Stereocontrolled chemoenzymatic synthesis of 2,3-disubstituted piperidines

Article abstract of DOI:10.1016/S0957-4166(01)00080-5

(R,R)-2,3-Disubstituted piperidines were readily synthesized starting from (R)-(+)-5-bromo-2-hydroxypentanenitrile (R)-2. An enantioselective (R)-oxynitrilase-catalyzed transcyanation was used to prepare the starting cyanohydrin (R)-2.

Full text of DOI:10.1016/S0957-4166(01)00080-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 525–528
Stereocontrolled chemoenzymatic synthesis of 2,3-disubstituted
piperidines
Maria I. Monterde, Rosario Brieva and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo, 33006 Oviedo, Spain
Received 23 January 2001; accepted 15 February 2001
Abstract—(R,R)-2,3-Disubstituted piperidines were readily synthesized starting from (R)-(+)-5-bromo-2-hydroxypentanenitrile
(R)-2. An enantioselective (R)-oxynitrilase-catalyzed transcyanation was used to prepare the starting cyanohydrin (R)-2. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
oxynitrilase-catalyzed reaction in good yield and high
e.e.4 Cyanohydrin (R)-2 was protected using tert-
butyldimethylsilyl chloride–imidazole in DMF, and the
silyl ether product (R)-3 was subsequently treated with
the appropriate Grignard reagent. Initially, we
attempted to reproduce the conditions described for the
preparation of cyclic imines by Fry et al.8,9 who carried
out the addition of Grignard reagents to unfunctional-
ized v-bromonitriles8 and b- or g-trimethylsilyloxy-v-
bromonitriles.9 In our case, all attempts to isolate the
intermediate imine failed. This led us to carry out a
one-pot procedure in which the addition of the Grig-
nard reagent to (R)-3 was followed by direct sodium
borohydride reduction and N-protection of the
product, without isolation of any of the intermediates.
Under these conditions, we obtained piperidines (R,R)-
4 as single diastereomers.
Piperidine rings form an integral feature of many natu-
ral compounds and synthetic derivatives that exhibit
interesting biological activities. The development of
synthetic methods for the preparation of these com-
pounds is an area of current interest.1 In previous
reports, we have demonstrated that optically active
v-bromocyanohydrins are good starting materials for
the preparation of (R)-piperidin-3-ol2 and 2-substituted
piperidines such as (S)-pipecolic acid or (R)-coniine.3
Our method is based on the utilization of (R)-oxynitri-
lase from almonds to catalyze the enantioselective
preparation of (R)-v-bromocyanohydrins.4
In this paper, we extend our methodology to the prepa-
ration of 2,3-disubstituted piperidines using (R)-(+)-5-
bromo-2-hydroxypentanenitrile as a starting material.
The 2,3-disubstituted piperidine structure constitutes
the basic skeleton of many physiologically interesting
compounds, and occurs for example in special non-pep-
tidic tachykinin receptor antagonists5 and cardiovascu-
lar agents.6 Additionally, aliphatic substitution at the
2-position could provide precursors of bicyclic alkaloids
such as swainsonine.7
The yield of this process was dependent on the Grig-
nard reagent employed. As we expected, aromatic Grig-
nard reagents gave higher yields than aliphatic ones. In
order to avoid possible competing side elimination pro-
cesses, we carried out the addition of butylmagnesium
chloride and butenylmagnesium bromide under milder
conditions at room temperature, but after reaction for
48 h, the unreacted cyanohydrin was recovered.
The stereochemistry of the process was determined by
1H NMR analyses of piperidines (R,R)-5. The coupling
constant between the C-(2) and C-(3) protons (from 5.6
to 5.9 Hz) indicates that the 2,3-cis-diastereomers were
obtained in all cases. This is also supported by the cross
peaks corresponding to the C-(2) and C-(3) protons in
the NOESY spectra. No racemization occurred during
the processes, as demonstrated by the fact that the e.e.s
of piperidines (R,R)-5, analyzed by HPLC, were 91%,
identical to the precursor (R)-2.
