ing of 7 by treatment with lithium triethylborohydride in
hydropyperido[2,1-b][1,3]oxazoles 3g؊i also reacted with li- THF yielded a mixture of diastereomeric 2-substituted pyr-
thium triethylborohydride in THF at 0 °C leading, after the rolidines in 74% yield with total retention of configuration.
corresponding hydrogenolysis, to the amino alcohols. The After purification by flash chromatography, the major dias-
diasteromeric mixture of these amino alcohols could not be tereoisomer 8 was transformed into enantiopure (Ϫ)-δ-con-
separated, so they were transformed into acetates 4g؊i by iceine[30] by hydrolysis and hydrogenation over 10% Pd/C in
reaction with Ac2O and DMAP in dichloromethane and methanol containing a 2  solution of HCl (Scheme 3).
readily purified to single diastereoisomers by flash chroma-
tography.
Finally, enantiopure (Ϫ)-anabasine 13 was prepared, in
three steps, from the pyridine derivative 10 as outlined in
The transformation of 4a؊f into (R)-2-methylpyrrolid- Scheme 4. Ketone 10 was obtained by SO3 Py oxidation of
ine,[23] (R)-2-ethylpyrrolidine,[24] (R)-2-propylpyrrolidine,[25] the alcohol prepared by reaction of 3-pyridylcarboxal-
(S)-2-isopropylpyrrolidine,[26] (R)-2-butylpirrolidine,[27] and dehyde and 4-chlorobutylmagnesium bromide in 63% total
(R)-2-phenethylpyrrolidine,[28] isolated as tosylates, was car- yield. Condensation of 10 with (R)-phenylglycinol in the
ried out by removal of the N-benzyl moiety by hydro- presence of triethylamine by refluxing in toluene for 36 h.
genolysis over palladium on carbon and treatment with to- led to perhydro[2,1-b][1,3]oxazole 11 as an 80:20 mixture of
Table 1. Synthesis of chiral bicyclic oxazolidines 3a؊i, reductive ring opening to 4a؊i and their transformation into enantiopure pyrrolid-
ines 5a؊f or piperidines 5g؊i
Starting
Entry
Oxazolidines
Yield (%)[a]
Amino alcohols
Yield (%)[a]
Pyrrolidine
or Piperidine
Yield (%)[a]
Compounds
de[b]
de[b]
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
72
89
60
84
60
81
83
82
84
88
87
88
88
87
60
92
92
4a
4b
4c
4d
4e
4f
4g
4h
4i
67
84
77
80
89
78
90
89
85
84
90
88
88
90
86
62
91
92
5a
5b
5c
5d
5e
5f
5g
5h
5i
80
87
86
80
91
84
68
75
73
[a]
[b]
Yields refer to compounds obtained in each transformation after isolation and purification. Ϫ
Determined by integration in 1H
NMR spectra of the reaction mixtures.
1720
Eur. J. Org. Chem. 2000, 1719Ϫ1726

Stereoselective Synthesis of Enantiopure Pyrrolidines and Piperidines
FULL PAPER
and piperidines in high enantiomeric purity and moderate
to good chemical yields from γ- or δ-chloroketones.
Experimental Section
General: Optical rotations were measured on a digital polarimeter
in a 1-dm cell and concentrations are given in g/100 mL. 1H and
13C NMR spectra were recorded at 300 MHz and 75 MHz, respect-
ively, in CDCl3 as solvent; chemical shifts are given in ppm relative
to TMS as internal standard. Ϫ Only the most significant IR sig-
nals are given. Ϫ Mass Spectra were measured by chemical ioniza-
tion (CI). Chromatographic separations were performed by flash
chromatography using Merck silica gel (240Ϫ400 mesh), and TLC
analysis was done on Merck 0.25 mm silica gel plates (60F Ϫ 254).
Melting points were determined in open capillary tubes and are un-
corrected.
All the reactions were carried out in oven-dried glassware under an
argon atmosphere. Solvents were distilled prior to use: toluene and
THF from benzophenone ketyl, CHCl3 from CaH2, and methanol
from magnesium turnings.
Scheme 3. (a) Et3N, CHCl3; (b) LiAlH4, Et2O, 0 °C; (c) H2, Pd(C)
10%, EtOH, HCl 2 
General Procedure for the Synthesis of Bicyclic Oxazolidine 3a؊g:
A mixture of the corresponding ketone 2a؊g (10.0 mmol), phenyl-
glycinol (1.50 g, 11.0 mmol), and triethylamine (10.0 mmol), in
1 mL of chloroform, was stirred until the reaction was finished
(24Ϫ96 h). The reaction mixture was diluted by addition of Et2O
(50 mL), the solids were separated by filtration and the filtrate was
concentrated in vacuo to give a residue which was purified by flash
chromatography or by distillation under reduced pressure. Com-
pounds 3a؊g were obtained as an inseparable mixture of epimers
at the angular carbon (see Table 1). The spectroscopic data are
given for the major diastereoisomer.
(3R,7aS)-7a-Methyl-3-phenylperhydropyrrolo[2,1-b][1,3]oxazole
(3a): Colorless liquid, b.p. 152Ϫ154 °C/0.9 Torr, yield 92%, Rf ϭ
0.7 (hexane/EtOAc, 1:1, v/v), [α]2D3 ϭ Ϫ94.6 (c ϭ 2.7, CHCl3). Ϫ
1H NMR (CDCl3): δ ϭ 1.44 (s, 3 H, CH3), 1.7Ϫ2.1 (m, 4 H, 6-H
and 7-H), 2.73Ϫ2.8 (m, 1 H, 5-H), 3.03Ϫ3.11 (m, 1 H, 5-HЈ), 3.71
(t, J ϭ 8.8 Hz, 1 H, 2-H), 3.96 (dd, J ϭ 8.8 and 6.9 Hz, 1 H, 3-H),
4.27 (dd, J ϭ 8.6 and 6.8 Hz, 1 H, 2-HЈ), 7.20Ϫ7.40 (m, 5 H, Ar
H). Ϫ 13C NMR (CDCl3): δ ϭ 24.8 (C-6), 26.3 (CH3), 38.9 (C-7),
55.9 (C-5), 71.2 (C-3), 72.5 (C-2), 105.5 (C-7a), 126.8 (2C), 127.1,
128.3 (2C), 141.8. Ϫ CI-MS: m/z (%) ϭ 204 (100) [Mϩ ϩ 1], 188
(4), 137 (3), 122 (3).
Scheme 4. (a) Et3N, Toluene; (b) LiAlH4, Et2O, 0 °C; (c) Swern
Ox., DNP
diastereomers at C-8a in 66% yield. The major cis stereoiso-
mer was obtained by recrystallization of the mixture in
pentane.
(3R,7aS)-7a-Ethyl-3-phenylperhydropyrrolo[2,1-b][1,3]oxazole (3b):
Colorless liquid, b.p. 107Ϫ109 °C/1.5 Torr, yield 72%, Rf ϭ 0.63
(hexane/EtOAc, 5:1, v/v), [α]2D3 ϭ Ϫ96.3 (c ϭ 1.2, CHCl3). Ϫ 1H
NMR (CDCl3): δ ϭ 0.99 (t, J ϭ 7.5 Hz, 3 H, CH3), 1.56Ϫ2.0 (m,
6 H), 2.74Ϫ2.82 (m, 1 H, 5-H), 2.95Ϫ3.03 (m, 1 H, 5-HЈ), 3.62 (t,
J ϭ 8.9 Hz, 1 H, 2-H), 3.98 (dd, J ϭ 9.3 and 7.0 Hz, 1 H, 3-H),
4.25 (dd, J ϭ 8.6 and 6.0 Hz, 1 H, 2-HЈ), 7.19Ϫ7.41 (m, 5 H, Ar
H). Ϫ 13C NMR (CDCl3): δ ϭ 9.2 (CH3), 24.3 (CH2), 31.7 (CH2),
35.9 (CH2), 55.7 (C-5), 71.0 (C-3), 72.5 (C-2), 108.2 (C-7a), 126.8
(2C), 127.0, 128.3 (2C), 142.0. Ϫ CI-MS: m/z (%) ϭ 218 (100) [Mϩ
ϩ 1], 206 (15), 188 (11), 140 (5), 121 (5), 105 (3).
