Stereoselective synthesis of 4-aminomethyl-3-hydroxyprolinols and ring expansion into enantiopure polyfunctionalized piperidines

Article abstract of DOI:10.3987/COM-04-S(P)13

A stereoselective route was developed to synthesize enantiopure 3,4,5-trisubstituted piperidines in few steps. The functionalities were introduced starting from (S)-pyroglutaminol as chiral material. The method is based on the 1,3-dipolar cycloaddition of N-benzylnitrone to a derived bicyclic α,β-ethylenic lactam, followed by a ring enlargement of five to six membered nitrogen heterocycles through aziridinium ions.

Full text of DOI:10.3987/COM-04-S(P)13

HETEROCYCLES, Vol. 64, 2004
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HETEROCYCLES, Vol. 64, 2004, pp. 207 - 214
Received, 31st May, 2004, Accepted, 28th July, 2004, Published online, 30th July, 2004
STEREOSELECTIVE
SYNTHESIS
OF
4-AMINOMETHYL-3-
HYDROXYPROLINOLS AND RING EXPANSION INTO ENANTIOPURE
POLYFUNCTIONALIZED PIPERIDINES#
Abdallah Deyine, Jean-Marc Delcroix, and Nicole Langlois*
Institut de Chimie des Substances Naturelles
C.N.R.S., Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax:+33 1 69077247
E-mail: nicole.langlois@icsn.cnrs-gif.fr
Abstract–A stereoselective route was developed to synthesize enantiopure 3,4,5-
trisubstituted piperidines in few steps. The functionalities were introduced starting
from (S)-pyroglutaminol as chiral material. The method is based on the 1,3-
dipolar cycloaddition of N-benzylnitrone to a derived bicyclic a,b-ethylenic
lactam, followed by a ring enlargement of five to six membered nitrogen
heterocycles through aziridinium ions.
INTRODUCTION
The synthesis of chiral polysubstituted piperidines is still the focus of special interest.1,2 Indeed,
functionalized piperidines exhibit a great range of biological activities. Among them, polyhydroxylated
piperidines derivatives could be candidates for the inhibition of glycosidases,3,4 and related highly
functionalized piperidines could also be used to prepare novel PNAs (Peptide Nucleic Acids) with
promising properties.5,6 They can also constitute useful building blocks in the preparation of more
complex alkaloids or attractive synthetic targets.
RESULTS AND DISCUSSION
Taking advantage of easy functionalization of (S)-pyroglutaminol derivatives such as 2, we already
developed a strategy towards N-benzyl-4-benzylamino-3-hydroxypiperidine, involving a well known
expansion reaction of pyrrolidine rings.7,8a This enlargement of five to six membered nitrogen
# Dedicated to Dr. Pierre Potier on the occasion of his 70th birthday

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HETEROCYCLES, Vol. 64, 2004
heterocycles requires the presence of a leaving-group or a leaving-group precursor in b position to the
heterocyclic nitrogen and proceeds through aziridinium ions.7-9 We extend here this methodology to the
preparation of (3S,4S,5S)-5-aminomethyl-3,4-dihydroxypiperidine derivatives.
The aminomethyl and vicinal cis hydroxyl groups could be simultaneously introduced by a highly regio-
and stereo-selective 1,3-dipolar cycloaddition of N-benzylnitrone to the versatile bicyclic a,b-ethylenic
lactam (2) prepared from (S)-pyroglutaminol (1). This cycloaddition occurred by heating in toluene as we
previously described,10 but the yield was now improved by using an excess of the nitrone (1.5 equiv.) and
the major cycloadduct (3) was isolated in excellent yield (90%). A deprotective reduction by LAH with
the opening of both oxazolidine and isoxazolidine rings in a single step led to (2R,3S,4S)-1-benzyl-4-
benzylaminomethyl-3-hydroxyprolinol (4) in 93% yield (Scheme 1).
Ph
Ph
N
O
Ph
N
OH
Ph
+
N
H
–
O
LAH, THF
D
OH
O
D
O
O
OH
N
H
N
N
N
90%
93%
O
O
Ph
Ph
1
4
2
3
Scheme 1
The N-benzyl 3,4-disubstituted prolinol (4) was treated under classical ring expansion conditions with
trifluoroacetic anhydride and triethylamine and then with 2.5 N NaOH, affording 5 in 33% yield, together
with the starting pyrrolidine (4) (20%, Scheme 2). The diol (5) was acetylated into 6 to make easier the
identification of the shifted H-3 and H-4 signals in the 1H-NMR spectrum.
OAc
OH
N
R
OH
Ph
OAc
OH
4
3
Ph
Ph
N
N
R
1) (CF3CO)2O
THF, NEt3
Ac
OH
N
N
N
2) 2.5 N NaOH
Ph
Ph
Ph
5 R = H
10
4 R = H
6
CF3CO2H
CH2Cl2
R = Boc
9 R = Boc
Scheme 2

