Ring expansion - Formation of optically active 3-hydroxypiperidines from pyrrolidinemethanol derivatives

Article abstract of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1693::AID-EJOC1693>3.0.CO;2-J

Treatment of pyrrolidinemethanol derivatives (-)-1, (-)-6, (-)7, 8, (- )-9, (+)-10, (-)-11, and (-)-21 with trifluoroacetic anhydride and then with Et₃N afforded, after hydrolysis of the trifluoroacetyl group with NaOH, the optically active -hy

Full text of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1693::AID-EJOC1693>3.0.CO;2-J

FULL PAPER
Ring Expansion – Formation of Optically Active 3-Hydroxypiperidines from
Pyrrolidinemethanol Derivatives
[a]
[a]
[a]
´
Janine Cossy,* Cecile Dumas, and Domingo Gomez Pardo*
Keywords: Pyrrolidines / Piperidines / Nitrogen heterocycles / Rearrangements / Aziridinium
Treatment of pyrrolidinemethanol derivatives (–)-1, (–)-6, (–)-
7, 8, (–)-9, (+)-10, (–)-11, and (–)-21 with trifluoroacetic
anhydride and then with Et3N afforded, after hydrolysis of
the trifluoroacetyl group with NaOH, the optically active
3-hydroxypiperidines (–)-14, (+)-15, (–)-16, 17, (+)-18, (–)-19,
(–)-20, and (+)-22, respectively. The yields are good and the
enantiomeric excess excellent (up to 95 %).
reverse reaction C Ǟ B Ǟ A is also possible. Because of
ring strain difference between A and C[22], the latter should
be obtained under conditions of thermodynamic control.
Introduction
The 3-hydroxypiperidine skeleton is present in a great
number of natural products such as Bao Gong Teng A[1]
,
pseudoconhydrine[2], cassine[3], and deoxocassine[4]. Differ-
ent methods allow the access to this skeleton, such as intra-
molecular substitution of a halide[5] or a mesylate[6] by an
amine, nucleophilic attack of an epoxide[7] or attack of an
hydroxy ester[8] by an amine, and attack of a π-allyl pal-
ladium complex by an oxazolidinone[9] as well as an intra-
Scheme 2
molecular Michael reaction[10] and radical cyclizations[11]
.
Allyl metals[12], vinylsilanes[13], and enolates[14] have been
also used to build up 3-hydroxylated piperidines. Thermal
reactions such as ene[15] or DielsϪAlder[16] reactions can
produce 3-hydroxypiperidines. Reduction of 3-hydroxypyri-
dines[17] or 3-piperidinones[18], or alternatively oxidation of
unsaturated piperidine[19] may engender 3-hydroxypiperi-
dines. A mixture of 3-hydroxypiperidine and pyrrolidine-2-
methanol was obtained when aziridinium ions were treated
With the aim of obtaining nonracemic chiral 3-mesylpi-
peridines, N-benzylprolinol (؊)-1 was treated with meth-
anesulfonyl chloride in the presence of triethylamine in
THF. Under these conditions, 3-chloropiperidine (؊)-2 was
obtained in 77% yield[21e]. No trace of mesylate 2Ј was de-
tected in the crude reaction mixture (Scheme 3). 3-Chloro-
piperidine (؊)-2 was the only product formed even in the
presence of AgCN, which was expected to quench the chlo-
ride anion, or in the presence of acetic acid (AcOH) which
can compete as nucleophile with the mesylate anion. This
suggests that tight ion pairs (aziridinium chloride) are in-
volved in the reaction (؊)-1 ϩ MsCl Ǟ (؊)-2 ϩ MsOH.
In order to introduce an oxygenated function at C-3 of the
piperidine ring, prolinol (؊)-1 was treated with acetic acid
under Mitsunobu conditions [DEAD (diethyl azodicarbox-
ylate), PPh3].[23] Under these conditions, the acetylated pro-
linol (؊)-3 and 3-acetyl piperidine 4[24] were formed in a
74:26 ratio. We have to point out that the acetylated proli-
nol (؊)-3 was the only product isolated (62%) when proli-
nol (؊)-1 was treated with pure acetic anhydride (Scheme
4).
with NaOH[20]
.
Herein, we give a full account of the rearrangement of
N-alkylpyrrolidine-2-methanol derivatives which generates
3-hydroxypiperidines with good yield and high enantio-
meric purity[21] (Scheme 1).
Scheme 1
Results and Discussion
Pyrrolidine-2-methyl derivatives A, with a good nucleofu-
gal group (OEWG), were expected to form reactive aziridin-
ium intermediates of type B, which should undergo ring
opening by nucleophilic attack at C-2 of intermediate B to
produce piperidines of type C (Scheme 2). In principle, the
Scheme 3
[a]
´
Laboratoire de Chimie Organique, associe au CNRS, ESPCI,
10 rue Vauquelin, F-75231 Paris Cedex 05, France
Fax: (internat.) ϩ 33-1/40794425
In contrast with this reaction course, treatment of (؊)-1,
with trifluoroacetic anhydride (TFAA), and with triethyl-
E-mail: janine.cossy@espci.fr
Eur. J. Org. Chem. 1999, 1693Ϫ1699
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0707Ϫ1693 $ 17.50ϩ.50/0
1693

J. Cossy, C. Dumas, D. Gomez Pardo
FULL PAPER
Table 1. Formation of 3-hydroxypiperidines from pyrrolidine-
methanol derivatives
Scheme 4
amine in THF, led to 3-hydroxypiperidine (؊)-14[24][25]
(63%) after saponification (NaOH, H2O) of the intermedi-
ate ester 5. The enantiomeric excess of (؊)-14 was 95%[26]
(Scheme 5). The ring expansion (؊)-1 Ǟ (؊)-14 did not
work in solvents such as toluene or hexane. In CH2Cl2, the
only product formed was the 3-chloropiperidine (؊)-2. The
formation of compounds (؊)-2, 4, (؊)-14 is consistent with
the mechanism of Scheme 2.