2. Results and discussion
The preparation of the (R,R)-2,3-disubstituted piperidi-
nes is depicted in Scheme 1. The starting material
(R)-(+)-5-bromo-2-hydroxypentanenitrile, (R)-2, was
obtained from the corresponding aldehyde via an (R)-
* Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00080-5

526
M. I. Monterde et al. / Tetrahedron: Asymmetry 12 (2001) 525–528
OH
OTBDMS
H
CN
H
(R)-Oxynitrilase
TBDMSCl
Br
Br
Br
H
CN
O
(R)-2
(R)-3
1
1) MeOH
OH
2) NaBH4
OTBDMS
RMgX
OTBDMS
TBAF/THF
3) CbzCl/H2O
N
R
N
R
N
R
Cbz
Cbz
(R,R)-5
(R,R)-4
RMgX = (a) PhMgBr, (b) p-FPhMgBr, (c) p-MePhMgBr, (d) p-MeOPhMgBr,
(e)
(f)
MgCl ,
MgBr
Scheme 1.
In conclusion, the utilization of (R)-(+)-5-bromo-2-
hydroxypentanenitrile, (R)-2, as starting material per-
mits the preparation of 2,3-cis-disubstituted piperidines
in high enantiomeric purity. These heterocycles possess
a hydroxyl group at C-(3) and aliphatic or aromatic
substituents at the C-(2) position. The process, a simple
tandem Grignard addition–sodium borohydride reduc-
tion occurs with complete diastereoselectivity.
evaporated under reduced pressure. The crude residue
was purified by flash chromatography on silica gel
(hexane–AcOEt, 9.5:0.5) to afford the compound (R)-3
as colorless oil in 90% yield; [h]2D5 +33.6 (c=1.6,
1
CHCl3), e.e. 91%; H NMR (CDCl3): l 0.16 (s, 3H),
0.21 (s, 3H), 0.93 (s, 9H), 1.97–2.07 (m, 4H), 3.48 (t,
2H), 4.52 (t, 1H); 13C NMR (CDCl3): l −5.4, −5.2,
18.0, 25.4, 27.5, 32.4, 34.6, 61.1, 119.5. MS (EI) m/z 291
[M+(81Br), <1], 293 [M+(79Br), <1], 236 (71), 234 (71),
209 (93), 207 (93), 194 (58), 192 (58), 166 (20), 164 (20),
139 (100), 137 (100), 127 (65), 75 (98). HRMS calcd for
C10H19BrNOSi (M+−Me) 276.0413. Found 276.0419.
3. Experimental
Optical rotations were measured using a Perkin–Elmer
241 polarimeter and are quoted in units of 10−1 deg cm2
3.2. Synthesis of (R,R)-1-(benzyloxycarbonyl)-3-tert-
butyldimethylsilyloxy-2-substituted piperidines (R,R)-4.
General procedure
1
g−1. H and 13C NMR were obtained with TMS (tetra-
methylsilane) as an internal standard using a Bruker
AC-300 (1H 300 MHz and 13C 75.5 MHz) spectrometer.
NOESY analysis was performed using a Bruker AMX
400 (1H 400.13 MHz). Mass spectra were recorded on
Hewlett–Packard 5987A and Finigan MAT/95 spec-
trometers. All reagents were purchased from Aldrich
Chemie or Fluka. Solvents were distilled from an
appropriate desiccant and stored under nitrogen. Flash
chromatography was performed using Merck silica gel
60 (230–400 mesh). E.e.s were determined by chiral
HPLC analysis using CHIRALCEL-OD and OD-H
columns (4.5×250 mm).
To
a
stirred solution of (R)-(+)-5-bromo-2-tert-
butyldimethylsilyloxypentanenitrile (R)-3 (150 mg, 0.5
mmol) in dry THF (5 mL), was added dropwise the
Grignard reagent (1 mmol) and the reaction mixture
was heated to reflux. The progress of the reaction was
monitored by TLC using ethyl acetate–hexane (2:8).
After 5 h, when the reaction was complete, the resulting
mixture was allowed to cool to rt. Dry methanol (5 mL)
was added, followed by portionwise addition of NaBH4
(26.8 mg, 0.7 mmol). The resulting mixture was stirred
overnight at rt. Distilled H2O (10 mL) was added and
the mixture was extracted with Et2O (3×5 mL). The
combined organic fractions were washed with brine and
evaporated under reduced pressure. To the crude
residue of distilled H2O (5 mL), CH2Cl2 (1 mL) and
Na2CO3 (54.5 mg, 0.5 mmol) were added. The resulting
mixture was cooled to 0°C, benzylchloroformate (72.4
mL, 0.5 mmol) was added dropwise and stirred for 4 h.
