Preparation of (2R,4S)/(2S,4S)-4-hydroxypipecolinic acid derivatives from L-(-)-malic acid

Article abstract of DOI:10.3987/COM-14-S(K)52

Synthetically important 4-hydroxypipecolinic acid derivatives were efficiently prepared from commercially available L-(-)-malic acid. The stereochemistries of the derivatives synthesized by our method were determined by coupling constant analyses with key methine protons on C2 and C4.

Full text of DOI:10.3987/COM-14-S(K)52

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HETEROCYCLES, Vol. 90, No. 2, 2015
HETEROCYCLES, Vol. 90, No. 2, 2015, pp. 928 - 938. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2014, Accepted, 15th August, 2014, Published online, 25th August, 2014
DOI: 10.3987/COM-14-S(K)52
PREPARATION OF (2R,4S)/(2S,4S)-4-HYDROXYPIPECOLINIC ACID
DERIVATIVES FROM L-(–)-MALIC ACID
Shuqiang Yin, Hiroshi Taneda, Bozhi Li, Dejun Zhou, Daishiro Minato, Kenji
Sugimoto, and Yuji Matsuya*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan; E-mail: matsuya@pha.u-toyama.ac.jp
Abstract – Synthetically important 4-hydroxypipecolinic acid derivatives were
efficiently prepared from commercially available L-(–)-malic acid. The
stereochemistries of the derivatives synthesized by our method were determined
by coupling constant analyses with key methine protons on C2 and C4.
Pipecolinic acids, which are not a protenogenic amino acid, are one of synthetically important compounds
because of their rigid structural features as seen in some biologically active natural compounds. For
examples, representative immunosuppressants such as FK506 (Tacrolimus),1 rapamycin (Sirolimus)2
contain a pipecolinic acid fragment as an angle of their characteristic macrocycle. Additionally,
oxygenated ones are also incorporated in several natural and unnatural compounds having interesting
biological properties. Antibiotic virginiamycin S2,3 tumor necrosis factor-! (TNF-!) converting enzyme
inhibitor,4 and peptidemimic HIV protease inhibitor palinavir5 possess 4-hydroxypipecolinic acid moieties
as important backbones (Figure 1). Furthermore, 6-membered pipecolinic acid ring has attracted much
attention as a structural replacement of natural 5-membered proline ring in structure-activity relationship
studies on pharmaceutical leads.6 From such interest, many efforts on the syntheses of optically active
pipecolinic acid and their substituted congeners have been reported.7 Among them, synthetic methods for
4-hydroxy derivatives8 have been well studied because of its high utilities for further derivatization using
the hydroxyl group. 4-Amino-,9 fluoro-,10 or sulfur-functional groups11 could be introduced in a few steps
from 4-hydroxypipecolinic acids via substitution reaction at C4-position and installation of a carbon side
chain8a was also possible by oxidation followed by Horner-Wadsworth-Emmons type reaction. We were
also interested in the potency of 4-hydroxypipecolinic acids as key synthetic building blocks for
biologically active molecules and finally established an efficient synthetic route for them. Herein we
This paper is dedicated to Professor Isao Kuwajima on the occasion of his 77th birthday.

HETEROCYCLES, Vol. 90, No. 2, 2015
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describe the syntheses of (2R,4S)- and (2S,4S)-4-hydroxypipecolinic acid derivatives from optically
active malic acid, both enantiomers of which are commercially available.