Scheme 5
As seen from Table 1, the ring expansion of N-alkylated
prolinol appears to be general and highly stereoselective ex-
cept for prolinol (؉)-12 or for the N-(4-nitrophenyl) deriva-
tive (؊)-13. In these two cases, the products of ring expan-
sion were not detected. The nucleophilicity of the amino
moiety of the prolinol derivative has to be high enough for
the rearrangement to occur. We have to point out that acid-
or base-sensitive hydroxy protecting groups [compounds
(؉)-10, (؊)-11] were tolerated under our conditions. The
(4R)-hydroxyprolinol derivative (؊)-9 was isomerized
smoothly into a single diastereomeric diol (؉)-18 with a
20
yield of 54%. The [α]D value (ϩ151) of this compound
proves the (3R,5R) configuration of (؉)-18 and strongly
supports the mechanism of Scheme 2 (inversion of configu-
ration during the nucleophilic attack at C-2 of aziridinium
intermediates B) (Table 1).
Pyrrolidine-2-methanol derivatives with secondary and
tertiary alcohols were submitted to our rearrangement con-
ditions. Pyrrolidine-2-methanol (؊)-21[29] was transformed
to substituted piperidinol (؉)-22 in 56% yield and with an
enantiomeric excess of 95%. In contrast, diastereoisomer
(؉)-23[29] was not reactive under the same conditions[21e,21g]
(Scheme 6).
Scheme 6
The nonreactivity of (؉)-23 can be attributed to a gauche
effect (steric interactions) between the phenyl and the
C-2ϪC-3 bond in the aziridinium ion intermediate 23A. On to piperidinol (؉)-22, as no serious steric repulsions are de-
the contrary, pyrrolidinemethanol (؊)-21 was transformed veloped during the formation of the aziridinium intermedi-
1694
Eur. J. Org. Chem. 1999, 1693Ϫ1699

Optically Active 3-Hydroxypiperidines from Pyrrolidinemethanol Derivatives
FULL PAPER
ate 21A, the phenyl group and the C-2ϪC-3 bond being
antiperiplanar (Scheme 7). This interpretation implies that
the amino moiety participates (anchimeric effect) in the het-
erolysis of the trifluoroacetate intermediate generated by es-
terification of the benzyl alcohol (؊)-21[30]
.
Scheme 9
with sodium acetate furnished only the ratio of products
(؊)-3 and 4 (3:1) (Scheme 10).
Scheme 7
Treatment of pyrrolidinemethanol derivatives (؉)-25[31]
with a tertiary alcohol at C-2Ј did not lead to the ring ex-
panded product, under our conditions, whereas (؊)-27[31]
underwent water elimination to produce alkene (؊)-28[31]
(55% yield) (Scheme 8). These results are consistent with
the fact that (؉)-25 and (؊)-27 can generate ion-pairs with-
out the participation of the amino moiety, giving stable ter-
Scheme 10
tiary carbenium ion intermediates[30]
.
Conclusion
Consecutive treatment of pyrrolidine-2-methanol com-
pounds with trifluoroacetic anhydride and then with tri-
ethylamine results in a rearrangement that produces the
ring-expanded 3-hydroxypiperidines as the trifluoroacetyl
esters. Following hydrolysis of the trifluoroacetyl group
with NaOH, the corresponding 3-hydroxypiperidines are
isolated in good yields and with excellent enantiomeric ex-
cesses (up to 95%).
Scheme 8
Experimental Section
General: Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification. Ϫ
THF was distilled from Na/benzophenone ketyl immediately prior
to use. Ϫ CH2Cl2 and Et3N were distilled from calcium hydride
The first step for the formation of 3-hydroxypiperidines
from pyrrolidinemethanol derivatives implies the esterifi-
cation of the hydroxy group of the pyrrolidine-2-methanol under argon. Ϫ Moisture-sensitive reactions were conducted in
oven-dried glassware under an argon atmosphere. Ϫ Analytical
thin-layer chromatography was performed on Merck precoated sil-
ica gel (60 F254) plates and flash column chromatography was ac-
complished on Merck Kieselgel 60 (230Ϫ400 mesh). Ϫ Melting
points are uncorrected. Ϫ IR: PerkinϪElmer 298. Ϫ Optical ro-
tations: PerkinϪElmer 241MC polarimeter. Ϫ Elemental analyses:
by trifluoroacetic anhydride and the formation of the corre-
sponding quaternary ammonium salt D. In the absence of
triethylamine, no rearrangement is observed. With triethyl-
amine, amino esters E are formed and undergo a SNi pro-
cess to give the tight ion-pairs F that react to generate the
stable esters G. Finally, saponification of the esters G by
NaOH (2.5 ) affords the observed 3-hydroxypiperi-
dines[21a,21d] (Scheme 9).
´
´
Service Regional de Microanalyse de lЈUniversite P. et M. Curie. Ϫ
´
HRMS: Centre de Spectrochimie Organique de lЈUniversite P. et
M. Curie. Ϫ NMR: Bruker AC 300 spectrometer (300 MHz and
75 MHz for 1H and 13C, respectively). Spectra were recorded in
This hypothesis is consistent with our observation that
the treatment of (؊)-1 with TFAA, then with Et3N, then CDCl3 as solvent, and chemical shifts (δ) were expressed in ppm
Eur. J. Org. Chem. 1999, 1693Ϫ1699 1695

J. Cossy, C. Dumas, D. Gomez Pardo
FULL PAPER
1
relative to residual CHCl3 at δ ϭ 7.27 for H and to CDCl3 at δ ϭ
77.1 for 13C. Ϫ MS: Mass spectra were obtained by GC/MS with
electron impact ionization on a 5971 Hewlett Packard instrument
at 70 eV; only selected ions are reported.
2.31Ϫ2.49 (m, 1.3 H), 3.20 (dd, J ϭ 10.3 and 8.1 Hz, 0.3 H),
3.48Ϫ3,57 (m, 1.7 H), 3.62 (s, 0.9 H), 3.74 (s, 2.1 H), 4.13Ϫ4.37
(m, 1.3 H), 4,56 (d, J ϭ 10.7 Hz, 0.7 H), 7.20Ϫ7.50 (m, 5 H). Ϫ
C15H19NO4 (277.32): calcd. C 64.97, H 6.91, N 5.05; found C
65.03, H 6.95, N 4.98.