Reductive ring opening of 11 with lithium aluminium hy-
dride in THF at 0 °C yielded the enantiopure phenylglyci-
nol derivative 12 in 62% yield with total retention of config-
uration. Attempts to remove the benzyl moiety by hydro-
genolysis with palladium on carbon were not synthetically
efficient because a complex mixture of overreduction prod-
ucts were formed. Therefore, debenzylation was carried out
in a two-step sequence[31] by Swern oxidation of 12 to the
corresponding α-aminoaldehyde followed by treatment with
2,4-dinitrophenylhydrazine. After purification by flash
chromatography (silica gel, CH2Cl2/MeOH/NH4OH,
180:15:1) enantiopure (Ϫ)-anabasine 13[32] was obtained in
40% yield.
(3R,7aS)-3-Phenyl-7a-propylperhydropyrrolo[2,1-b][1,3]oxazole (3c):
Colorless liquid, yield 89%, Rf ϭ 0.6 (hexane/EtOAc, 1:1, v/v),
[α]2D3 ϭ Ϫ84.1 (c ϭ 1.4, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 0.95 (t,
J ϭ 7.2 Hz, 3 H, CH3), 1.4Ϫ2.0 (m, 8 H), 2.74Ϫ2.81 (m, 1 H, 5-
H), 2.94Ϫ3.02 (m, 1 H, 5-HЈ), 3.63 (dd, J ϭ 9.2 and 8.6 Hz, 1 H,
In summary, a simple method has been designed for the
preparation of chiral, nonracemic 2-substituted pyrrolidines 2-H), 3.98 (dd, J ϭ 9.2 and 7.0 Hz, 1 H, 3-H), 4.25 (dd, J ϭ 8.6
Eur. J. Org. Chem. 2000, 1719Ϫ1726 1721

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J. M. Andres, I. Herraiz-Sierra, R. Pedrosa, A. Perez-Encabo
FULL PAPER
and 7.0 Hz, 1 H, 2-HЈ), 7.03Ϫ7.68 (m, 5 H, Ar H). Ϫ 13C NMR 2 H, 5-H), 3.68 (dd, J ϭ 7.8 and 7.6 Hz, 1 H, 2-H), 4.21 (t, J ϭ
(CDCl3): δ ϭ 14.6 (CH3), 18.2 (CH2), 24.2 (CH2), 36.5 (CH2), 41.5 7.5 Hz, 1 H, 2-HЈ), 4.36 (t, J ϭ 7.8 Hz, 1 H, 3-H), 7.23Ϫ7.41 (m,
(CH2), 55.5 (C-5), 70.9 (C-3), 72.4 (C-2), 107.8 (C-7a), 126.9 (2C),
5 H, Ar H). Ϫ 13C NMR (CDCl3): δ ϭ 18.7 (CH2), 22.6 (CH2),
24.1 (CH3), 31.4 (CH2), 43.2 (C-5), 62.5 (C-3), 72.1 (C-2), 93.5 (C-
8a), 127.5, 127.7 (2C), 128.4 (2C), 140.6. Ϫ CI-MS: m/z (%) ϭ 218
(100) [Mϩ ϩ 1], 216 (40), 202 (31).
127.1, 128.3 (2C), 141.9. Ϫ CI-MS: m/z (%) ϭ 232 (100) [Mϩ
ϩ
1], 216 (3), 202 (2), 188 (55), 140 (5), 154 (10).
(3R,7aR)-7a-Isopropyl-3-phenylperhydropyrrolo[2,1-b][1,3]oxazole
(3d): Colorless liquid, yield 60%, b.p. 141Ϫ143 °C/1.5 Torr, Rf ϭ
0.66 (hexane/EtOAc, 5:1, v/v), [α]2D3 ϭ Ϫ103.9 (c ϭ 2.0, CHCl3). Ϫ
1H NMR (CDCl3): δ ϭ 0.98 (d, J ϭ 6.8 Hz, 3 H, CH3), 1.04 (d,
J ϭ 6.8 Hz, 3 H, CH3), 1.61Ϫ2.04 (m, 5 H), 2.76Ϫ2.94 (m, 2 H,
5-H), 3.58 (dd, 1 H, J ϭ 9.4 and 8.5 Hz, 2-H), 4.01 (dd, J ϭ 9.4
and 7.1 Hz, 1 H, 3-H), 4.23 (dd, 1 H, J ϭ 8.5 and 7.1 Hz, 2-HЈ),
7.00Ϫ7.67 (m, 5 H, Ar H). Ϫ 13C NMR (CDCl3): δ ϭ 17.6 (CH3),
18.0 (CH3), 23.9 (CH2), 31.7 (CH2), 34.7 (CH), 55.8 (C-5), 71.0 (C-
3), 72.3 (C-2), 111.0 (C-7a), 126.9, 127.1 (2C), 128.3 (2C), 142.2.
Ϫ CI-MS: m/z (%) ϭ 232 (100) [Mϩ ϩ 1], 188 (24).
(3R,8aS)-8a-Ethyl-3-phenylperhydropyrido[2,1-b][1,3]oxazole (3h):
Colorless oil, b.p 175 °C/2 Torr, yield 83%, Rf ϭ 0.42 (CH2Cl2). Ϫ
[α]2D3 ϭ Ϫ102.5 (c ϭ 1.0, CHCl3). Ϫ 1H NMR (CHCl3): δ ϭ 1.0 (t,
J ϭ 7.4 Hz, 3 H, CH3), 1.11Ϫ1.16 (m, 1 H), 1.38Ϫ1.77 (m, 6 H),
1.91Ϫ2.03 (m, 1 H), 2.67Ϫ2.8 (m, 2 H, 5-H), 3.61 (dd, J ϭ 7.5 and
8.5 Hz, 1 H, 2-H), 4.2 (t, J ϭ 7.3 Hz, 1 H, 2-HЈ), 4.4 (dd, J ϭ 7.4
and 8.5 Hz, 1 H, 3-H), 7.23Ϫ7.42 (m, 5 H, Ar H).Ϫ 13C NMR
(CDCl3): δ ϭ 7.4 (CH3), 18.7 (CH2), 22.6 (CH2), 27.8 (CH2), 30.9
(CH2), 42.6 (CH2, C-5), 62.3 (C-3), 73.1 (C-2), 94.8 (C-8a), 127.6,
127.8 (2C), 128.4 (2C), 140.6. Ϫ CI-MS: m/z (%) ϭ 232 (100) [Mϩ
ϩ 1], 202 (73).
(3R,7aS)-7a-Butyl-3-phenylperhydropyrrolo[2,1-b][1,3]oxazole (3e):
Colorless liquid, yield 84%, b.p. 105Ϫ110 °C/0.6 Torr, Rf ϭ 0.63
(hexane/EtOAc, 5:1, v/v), [α]2D3 ϭ Ϫ84.4 (c ϭ 2.1, CHCl3). Ϫ 1H
NMR (CDCl3): δ ϭ 0.92 (t, J ϭ 7.2 Hz, 3 H, CH3), 1.3Ϫ2.0 (m,
10 H), 2.74Ϫ2.82 (m, 1 H, 5-H), 2.93Ϫ3.03 (m, 1 H, 5-HЈ), 3.64
(dd, J ϭ 9.1 and 8.6 Hz, 1 H, 2-H), 3.97 (dd, J ϭ 9.2 and 7.0 Hz,
1 H, 3-H), 4.25 (dd, J ϭ 8.6 and 7.0 Hz, 1 H, 2-HЈ), 7.21Ϫ7.42 (m,
5 H, Ar H). Ϫ 13C NMR (CDCl3): δ ϭ 14.1 (CH3), 23.1 (CH2),
24.2 (CH2), 27.1 (CH2), 36.4 (CH2), 38.8 (CH2), 55.5 (C-5), 70.9
(C-3), 72.3 (C-2), 107.9 (C-7a), 126.8 (2C), 127.0, 128.3 (2C), 141.8.