NHOH
HO
O
O
O
O
O
Et
HO
N
Me
O
H
MeO
S
O O
NH
NH
N
TNF-! converting enzyme inhibitor
HO
N
NH
Me
O
N
O
O
O
CONHt-Bu
N
H
N
N
N
H
N
O
OH
O
Me
Me
N
virginiamycin S2
palinavir
Figure 1. Selected biologically active compounds having 4-hydroxypipecolinic acid fragment
Scheme 1. Preparation of diastereomeric intermediates
As shown in Scheme 1, we started the synthesis of 4-hydroxypipecolinic acid derivatives from
inexpensive L-(–)-malic acid. According to the literature methods,12 we obtained the aldehyde 3 in three

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HETEROCYCLES, Vol. 90, No. 2, 2015
steps via reduction of two carboxyl groups, transacetalization of 1 with benzaldehyde dimethyl acetal
followed by oxidation of remained primary hydroxy group in 2. This aldehyde 3 was coupled with the
phosphonate 4,13 readily prepared from the known N-Cbz precursor, to give dehydroamino acid methyl
ester 5 as a single isomer. After cleavage of benzylidene acetal on 5 in weakly acidic media, resultant diol
6 was exposed to hydrogenation reaction under medium pressure (3.5 atm) to afford Boc-protected
!-amino acid derivative 7, which immediately cyclized to give the inseparable diastereomixture of
lactone 814 within 87% yield. A cleavage of the lactone ring with allylamine and 2-hydroxypyridine
followed by selective tosylation gave the diastereomers 10a and 10b (2.3:1), which were easily separated
on silica gel column chromatography (Rf = 0.5 and 0.4 respectively with hexanes/AcOEt = 1:2 as eluent).
Scheme 2. Transformation into pipecolinic acid derivatives
After protection of hydroxy group as acetate and subsequent removal of Boc group, less polar
diastereomer 10a was successfully cyclized into a pipecolinic acid derivative 12a by exposure to Et3N in
DMF (Scheme 2). These conversions proceeded quite effectively in almost quantitative yield for three
steps. Similarly, 10b was uneventfully transformed into 12b. At this time, the relative stereochemistries of
1
the substituents on 12a and 12b were elucidated by coupling constant analyses in the H NMR spectra.

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For pipecolinic acid 12a, the coupling constants of methine proton Ha, resonating at 4.81 ppm, appeared
as 11.0 and 4.5 Hz. Furthermore, the methine proton Hb, resonating at 3.29 ppm, was observed as a
double doublet with J values of 11.0 and 3.0 Hz. Thus, these evidences clearly suggested that the protons
Ha and Hb occupied axial position in chair conformation; namely 12a had (2R,4S)-configurations. On the
other hand, methine proton Hd in 12b appeared at 3.59 ppm coupling with adjacent methylene protons as
double doublet with J values 10.0 and 4.0 Hz. These protons also coupled with Hc with J values 4.0 and
4.0 Hz, respectively. Thus, the proton Hc was equatorially oriented and Hd occupied axial orientation in
chair conformation, that is, the configurations for 12b were determined as (2S,4S). Finally hydrolysis of
12a and 12b correspondingly afforded the 4-hydroxy derivatives 13a and 13b which would be applicable
for further transformations.
In conclusion, we achieved the novel preparation of (2R,4S)- and (2S,4S)-4-hydroxypipecolinic acid
derivatives starting from commercially available inexpensive L-(–)-malic acid. The synthetic route
disclosed in this study is very concise and high-yielding. Because of the importance of the pipecolinic
acid derivatives, further investigations on the stereoselective synthesis and applications to natural product
syntheses are ongoing in our laboratory.