(؊)-(3R)-1-Benzyl-3-chloropiperidine (2): To a solution of pyrroli-
dine 1 (0.7 g, 3.66 mmol) in THF (30 mL) at 0°C was added MsCl To a suspension of LiAlH4 (0.13 g, 3.42 mmol) in THF (3 mL) at
(0.31 mL, 4.03 mmol), followed by Et3N (1.9 mL, 14.6 mmol).
After 12 h reflux, the reaction mixture was poured into an aqueous
2.5  NaOH solution (7 mL). After extraction with CH2Cl2 (2ϫ
20 mL), the organic phase was dried with MgSO4 and filtered. The
solvent was removed in vacuo to afford an oil, which was purified
0°C, a solution of (2SR,4R)-1-benzoyl-2-ethyl-4-hydroxypyrroli-
dine-2-carboxylic acid methyl ester (0.29 g, 1.05 mmol) in THF
(1 mL) was added dropwise. After 15 min at 0°C, the reaction mix-
ture was heated at reflux for 3 h and cooled to 0°C. Water
(0.02 mL), an aqueous 3.75  NaOH solution (0.2 mL) and water
(0.6 mL) were successively added. The reaction mixture was filtered
by flash column chromatography on silica gel (EtOAc/cyclohexane,
20
50:50) to give 0.59 g (77%) of oily 2. Ϫ [α]D ϭ Ϫ2 (c ϭ 7.2, over Celite, and the residue was washed with THF (15 mL). The
MeOH). Ϫ IR (neat): ν˜ ϭ 1490, 1465, 1450, 1435, 1365, 1345, 1150 organic solvent was removed in vacuo to afford an oil, which was
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.45Ϫ1.69 (m, 2 H), 1.72Ϫ1.84
purified by flash column chromatography on silica gel (EtOAc/
(m, 1 H), 2.01Ϫ2.27 (m, 3 H), 2.64Ϫ2.75 (m, 1 H), 2.96Ϫ3.09 (m, cyclohexane, 50:50) to give 145 mg (59%) of an inseparable mixture
1 H), 3.53 (s, 2 H), 3.92Ϫ4.04 (m, 1 H), 7.20Ϫ7.38 (m, 5 H). Ϫ 13C
of isomers 8 (ratio 70:30 according to 1H NMR) as a colourless
NMR (CDCl3): δ ϭ 24.8, 34.8, 52.7, 56.0, 61.2, 62.6, 127.0, 128.2, oil. Ϫ IR (neat): ν˜ ϭ 3340, 1450, 1365, 1150, 1040 cmϪ1. Ϫ 1H
128.9, 137.9. Ϫ MS (70 eV); m/z (%): 211 (9) [Mϩ], 210 (11), 209 NMR (CDCl3) (major isomer): δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H),
(26) [Mϩ], 208 (25), 134 (14), 132 (39), 120 (15), 118 (53), 92 (19), 1.43Ϫ1.57 (m, 2 H), 1.87 (ddd, J ϭ 14.3, 1.5, and 1.5 Hz, 1 H),
91 (100), 65 (12). Ϫ C12H16NCl calcd 209.7181; found 209,7189
(MS).
2.20 (dd, J ϭ 14.3 and J ϭ 6.3 Hz, 1 H), 2.77 (dd, J ϭ 10.3 and
4.4 Hz, 1 H), 2.87 (ddd, J ϭ 9.9, 1.5, and 1.5 Hz, 1 H), 3.24 (broad
s, 2 H), 3.32Ϫ3.47 (m, 2 H), 3.48 (d, J ϭ 13.2 Hz, 1 H), 3.87 (d,
J ϭ 13.2 Hz, 1 H), 4.16Ϫ4.19 (m, 1 H), 7.20Ϫ7.35 (m, 5 H). Ϫ 13C
NMR (CDCl3) (major isomer): δ ϭ 8.6, 25.4, 42.6, 51.0, 60.3, 64.2,
(؊)-(2S)-(1-Benzylpyrrolidin-2-yl)methyl Acetate (3): To a stirred
solution of pyrrolidine 1 (0.1 g, 0.52 mmol) in THF (5 mL) at
Ϫ78°C, Ac2O (0.054 mL, 0.57 mmol) was added dropwise. After
2 h, Et3N (0.26 mL, 2 mmol) was added dropwise. The reaction
mixture was stirred for a further 1 h at Ϫ78°C and then heated at
reflux for 20 h. After hydrolysis with water (5 mL), the reaction
mixture was extracted with CH2Cl2 (2ϫ 10 mL). The combined
organic layers were dried with MgSO4 and filtered. The solvent was
removed in vacuo to afford an oil, which was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane, 30:70)
1
66.1, 68.9, 126.8, 128.1, 128.3, 139.7. Ϫ H NMR (CDCl3) (minor
isomer): δ ϭ 0.94 (t, J ϭ 7.4 Hz, 3 H), 1.39Ϫ1.61(m, 1 H),
1.71Ϫ1.79 (m, 2 H), 2.15Ϫ2.22 (m, 1 H), 2.52 (dd, J ϭ 9.2 and
6.2 Hz, 1 H), 3.12 (dd, J ϭ 9.2 and 6.6 Hz, 1 H), 3.24 (broad s, 2
H), 3.32Ϫ3.48 (m, 3 H), 3.77 (d, J ϭ 12.9 Hz, 1 H), 4.18Ϫ4.29 (m,
1 H), 7.20Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3) (minor isomer):
δ ϭ 8.5, 24.7, 41.0, 51.2, 58.8, 63.5, 66.5, 68.8, 126.9, 128.2, 128.4,
139.4. Ϫ MS (70 eV); m/z (%): 205 (7), 204 (45), 92 (8), 91 (100),
65 (7). Ϫ C13H18NO [Mϩ Ϫ CH2OH] calcd 204.2913; found
204,2918 (MS).