The mixture was extracted with CH2Cl2 (3×10 mL) and
the combined organic fractions were dried over
Na2SO4, filtered and evaporated under reduced pres-
sure. The residue was purified by flash chromatography
on silica gel with hexane–AcOEt (9.5:0.5).
3.1. (R)-(+)-5-Bromo-2-tert-butyldimethylsilyloxypen-
tanenitrile (R)-3
A solution of cyanohydrin (R)-2 (116.1 mg, 0.87
mmol), tert-butyldimethylsilyl chloride (263 mg, 1.7
mmol), imidazole (178 mg, 2.6 mmol) and a catalytic
quantity of 4-(N,N-dimethylamino)pyridine (DMAP),
in dry CH2Cl2 (8 mL) under a nitrogen atmosphere,
was stirred for 24 h at rt. Then, saturated aqueous
NH4Cl (15 mL) was added and the resulting mixture
was extracted with CH2Cl2 (3×10 mL). The combined
organic extracts were dried over Na2SO4, filtered and

M. I. Monterde et al. / Tetrahedron: Asymmetry 12 (2001) 525–528
527
3.2.1. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-phenylpiperidine (R,R)-4a. Colorless oil; yield
3.67 (m, 1H), 3.95 (m, 1H), 4.21 (m, 1H), 5.14 (br s,
2H), 7.34 (s, 5H); 13C NMR (CDCl3): l −4.99, −4.87,
13.98, 17.99, 22.32, 24.10, 24.56, 25.60, 27.84, 28.21,
37.29, 56.31, 66.86, 69.97, 127.62, 127.75, 128.30,
136.06, 136.83, 155.72; MS (EI) m/z 405 (M+, <1), 390
(<1), 348 (29), 304 (40), 91 (100), 73 (23). HRMS calcd
for C22H36NO3Si (M+−Me) 390.2466. Found 390.2464.
1
92%; [h]2D5 −41.1 (c=1.0, CHCl3), e.e. 91%; H NMR
(CDCl3): l −0.01 (s, 3H), 0.01 (s, 3H), 0.89 (s, 9H),
1.67–1.69 (m, 2H), 1.75–1.80 (m, 1H), 1.93–1.95 (m,
1H), 2.74–2.83 (m, 1H), 3.97–4.1 (m, 2H), 5.18 (d, 2H),
5.46 (br s, 1H), 7.22–7.32 (m, 8H), 7.57 (m, 2H); 13C
NMR (CDCl3): l −5.18, −5.00, 17.86, 23.87, 25.63,
28.53, 39.06, 58.83, 67.12, 71.59, 126.55, 127.62, 127.80,
127.92, 128.32, 128.39, 136.63, 138.16, 155.76; MS (EI)
m/z 425 (M+, <1), 368 (84), 324 (79), 250 (75), 210 (33),
158 (25), 92 (32), 91 (100), 73 (75). HRMS calcd for
C21H26NO3Si (M+−tBu) 368.1678. Found 368.1682.
3.2.6. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-(3-butenyl)piperidine (R,R)-4f. Colorless oil;
1
yield 22%; [h]2D5 −16.4 (c=0.9, CHCl3), e.e. 91%; H
NMR (CDCl3): l 0.04–0.09 (m, 6H), 0.87 (s, 9H),
1.55–1.66 (m, 6H), 1.93–2.03 (m, 2H), 2.71 (m, 1H),
3.71 (m, 1H), 3.98 (m, 1H), 4.29 (m, 1H), 4.88–5.21 (m,
4H), 5.79 (m, 1H), 7.34 (s, 5H); 13C NMR (CDCl3): l
−4.98, −4.87, 17.00, 22.28, 24.09, 25.72, 28.39, 29.90,
37.39, 55.98, 66.96, 69.89, 114.59, 127.69, 127.81,
128.25, 128.32, 136.69, 138.26, 155.65; MS (EI) m/z 403
(M+, <1), 346 (20), 302 (28), 91 (100), 73 (14), 57 (14).
HRMS calcd for C19H28NO3Si (M+−tBu) 346.1841.
Found 346.1838.