EXPERIMENTAL
Materials were obtained from commercial suppliers and used without further purification unless
otherwise noted. Anhydrous THF and CH2Cl2 were purchased from Kanto Chemical Co., Inc. Anhydrous
Et2O, DMF, DMSO, and MeOH were purchased from Wako Pure Chemical Industries and kept on dried
Molecular sieves. Anhydrous i-Pr2NH and Et3N were dried and distilled according to the standard
protocols. Otherwise noted, all reactions were performed using oven-dried glassware, sealed with a
rubber septum under a slight positive pressure of argon. Flash column chromatography was carried out
using Kanto silica gel 60N (spherical, neutral, 40–50 µm). Analytical TLC was performed on Merck 60
F254 glass plates precoated with a 0.25 mm thickness of silica gel. IR spectra were measured on a JASCO
FT/IR-460Plus spectrometer. NMR spectra were measured on a VARIAN GEMINI300 spectrometer or a
1
VARIAN UNITY-plus500 spectrometer. For H spectra, chemical shifts were expressed in parts per
million (ppm) downfield from internal tetramethylsilane (" 0), relative internal CHCl3 (" 7.26 in CDCl3)
or internal methanol (" 3.30 in CD3OD). The following abbreviations are used for spin multiplicity: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. J values were in hertz. For 13C
spectra, chemical shifts were expressed in ppm, relative to the central line of a triplet at 77.0 ppm for
internal CDCl3. Mass spectra were recorded on a JEOL JMS-GCmate II or JEOL JMS-AX505HAD
spectrometer.

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(2S)-1,2,4-Butanetriol (1).11 To a stirred solution of BH3·SMe2 (16.9 mL, 178 mmol) in THF (37 mL)
was added trimethylborate (18.2 mL, 163 mmol) at 0 °C. After stirring for 15 min at the same temperature,
L-(–)-malic acid (7.42 g, 55.3 mmol) was added to the solution at 0 °C and the stirring was continued for
2 days at room temperature. After the reaction was quenched with MeOH at 0 °C, the mixture was
evaporated under reduced pressure. The residue was purified by flash column chromatography on silica
1
gel (CHCl3/MeOH = 10:1) to give the triol 1 (4.67 g, 80%) as a colorless oil. H NMR spectrum of this
triol was identical with that reported.11 1H NMR (300 MHz, CDCl3) " 5.19 (2H, br s), 3.98–3.40 (5H, m),
1.79–1.61 (3H, m).
(2S,4S)-4-(Hydroxymethyl)-2-phenyl-1,3-dioxane (2).11 To a stirred solution of triol 1 and benzaldehyde
dimethyl acetal (5.31 mL, 35.4 mmol) in CH2Cl2 (120 mL) was added CSA (384 mg, 6.10 mmol) at room
temperature. After stirring for 19 h at the same temperature, the reaction was quenched with Et3N and the
reaction mixture was evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (hexane/AcOEt = 2:1) to give the acetal 3 (5.65 g, 88%) as a colorless oil.
1H NMR spectrum of this acetal was identical with that reported.11 1H NMR (300 MHz, CDCl3) "
7.54–7.32 (5H, m), 5.54 (1H, s), 4.30 (1H, dd, J = 5.1, 1.2 Hz), 4.03–3.97 (2H, m), 3.68–3.65 (2H, m),
2.17 (1H, br s), 2.00–1.76 (1H, m), 1.48–1.45 (1H, m).
Methyl (Z)-2-(tert-butoxycarbonylamino)-3-[(2S,4S)-2-phenyl-1,3-dioxan-4-yl]acrylate (5). To a
stirred solution of (COCl)2 (0.107 mL, 1.27 mmol) in CH2Cl2 (6.0 mL) was added DMSO (0.181 mL,
2.55 mmol) at –78 °C. After stirring for 10 min at the same temperature, a solution of the acetal 3 (165
mg, 0.850 mmol) in CH2Cl2 (2.0 mL) was added to the reaction mixture at –78 °C. After stirring for 30
min at –60 °C, Et3N (0.540 mL, 3.83 mmol) was added to the reaction mixture. After removal of the
cooling bath, the mixture was stirred for 30 min. The reaction mixture was diluted with CH2Cl2 and
washed with saturated aqueous NH4Cl and water. The organic phase was dried over MgSO4, filtered and
evaporated under reduced pressure to give a crude aldehyde 311 as a pale yellow oil. The crude aldehyde
1
was directly subjected to the next reaction without further purification. H NMR spectrum of this crude
aldehyde was identical with that reported.11 1H NMR (300 MHz, CDCl3) " 9.73 (1H, s), 7.55–7.34 (5H,
m), 5.61 (1H, s), 4.38–4.33 (2H, m), 4.02 (1H, td, J = 12.0, 2.6 Hz), 2.02–1.78 (2H, m).