20
to give 75 mg (62%) of pure 3 as an oil. Ϫ [α]D ϭ Ϫ46 (c ϭ 1.0,
MeOH). Ϫ IR (neat): ν˜ ϭ 1735, 1450, 1365, 1230, 1030 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 1.59Ϫ1.84 (m, 2 H), 1.84Ϫ2.04 (m, 2 H),
2.07 (s, 3 H), 2.23Ϫ2.35 (m, 1 H), 2.79Ϫ2.90 (m, 1 H), 2.91Ϫ3.01 (؊)-(3aR,4R,6aS)-4-Hydroxymethyl-2,2,5-trimethyltetrahydro-
(m, 1 H), 3.46 (d, J ϭ 12.8 Hz, 1 H), 4.05 (dd, J ϭ 11 and 5,1 Hz, 4H-1,3-dioxolo[4,5-c]pyrrole (11): To a suspension of LiAlH4
1 H), 4.08 (d, J ϭ 12.8 Hz, 1 H), 4.13 (dd, J ϭ 11 and 5.1 Hz, 1
(0.11 g, 2.89 mmol) in THF (2 mL) at 0°C, a solution of
H), 7.21Ϫ7.37 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.4, 23.3, 28.8, (2R,3R,4S)-N-(tert-butoxycarbonyl)-3,4-isopropylidenedioxy-2-hy-
54.8, 59.8, 62.3, 67.4, 127.4, 128.6, 129.3, 170.9. Ϫ MS (70 eV); m/z droxymethylpyrrolidine[33] (0.19 g, 0.7 mmol) in THF (1 mL) was
(%): 233 (1) [Mϩ], 161 (12), 160 (100), 92 (8), 91 (99), 65 (7). Ϫ
added dropwise. After stirring at 0°C for 20 min, the reaction mix-
C14H19NO2 (233.31): calcd. C 72.07, H 8.21, N 6.00; found C ture was heated at reflux for 4 h and then cooled to 0°C. Water
72.14, H 8.21, N 6.02.
(0.01 mL), an aqueous 3.75  NaOH solution (0.1 mL), and water
(0.3 mL) were successively added, and the obtained precipitate was
collected on a Celite pad and washed with THF (15 mL). The or-
ganic solvent was removed in vacuo to afford an oil, which was
purified by flash column chromatography on silica gel (EtOAc/
cyclohexane, 50:50) to give 130 mg (99%) of 11 as a colourless oil.
(2SR,4R)-1-Benzyl-2-ethyl-4-hydroxy-2-hydroxymethylpyrrolidine
(8): To a stirred solution of diisopropylamine (0.6 mL, 4.27 mmol)
in THF (6 mL) at Ϫ40°C, was added dropwise a 2.5  solution
of n-butyllithium in hexane (1.69 mL, 4.22 mmol). After 10 min at
Ϫ40°C, the reaction mixture was cooled to Ϫ78°C and a solution
20
Ϫ [α]D ϭ Ϫ41 (c ϭ 2.3, MeOH). Ϫ IR (neat): ν˜ ϭ 3400, 1465,
of
(2S,4R)-1-benzoyl-4-hydroxypyrrolidine-2-carboxylic
acid
1450, 1380, 1370, 1250, 1205, 1155, 1065 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.31 (s, 3 H), 1.50 (s, 3 H), 2.35 (s, 3 H), 2.46Ϫ2.55
(m, 2 H), 2.67 (broad s, 1 H), 3.30Ϫ3.40 (m, 1 H), 3.62 (dd, J ϭ
11.4 and J ϭ 2.7 Hz, 1 H), 3.70 (dd, J ϭ 11.4 and J ϭ 3.7 Hz, 1
H), 4.52Ϫ4.63 (m, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 25.2, 27.4,
40.1, 59.4, 62.1, 71.7, 77.8, 82.3, 113.2. Ϫ MS (70 eV); m/z (%): 187
(0.7) [Mϩ], 172 (5), 156 (100), 98 (18), 82 (32), 70 (18), 55 (11). Ϫ
C9H17NO3 (187.24): calcd. C 57.73, H 9.15, N 7.48; found C 57.71,
H 9.10, N 7.47.
methyl ester[32] (0.5 g, 2.01 mmol) in THF (6 mL) was added drop-
wise. After 30 min at Ϫ78°C, EtI (0.2 mL, 2.5 mmol) was added.
After 2 h at Ϫ30°C, the reaction was quenched with water (5 mL).
After extraction with CH2Cl2 (3ϫ 10 mL), the combined organic
layers were dried with MgSO4 and filtered. The solvent was re-
moved in vacuo to afford an oil, which was purified by flash col-
umn chromatography on silica gel (EtOAc/cyclohexane, 50:50) to
give 290 mg (52%) of an inseparable mixture of (2SR,4R)-1-ben-
zoyl-2-ethyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester
1
(ratio 70:30 according to H NMR) as a yellow oil. Ϫ IR (neat): (؊)-(3R)-1-Benzylpiperidin-3-ol (14): Trifluoroacetic anhydride
ν˜ ϭ 3420, 1740, 1630, 1410, 1200, 1170 cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ 0,84 (t, J ϭ 7.4 Hz, 2.1 H), 0.88 (t, J ϭ 7.4 Hz, 0.9 H), dine 1 (0.81 g, 4.26 mmol) in THF (45 mL), cooled to Ϫ78°C.