HETEROCYCLES, Vol. 64, 2004
209
One possible reason for the modest yield observed might be the incomplete trifluoroacylation of the
secondary amino group in spite of the use of an excess of trifluoroacetic anhydride. Indeed, some
elimination of the leaving group generated at C-3 could be postulated with the participation of the rather
flexible aminomethyl group and a fragmentation reaction illustrated in the Scheme 3.
–
Ph
N
H
OCOCF3
CF3CO2
+
+ Ph
N
H
OH
4
N
OCOCF3
N
Ph
Ph
Scheme 3
To overcome this drawback, we tried to modify the chronology of the sequences with the enlargement of
5-membered ring of the compound (7). This derivative was obtained in high yield (90%) by reduction of
the lactam carbonyl with selective opening of the oxazolidine ring by means of the complex BH3-SMe2.11
However, under the same conditions as above, the yield of piperidine (8) was not improved by this way
(28%, Scheme 4).
Ph
Ph
Ph
N
2
N
N
1O
2
O
1O
3
3
OH
3a
7a
1) (CF3CO)2O THF, NEt3
2) 2.5 N NaOH
7
6
3a 6a
BH3-DMS
THF
4
6
4
5
OH
5
O
N
N
N
O
Ph
Ph
Ph
8
3
7
Scheme 4
The classical protection of the secondary N-benzylamino group of the trisubstituted pyrrolidine (4) as t-
butyl carbamate (9) was more efficient. It is worthy of note that this N-protecting group was stable under
the ring expansion conditions which led more rapidly to the piperidine (10) with 42% yield (Scheme 2),
along with starting pyrrolidine (35%). N-Boc protecting group was removed with diluted trifluoroacetic
acid in dichloromethane affording 5.

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HETEROCYCLES, Vol. 64, 2004
CONCLUSION
In conclusion, from the bicyclic a,b-ethylenic lactam (2), a versatile derivative of (S)- pyroglutaminol,
was developed a rapid and efficient access to interesting (2R,3S,4S)-1-benzyl-4-aminomethyl-3-
hydroxyprolinols. Ring expansion of these 5-membered nitrogen heterocycles was shown to be useful to
prepare optically active highly functionalized piperidines in few steps, under experimental conditions
which are compatible with a N-Boc protecting group.
EXPERIMENTAL
General. Optical rotations were measured on a JASCO P-1010 polarimeter and the concentrations were
given in g/100 mL. IR spectra (film, CHCl3) were recorded on Perkin Elmer Spectrum BX (FT). 1H NMR
spectra were obtained (generally in CDCl3, CHCl3 d = 7.27 ppm) from Bruker AM 300 and the coupling
13
constants are given in Hertz. C NMR spectra were recorded on AM 300 (75.0 MHz, CDCl3 centred at
77.14 ppm). MS and HRMS were measured on a Navigator (ESI), or a Micromass LC-TOF, or an
Automass Thermo-Finnigan spectrometer. Chromatography was performed on silica gel (SDS 230-400
mesh) and preparative thin layer chromatography on silica gel (Merck HF 254 + 366). Usual workup
means that the organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum
(2R,3S,4S)-1-Benzyl-4-benzylaminomethyl-3-hydroxy-2-hydroxymethylpyrrolidine (4)
To a solution of cycloadduct (3) (777.7 mg, 2.31 mmol) in dry THF (6.0 mL), stirred at 0 °C under argon,
was added a solution of LiAlH4 (600 mg, 15.81 mmol) in THF (28 mL). The mixture was heated at
reflux for 17 h, cooled at 0 °C and the excess of reagent was carefully destroyed by addition of some
drops of a saturated aqueous solution of Na2SO4. The residue obtained after usual workup was purified by
chromatography (eluent : CH2Cl2-MeOH-NH4OH 9:1:0.1) to give (2R,3S,4S)-1-benzyl-4-
23
benzylaminomethyl-3-hydroxy-2-hydroxymethylpyrrolidine (4) (705.6 mg, 93%) as a colorless oil. [a]D
= – 97 ° (c 0.91, CHCl3). IR: 3350, 3070, 3063, 3034, 2924, 2831, 1497, 1457 cm–1. MS (ESI, MeOH)
m/z: 349 [(MNa)+ , 45 %], 327 [(MH)+ , 100%]. 1H NMR: 7.29 (m, 10H, H-Ar), 4.33 (dd, 1H, J = 6.2, J’
= 3.8, H-3), 3.96 and 3.41 (2 d, 2H, J = 12.9, NCH2Ph), 3.74 (2 d, 2H, J = 13, NCH2Ph), 3.66 (2H,
OCH2), 3.20 (exch. OH, NH), 2.95 (dd, 1H, J = 8, J’ = 6.4, NCH) and 2.31 (m, 1H, NCH), 2.82 (2H,
NCH2), 2.69 (m, 1H, H-2), 2.20 (m, 1H, H-4). 13C NMR (dihydrochloride, D2O, dioxane d = 67.19 ppm):
aromatic qC not visible, 131.53, 131.33, 131.02, 130.63, 130.49, 130.05, 129.96 (CH, Ar), 76.01, 71.64
(C-2 and C-3), 60.36 (CH2), 58.34 (CH2), 55.41 (CH2), 52.31 (CH2), 44.09 (CH2), 38.99 (C-4). HRMS
(ESI, MeOH) calcd for C20H27N2O2 (MH+): 327.2073, found: 327.2072. Dihydrochloride: Anal. Calcd for
C20H28O2N2Cl2, CH3OH: C, 58.46; H, 7.48; N, 6.49. Found: C, 58.12; H, 7.31; N, 6.41.