To a stirred solution of phosphonate 4 (278 mg, 0.935 mmol) in CH2Cl2 (5.0 mL) was added DBU (0.133
mL, 0.893 mmol) at room temperature. After stirring for 10 min at room temperature, a solution of the
above crude aldehyde 3 in CH2Cl2 (4.0 mL) was added to the reaction mixture. After stirring for 16 h at
room temperature, the mixture was diluted with AcOEt and washed with 1 M aqueous H2SO4. The organic
phase was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by

HETEROCYCLES, Vol. 90, No. 2, 2015
933
flash column chromatography on silica gel (hexane/AcOEt = 1:1) to give the ester 5 (263 mg, 85% for 2
20
1
steps) as a colorless oil. [!]D +85.7 (c 0.320, CHCl3); IR (neat) 3658, 2928, 1708, 1660 cm–1; H NMR
(300 MHz, CDCl3) " 7.50–7.30 (5H, m), 6.64 (1H, s), 6.28 (1H, d, J = 6.3 Hz), 5.58 (1H, s), 4.78–4.84
(1H, m), 4.30 (1H, dd, J = 11.7, 4.8 Hz), 4.04 (1H, td, J = 11.7, 2.5 Hz), 2.00 (1H, qd, J = 11.7, 4.8 Hz),
13
1.46 (9H, s); C NMR (75 MHz, CDCl3) " 164.9, 152.8, 138.0, 128.7, 128.5, 128.1, 128.0, 101.0, 80.8,
74.2, 66.8, 52.5, 29.7, 28.1; MS (EI) m/z 363 (M+); HRMS (FAB) calcd for C19H26NO6 [M+H]+ 364.1760,
found 364.1770.
Methyl (S)-(Z)-2-(tert-butoxycarbonylamino)-4,6-dihydroxyhex-2-enoate (6). A solution of the ester 5
(2.28 g, 5.19 mmol) in AcOH/H2O (100 mL, 9:1 v/v) was stirred for 2.5 h at 50 °C. The mixture was
evaporated under reduced pressure. The residue was purified by flash column chromatography on silica
gel (hexane/AcOEt = 1:3) to give the diol 6 (1.36 g, 95%) as a colorless oil. [!]D20 –3.30 (c 2.59, CHCl3);
1
IR (neat) 3326, 1710, 1662 cm–1; H NMR (300 MHz, CDCl3) " 6.52 (1H, s), 6.42 (1H, d, J = 9.3 Hz),
13
4.58 (1H, td, J = 8.7, 4.4 Hz), 3.88–3.75 (5H, m), 1.98–1.72 (2H, m), 1.47 (9H, s); C NMR (75 MHz,
CDCl3) " 165.1, 154.2, 133.3, 126.1, 81.4, 66.4, 60.1, 52.6, 37.5, 28.1; MS (EI) m/z 275 (M+); HRMS
(FAB) calcd for C12H22NO6 [M+H]+ 276.1447, found 276.1441.