Ϫ CI-MS: m/z (%) ϭ 246 (100) [Mϩ ϩ 1], 244 (65), 188 (93).
(3R,8aS)-3-Phenyl-8a-propylperhydropyrido[2,1-b][1,3]oxazole (3i):
Colorless oil, yield 81%, Rf ϭ 0.6 (CH2Cl2). Ϫ [α]2D3 ϭ Ϫ124.7 °C
(c ϭ 1.1, CHCl3). Ϫ H NMR (CDCl3): δ ϭ 1.11 (t, J ϭ 7.2 Hz,
1
3 H, CH3), 1.13Ϫ1.27 (m, 1 H), 1.56Ϫ1.99 (m, 8 H), 2.0Ϫ2.07 (m,
1 H), 2.85Ϫ2.9 (m, 2 H), 3.73 (dd, J ϭ 7.5 and 8.5 Hz, 1 H, 2-H),
4.32 (t, J ϭ 7.3 Hz, 1 H, 2-HЈ), 4.51 (dd, J ϭ 7.4 and 8.4 Hz, 1 H,
3-H), 7.53Ϫ7.35 (m, 5 H, Ar H). Ϫ 13C NMR (CDCl3): δ ϭ 14.6
(CH3), 16.4 (CH2), 18.7 (CH2), 22.6 (CH2), 31.1 (CH2), 37.6 (CH2),
42.6 (C-5), 62.2 (C-3), 73.0 (C-2), 94.8 (C-8a), 127.6, 127.8 (2C),
128.4 (2C), 140.6. Ϫ CI-MS: m/z (%) ϭ 246 (100) [Mϩ ϩ 1], 230
(7), 202 (57).
(3R,7aR)-3-Phenyl-7a-(phenylethyl)perhydropyrrolo[2,1-b][1,3]-
oxazole (3f): Colorless solid, yield 60%, m.p. 62Ϫ65 °C (from pent-
ane), Rf ؍ 0.64 (hexane/EtOAc, 3:1, v/v). Ϫ [α]2D3 ϭ Ϫ58.2 (c ϭ
2.0, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.67Ϫ2.19 (m, 6 H),
2.76Ϫ2.85 (m, 3 H), 2.99Ϫ3.08 (m, 1 H, 5-H), 3.67 (t, J ϭ 9.2 Hz,
1 H, 2-H), 4.02 (dd, J ϭ 9.2 and 7.0 Hz, 1 H, 3-H), 4.3 (dd, 1 H,
J ϭ 8.6 and 7.0 Hz, 1 H, 2-H), 7.19Ϫ7.40 (m, 10 H, Ar H). Ϫ 13C
NMR (CDCl3): δ ϭ 24.3 (CH2), 31.4 (CH2), 36.6 (CH2), 40.9
(CH2), 55.5 (C-5), 70.9 (C-3), 72.5 (C-2), 107.5 (C-7a) 125.6 (2C),
126.8 (2C), 127.1 (2C), 128.2 (2C),128.3 (2C), 141.6, 142.5. Ϫ CI-
MS: m/z (%) ϭ 294 (100) [Mϩ ϩ 1], 188 (15).
(3R,8aR)-3-Phenyl-8a-(3Ј-pyridyl)-perhydropyrido[2,1-b][1,3]-
oxazole (11): A mixture of ketone 10 (2.24 g, 11.3 mmol), (R)-
phenylglycinol (1.87 g, 13.6 mmol) and Et3N (2.78 mL, 20.0 mmol)
in toluene (25 mL) was refluxed for 36 h. The solution was filtered
and the solvent was removed under vacuum yielding 11 as a mix-
ture of diastereomers (66%). The major product was purified by
recrystallization (40%). Orange solid, m.p. 103Ϫ105 °C, Rf ϭ 0.35
(hexane/EtOAc, 1:1, v/v). Ϫ [α]2D3 ϭ Ϫ53.6 (c ϭ 1.0, CHCl3). Ϫ 1H
NMR (CDCl3): δ ϭ 1.28Ϫ1.35 (m, 2 H), 1.72Ϫ1.83 (m, 2 H),
2.0Ϫ2.1 (m, 1 H), 2.22Ϫ2.28 (m, 1 H), 2.76Ϫ2.9 (m, 2 H), 3.6 (dd,
J ϭ 8.1 and 8.9 Hz, 1 H, 2-H), 4.25 (t, J ϭ 7.5 Hz, 1 H, 2-HЈ),
4.44 (dd, J ϭ 7.2 and 8.9 Hz, 1 H, 3-H), 7.26 Ϫ7.38 (m, 4 H),
7.43Ϫ7.46 (m, 2 H), 8.04Ϫ8.08 (m, 1 H, Ar H), 8.57 (dd, J ϭ 1.6
and 4.8 Hz, 1 H, Ar H), 9.03 (1 H, d, J ϭ 1.6 Hz, Ar H). Ϫ 13C
NMR (CDCl3): δ ϭ 19.0 (CH2), 19.7 (CH2), 30.7 (CH2), 43.7
(CH2), 64.6 (C-3), 72.0 (C-2), 94.3 (C-8a), 123.0, 127.6 (2C), 127.7,
128.5 (2C), 134.8, 138.7, 139.6, 149.0, 149.1. Ϫ CI-MS: m/z (%) ϭ
281 (100) [Mϩ ϩ 1], 202 (30).
(3R,7aS)-7a-(2,5-Dioxalylpropyl)-3-phenylperhydropyrrolo[2,1-b]-
[1,3]oxazole (7): Colorless liquid, yield 66%, Rf ϭ 0.37 (hexane/
1
EtOAc, 1:1, v/v). Ϫ [α]2D3 ϭ Ϫ61.4 (c ϭ 2.2, CHCl3). Ϫ H NMR
(CDCl3): δ ϭ 1.52Ϫ2.13 (m, 10 H), 2.74Ϫ2.81 (m, 1 H, 5-H),
2.93Ϫ3.03 (m, 1 H, 5-HЈ), 3.63 (t, J ϭ 8.9 Hz, 1 H, 2-H), 3.79Ϫ4.01
(m, 5 H), 4.25 (dd, J ϭ 7.0 and 8.6 Hz, 1 H, 2-HЈ), 4.87 (t, J ϭ
4.6 Hz, 1 H), 7.21Ϫ7.42 (m, 5 H, Ar H). Ϫ 13C NMR (CDCl3):
δ ϭ 19.5 (CH2), 24.2 (CH2), 34.1 (CH2), 36.4 (CH2), 38.9 (CH2),
55.5 (C-5), 64.8 (CH2), 70.9 (C-3), 72.4 (C-2), 104.5 (C-7a), 107.7
(CH), 126.8 (2C), 127.1, 128.3 (2C), 141.8. Ϫ CI-MS: m/z (%) ϭ
304 (100) [Mϩ ϩ 1], 188 (9).
Reductive Ring Opening of 3a؊f and 7 With Lithium Triethyl-
borohydride: To a solution of the corresponding oxazolidine
(1.0 mmol ) in anhydrous THF (10 mL) cooled to 0 °C, was added
1  solution of Super-Hydride (1.5 mL) in the same solvent, and
the mixture was stirred overnight at this temperature. The reaction
was quenched by addition of water (1 mL), and the solvent was
eliminated under vacuum. The residue was diluted with Et2O
(10 mL) and 2  solution of HCl (5 mL), the aqueous layer was
decanted and then it was brought to pH ϭ 10 by addition of a
concentrated solution of KOH. The resulting aqueous phase was
extracted with dichloromethane (3 ϫ 20 mL), and the organic layer
was separated and dried over anhydrous MgSO4. After filtration,
the solvent was eliminated under vacuum, and the residue was puri-
fied by flash chromatography to give 4a؊i in enantiopure form.