(0.66 mL, 4.69 mmol) was added dropwise to a solution of pyrroli-
1.78Ϫ2.09 (m, 2 H), 2.20 (dd, J ϭ 14.7 and J ϭ 5.2 Hz, 0.7 H),
After 3 h at Ϫ78°C, triethylamine (2.2 mL, 17.05 mmol) was added
Eur. J. Org. Chem. 1999, 1693Ϫ1699
1696

Optically Active 3-Hydroxypiperidines from Pyrrolidinemethanol Derivatives
dropwise. The reaction mixture was stirred for 15 min at Ϫ78°C residue was purified by flash column chromatography on silica gel
FULL PAPER
and then heated at reflux for 20 h. After addition of an aqueous
2.5  NaOH solution (15 mL), the mixture was stirred for 3 h at
room temp., then extracted with CH2Cl2 (2ϫ 20 mL), dried with
MgSO4, and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane, 50:50)
(EtOAc/cyclohexane, 70:30) to give 74 mg (58%) of an inseparable
mixture of isomers 17 (ratio 70:30 according to 1H NMR) as an
oil. Ϫ IR (neat): ν˜ ϭ 3320, 1730, 1450 cmϪ1. Ϫ 1H NMR (CDCl3)
(major isomer): δ ϭ 0.89 (t, J ϭ 7.4 Hz, 3 H), 1.35Ϫ1.55 (m, 3 H),
1.91 (ddd, J ϭ 14.3, 5.0 and 2.2 Hz, 1 H), 2.01 (d, J ϭ 11.43 Hz,
1 H) 2.15 (dd, J ϭ 11.8 and 2.2 Hz, 1 H), 2.73 (ddd, J ϭ 11.4, 2.0
20
to give 510 mg (63%) of 14 as an oil. Ϫ [α]D ϭ Ϫ10 (c ϭ 7.74,
20
EtOH) {ref.[23] [α]D ϭ Ϫ13.3 (c ϭ 0.22, MeOH)}. Ϫ IR (neat): and 2.0 Hz, 1 H), 2.92Ϫ3.02 (m, 1 H), 3.15 (broad s, 2 H), 3.59 (d,
1
ν˜ ϭ 3360, 1600, 1450 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.43Ϫ1.69 J ϭ 13.8 Hz, 1 H), 3.64 (d, J ϭ 13.8 Hz, 1 H), 3.95Ϫ4.03 (m, 1 H),
(m, 3 H), 1.71Ϫ1.90 (m, 1 H), 2.14Ϫ2.61 (m, 5 H), 3.51 (s, 2 H),
7.14Ϫ7.30 (m, 5 H). Ϫ 13C NMR (CDCl3) (major isomer): δ ϭ 6.8,
3.74Ϫ3.89 (m, 1 H), 7.12Ϫ7.43 (m, 5 H). Ϫ 13C NMR (CDCl3): 33.1, 39.3, 59.3, 62.3, 63.0, 66.4, 71.2, 127.0, 128.2, 128.8, 137.7. Ϫ
δ ϭ 21.6, 31.6, 53.3, 60.1, 62.9, 66.1, 127.0, 128.1, 129.0, 137.8. Ϫ 1H NMR (CDCl3) (minor isomer): δ ϭ 0.90 (t, J ϭ 7.4 Hz, 3 H),
MS (70 eV); m/z (%): 191 (34) [Mϩ], 190 (17), 146 (10), 134 (24), 1.38Ϫ1.62 (m, 3 H), 1.67Ϫ1.83 (m, 1 H), 1.86Ϫ1.93 (m, 1 H),
114 (21), 100 (45), 91 (100), 71 (10), 65 (11). Ϫ C12H17NO (191.27):
calcd. C 75.35, H 8.96, N 7.32; found C 75.05, H 8.91, N 7.16.
2.16Ϫ2.26 (m, 1 H), 2.72Ϫ2.80 (m, 1 H), 2.65Ϫ2.90 (m, 1 H), 3.15
(broad s, 2 H), 3.77 (d, J ϭ 12.9 Hz, 1 H), 3.87 (d, J ϭ 13.2 Hz, 1
H), 4.15Ϫ4.22 (m, 1 H), 7.14Ϫ7.30 (m, 5 H). Ϫ 13C NMR (CDCl3)
(minor isomer): δ ϭ 8.6, 41.0, 42.6, 58.8, 62.4, 63.8, 68.9, 71.0,
126.8, 128.3, 128.4, 139.4. Ϫ MS (70 eV); m/z (%): 235 (5) [Mϩ],
144 (9), 134 (61), 120 (10), 91 (100), 65(7). Ϫ C14H21NO2 calcd
235.3254; found 235.3254 (MS)
(؉)-(3R)-1-Methylpiperidin-3-ol (15): Trifluoroacetic anhydride
(0.26 mL, 1.85 mmol) was added dropwise to a solution of pyrroli-
dine 6 (0.2 mL, 1.68 mmol) in THF (15 mL), cooled to Ϫ78°C.
After 1 h at Ϫ78°C, triethylamine (0.87 mL, 6.74 mmol) was added
dropwise. The reaction mixture was stirred for 1 h at Ϫ78°C and
then heated at reflux for 72 h. After addition of an aqueous 3.75 
NaOH solution (5 mL), the mixture was stirred for 1 h at room
temp., then extracted with CH2Cl2 (3ϫ 10 mL), dried with MgSO4,
and evaporated to dryness in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc/cyclohexane,
(؉)-(3R,5R)-1-Benzylpiperidine-3,5-diol (18): Trifluoroacetic anhy-
dride (0.28 mL, 1.97 mmol) was added dropwise to a solution of
pyrrolidine 9 (0.21 g, 1.79 mmol) in THF (20 mL), cooled to
Ϫ78°C. After 3 h at Ϫ78°C, Et3N (0.92 mL, 6.60 mmol) was added
dropwise. The reaction mixture was stirred for 15 min at Ϫ78°C
and then heated at reflux for 12 h. After addition of an aqueous
2.5  NaOH solution (2.3 mL), the mixture was stirred for 3 h at
room temp. and then extracted with CH2Cl2 (2ϫ 10 mL), dried
with MgSO4, and evaporated to dryness in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc/
cyclohexane, 95:5) to give 200 mg (54%) of 18 as an oil. Ϫ [α]D20 ϭ
ϩ151 (c ϭ 0.5, EtOH). Ϫ IR (neat): ν˜ ϭ 3400, 1465, 1455, 1210
20
90:10) to give 120 mg (61%) of 15 as a yellow oil. Ϫ [α]D ϭ ϩ5
20
(c ϭ 2.01, EtOH) {ref.[34] [α]D ϭ ϩ5.4 (c ϭ 2.1, EtOH)}. Ϫ IR
(neat): ν˜ ϭ 3350, 1465, 1445, 1370, 1250, 1165, 1135, 1070, 1020
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.39Ϫ1.73 (m, 3 H), 1.75Ϫ1.90
(m, 1 H), 2.23Ϫ2.65 (m, 4 H), 2.27 (s, 3 H), 3.49 (broad s, 1 H),
3.77Ϫ3.87 (m, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.6, 31.3, 46.1,
55.3, 62.3, 66.1. Ϫ MS (70 eV); m/z (%): 115 (25) [Mϩ], 114 (13),
71 (16), 58 (75), 44 (55), 43 (100), 42 (87), 41 (24), 39 (20). Ϫ
C6H13NO (115.17): calcd. C 62.57, H 11.38, N 12.16; found C
62.61, H 11.36, N 12.16.