3.2.2. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-(p-fluorophenyl)piperidine (R,R)-4b. Colorless
oil; yield 73.7%; [h]D25 −39.2 (c=1.0, CHCl3), e.e. 91%;
1H NMR (CDCl3): l −0.02 (s, 3H), 0.07 (s, 3H), 0.88 (s,
9H), 1.60–1.86 (m, 4H), 2.69–2.79 (m, 1H), 3.96–4.1 (m,
2H), 5.17 (d, 2H), 5.40 (br s, 1H), 6.94 (t, 2H), 7.32 (m,
5H), 7.50 (t, 2H); 13C NMR (CDCl3): l −5.21, −5.01,
17.82, 23.83, 25.59, 28.45, 38.99, 58.19, 67.17, 71.37,
114.63 (d, J=21.14 Hz), 127.64, 127.84, 128.32, 129.98,
130.08, 133.72, 136.51, 155.64, 161.49 (d, J=245.4 Hz);
MS (EI) m/z 443 (M+, <1), 386 (40), 342 (28), 91 (100),
73 (36). HRMS calcd for C21H25FNO3Si (M+−tBu)
386.1587. Found 386.1588.
3.3. Synthesis of (R,R)-1-(benzyloxycarbonyl)-2-substi-
tuted piperidin-3-ols (R)-5. General procedure
To a stirred solution of the corresponding (R)-4 (0.08
mmol) in THF (2 mL) at rt was added dropwise a
solution of tetrabutylammonium fluoride (1 M, 0.1
mL). The resulting mixture was stirred for 5 h. After
removal of the solvent under reduced pressure, the
crude residue was purified by flash chromatography on
silica gel (hexane–AcOEt, 7:3) to yield compound (R)-5
as colorless oil in a quantitative yield. The e.e.s were
analyzed by HPLC taking a sample (20 mL) of a
solution of (R,R)-5 or ( )-5 in a mixture of hexane–
isopropanol.
3.2.3. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-(p-methylphenyl)piperidine (R,R)-4c. Color-
less oil; yield 82.4%; [h]2D5 −45.0 (c=1.0, CHCl3), e.e.
1
91%; H NMR (CDCl3): l 0.01 (s, 3H), 0.09 (s, 3H),
0.88 (s, 9H), 1.64–1.66 (m, 2H), 1.74 (m, 1H), 1.90–1.97
(m, 1H), 2.33 (s, 3H), 2.76 (m, 1H), 3.96 (br s, 1H), 4.05
(m, 1H), 5.19 (d, 2H), 5.45 (br s, 1H), 7.11 (d, 2H), 7.33
(s, 5H), 7.45 (d, 2H); 13C NMR (CDCl3): l −5.10,
−4.96, 17.92, 20.92, 24.11, 25.69, 28.63, 39.04, 58.41,
67.12, 71.77, 127.64, 127.81, 128.34, 128.64, 134.87,
136.06, 136.69, 155.75; MS (EI) m/z 439 (M+, <1), 382
(20), 338 (13), 264 (26), 105 (17), 91 (100), 73 (23).
HRMS calcd for C22H28NO3Si (M+−tBu) 382.1838.
Found 382.1838.
3.3.1. (R,R)-1-(Benzyloxycarbonyl)-2-phenylpiperidin-3-
ol (R,R)-5a. HPLC analysis: CHIRALCEL-OD
column, 18°C, hexane–isopropanol 95:5, flow rate 0.4
cm3 min−1, sample concentration 0.5 mg mL−1. Two
peaks (tR 58.907 and 64.017) for (R,R)-5a were
resolved. [h]2D5 −66.4 (c=1.0, CHCl3), e.e. 91%; 1H
NMR (CDCl3): l 1.67–1.87 (m, 5H), 3.07 (dt, 1H), 4.09
(m, 2H), 5.11 (d, 2H), 5.44 (d, J=5.7 Hz, 1H), 7.24–
7.35 (m, 8H), 7.48 (m, 2H); 13C NMR (CDCl3): l 23.10,
27.49, 39.66, 59.08, 67.21, 69.90, 127.25, 127.60, 127.82,
128.33, 128.37, 136.50, 137.66, 155.87; MS (EI) m/z 311
(2), 293 (35), 249 (25), 220 (20), 176 (100), 158 (16), 106
(70), 91 (99), 71 (36). HRMS calcd for C19H21NO3 (M+)
311.1505. Found 311.1521.
3.2.4. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-(p-methoxyphenyl)piperidine(R,R)-4d. Color-
less oil; yield 72.3%; [h]2D5 −40.5 (c=1.0, CHCl3), e.e.