tert-Butyl
(3R,5R)-5-(2-hydroxyethyl)-2-oxotetrahydrofuran-3-ylcarbamate
and
tert-Butyl
(3S,5R)-5-(2-hydroxyethyl)-2-oxotetrahydrofuran-3-ylcarbamate (8).14 Under a hydrogen atmosphere
(3.5 atm), a suspension of the diol 6 (195 mg, 0.708 mmol) and 10% palladium on activated carbon (113
mg, 0.107 mmol) in MeOH was stirred for 15 min at room temperature. The reaction mixture was filtered
through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (AcOEt only) to give the lactone 813 (151 mg, 87%) as a
1
colorless oil. IR (neat) 3361, 1777, 1659 cm–1; H NMR (300 MHz, CDCl3) " 5.18 (1H, br s), 4.89–4.84
(0.5H, m), 4.68–4.58 (0.5H, m), 4.41 (1H, br s), 3.81 (2H, q, J = 7.2 Hz), 2.55–2.33 (1H, m), 2.16–1.81
13
(4H, m), 1.44 (9H, s); C NMR (75 MHz, CDCl3) " 173.1, 172.9, 156.3, 155.2, 80.3, 75.6, 75.3, 58.13,
58.11, 52.4, 52.2, 38.3, 38.1, 37.6, 28.2; MS (EI) m/z 245 (M+); HRMS (FAB) calcd for C11H20NO5
[M+H]+ 246.1341, found 246.1309.
tert-Butyl
(2R,4R)-1-(allylamino)-4,6-dihydroxy-1-oxohexane-2-ylcarbamate
and
tert-Butyl
(2S,4R)-1-(allylamino)-4,6-dihydroxy-1-oxohexane-2-ylcarbamate (9). To a stirred solution of lactone
8 (91.0 mg, 0.371 mmol) in THF (7.4 mL) were added 2-hydroxypyridine (18.0 mg, 0.182 mmol) and
allylamine (282 µL, 3.71 mmol) at room temperature. After stirring for 19.5 h at 50 °C, the reaction
mixture was evaporated under reduced pressure. The residue was purified by flash column

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chromatography on silica gel (CHCl3/MeOH = 10:1) to give the diol 9 (87.0 mg, 78%) as a colorless oil.
IR (neat) 3326, 1704, 1646 cm–1; 1H NMR (300 MHz, CD3OD) " 5.88–5.80 (1H, m), 5.24–5.16 (1H, m),
13
5.09 (1H, d, J = 10.2 Hz), 4.28–4.16 (1H, m), 3.87–3.64 (5H, m), 1.87–1.60 (4H, m), 1.44 (9H, s); C
NMR (75 MHz, CDCl3) " 172.3, 155.5, 133.53, 133.45, 116.0, 80.1, 79.9, 67.8, 67.5, 60.5, 60.3, 41.7,
40.0, 38.7, 28.2; MS (EI) m/z 303 (M+); HRMS (EI) calcd for C14H27N2O5 (M+) 303.1920, found
303.1922.
(3R,5R)
and
(3R,5S)-6-(Allylamino)-5-(tert-butoxycarbonylamino)-3-hydroxy-6-oxohexyl
4-methylbenzenesulfonate (10a and 10b). To a stirred solution of the diol 9 (292 mg, 0.965 mmol) in
CH2Cl2 (10 mL) were added Et3N (0.41 mL, 2.9 mmol) and DMAP (6.0 mg, 0.048 mmol) at room
temperature. After stirring for 10 min at room temperature, TsCl (294 mg, 1.54 mmol) was added to the
mixture at 0 °C. After stirring for 13 h at room temperature, the reaction was quenched with saturated
aqueous NH4Cl and the aqueous phase was extracted with AcOEt. The combined organic extracts were
washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica gel (hexane/acetone = 2:1) to give the
tosylates 10a (263 mg, 60%, pale yellow oil) and 10b (114 mg, 26%, pale yellow oil). 10a: [!]D20 –10.5 (c