Synthesis of Bicyclic Oxazolidines 3g؊i: A solution of ketone 2g؊i
(11.1 mmol), (R)-phenylglycinol (1.68 g, 12.3 mmol) and triethyl-
amine (1.67 mL, 12.0 mmol) in toluene (5 mL) was refluxed over-
night. The solution was cooled to room temp. and the solids were
separated by filtration. The solvent was removed under vacuum
and the residue was purified by distillation, or by flash chromato-
graphy (silica gel, EtOAc/hexane, 1:20, v/v).
(3R,8aS)-8a-Methyl-3-phenylperhydropyrido[2,1-b][1,3]oxazole (3g):
Colorless oil, yield 81%, b.p. 175 °C/2 Torr, Rf ϭ 0.19 (CH2Cl2). Ϫ
[α]2D3 ϭ Ϫ153.5 (c ϭ 1.0, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ
(2R)-2-[(2ЈR)-2Ј-Methyl-N-pyrrolidinyl]-2-phenyl-1-ethanol
(4a):
1.13Ϫ1.2 (m, 1 H), 1.48 (s, 3 H), 1.4Ϫ1.8 (m, 5 H), 2.76Ϫ2.9 (m, Colorless oil, yield 67%, Rf ϭ 0.4 (hexane/EtOAc, 1:1, v/v). Ϫ
1722 Eur. J. Org. Chem. 2000, 1719Ϫ1726

Stereoselective Synthesis of Enantiopure Pyrrolidines and Piperidines
FULL PAPER
[α]2D3 ϭ Ϫ93.25 (c ϭ 2.5, CHCl3). Ϫ IR (film) ν˜ ϭ 3400, 1585, 1350
125.8, 127.6, 128.0 (2C), 128.4 (3C), 128.5 (2C), 129.3, 134.9, 142.2.
1
cmϪ1. Ϫ H NMR: δ ϭ 1.19 (d, J ϭ 6.1 Hz, 3 H), 1.24Ϫ1.83 (m, Ϫ CI-MS: m/z (%) ϭ 296 (100) [Mϩ ϩ 1], 278 (14), 230 (71).
4 H), 2.16 (q, J ϭ 8.6 Hz, 1 H), 2.54Ϫ2.65 (m, 1 H), 2.86Ϫ2.92
(2R)-2-[(2ЈR)-2Ј-(2,5-Dioxalylpropyl)-N-pyrrolidinyl]-2-phenyl-1-
ethanol (8): Colorless oil, yield 60%, Rf ϭ 0.25 (EtOAc/MeOH,
20:1, v/v). Ϫ [α]2D3 ϭ Ϫ120.1 (c ϭ 1.5, CHCl3). Ϫ IR (film): ν˜ ϭ
(m, 1 H), 3.64 (dd, J ϭ 4.3 and 9.2 Hz, 1 H), 3.95 (dd, J ϭ 9.3 and
10.4 Hz, 1 H), 4.02 (dd, J ϭ 4.2 and 10.5 Hz, 1 H), 7.12Ϫ7.37 (m,
5 H). Ϫ 13C NMR: δ ϭ 19.2 (CH3), 21.5 (CH2), 32.0 (CH2), 45.1
(CH2N), 54.2 (CHN), 60.8 (CH2O), 61.8 (PhCHN), 127.7, 128.0
(2C), 129.2 (2C), 135.0 Ϫ CI-MS: m/z (%) ϭ 206 (100) [Mϩ ϩ 1],
188 (20), 174 (28), 128 (5).
1
3150 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.24Ϫ1.91 (m, 10 H), 2.17
(q, J ϭ 8.0 Hz, 1 H), 2.53Ϫ2.62 (m, 1 H), 2.86Ϫ2.92 (m,1 H), 3.63
(dd, J ϭ 4.6 and 9.5 Hz, 1 H), 3.81Ϫ4.8 (m, 6 H), 4.88 (t, J ϭ
4.7 Hz, 1 H), 7.14Ϫ7.17 (m,2 H), 7.27Ϫ7.37 (m, 3 H). Ϫ 13C NMR
(CDCl3): δ ϭ 20.5 (CH2), 21.9 (CH2), 29.6 (CH2), 34.0 (CH2), 45.3
(CH2N), 58.7 (CHN), 60.9 (CH2O), 62.0 (CHN), 64.7 (CH2O),
104.4 (CHO2), 127.6, 128.0 (2C), 129.2 (2C), 135.1. Ϫ CI-MS: m/z
(2R)-2-[(2ЈR)-2Ј-Ethyl-N-pyrrolidinyl]-2-phenyl-1-ethanol (4b): Col-
orless oil, yield 84%, Rf ϭ 0.38 (hexane/EtOAc, 1:1, v/v). Ϫ [α]2D3
ϭ
Ϫ92.5 (c ϭ 1.2, CHCl3). ϪIR (film): ν˜ ϭ 3380, 1440, 1390, 1340
cmϪ1. Ϫ 1H NMR(CDCl3): δ ϭ 0.93 (t, J ϭ 7.4 Hz, 3 H), (%) ϭ 306 (100) [Mϩ ϩ 1], 304 (12), 274 (39), 190 (12).
1.29Ϫ1.94 (m, 6 H), 2.21 (q, J ϭ 8.7 Hz, 1 H), 2.47Ϫ2.58 (m, 1
Synthesis of Compounds 4g؊i:
A solution of 3g؊i (0.2 g,
H), 2.91Ϫ3.01 (m,1 H), 3.63 (dd, J ϭ 4.5 and 9.5 Hz, 1 H), 3.96
(t, J ϭ 10 Hz, 1 H), 4.04 (dd, J ϭ 4.5 and 10.7 Hz, 1 H), 7.14Ϫ7.61
(m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 10.2 (CH3), 21.9 (CH2), 26.1
(CH2), 29 (CH2), 45.8 (CH2N), 60.6 (CHN), 61.3 (CH2O), 62.6
(PhCHN), 127.8, 128.1 (2C), 129.3 (2C), 135.1. Ϫ CI-MS: m/z
(%) ϭ 220 (100) [Mϩ ϩ 1], 202 (17), 188 (16).
0.92 mmol) in anhydrous ether (4 mL) was added dropwise to a
suspension of LiAlH4 (35.0 mg, 0.92 mmol) in Et2O (4 mL) at 0
°C. The mixture was stirred for 12 h at that temperature and then
quenched by addition of 15% NaOH aqueous solution. The mix-
ture was filtered off, and the solids were washed with Et2O. The
solvent was eliminated under vacuum, and the residue was redis-
(2R)-2-Phenyl-2-[(2ЈR)-2Ј-propyl-N-pyrrolidinyl]-1-ethanol
(4c): solved in CH2Cl2 (5 mL) and treated with Ac2O (0.15 mL,
Colorless oil, yield 77%, Rf ϭ 0.31 (hexane/EtOAc, 1:1, v/v). Ϫ
1.52 mmol) and DMAP (28.0 mg, 0.23 mmol). The solution was
stirred for 1.5 h and quenched with water (5 mL). After separation,
[α]2D3 ϭ Ϫ131.8 (c ϭ 1.1, CHCl3). Ϫ IR (film): ν˜ ϭ 3420, 1350
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.97 (t, J ϭ 7.1 Hz, 3 H), the organic layer was washed with a saturated NaHCO3 solution
1.25Ϫ1.83 (m, 8 H), 2.11Ϫ2.2 (m, 1 H), 2.51Ϫ2.6 (m, 1 H),
(2 ϫ 5 mL) and brine (5 mL), and then dried over anhydrous
2.85Ϫ2.91 (m,1 H), 3.63 (dd, J ϭ 4.7 and 9.Hz, 1 H), 3.96 (t, J ϭ MgSO4. The solvent was distilled and the residue was purified by
10.2 Hz, 1 H), 4.05 (dd, J ϭ 4.7 and 10.7 Hz, 1 H), 7.13Ϫ7.17 (m,2
H), 7.26Ϫ7.37 (m, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 14.5 (CH3),
19.3 (CH2), 22.0 (CH2), 29.6 (CH2), 36.3 (CH2), 45.2 (CH2N), 58.6
(CHN), 60.8 (CH2O), 61.9 (PhCHN), 127.6 (2C), 128.0, 129.2 (2C),
135.1. Ϫ CI-MS: m/z (%) ϭ 234 (100) [Mϩ ϩ 1], 216 (21), 202 (28).
flash chromatography.