1
91%; H NMR (CDCl3): l 0.03 (s, 3H), 0.10 (s, 3H),
0.89 (s, 9H), 1.63–1.66 (m, 2H), 1.77–1.87 (m, 1H),
1.90–1.97 (m, 1H), 2.77 (m, 1H), 3.80 (s, 3H), 3.96 (br
s, 1H), 4.02–4.09 (m, 1H), 5.20 (d, 2H), 5.47 (br s, 1H),
6.84 (d, 2H), 7.33 (s, 5H), 7.51 (d, 2H); 13C NMR
(CDCl3): l −5.12, −4.99, 17.87, 24.13, 25.65, 28.59,
38.92, 55.02, 58.08, 67.07, 71.69, 113.23, 127.61, 127.77,
128.30, 129.58, 129.88, 136.66, 155.75, 158.09; MS (EI)
m/z 455 (M+, <1), 398 (14), 354 (28), 323 (43), 280 (28),
121 (38), 91 (100), 73 (30). HRMS calcd for
C22H28NO4Si (M+−tBu) 398.1800. Found 398.1788.
3.3.2. (R,R)-1-(Benzyloxycarbonyl)-2-(p-fluorophenyl)-
piperidin-3-ol (R,R)-5b. HPLC analysis: CHIRALCEL-
OD column, 40°C, hexane–isopropanol 90:10, flow rate
0.2 cm3 min−1, sample concentration 0.25 mg mL−1.
Two peaks (tR 38.290 and 40.488) for (R,R)-5b were
resolved. [h]2D5 −51.8 (c=1.1, CHCl3), e.e. 91%; 1H
NMR (CDCl3): l 1.70–1.89 (m, 4H), 2.03 (br s, 1H),
2.98 (m, 1H), 4.03–4.11 (m, 2H), 5.14 (d, 2H), 5.46 (d,
J=5.6 Hz, 1H), 7.01 (t, 2H), 7.28–7.36 (m, 5H), 7.48
3.2.5. (R,R)-1-(Benzyloxycarbonyl)-3-tert-butyldimethyl-
silyloxy-2-butylpiperidine (R,R)-4e. Colorless oil; yield
1
37%; [h]2D5 −16.2 (c=1.2, CHCl3), e.e. 91%; H NMR
(CDCl3): l 0.03–0.09 (m, 6H), 0.81–0.89 (m, 12H),
1.19–1.26 (m, 4H), 1.52–1.63 (m, 6H), 2.70 (m, 1H),

528
M. I. Monterde et al. / Tetrahedron: Asymmetry 12 (2001) 525–528
(t, 2H); 13C NMR (CDCl3): l 23.39, 27.51, 39.47, 58.17,
67.31, 69.99, 115.07 (d, J=21.55 Hz), 127.65, 127.92,
128.35, 130.02, 130.13, 133.32, 136.34, 155.79, 161.80
(d, J=252.6 Hz); MS (EI) m/z 329 (M+, <1), 311 (19),
267 (15), 194 (56), 124 (21), 109 (15), 91 (100), 71 (18).
HRMS calcd for C19H18FNO2 (M+−H2O) 311.1318.
Found 311.1321.
m/z 291 (11), 234 (46), 190 (85), 91 (100). HRMS calcd
for C17H25NO3 (M+) 291.1840. Found 291.1834.
3.3.6. (R,R)-1-(Benzyloxycarbonyl)-2-(3-butenyl)piperi-
din-3-ol (R,R)-5f. HPLC analysis: CHIRALCEL-OD
column, 27°C, hexane–isopropanol 95:5, flow rate 0.6
cm3 min−1, sample concentration 0.25 mg mL−1. Two
peaks (tR 17.094 and 18.496) for (R,R)-5e were
resolved. [h]2D5 −24.4 (c=0.9, CHCl3), e.e. 91%; 1H
NMR (CDCl3): l 1.52–1.80 (m, 7H), 1.98–2.04 (m, 2H),
2.73 (dt, 1H), 3.78 (m, 1H), 3.90 (m, 1H), 4.40 (m, 1H),
4.92–5.05 (m, 2H), 5.13 (d, 2H), 5.72–5.90 (m, 1H), 7.34
(s, 5H); 13C NMR (CDCl3): l 22.20, 24.64, 27.64, 29.81,
37.49, 55.35, 67.14, 69.08, 114.67, 127.81, 127.93,
128.40, 136.57, 138.15, 155.64; FABS m/z 312 (M++Na,
60), 102 (100).