1
2.18, CHCl3); IR (neat) 3302, 1655 cm–1; H NMR (300 MHz, CDCl3) " 7.76 (2H, d, J = 7.8 Hz), 7.33
(2H, d, J = 7.8 Hz), 6.37 (1H, br s), 5.84–5.63 (2H, m), 5.19–5.11 (2H, m), 4.32–4.08 (3H, m), 3.86–3.79
(3H, m), 2.44 (3H, s), 1.81–1.63 (4H, m), 1.44 (9H, s); 13C NMR (75 MHz, CDCl3) " 171.4, 156.6, 144.5,
133.5, 132.6, 129.6, 128.7, 127.6, 125.6, 116.1, 80.3, 67.5, 63.8, 51.3, 41.8, 35.9, 29.2, 28.2, 21.6; MS
20
(EI) m/z 456 (M+); HRMS (FAB) calcd for C21H33N2O7S [M+H]+ 457.2009, found 457.1970. 10b: [!]D
–2.90 (c 2.05, CHCl3); IR (neat) 3327, 1655 cm–1; 1H NMR (300 MHz, CDCl3) " 7.77 (2H, d, J = 8.1 Hz),
7.34 (2H, d, J = 8.1 Hz), 6.69 (1H, br s), 5.85–5.76 (1H, m), 5.44 (1H, br s), 5.22–5.11 (2H, m),
4.31–4.08 (3H, m), 3.89–3.87 (3H, m), 2.45 (3H, s), 1.88–1.74 (4H, m), 1.43 (9H, s); 13C NMR (75 MHz,
CDCl3) " 171.9, 155.5, 144.6, 133.4, 132.5, 129.6, 128.7, 127.6, 125.6, 116.1, 80.0, 67.5, 64.5, 51.9, 41.7,
40.1, 36.2, 28.2, 21.6; MS (EI) m/z 456 (M+); HRMS (FAB) calcd for C21H33N2O7S [M+H]+ 457.2009,
found 457.2020.
(3R,5S)-6-(Allylamino)-5-(tert-butoxycarbonylamino)-6-oxo-1-(tosyloxy)hexan-3-yl acetate (11a). To
a stirred solution of tosylate 10a (21.5 mg, 0.0471 mmol) in CH2Cl2 (0.3 mL) were added i-Pr2NEt (8.3
µL, 0.048 mmol), DMAP (1.0 mg, 0.0080 mmol), and acetic anhydride (7.6 µL, 0.080 mmol) at room
temperature. After stirring for 1 h at the same temperature, the reaction was quenched with saturated
aqueous NaHCO3 and the aqueous phase was extracted with CH2Cl2. The combined organic phases were
washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was

HETEROCYCLES, Vol. 90, No. 2, 2015
935
purified by flash column chromatography on silica gel (hexane/AcOEt = 1:2) to give the acetate 11a (22.1
20
1
mg, 94%) as a colorless oil. [!]D +2.10 (c 1.20, CHCl3); IR (neat) 3304, 1741, 1716, 1652 cm–1; H
NMR (300 MHz, CDCl3) " 7.77 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 6.38 (1H, br s), 5.87–5.75
(1H, m), 5.21–4.95 (4H, m), 4.15–4.02 (3H, m), 3.86 (2H, br s), 2.45 (3H, s), 2.15–1.81 (7H, m), 1.43
13
(9H, s); C NMR (75 MHz, CDCl3) " 170.9, 170.2, 144.7, 133.4, 132.5, 129.7, 127.7, 116.3, 61.2, 66.4,
58.9, 52.2, 41.8, 33.7, 28.2, 21.6, 20.9; MS (EI) m/z 498 (M+); HRMS (FAB) calcd for C23H35N2O8S
[M+H]+ 499.2114, found 499.2118.
(2R,4S)-2-(Allylaminocarbonyl)piperidin-4-yl acetate (12a). To a stirred solution of acetate 11a (19.0
mg, 0.0381 mmol) in CH2Cl2 (2.0 mL) was added TFA (124 µL, 1.67 mmol) at room temperature. After
stirring for 5 h at the same temperature, the reaction mixture was evaporated under reduced pressure. The
residue was diluted with DMF (1.0 mL) and Et3N (6.4 µL, 0.0046 mmol) was added at room temperature.