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.71Ϫ1.86 (m, 2 H), 2.06 (broad
s, 2 H), 2.31Ϫ2.43 (m, 2 H), 2.56Ϫ2.69 (m, 2 H), 3.57 (d, J ϭ
13.0 Hz, 1.H) 3.62 (d, J ϭ 13.0 Hz, 1 H), 3.97Ϫ4.09 (m, 2 H),
7.23Ϫ7.40 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 40.1, 59.5, 62.1,
65.0, 127.3, 128.3, 128.9, 137.4. Ϫ MS (70 eV); m/z (%): 207 (11)
[Mϩ], 134 (13), 130 (11), 120 (15), 116 (30), 91 (100). Ϫ C12H17NO2
(207.27): calcd. C 69.54, H 8.27, N 6.76; found C 69.66, H 8.19,
N 6.73.
(؊)-(3R)-1-(2,2-Dimethylpropyl)piperidin-3-ol (16): Trifluoroacetic
anhydride (0.25 mL, 1.75 mmol) was added dropwise to a solution
of pyrrolidine 7 (0.2 g, 1.17 mmol) in THF (11 mL), cooled to 0°C.
After 3 h, triethylamine (0.45 mL, 3.51 mmol) was added dropwise.
The reaction mixture was stirred for 15 min at 0°C and then stirred
for 24 h at room temp. After addition of an aqueous 2.5  NaOH
solution (5 mL), the reaction mixture was stirred for 3 h at room
temp., then extracted with CH2Cl2 (2ϫ 6 mL), dried with MgSO4,
and evaporated to dryness in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc/cyclohexane,
50:50) to give 140 mg (72%) of 16 as a solid, m.p. 42°C. Ϫ [α]D20 ϭ
Ϫ3 (c ϭ 1.53, EtOH). Ϫ IR (CHCl3): ν˜ ϭ 3300, 1460, 1355, 970
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.87 (s, 9 H), 1.43Ϫ1.56 (m, 3
H), 1.76Ϫ1.83 (m, 1 H), 2.05 (s, 2 H), 2.28Ϫ2.35 (m, 1 H),
2.51Ϫ2.63 (m, 4 H), 3.72Ϫ3.80 (m, 1 H). Ϫ 13C NMR (CDCl3):
δ ϭ 21.8, 27.7, 30.9, 32.9, 56.5, 63.2, 66.5, 69.9. Ϫ MS (70 eV); m/z
(%): 171 (1) [Mϩ], 156 (6), 114 (100). Ϫ C10H21NO (171.28): calcd.
C 70.12, H 12.36, N 8.18; found C 70.11, H 12.42, N 8.36.
(؊)-(3R,5R)-1-Benzyl-5-[(tert-butyldimethylsilyl)oxy]piperidin-3-
ol (19): Trifluoroacetic anhydride (0.44 mL, 3.10 mmol) was added
dropwise to a solution of pyrrolidine 10 (0.904 g, 2.82 mmol) in
THF (30 mL), cooled to Ϫ78°C. After 3 h, Et3N (1.45 mL,
10.4 mmol) was added dropwise. The reaction mixture was stirred
for 15 min at Ϫ78°C and then heated at reflux for 20 h. After ad-
dition of an aqueous 2.5  NaOH solution (10 mL), the mixture
was stirred for 3 h at room temp. and then extracted with CH2Cl2
(2ϫ 15 mL), dried with MgSO4, and evaporated to dryness in
vacuo. The residue was purified by flash column chromatography
on silica gel (EtOAc/cyclohexane, 50:50) to give 590 mg (65%) of
20
19 as an oil. Ϫ [α]D ϭ Ϫ34 (c ϭ 0.5, EtOH). Ϫ IR (neat): ν˜ ϭ
3360, 1600, 1490, 1465, 1460, 1450, 1385, 1355, 1255, 1150, 1100,
1035 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ Ϫ0.03 (s, 3 H), 0.00 (s, 3
H), 0.82 (s, 9 H), 1.32 (ddd, J ϭ 13.2, 10.6, and 2.9 Hz, 1 H),
1.87Ϫ2.10 (m, 3 H), 2.16 (dd, J ϭ 11.5 and 1.5 Hz, 1 H), 2.71Ϫ2.93
(m, 3 H), 3.51 (d, J ϭ 13.2 Hz, 1 H), 3.63 (d, J ϭ 13.2 Hz, 1 H),
3.86Ϫ3.95 (m, 1 H), 3.98 (dddd, J ϭ 14.7, 9.7, 4.7 and 4.7 Hz, 1
H), 7.15Ϫ7.30 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ Ϫ4.9, Ϫ4.8,
17.9, 25.7, 40.6, 58.2, 60.7, 62.0, 64.9, 65.7, 127.3, 128.2, 129.0,
137.2. Ϫ MS (70 eV); m/z (%): 321 (3) [Mϩ], 264 (24), 134 (17), 101
(9), 92 (9), 91 (100), 75 (11), 73 (12). Ϫ C18H31NO2Si calcd
321.5339; found 321.5342 (MS).
(3RS,5R)-1-Benzyl-3-ethyl-5-hydroxypiperidin-3-ols (17): Trifluoro-
acetic anhydride (0.09 mL, 0.60 mmol) was added dropwise to a
solution of the mixture of pyrrolidines 8 (0.2 g, 1.17 mmol) in
CH2Cl2 (5 mL), cooled to 0°C. After 3 h, Et3N (0.28 mL,
2.18 mmol) was added dropwise. The reaction mixture was stirred
for 15 min at 0°C and then for 20 h at room temp. After addition
of an aqueous 2.5  NaOH solution (8 mL), the mixture was
stirred for 3 h at room temp., then extracted with CH2Cl2 (2ϫ
7 mL), dried with MgSO4, and evaporated to dryness in vacuo. The
Eur. J. Org. Chem. 1999, 1693Ϫ1699
1697

J. Cossy, C. Dumas, D. Gomez Pardo
FULL PAPER
[1]
[2]
[3]
M. E. Jung, Z. Longmei, P. Tangsheng, Z. Huiyan, L. Yan, S.
Jingyu, J. Org. Chem. 1992, 57, 3528Ϫ3530.