(2R)-2-[(2ЈR)-2Ј-Methyl-N-piperidinyl]-2-phenyl-1-ethyl
Acetate
(4g): Colorless oil, yield 90%, Rf ϭ 0.26 (EtOAc/hexane, 1:8, v/v).
Ϫ [α]2D3 ϭ Ϫ67.4 (c ϭ 1.7, CHCl3). Ϫ IR (film): ν˜ ϭ 1735 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.1Ϫ1.18 (m, 1 H), 1.17 (d, J ϭ 6.2 Hz, 3
(2R)-2-[(2ЈS)-2Ј-Isoproyl-N-pyrrolidinyl]-2-phenyl-1-ethanol
(4d): H), 1.25Ϫ1.58 (m, 5 H), 1.92Ϫ1.97 (m, 1 H), 1.97 (s, 3 H),
Colorless oil, yield 80%, Rf ϭ 0.37 (hexane/EtOAc, 3:1, v/v). Ϫ
2.33Ϫ2.37 (m, 1 H), 2.77Ϫ2.8 (m, 1 H), 4.26Ϫ4.37 (m, 2 H), 4.53
[α]2D3 ϭ Ϫ77.8 (c ϭ 2.0, CHCl3). Ϫ IR (film): ν˜ ϭ 3440, 1345 cmϪ1
.
(dd, J ϭ 6.4 and 10.3 Hz, 1 H), 7.2Ϫ7.32 (m, 5 H). Ϫ 13C NMR
1
Ϫ H NMR (CDCl3): δ ϭ 0.90 (d, J ϭ 3.8 Hz, 3 H), 0.91 (d, J ϭ (CDCl3): δ ϭ 18.7 (CH3), 20.9 (CH3), 23.4 (CH2), 26.4 (CH2), 35.2
4.0 Hz, 3 H), 1.34Ϫ1.60 (m, 4 H), 2.04Ϫ2.26 (m, 2 H), 2.56Ϫ2.62
(CH2), 46.6 (CH2N), 52.7 (CHN), 60.3 (CHN), 64.8 (CH2N),
(m, 1 H), 2.90Ϫ2.95 (m, 1 H), 3.58Ϫ3.68 (m, 1 H), 3.96Ϫ4.05 (m, 127.2, 127.9 (2C), 128.6 (2C), 136.7, 170.9 (CO). Ϫ CI-MS: m/z
2 H), 7.13Ϫ7.38 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 14.9 (CH3), (%) ϭ 262 (2) [Mϩ ϩ 1], 248 (5), 220 (100).
20.3 (CH3), 22.7 (CH2), 23.6 (CH2), 27.8 (CH), 45.5 (CH2N), 61.1
(2R)-2-[(2ЈR)-2Ј-Ethyl-N-piperidinyl]-2-phenyl-1-ethyl Acetate (4h):
Colorless oil, yield 89%, Rf ϭ 0.47 (EtOAc/hexane, 1:8, v/v). Ϫ
[α]2D3 ϭ Ϫ65.2 (c ϭ 2.3, CHCl3). Ϫ IR (film): ν˜ ϭ 1730 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.86 (t, J ϭ 7.4 Hz, 3 H), 1.14Ϫ1.19 (m,1
(CH2O), 62.1 (CHN), 63.3 (CHN), 127.7 (2C), 128.1, 129.4 (2C),
135.0. Ϫ CI-MS: m/z (%) ϭ 234 (100) [Mϩ ϩ 1], 216 (9), 202 (28).
(2R)-2-[(2ЈR)-2Ј-Butyl-N-pyrrolidinyl]-2-phenyl-1-ethanol (4e): Col-
orless oil, yield 89%, Rf ϭ 0.26 (EtOAc). Ϫ [α]2D3 ϭ Ϫ119.5 (c ϭ H), 1.34Ϫ1.77 (m, 7 H), 1.98 (s, 3 H), 1.98Ϫ2.03 (m, 1 H), 2.25Ϫ2.3
2.4, CHCl3). Ϫ IR (film): ν˜ ϭ 3420, 1655, 1490 cmϪ1. Ϫ 1H NMR (m, 1 H), 2.76Ϫ2.81 (m, 1 H), 4.24Ϫ4.35 (m, 2 H), 4.54 (dd, J ϭ
(CDCl3): δ ϭ 0.94 (t, J ϭ 7.0 Hz, 3 H), 1.23Ϫ1.86 (m, 10 H), 2.15 6.1 Hz, 1 H), 7.21Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 9.2
(q, J ϭ 8.7 Hz, 1 H), 2.51Ϫ2.57 (m, 1 H), 2.86Ϫ2.92 (m,1 H), 3.63
(CH3), 20.9 (CH3), 22.8 (CH2), 25.8 (CH2), 29.5 (CH2), 46.2
(dd, J ϭ 4.7 and 9.7 Hz, 1 H), 3.96 (t, J ϭ 10.2 Hz, 1 H), 4.06 (dd, (CH2N), 57.4 (CH), 60.1 (CH), 65.1 (CH2O), 127.1, 127.9 (2C),
J ϭ 4.7 and 10.8 Hz, 1 H), 7.13Ϫ7.16 (m,2 H), 7.27Ϫ7.38 (m, 3 128.6 (2C), 137.4, 170.8 (CO). Ϫ CI-MS: m/z (%) ϭ 276 (5) [Mϩ
H). Ϫ 13C NMR (CDCl3): δ ϭ 14.1 (CH3), 22 (CH2), 23 (CH2), ϩ 1], 234 (100).
28.3 (CH2), 29.7 (CH2), 33.7 (CH2), 45.3 (CH2N), 59 (CH), 60.8
(2R)-2-Phenyl-2-[(2ЈR)-2Ј-propyl-N-piperidinyl]-1-ethyl Acetate (4i):
Colorless oil, yield 85%, Rf ϭ 0.54 (EtOAc/hexane, 1:5, v/v). Ϫ
[α]2D3 ϭ Ϫ44.2 (c ϭ 2.4, CHCl3). Ϫ IR (film): ν˜ ϭ 1730 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.9 (t, J ϭ 7.3 Hz, t), 1.12Ϫ1.63 (m, 10
H), 1.97 (s, 3 H), 2.04Ϫ2.11 (m, 1 H), 2.31Ϫ2.41 (m, 1 H),
(CH2O), 62 (CH), 127.7, 128.0 (2C), 129.2 (2C), 135.1. Ϫ CI-MS:
m/z (%) ϭ 248 (100) [Mϩ ϩ 1], 246 (64), 230 (71), 216 (73).