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211
(3S,4S,5S)-1-Benzyl-5-benzylaminomethyl-3,4-dihydroxypiperidine (5)
Trifluoroacetic anhydride (1.0 mL, 7.08 mmol) was added to a stirred solution of pyrrolidine (4) (315.1
mg, 0.97 mmol) in dry THF (17.5 mL) at – 78 °C. The mixture was stirred at this temperature for 3 h,
before the addition of triethylamine (2.0 mL, 14.35 mmol). After being stirred at – 78 °C for 0.25 h, the
mixture was heated at 65 °C for 4 days, cooled at rt, and 2.5 M NaOH solution (4.5 mL) was then added.
This mixture was stirred at rt for 2 h before extraction with CH2Cl2. The crude product obtained after
usual workup was purified by flash chromatography (eluent : CH2Cl2-MeOH-NH4OH 9:1 :0.1) to give the
24
piperidine (5) as a colorless oil (102.8 mg, 33%) and starting pyrrolidine (4) (63.3 mg, 20 %). 5 : [a]D
=
1
1.0 ° (c 1.3, CHCl3). IR: 3621, 3020, 1453 cm–1. MS (ESI, MeOH) m/z: 327 [(MH)+, 100%]. H NMR
(C6D6, d = 0: TMS): 7.14, 7.10 (2 m, H-Ar), 3.89 (m, 1H, H-3), 3.79 (m, 1H), 3.34–3.15 (m, 4H, 2 NCH2),
2.93 (m, 1H, Ha-2), 2.74 (m, 1H), 2.25 [dd (J = 12.1, J’ = 3.7) + m, 2H, Hb-7, Hb-2], 2.15 (m, 1H, Ha-6),
1.95 (m, 1H, Hb-6), 1.88 (m, 1H, H-5). 13C NMR (C6D6, d = 0: TMS): 139.71, 139.19 (qC, Ar), 129.06,
128.73, 128.57, 128.35, 128.03, 127.71, 127.47, 127.36 (CH, Ar), 75.43, 69.68 (OCH), 62.73 (NCH2Ph),
57.2 (br, NCH2), 54.14 (NCH2), 51.13 (NCH2), 36.89 (C-5). HRMS (ESI, MeOH) calcd for C20H27N2O2
(MH+): 327.2073, found: 327.2027. Dihydrochloride: Anal. Calcd for C20H28N2O2Cl2, H2O: C, 57.55; H,
7.25; N, 6.71. Found: C, 57.35; H, 7.31; N, 6.56.
(3S,4S,5R)-1-Benzyl-3,4-diacetoxy-5-(N-acetyl-N-benzylamino)methylpiperidine (6)
Pyridine (1.8 mL) and acetic anhydride (1.2 mL) were added at rt to piperidine (5) (78.9 mg, 0.24 mmol)
and the mixture was stirred at rt for 22 h. After addition of methanol (17 mL), the solution was stirred for
0.25 h before the addition of aqueous Na2CO3 solution (10 % w/v, 12 mL). After extraction with CH2Cl2,
and usual workup, the solvents were evaporated under reduced pressure. The crude product was purified
by prepative TLC (eluent : Et2O) to give the triacetylated compound (6) as a white crystals (83.1 mg,
76 %). Mp: 111-112 °C. [a]D23 = – 44.4 ° (c 1.0, CHCl3). IR : 3029, 3008, 2814, 1737, 1635, 1453 cm–1.
MS (ESI, MeOH) m/z: 475 [(MNa)+, 95%], 453 [(MH)+, 100%]. 1H NMR (conformers) : 7.25, 7.13, 7.05
(m, d, d, 10 H, J = 8, H-Ar), 4.87 (m, 3H, H-3, H-4, NCHaPh), 4.29 (2 d, 2H, J = 14.7, NCH2), 4.14 (d,
1H, J = 14.7, NCHbPh), 3.66 and 3.25 (2 m, 2H, NCH2), 3.56 (dd, 1H, J = 12.9, J’ = 4.5, NCH), 3.42 (dd,
1H, J = 12.9, J’ = 10.9, NCH), 2.90, 2.71 (NCHa’Ph), 2.53 (m, 1H), 2.30 (m, 1H, NCHb’Ph), 2.15, 2.05,
2.00, 1.97, 1.95, 1.90 (6 s, 9H, 3 COCH3). 13C NMR (conformers): 171.46, 171.30 (CO), 170.26, 170.10,
170.04 (CO), 137.72, 137.27, 136.80, 136.71 (qC, Ar), 129.25, 129.18, 129.00, 128.67, 128.56, 128.39,
128.05, 127.71, 127.60, 127.43, 127.40, 126.01 (CH, Ar), 73.13, 70.92 (OCH), 68.17, 67.74 (OCH),
62.35, 62.19 (CH2), 54.41, 52.90 (CH2), 52.31 (CH2), 47.58 (CH2), 44.58, 44.17 (CH2), 36.32, 36.05 (C-
5), 21.79, 21.47, 21.12, 21.09, 20.97, 20.88 (COCH3). HRMS (ESI, MeOH) calcd for C26H33N2O5 (MH+):