3.3.3. (R,R)-1-(Benzyloxycarbonyl)-2-(p-methylphenyl)-
piperidin-3-ol (R,R)-5c. HPLC analysis: CHIRALCEL-
OD-H column, 40°C, hexane–isopropanol 95:5, flow
rate 0.4 cm3 min−1, sample concentration 0.25 mg mL−1.
Two peaks (tR 33.400 and 35.483) for (R,R)-5c were
resolved. [h]2D5 −65.6 (c=0.9, CHCl3), e.e. 91%; 1H
NMR (CDCl3): l 1.71–1.88 (m, 5H), 2.35 (s, 3H), 3.08
(m, 1H), 4.07 (m, 2H), 5.12 (d, 2H), 5.41 (d, J=5.9 Hz,
1H), 7.15 (d, 2H), 7.25–7.39 (m, 7H); 13C NMR
(CDCl3): l 20.94, 23.15, 27.54, 39.63, 58.86, 67.15,
69.84, 127.60, 127.81, 128.32, 128.38, 129.10, 134.44,
136.51, 136.94, 155.82; MS (EI) m/z 323 (M+, <1), 307
(25), 263 (13), 262 (14), 190 (54), 172 (13), 120 (28), 105
(26), 91 (100), 71 (13). HRMS calcd for C20H21NO2
(M+−H2O) 307.1572. Found 307.1571.
Acknowledgements
Financial support of this work by CICYT (Project
BIO-98-0770) is gratefully acknowledged.
3.3.4. (R,R)-1-(Benzyloxycarbonyl)-2-(p-methoxyphenyl)-
piperidin-3-ol (R,R)-5d. HPLC analysis: CHIRALCEL-
OD column, 24°C, hexane–isopropanol 90:10, flow
rate: 0.6 cm3 min−1, sample concentration 0.5 mg mL−1.
Two peaks (tR 24.209 and 31.750) for (R,R)-5d were
resolved. [h]2D5 −64.3 (c=0.7, CHCl3), e.e. 91%; 1H
NMR (CDCl3): l 1.64–1.87 (m, 4H), 1.96 (br s, 1H),
3.03 (dt, 1H), 3.79 (s, 3H), 3.96 (br s, 1H), 4.04 (m, 2H),
5.11 (d, 2H), 5.42 (d, J=5.7 Hz, 1H), 6.85 (d, 2H),
7.24–7.32 (m, 5H), 7.35 (d, 2H); 13C NMR (CDCl3): l
23.33, 27.60, 39.52, 55.14, 58.44, 67.18, 69.91, 113.71,
127.62, 127.82, 128.32, 129.44, 129.70, 136.50, 155.79,
158.63; MS (EI) m/z 341 (<1), 323 (87), 278 (64), 206
(37), 188 (24), 136 (29), 121 (25), 91 (100). HRMS calcd
for C20H21NO3 (M+−H2O) 323, 1524. Found 323.1521.
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3.3.5. (R,R)-1-(Benzyloxycarbonyl)-2-butylpiperidin-3-ol
(R,R)-5e. HPLC analysis: CHIRALCEL-OD column,
27°C, hexane–isopropanol 95:5, flow rate 0.6 cm3
min−1, sample concentration 0.5 mg mL−1. Two peaks
(tR 14.913 and 16.303) for (R,R)-5e were resolved. [h]D25
1
−20.9 (c=0.9, CHCl3), e.e. 91%; H NMR (CDCl3): l
0.86 (t, 3H), 1.21–1.35 (m, 4H), 1.50–1.80 (m, 7H), 2.71
(dt, 1H), 3.78 (m, 1H), 3.99 (m, 1H), 4.37 (m, 1H), 5.12
(d, 2H), 7.34 (s, 5H); 13C NMR (CDCl3): l 14.00,
22.34, 22.64, 24.30, 27.66, 27.74, 37.42, 55.67, 67.07,
69.18, 127.78, 127.87, 128.38, 136.70, 155.72; MS (EI)
8. Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994,
836–838.
9. Fry, D. F.; Fowler, C. B.; Brown, M.; McDonald, J. C.;
Dieter, R. K. Tetrahedron Lett. 1996, 37, 6227–6230.
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