(2R)-2-Phenyl-2-[(2ЈR)-2Ј-phenylethyl-N-pyrrolidinyl]-1-ethanol (4f):
Colorless oil, yield 78%, Rf ϭ 0.33 (EtOAc). Ϫ [α]2D3 ϭ Ϫ178.5 (c ϭ
2.0, CHCl3). Ϫ IR (film): ν˜ ϭ 3180, 1600, 1580 cmϪ1. Ϫ 1H NMR 2.71Ϫ2.79 (m, 1 H), 4.21Ϫ4.34 (m, 2 H), 4.5 (dd, J ϭ 6.5 and
(CDCl3): δ ϭ 1.52Ϫ1.83 (m, 4 H), 2.09 Ϫ2.19 (m, 2 H), 2.49Ϫ2.59 10.8 Hz, 1 H), 7.23Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 14.6
(m, 3 H), 2.73Ϫ2.82 (m, 1 H), 2.87Ϫ2.92 (m,1 H), 3.56Ϫ3.66 (m,
1 H), 3.91Ϫ4.0 (m, 2 H), 6.90Ϫ7.0 (m,2 H), 7.22Ϫ7.34 (m, 3 H).
Ϫ
(CH3), 18.4 (CH2), 20.9 (CH3, CH3CO), 22.4 (CH2), 25.6 (CH2),
29.8 (CH2), 32.0 (CH2), 45.9 (CH2N), 56.1 (CH), 60.6 (CH), 65.4
13C NMR (CDCl3): δ ϭ 22.2 (CH2), 29.7 (CH2), 32.5 (CH2), (CH2O), 127.1, 127.9 (2C), 128.6 (2C), 137.9, 170.8 (CO). Ϫ CI-
36.0 (CH2), 45.4 (CH2N), 57.9 (CHN), 61 (CH2O), 62.2 (CHN),
MS: m/z (%) ϭ 289 (1) [Mϩ ϩ 1], 276 (11), 248 (100).
Eur. J. Org. Chem. 2000, 1719Ϫ1726
1723

´
´
´
J. M. Andres, I. Herraiz-Sierra, R. Pedrosa, A. Perez-Encabo
FULL PAPER
(2R)-2-Phenyl-2-[(2ЈR)-2Ј-(3ЈЈ-pyridyl)-1-piperidinyl]-1-ethanol (12):
A solution of 11 (0.2 g, 0.92 mmol ) in anhydrous ether (15 mL)
3.33Ϫ3.41 (m, 1 H), 3.56Ϫ3.64 (m, 1 H), 7.20Ϫ7.32 (m, 2 H),
7.69Ϫ7.73 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 13.9 (CH3), 19.3
(CH2), 21.4 (CH3), 24.0 (CH2), 30.6 (CH2), 38.6 (CH2), 48.8
(CH2N), 60.3 (CH), 127.4 (2C), 129.5 (2C), 134.9, 143.1. Ϫ CI-
MS: m/z (%) ϭ 268 (100) [Mϩ ϩ 1], 224 (34). Ϫ C14H21NO2S
was added dropwise to
a suspension of LiAlH4 (52.0 mg,
1.38 mmol) in ether (10 mL) at 0 °C, and the suspension was stirred
for 12 h at this temperature. After work up, the solvent was re-
moved under vacuum. The compound was purified by flash chro- (267.13): calcd. C 62.89, H 7.92, N 5.24; found C 62.93, H 7.77,
matography (silica gel, EtOAc). Colorless oil, yield 62%, Rf ϭ 0.39
N 5.29.
(EtOAc). Ϫ [α]2D3 ϭ Ϫ123.1 (c ϭ 1.3, CHCl3). Ϫ IR (film): ν˜ ϭ
(S)-2-Isopropylpyrrolidine tosylate (5d): White solid, yield 80%, m.p.
86Ϫ88 °C (from pentane), Rf ϭ 0.36 (EtOAc/hexane, 1:8, v/v). Ϫ
[α]2D3 ϭ Ϫ91.3 (c ϭ 1.0, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1600 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.89 (d, J ϭ 6.8 Hz, 3 H), 0.93 (d, J ϭ
6.8 Hz, 3 H), 1.30Ϫ1.69 (m, 4 H), 2.12Ϫ2.18 (m, 1 H), 2.42 (s, 3
H), 3.27Ϫ3.31 (m, 2 H), 3.47Ϫ3.53 (m, 1 H), 7.29Ϫ7.32 (m, 2 H),
7.69Ϫ7.72 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 16.3 (CH3), 19.5
(CH3), 21.2 (CH3), 24.3 (CH2), 25.9 (CH2), 31.8 (CH), 49.2
(CH2N), 65.3 (CHN), 127.2 (2C), 129.3 (2C), 134.8, 142.9. Ϫ CI-
MS: m/z (%) ϭ 268 (100) [Mϩ ϩ 1], 266 (12), 224 (8). Ϫ
C14H21NO2S (267.13): calcd. C 62.89, H 7.92, N 5.24; found C
62.98, H 7.79, N 5.29.
1
3420, 1590 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.17Ϫ1.28 (m, 2 H),
1.51Ϫ1.74 (m, 5 H), 1.91Ϫ2.0 (m, 1 H), 3.12Ϫ3.16 (m, 1 H), 3.32
(dd, J ϭ 2.6 and 11.0 Hz, 1 H), 3.42 (dd, J ϭ 5.4 and 10.5 Hz, 1
H), 3.87 (dd, J ϭ 5.4 and 11.0 Hz, 1 H), 4.05 (t, J ϭ 11.0 Hz, 1
H), 6.97Ϫ7.0 (m, 1 H, Ar H), 7.29Ϫ7.39 (m, 4 H, Ar H), 7.78Ϫ7.82
(m, 1 H, Ar H), 8.55Ϫ8.6 (m, 2 H, Ar H). Ϫ 13C NMR (CDCl3):
δ ϭ 24.6 (CH2), 26.1 (CH2), 37.8 (CH2), 45.6 (CH2), 59.5 (CH2O),
62.4 (CH), 62.6 (CH), 124.1, 127.9, 128.0 (2C), 129.2 (2C), 133.9,
135.3, 139.6, 148.7, 149.6. Ϫ CI-MS: m/z (%) ϭ 283 (100) [Mϩ
ϩ
1], 265 (17), 251 (17).
Hydrogenolytic Cleavage of the Chiral Appendage. Preparation of
Pyrrolidines 5a؊f and Piperidines 5g؊i: A mixture of the corres-
ponding amino alcohols 4a؊f or acetates 4g؊i (1.0 mmol) in
EtOAc (30 mL) and 40.0 mg of 10% palladium on carbon was
stirred at room temp. for 48Ϫ72 h under hydrogen at 9 atm. After
the reaction was over, the catalyst was filtered and to the solution
were added iPr2NEt (0.87 mL, 5.0 mmol) and TsCl (0.47 g,
2.5 mmol) and the mixture was stirred overnight. The crude reac-
tion mixture was washed with 0.5  solution of HCl and water,
and then dried over anhydrous MgSO4. The solvent was eliminated
under reduced pressure and tosylates 5a؊f were purified by flash
chromatography (silica gel, hexane/ethyl acetate, 20:1, v/v) and
recrystallization.
(R)-2-Butylpyrrolidine Tosylate (5e): White solid, yield 91%, m.p.
66Ϫ68 °C (from pentane), Rf ϭ 0.39 (EtOAc/hexane, 1:8, v/v). Ϫ
[α]2D3 ϭ Ϫ108.0 (c ϭ 1.1, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1590 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.91 (t, J ϭ 7.0 Hz, 3 H), 1.22Ϫ1.89 (m,
10 H), 2.43 (s, 3 H), 3.14Ϫ3.22 (m, 1 H), 3.34Ϫ3.41 (m, 1 H), 3.55-
3.63 (m, 1 H), 7.30(d, J ϭ 8.1 Hz, 2 H), 7.71 (d, J ϭ 8.1 Hz, 2 H).
Ϫ
13C NMR (CDCl3): δ ϭ 14.0 (CH3), 21.4 (CH3), 22.6 (CH2),
24.0 (CH2), 28.2 (CH2), 30.6 (CH2), 36.1 (CH2), 48.8 (CH2N), 60.5
(CHN), 127.4 (2C), 129.5 (2C), 134.8, 143.1. Ϫ CI-MS: m/z (%) ϭ
282 (100) [Mϩ ϩ 1], 224 (94), 184 (7), 155 (13). Ϫ C15H23NO2S
(281.14): calcd. C 64.02, H 8.24, N 4.98; found C 63.93, H 7.99,
N 4.97.