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HETEROCYCLES, Vol. 64, 2004
453.2389, found: 453.2353. Anal. Calcd for C26H32N2O5: C, 69.00; H, 7.13; N, 6.19. Found: C, 68.94; H,
7.32; N, 6.12.
(6R,6aS,3aR)-(2,5-Dibenzylhexahydropyrrolo[3,4-d]isoxazol-6-yl)methanol (7)
To a solution of lactam (3) (544.5 mg, 1.62 mmol) in anhydrous THF (38.0 mL) was added at rt a
solution of BH3.DMS in THF (2 M, 5.0 mmol, 2.50 mL). The mixture was heated at reflux for 2 h. After
cooling at rt, the solution was acidified by addition of 2.0 M aqueous HCl and evaporated to dryness.
Aqueous 6N HCl (25 mL) was added, the mixture was heated at 70 °C for 0.25 h and 30 % aqueous
NaOH was then added at 0 °C until pH > 10. The solution was extracted with CH2Cl2. The product
obtained after usual workup was purified by flash chromatography (eluent : CH2Cl2-MeOH 9:1) and
hydroxymethylpyrrolidine (7) was obtained as colorless oil (473.8 mg, 90 %). [a]D23 = – 23.8 ° (c 1.27,
CHCl3). IR: 3681, 3618, 3016, 1515, 1475, 1420 cm–1. MS (ESI, MeOH) m/z: 347 [(MNa)+, 81 %], 325
[(MH)+.(100 %)], 190 (40 %). 1H NMR (CDCl3 + D2O + Na2CO3): 7.35 (m, 10 H), 4.67 (dd, 1H, J = 4.7,
J’= 8.2), 4.09 (d, 1H, J = 13, NCHaPh ), 3.99 (d, 1H, J = 13, NCHa’Ph), 3.90 (br d, 1H, NCHbPh), 3.84
(dd, 1H, J = 12, J’ = 1.9), 3.72 (d, 1H, J = 12), 3.32 (d, 1H, J = 13, NCHb’Ph), 3.19 (dd, 1H, J = J’ = 8),
2.95 and 2.88 (2 m, 2H), 2.73 (m, 1H), 2.50 (m, 1H), 2.37 (dd, 1H, J = J’ = 8). 13C NMR (CDCl3 + D2O
+ Na2CO3): 138.54 (qC, Ar), 137.35 (qC, Ar), 128.81, 128.73, 128.51, 128.42, 127.37, 127.34 (CH, Ar),
84.20 (C-6a), 69.91(C-6), 61.96, 61.69 (CH2), 59.92 (CH2), 59.40 (CH2), 58.86 (CH2), 57.41 (CH2), 44.57
(C-3a). HRMS (ESI, MeOH): calcd for C20H25N2O2 (MH+): 325.1916, found: 325.1909. Dihydrochloride:
Anal. Calcd for C20H26N2O2Cl2: C, 60.45; H, 6.60; N, 7.05. Found: C, 60.61; H, 6.81; N, 7.01.
(7S,7aS,3aR)-2,5-Dibenzyloctahydroisoxazolo[4,5-c]pyridin-7-ol (8)
Trifluoroacetic anhydride (325 mL, 2.30 mmol) was added to a stirred solution of pyrrolidine (7) (202.2
mg, 0.62 mmol) in dry THF (8.5 mL) at – 78 °C. The mixture was stirred at this temperature for 3 h
before the addition of triethylamine (670 mL, 4.80 mmol). After being stirred at – 78 °C for 0.25 h, and
heated at 65 °C for 4 days, the mixture was cooled at rt, and 2.5 M NaOH solution (2.3 mL) was then
added. This mixture was stirred at rt for 3 h before extraction with CH2Cl2. The product obtained after
usual workup was purified by preparative TLC (eluent : heptane-EtOAc 3:7) giving the piperidine (8) as a
colorless oil (56.2 mg, 28%) and starting pyrrolidine (7) (47.3 mg, 23 %). 8 : [a]D23 = 51 ° (c 0.74,
CHCl3). IR: 3627, 3028, 1518 cm–1. MS (ESI, MeOH) m/z: 347 [(MNa)+, 20 %], 325 [(MH)+, 100 %]. 1H
NMR: 7.32, 7.30 (2 m, 10 H), 4.17, 4.10 (2 m, 2H), 3.97, 3.88 (2 m, 2H), 3.53 (middle of 2 d, 2H, J = 13,
NCH2Ph), 2.95, 2.84 (2 m, 3H), 2.67, 2.60 (2 m, 3H), 2.32 (dd, 1H, J and J’ ~ 9). 13C NMR: 138.05,
137.04 (qC, Ar), 129.32, 129.05, 128.85, 128.73, 128.51, 128.44, 127.56, 127.42 (CH, Ar), 65.84, 64.37
(CH2), 62.42 (CH2), 58.23 (CH2), 55.22 (CH2), 53.77 (CH2), 40.21(CH). HRMS (ESI, MeOH) calcd for