K. Tadano, Y. Iimura, T. Suami, J. Carbohydrate Chem. 1985,
129Ϫ139.
(؊)-(3aR,7R,7aS)-2,2,5-Trimethylhexahydro-4H-1,3-dioxolo[4,5-c]-
pyridin-7-ol (20): Trifluoroacetic anhydride (0.08 mL, 0.58 mmol)
was added dropwise to a solution of pyrrolidine 11 (98 mg,
0.52 mmol) in THF (5 mL) cooled to Ϫ78°C. After 1 h, Et3N
(0.27 mL, 1.94 mmol) was added dropwise. The reaction mixture
was stirred for 1 h at Ϫ78°C and then heated at reflux for 72 h.
After addition of an aqueous 3.75  NaOH solution (2 mL), the
mixture was stirred for 1 h at room temp. and then extracted with
CH2Cl2 (3ϫ 5 mL), dried with MgSO4, and evaporated to dryness
in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (CHCl3/MeOH, 92:8) to give 65 mg (67%) of 20
H.-A. Hasseberg, H. Gerlach, Liebigs Ann. Chem. 1989,
255Ϫ261.
[4]
[5]
K. E. Harding, M. W. Jones, Heterocycles 1989, 663Ϫ668.
R. Paul, S. Tchelitcheff, Bull. Chim. Soc. Chim. Fr. 1953,
1014Ϫ1016.
[6] [6a]
[6b]
C. Thomassigny, J. Gelas, Synthesis 1997, 191Ϫ194. Ϫ
C. Agami, F. Couty, H. Mathieu, Tetrahedron Lett. 1996, 37,
[6c]
4001Ϫ4002. Ϫ
ert, J. Org. Chem. 1995, 60, 5820Ϫ5824. Ϫ
J. Yoon, S.-G. Lee, J. Chem. Soc., Perkin Trans. 1 1994,
A. Kilonda, F. Compernolle, G.-J. Hoorna-
[6d]
K.-H. Park, Y.-
T. M. Jespersen, M. Bols, M. R. Sierks, T.
20
[6e]
as a yellow oil. Ϫ [α]D ϭ Ϫ21 (c ϭ 0.35, MeOH). Ϫ IR (neat):
2621Ϫ2623. Ϫ
Skydstrup, Tetrahedron 1994, 50, 13449Ϫ13460.
ν˜ ϭ 3400, 1465, 1455, 1385, 1275, 1210 cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ 1.36 (s, 3 H), 1.52 (s, 3 H), 2.29Ϫ2.41 (m, 1 H), 2.32 (s, 3 H),
2.52Ϫ2.71 (m, 3 H), 3.38 (broad s, 1 H), 3.92Ϫ4.01 (m, 2 H), 4.31
(dd, 1 H, J ϭ 10.8 and 5.3 Hz). Ϫ 13C NMR (CDCl3): δ ϭ 26.1,
28.1, 45.7, 56.7, 57.5, 68.0, 72.1, 76.6, 109.2. Ϫ MS (70 eV); m/z
(%): 187 (11) [Mϩ], 172 (5), 129 (6), 112 (16), 82 (15), 58 (25), 57
(100), 55 (9). Ϫ C9H17NO3 calcd 187.2382; found 187,2379 (MS).
[7] [7a]
Y. Morimoto, H. Shirahama, Tetrahedron 1996, 52,
[7b]
10631Ϫ10652. Ϫ
1991, 47, 3075Ϫ3088.
A. Nuhrich, J. Moulines, Tetrahedron
[8] [8a]
J.-D. Ha, D. Lee, J.-K. Cha, J. Org. Chem. 1997, 62,
[8b]
4550Ϫ4551. Ϫ
S. Hanessian, G. McNaughton-Smith, Bio-
org. Med. Chem. Lett. 1996, 6, 1567Ϫ 1572.
[9]
Y. Hirai, J. Watanabe, T. Nozaki, H. Yokoyama, S. Yamaguchi,
J. Org. Chem. 1997, 62, 776Ϫ777.
[10] [10a]
´
´
J. C. Carretero, R. Gomez Arrayas, I. Storch de Gracia,
(؉)-1-Methyl-2-phenylpiperidin-3-ol (22): Trifluoroacetic anhydride
(0.04 mL, 0.28 mmol) was added dropwise to a solution of pyrroli-
dine 21 (35 mg, 0.18 mmol) in THF (6 mL) cooled to Ϫ78°C. After
1 h, Et3N (0.81 mL, 0.58 mmol) was added dropwise. The reaction
mixture was stirred for an additionnal 1 h at Ϫ78°C and then
heated at reflux for 48 h. After addition of an aqueous 3.75 
NaOH solution (4 mL), the mixture was stirred for 1 h at room
temp. and then extracted with CH2Cl2 (3ϫ 4 mL), dried with
MgSO4, and evaporated to dryness in vacuo. The residue was puri-
fied by flash column chromatography on silica gel (EtOAc) to give
[10b]
Tetrahedron Lett. 1996, 37, 3379Ϫ3382. Ϫ
T. Oishi, T.
[10c]
ˆ
Iwakuma, M. Hirama, S. Ito, Synlett 1995, 404Ϫ406. Ϫ
T.
Naito, K. Tajiri, T. Harimoto, I. Ninomiya, T. Kiguchi, Tetra-
hedron Lett. 1996, 35, 2205Ϫ2206.
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Y. Yuasa, J. Ando, S. J. Shibuya, J. Chem. Soc., Perkin
[11b]
Trans. 1 1996, 793Ϫ802. Ϫ
Chem. 1992, 57, 4802Ϫ4809.
S. Knapp, F. S. Gibson, J. Org.
[12]
I. Kadota, M. Kawada, S. Saya, Y. Yamamoto, Tetrahedron
Lett. 1996, 37, 2109Ϫ2112.
[13]
[14]
L.-E. Overman, N.-H. Lin, J. Org. Chem. 1985, 50, 3669Ϫ3670.