Hydrochlorides 5g؊i were isolated after treatment of the solution
resulting from hydrogenolysis with a saturated solution of HCl in
Et2O, elimination of the solvents and recrystallization.
(R)-2-Phenethylpyrrolidine Tosylate (5f): White solid, yield 84%,
m.p. 83Ϫ85 °C (from pentane), Rf ϭ 0.19 (EtOAc/hexane, 1:8, v/
v). Ϫ [α]2D3 ϭ Ϫ143.3 (c ϭ1.0, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1590 cmϪ1
.
Ϫ
1H NMR (CDCl3): δ ϭ 1.40Ϫ1.84 (m, 5 H), 2.16Ϫ2.28 (m, 1
(R)-2-Methylpyrrolidinium Tosylate (5a): White solid, yield 80%,
m.p. 69Ϫ71 °C (from pentane), Rf ϭ 0.29 (EtOAc/hexane, 1:8, v/
v). Ϫ [α]2D3 ϭ Ϫ57.3 (c ϭ 1.0, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1590, 1160
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.31 (d, J ϭ 6.4 Hz, 3 H),
1.43Ϫ1.87 (m, 4 H), 2.43 (s, 3 H), 3.1Ϫ3.18 (m,1 H), 3.40Ϫ3.47
(m, 1 H), 3.66- 3.75 (m, 1 H), 7.31 (d, J ϭ 8.1 Hz, 2 H), 7.72 (d,
J ϭ 8.1 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.4 (CH3), 22.8
(CH3), 23.8 (CH2), 33.4 (CH2), 49.0 (CH2N), 56.0 (CHN), 127.4
(2C), 129.5 (2C), 134.8, 143.1. Ϫ CI-MS: m/z (%) ϭ 240 (100) [Mϩ
ϩ 1], 224 (42). Ϫ C12H17NO2S (239.09): calcd. C 60.22, H 7.17, N
5.85; found C 60.45, H 6.99, N 5.81.
H), 2.40 (s, 3 H), 2.58Ϫ2.78 (m, 2 H), 3.15Ϫ3.24 (m, 1 H),
3.37Ϫ3.44 (m, 1 H), 3.53Ϫ3.61 (m, 1 H), 7.17Ϫ7.32 (m, 7 H),
7.59Ϫ7.60 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.4 (CH3), 24
(CH2), 30.7 (CH2), 32.3 (CH2), 37.6 (CH2), 49 (CH2N), 59.7 (CH),
125.7, 127.4 (2C), 128.3 (2C), 128.4 (2C), 129.5 (2C), 134.5, 141.5,
143.1. Ϫ CI-MS: m/z (%) ϭ 330 (100) [Mϩ ϩ 1], 224 (10), 174 (10),
105 (2). Ϫ C19H23NO2S (329.14): calcd. C 69.27, H 7.04, N 4.25;
found C 69.19, H 6.95, N 4.18.
(؉)-Pipecoline Hydrochloride (5g): White solid, yield 76%, m.p.
194Ϫ196 °C, [α]2D3 ϭ ϩ3.97 (c ϭ 2, EtOH), {ref.[13b] ent Ϫ 5g
[α]2D3 ϭ Ϫ3.91 (c ϭ 0.46, EtOH)}. Ϫ IR (nujol) ν˜ ϭ 3380, 3185,
(R)-2-Ethylpyrrolidinium Tosylate (5b): White solid, yield 87%, m.p.
59Ϫ61 °C (from pentane), Rf ϭ 0.29 (EtOAc/hexane, 1:8, v/v). Ϫ
[α]2D3 ϭ Ϫ81.9 (c ϭ 1.1, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1600 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H), 1.51- 1.61 (m, 4
H), 1.7Ϫ1.93 (m, 2 H), 2.43 (s, 3 H), 3.15Ϫ3.23 (m, 1 H), 3.34Ϫ3.43
(m, 1 H), 3.50Ϫ3.58 (m, 1 H), 7.31 (d, J ϭ 7.9 Hz, 2 H), 7.71Ϫ7.74
(m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 10.3 (CH3), 21.1 (CH3), 24.0
(CH2), 29.1 (CH2), 30.1 (CH2), 48.9 (CH2N), 61.7 (CHN), 127.4
(2C), 129.5 (2C), 134.8, 143.1. Ϫ CI-MS: m/z (%) ϭ 254 (100) [Mϩ
ϩ 1], 224 (19), 162 (34), 105 (2). Ϫ C13H19NO2S (253.11): calcd. C
61.63, H 7.56, N 5.53; found C 61.75, H 7.42, N 5.59.
1
1380 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.48Ϫ1.51 (m, 1 H), 1.5 (d,
J ϭ 6.4 Hz, 3 H), 1.68Ϫ1.99 (m, 5 H), 2.83Ϫ2.87 (m, 1 H), 3.11
(br. s, 1 H), 3.41Ϫ3.45 (m, 1 H), 9.18 (br. s, 1 H), 9.56 (br. s, 1 H).
Ϫ
13C NMR (CDCl3): δ ϭ 19.2 (CH3), 21.7 (CH2), 22.3 (CH2),
30.3 (CH2), 44.3 (CH2N), 53 (CH).
(R)-2-Ethylpiperidine Hydrochloride (5h): Colorless solid, yield
70%, m.p. 210Ϫ212 °C. Ϫ [α]2D3 ϭ Ϫ1.42 (c ϭ 1.8, MeOH). Ϫ IR
(nujol) ν˜ ϭ 3380, 3185, 1380 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.03
(m, 3 H), 1.6Ϫ2.1 (m, 8 H), 2.8Ϫ3.0 (m, 2 H), 3.47Ϫ3.49 (m, 1 H),
9.06 (br. s, 1 H), 9.31 (br. s, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 9.8
(CH3), 22.1 (CH2), 22.3 (CH2), 26.4 (CH2), 27.6 (CH2), 44.7
(CH2N), 58.6 (CH).
(R)-2-Propylpyrrolidine Tosylate (5c): White solid, yield 86%, m.p.
54Ϫ56 °C (from pentane), Rf ϭ 0.32 (EtOAc/hexane, 1:8, v/v),
[α]2D3 ϭ Ϫ99.3 (c ϭ 1.0, CHCl3). Ϫ IR (nujol) ν˜ ϭ 1590 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.94 (t, J ϭ 7.2 Hz, 3 H), 1.28Ϫ1.58 (m, 6 (؊)-Coniine Hydrochloride (5i): Colorless solid, yield 75%. m.p.
H), 1.72Ϫ1.87 (m, 2 H), 2.42 (s, 3 H), 3.14Ϫ3.22 (m, 1 H),
212Ϫ213 °C. Ϫ [α]2D3 ϭ Ϫ7.3 (c ϭ 0.33, EtOH), {ref.[29] [α]2D3
ϭ
1724
Eur. J. Org. Chem. 2000, 1719Ϫ1726

Stereoselective Synthesis of Enantiopure Pyrrolidines and Piperidines
Ϫ7.6 (c ϭ 1.0, EtOH)}. Ϫ IR (nujol) ν˜ ϭ 1585, 3200, 3380 cmϪ1
FULL PAPER
.
showed that the product was a single enantiomer. Brown oil, yield
Ϫ 1H NMR (CDCl3): δ ϭ 0.95 (t, J ϭ 7.2 Hz, 3 H), 1.46Ϫ2.01 (m, 40%, Rf ϭ 0.42 (CH2Cl2/MeOH/NH4OH, 90:10:1). Ϫ [α]2D3
ϭ
10 H), 2.82Ϫ2.95 (m, 2 H), 3.44Ϫ3.48 (m, 1 H), 9.2 (br. s, 1 H), Ϫ75.5 (c ϭ 0.1, CHCl3). N-4-Nitrobenzoylanabasine: [α]2D3
ϭ
9.47 (br. s, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 13.7 (CH3), 18.5 (CH2),
Ϫ133.6 (c ϭ 0.76, MeOH) {ref.[32] [α]2D3 ϭ Ϫ130.8 (c ϭ 1.2,
22.1 (CH2), 22.4 (CH2), 28.0 (CH2), 35.3 (CH2), 44.7 (CH2N), MeOH)}, Ϫ IR (film): ν˜ ϭ 3259 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ
1
57.1 (CH).