HETEROCYCLES, Vol. 64, 2004
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C20H25N2O2 (MH)+: 325.1916, found: 325.1921. Anal. Calcd for C20H24N2O2, 0.5 CH3OH: C, 72.32; H,
7.70; N, 8.23. Found: C, 72.25; H, 7.44; N, 8.16.
(2R,3S,4R)-1-Benzyl-4-(N-benzyl-N-tert-butyloxycarbonylamino)methyl-3-hydroxy-2-hydroxy-
methylpyrrolidine (9)
A solution of Boc2O (215.9 mg, 0.99 mmol) in dichloromethane (1.0 mL) and triethylamine (15 mL, 0.1
mmol) were added to a solution of aminopyrrolidine (4) (293.2 mg, 0.9 mmol) in dichloromethane (1.0
mL). The mixture was stirred for 4 h at 0 °C. After evaporation of the solvent under reduced pressure, the
crude product was purified by flash chromatography (eluent: CH2Cl2-MeOH 95:5) and gave the N-Boc
aminopyrrolidine (9) as a white foam (264.2 mg, 69 %). [a]D23 = 1.5 ° (c 0.99, CHCl3). IR : 3363, 3020,
1
1663 cm–1. MS (ESI, MeOH) m/z: 427 [(MH)+, 100 %)], 371 (62 %). H NMR: 7.29, 7.15 (2 m, 10H, H-
Ar), 5.06 (br s, 1H), 4.73, 3.96 (2 d, 2H, J = 15.7, NCH2Ph), 4.02 (m, 1H, H-3), 3.91, 3.56 (2 d, 2H, J =
12.5, NCH2Ph), 3.52 (m, 2H, H2-6), 3.82, 2.63 (2 m, 2H, NCH2), 2.88 (m, 1H, H-2), 2.71, 2.37 (2 m, 2H,
NCH2), 2.12 (m, 1H, H-4), 1.45 (s, 9H, t-Bu). 13C NMR: 157.25 (NCO2), 139.26, 137.69 (qC, Ar), 128.92,
128.71, 128.52, 127.63, 127.36, 127.27 (CH, Ar), 81.29 (qC, t-Bu), 74.60 (C-3), 73.64 (C-2) , 61.80 (C-6),
59.60 (NCH2Ph), 54.70 (NCH2), 50.93 NCH2Ph), 43.78 (C-4), 42.63 (NCH2), 28.44 (CH3, t-Bu). HRMS
(ESI, MeOH) calcd for C25H35N2O4 (MH)+: 427.2597, found: 427.2581. Hydrochloride : Anal. Calcd for
C25H35N2O4Cl, CH3OH : C, 63.08 ; H, 7.94. Found : C, 63.37 ; H, 7.64.
(3S,4S,5R)-1-Benzyl-5-(N-benzyl-N-tert-butyloxycarbonylamino)methyl-3,4-dihydroxypiperidine
(10)
To a solution of pyrrolidine (9) (103.4 mg, 0.24 mmol) in dry THF (3.8 mL) was added at – 78 °C
trifluoroacetic anhydride (270 mL, 1.91 mmol). The mixture was stirred at this temperature for 3 h before