P. Gmeiner, D. Junge, J. Org. Chem. 1995, 60, 3910Ϫ3915.
[15] [15a]
[15b]
S. Laschat, T. Fox, Synthesis 1997, 475Ϫ479. Ϫ
L.-E.
20
19 mg (56%) of 22 as a yellow oil. Ϫ [α]D ϭ ϩ45 (c ϭ 0.12,
Overman, D. Lesuisse, Tetrahedron Lett. 1985, 26, 4167Ϫ4170.
EtOH). Ϫ IR (neat): ν˜ ϭ 3380, 1450, 1260, 1120, 1060, 1010 cmϪ1
Ϫ
.
[16] [16a]
K.-J. Dubois, C.-C. Fannes, F. Compernolle, G.-J. Hoorna-
1H NMR (CDCl3): δ ϭ 1.33Ϫ1.49 (m, 1 H), 1.74Ϫ1.85 (m, 4
ert, Tetrahedron 1996, 52, 2591Ϫ2602. Ϫ
T.-N. Birkinshaw,
[16b]
A.-B. Holmes, Tetrahedron Lett. 1987, 28, 813Ϫ816.
[17] [17a] G.-M. Makara, G. R. Marshall, Tetrahedron Lett. 1997, 38,
5069Ϫ5072. Ϫ [17b] H. Sakagami, T. Kamikubo, K. Ogasawara,
Synlett 1997, 221Ϫ222. Ϫ [17c] W.-R. Ashcroft, J.-A. Joule, Het-
erocycles 1981, 16, 1883Ϫ1887.
H), 2.00 (s, 3 H), 2.08Ϫ2.21 (m, 2 H), 2.64 (d, J ϭ 8.8 Hz, 1 H,),
2.92Ϫ3.03 (m, 1 H), 3.65 (ddd, J ϭ 11.0, 8.8, and 4.4 Hz, 1 H),
7.27Ϫ7.43 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 23.4, 32.1, 44.0,
56.6, 73.0, 77.6, 128.0, 128.4, 128.8, 140.1. Ϫ MS (70 eV); m/z (%):
191 (22) [Mϩ], 190 (15), 146 (40), 134 (40), 132 (24), 118 (100), 117
(11), 114 (13), 91 (51), 77 (14), 65 (11), 51 (12). Ϫ C12H17NO calcd
191.1310; found 191,1311 (MS).
[18] [18a] Y.-M. Xu, W.-S. Zhou, J. Chem. Soc., Perkin Trans. 1 1997,
[18b]
741Ϫ746. Ϫ
W.-S. Zhou, W.-G. Xie, Z.-H. Lu, X.-F. Pan,
[18c]
Tetrahedron Lett. 1995, 36, 1291Ϫ1294. Ϫ
N. Toyooka, Y.
Yoshida, T. Momose, Tetrahedron Lett. 1995, 36, 3715Ϫ3718.
[18d]
Ϫ
C.-W. Jefford, K. Sienkiewicz, S.-R. Thornton, Helv.
(؊)-1-Benzyl-2-(1-methylethenyl)pyrrolidine (28): Trifluoroacetic
anhydride (0.15 mL, 1.06 mmol) was added dropwise to a solution
of pyrrolidine 27 (0.22 g, 1 mmol) in THF (9 mL) cooled to Ϫ78°C.
After 1 h, Et3N (0.51 mL, 3.65 mmol) was added dropwise. The
reaction mixture was stirred for an additional 1 h at Ϫ78°C and
then heated at reflux for 7 days. After addition of an aqueous
3.75  NaOH solution (5 mL), the mixture was stirred for 1 h at
room temp. and then extracted with CH2Cl2 (3ϫ 7 mL), dried with
MgSO4, and evaporated to dryness in vacuo. The residue was puri-
fied by flash column chromatography on alumina (EtOAc/cylohex-
ane, 50:50) to give 110 mg (55%) of 28 as a colourless oil. Ϫ
[α]D20 ϭ Ϫ43 (c ϭ 1, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.64Ϫ1.98
(m, 4 H), 1.82 (s, 3 H), 2.01Ϫ2.14 (m, 1 H), 2.85Ϫ3.05 (m, 2 H),
3.00 (d, J ϭ 13.2 Hz, 1 H), 3.97 (d, J ϭ 13.2 Hz, 1 H), 4.87Ϫ4.93
(m, 1 H), 5.04Ϫ5.06 (m, 1 H), 7.15Ϫ7.45 (m, 5 H). Ϫ 13C NMR
(CDCl3): δ ϭ 17.3, 22.2, 29.8, 53.3, 57.9, 71.0, 112.1, 126.5, 128.0,
128.6, 139.9, 146.4. Ϫ MS (70 eV); m/z (%): 201 (11) [Mϩ], 161
(20), 160 (93), 91 (100), 65 (15). Ϫ C14H19N calcd 201.3108; found
201,3099 (MS).
[18e]
Chim. Acta 1995, 78, 1511Ϫ1524. Ϫ
S.-A. Miller, A.-R.
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[20c]
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J. Cossy, C. Dumas, P. Michel, D. Gomez Pardo, Tetra-
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J. Cossy, C. Dumas, D.
Gomez Pardo, Biorg. Med. Chem. Lett. 1997, 7, 1343Ϫ1344. Ϫ
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J. Cossy, C. Dumas, D. Gomez Pardo, Synlett 1997,
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[21e]
S. Pohl, J. Martens, Liebigs Ann. 1997, 573Ϫ579. Ϫ
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Dumas, Ph. D. Dissertation, Universite P. et M. Curie (Paris 6),
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1998. Ϫ
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[21g]
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Acknowledgments
K. Muto, T. Kuroda, H. Kawato, A. Karasawa, K. Kubo, N.
Nakamizo, Arzneim. Forsch. 1988, 38, 1662Ϫ1665.
The enantiomeric excess was determined by 1H NMR using
(ϩ)-Eu(hfc)3 as chiral shift reagent.
We thank the CNRS (ESA 7084) and the ESPCI for financial sup-
port.
1698
Eur. J. Org. Chem. 1999, 1693Ϫ1699

Optically Active 3-Hydroxypiperidines from Pyrrolidinemethanol Derivatives
FULL PAPER
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Eur. J. Org. Chem. 1999, 1693Ϫ1699
1699