1.45Ϫ1.9 (m, 6 H), 2.74Ϫ2.83 (m, 1 H), 3.16Ϫ3.21 (m, 1 H),
3.60Ϫ3.64 (m, 1 H), 7.21Ϫ7.25 (m, 1 H), 7.69Ϫ7.72 (m, 1 H), 8.47
(dd, J ϭ 1.7 and 4.8 Hz, 1 H), 8.57 (d, J ϭ 2.0 Hz, 1 H). Ϫ 13C
NMR (CDCl3): δ ϭ 25.0 (CH2), 25.5 (CH2), 34.7 (CH2), 47.6
(CH2N), 59.6 (CH), 123.4, 134.0, 140.5, 148.4, 148.5. Ϫ CI-MS:
m/z (%) ϭ 163 (100) [Mϩ ϩ 1], 161 (22).
8-Chloro-5-oxooctanal Ethylene Acetal (6): A solution of the Grig-
nard derivative prepared from magnesium turnings (202.0 mg,
8.3 mmol) and 2-(3-chloropropyl)-1,3-dioxolane (1.28 g, 8.5 mmol)
in THF (10 mL). was cooled to Ϫ50 °C and CuBr SMe2 (0.85 g,
4.1 mmol) was added. The mixture was stirred for 40 min and
warmed to Ϫ25 °C. A solution of 4-chlorobutanoyl chloride
(0.78 mL, 6.96 mmol) in THF (20 mL) was slowly added and the
mixture was stirred at Ϫ25 °C for 2.5 h. The reaction was quenched
with saturated NH4Cl solution and heated to room temp. The mix-
ture was extracted with Et2O (3 ϫ 50 mL), and the organic layer
was dried over anhydrous MgSO4. The solvents were eliminated
under vacuo, and the residue was distilled to afford 6 (1.2 g, 78%)
as a colorless liquid, b.p. 130Ϫ132 °C/0.8 Torr, Rf ϭ 0.25 (ethyl
Acknowledgments
We thank the Spanish DGESIC (Projects PB95Ϫ707 and
´
PB98Ϫ361) and Junta de Castilla y Leon (Project VA 79/99 ) for
financial support of this work. I. H.-S. thanks the University of
Valladolid for a predoctoral fellowship.
acetate/hexane, 1:8, v/v). Ϫ IR (film): ν˜ ϭ 1700, 1400 cmϪ1. Ϫ H
1
[1]
A. D. Elbein, R. Molyneux, in Alkaloids; Chemical and Biolo-
gical Perspectives (Ed.: S. W. Pelletier), J. Wiley and Sons, New
NMR (CDCl3): δ ϭ 1.64Ϫ1.74 (m, 4 H), 2.03 (q, J ϭ 6.7 Hz, 2
H), 2.50 (t, J ϭ 7.1 Hz, 2 H), 2.61 (t, J ϭ 7.1 Hz, 2 H), 3.57 (t,
J ϭ 6.3 Hz, 2 H), 3.81Ϫ3.98 (m, 4 H), 4.84 (t, J ϭ 4.3 Hz, 1 H).
York, 1987, vol. 57.
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´
C. Andres, J. P. Duque-Soladana, R. Pedrosa, J. Org. Chem.
1999, 64, 4282Ϫ4288.[2b] C. Andres, J. P. Duque-Soladana, R.
´
13C NMR (CDCl3): δ ϭ 17.9 (CH2), 26.1 (CH2), 32.7 (CH2), 39
Pedrosa, J. Org. Chem. 1999, 64, 4273Ϫ4281.[2c] C. Andres, J.
Ϫ
´
(CH2), 42.2 (CH2), 44.3 (CH2Cl), 64.6 (CH2O), 104 (CH), 209.1
(CO).
P. Duque-Soladana, J. M. Iglesias, R. Pedrosa, Tetrahedron
Lett. 1996, 50, 9085Ϫ9086. Ϫ [2d] M. Garcıa-Valverde, R. Ped-
´
rosa, M. Vicente, Tetrahedron 1996, 52, 10761Ϫ10770.
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C. Scolastico, Pure and Appl. Chem. 1998, 60, 1689.[3b] R.
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(؊)-δ-Coniceine (9): To a solution of 8 (0.8 g, 2.6 mmol) in meth-
anol (100 mL) containing 5 mL of HCl 2  was added Pd/C (10%,
200.0 mg ), and the mixture was stirred at 45 °C under 1 atm. of
hydrogen for 3 days. The pressure was then increased to 10 atm.
After 2 days the reaction mixture was filtered through a Celite pad,
and the filtrate was concentrated. The residue was washed with
Et2O (3 ϫ 50 mL) and neutralized with NaHCO3 and KOH. The
aqueous layer was extracted with CH2Cl2 (2 ϫ 50 mL) and CHCl3
(2 ϫ 50 mL), dried over MgSO4 and evaporated. The residue was
distilled to afford 9 (203 mg, 62%) as a colorless liquid, b.p. 50Ϫ51
°C/35 Torr. Ϫ [α]2D3 ϭ Ϫ10.1 (c ϭ 1.8, EtOH) {ref.[30] [α]2D3 ϭ Ϫ10.2
(c ϭ 1.76, EtOH)}, Rf ϭ 0.4 (Ethyl acetate/MeOH, 1:1, v/v). Ϫ IR
(film): ν˜ ϭ 2920, 1320 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.12Ϫ1.87
(m, 11 H), 1.95 (dt, J ϭ 3.4 and 11.4 Hz, 1 H), 2.05 (q, J ϭ 8.9 Hz,
1 H), 3.0Ϫ3.12 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 20.5 (CH2),
24.5 (CH2), 25.4 (CH2), 30.4 (CH2), 31.0 (CH2), 53.0 (CH2N), 54.2
(CH2N), 64.3 (CH). Ϫ CI-MS: m/z (%) ϭ 126 (100) [Mϩ ϩ 1],
124 (90).
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(S)-Anabasine (13): A mixture of DMSO (1.18 mL, 16.6 mmol), ox-
alyl chloride (0.7 mL, 8.0 mmol) and 12 (1.8 g, 6.4 mmol) in
CH2Cl2 (16 mL) cooled to Ϫ78 °C was stirred for 20 min and then
Et3N (2.33 mL, 16.7 mmol) was added and the reaction mixture
was allowed to reach room temp. The solution was quenched with
water (20 mL), decanted, and the organic layer was washed with a
solution of NaHCO3 and brine. The solvents were removed under
vacuum and the crude aldehyde was redissolved in a 1:1 mixture
of acetic acid and 2-propanol (40 mL) and DNP (3.62 g,
18.3 mmol) was added, and the solution was refluxed for 24 h.
After concentration, the mixture was treated with 15% NaOH solu-
tion (150 mL) and extracted with Et2O (5 ϫ 50 mL). The organic
layer was dried over anhydrous MgSO4, the solvent was eliminated
under reduced pressure and the residue was purified by flash chro-
matography (silica gel, CH2Cl2/MeOH/NH4OH, 180:15:1) to give
(S)-anabasine (407 mg, 40%). Analysis by HPLC as N-4-nitro-
benzoylanabasine (Chiracel OD, isopropanol/hexane, 95:5, flow
rate 0.7 mL/min, UV detector) and coinjection with a racemate
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1725

´
´
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J. M. Andres, I. Herraiz-Sierra, R. Pedrosa, A. Perez-Encabo
FULL PAPER
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1726
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