the addition of triethylamine (535 mL, 3.84 mmol). After being stirred at – 78 °C for 0.75 h, the mixture
was heated at reflux for 17 h, cooled at rt, and 2.5 M NaOH solution (1.5 mL) was then added. This
mixture was stirred at rt for 2 h before extraction with CH2Cl2. After usual workup, the crude product was
purified by preparative TLC (eluent : CH2Cl2-MeOH 9:1) and gave the piperidine (10) as a colorless oil
(43.7 mg, 42 %) and starting pyrrolidine (9) (36.4 mg, 35 %). 10: [a]D23 = 29.5 ° (c 0.56, CHCl3). IR:
1
3379, 2937, 1661, 1425 cm–1. MS m/z: 427 [(MH)+, 33 %]+, 371 (100 %), 327 (97.5 %). H NMR : 7.29,
7.17 (2 m, 10H, H-Ar), 4.72 (d, 1H, J = 16, NCHaPh), 4.01 (d, 1H, J = 16, NCHbPh), 3.87 (m, 1H,
OCH), 3.69 (m, 1H), 3.63 (m, 3H, NCH, CH2), 2.86 (m, 1H, NCHa), 2.70 (d, 1H, J = 11.8, NCHb), 2.57
(d, 1H, J = 14, NCH), 2.43 (m, 1H, NCH), 2.21 (m, 2H, H-5, NCH), 1.44 (s, 9H, t-Bu). 13C NMR :
157.60 (NCO2), 137.59, 134.5 (qC, Ar), 129.65, 128.72, 128.67, 128.04, 127.53, 127.29 (CH, Ar), 81.33

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HETEROCYCLES, Vol. 64, 2004
(qC, t-Bu), 68.02 (OCH), 65.8, 62.49 (NCH2), 53.75 (NCH2), 50.75 (NCH2), 44.96 (NCH2), 34.48 (C-5),
28.40 (CH3, t-Bu). HRMS (ESI, MeOH) calcd for C25H35N2O4 (MH+): 427.2597, found: 427.2597.
(3S,4S,5S)-1-Benzyl-5-benzylaminomethyl-3,4-dihydroxypiperidine (5) from 10
Trifluoroacetic acid was added to a solution of piperidine (10) (17.3 mg, 0.04 mmol) in CH2Cl2 (1.5 mL)
at rt and the mixture was stirred for 20 h. The solution were evaporated under reduced pressure and the
crude product was purified by preparative TLC (eluent : CH2Cl2-MeOH-NH4OH 9:1 :0.1) and gave the
piperidine (5) as a colorless oil (6.2 mg, 63 %).
ACKNOWLEDGMENTS
We are grateful to Professor J.-Y. Lallemand, Director of I. C. S. N., for a grant (A. D).
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