After stirring for 13 h, the mixture was evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (CHCl3/MeOH = 5:1) to give the piperidine 12a (11.0 mg,
20
1
quant.) as a white solid. [!]D –19.5 (c 0.570, CHCl3); IR (neat) 3291, 1731, 1652 cm–1; H NMR (500
MHz, CDCl3) " 6.76 (1H, s), 5.86–5.78 (1H, m), 5.19–5.12 (2H, m), 4.81 (1H, tt, J = 11.0, 4.5 Hz),
3.91–3.84 (2H, m), 3.29 (1H, dd, J = 11.0, 3.0 Hz), 3.16 (1H, dt, J = 12.5, 4.0 Hz), 2.72 (1H, td, J = 12.5,
13
3.0 Hz), 2.36–2.31 (1H, m), 2.02 (3H, s), 1.99–1.94 (1H, m), 1.49–1.39 (2H, m); C NMR (125 MHz,
CDCl3) " 172.0, 170.3, 134.0, 116.4, 76.7, 70.5, 58.7, 43.2, 41.4, 35.1, 31.6, 21.2; MS (EI) m/z 226 (M+);
HRMS (EI) calcd for C11H18N2O3 (M+) 226.1318, found 226.1353.
(2R,4S)-2-Allylaminocarbonyl-4-hydroxypiperidine (13a). To a stirred solution of acetate 12a (13.4 mg,
0.0973 mmol) in MeOH (1.0 mL) was added potassium carbonate (9.8 mg, 0.071 mmol) at room
temperature. After stirring for 6 h at the same temperature, the reaction mixture was purified directly by
flash column chromatography on silica gel (CH2Cl2/MeOH = 5:1) to give the alcohol 13a (8.6 mg, 96%)
20
1
as a colorless oil. [!]D +18.3 (c 0.430, CHCl3); IR (neat) 3384, 2928, 1659 cm–1; H NMR (500 MHz,
CDCl3) " 6.90 (1H, br s), 5.86–5.79 (1H, m), 5.20–5.12 (2H, m), 3.88–3.84 (2H, m), 3.75 (1H, tt, J = 11.0,
4.5 Hz), 3.25 (1H, dd, J = 11.0, 3.0 Hz), 3.14 (1H, dt, J = 12.5, 4.0 Hz), 2.66 (1H, td, J = 12.5, 3.0 Hz),
13
2.31–2.28 (1H, m), 1.91–1.87 (1H, m), 1.44–1.34 (2H, m); C NMR (75 MHz, CDCl3) " 172.9, 133.9,
116.3, 68.2, 58.7, 44.2, 41.5, 38.8, 35.0; MS (EI) m/z 184 (M+); HRMS (EI) calcd for C9H16N2O2 (M+)
184.1212, found 184.1215.
(3R,5R)-6-(Allylamino)-5-(tert-butoxycarbonylamino)-6-oxo-1-(tosyloxy)hexan-3-yl acetate (11b).
According to the same procedure described for 11a, acetate 11b was synthesized from 10b in 0.0672

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HETEROCYCLES, Vol. 90, No. 2, 2015
20
mmol scale (37.1 mg, 76%, colorless oil). [!]D –5.8 (c 0.70, CHCl3); IR (neat) 3316, 1739, 1714 cm–1;
1H NMR (300 MHz, CDCl3) " 7.76 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 6.74 (1H, br s),
5.87–5.76 (1H, m), 5.36 (1H, br s), 5.24–5.12 (2H, m), 5.02–4.96 (1H, m), 4.13–3.98 (3H, m), 3.90–3.86
(2H, m), 2.45 (3H, s), 2.04–1.93 (7H, m), 1.43 (9H, s); 13C NMR (75 MHz, CDCl3) " 173.1, 171.2, 144.7,
133.3, 132.3, 129.7, 129.2, 127.7, 116.4, 67.9, 66.0, 58.0, 51.2, 41.8, 37.6, 31.2, 28.3, 21.6, 21.0; MS (EI)
m/z 498 (M+); HRMS (FAB) calcd for C23H35N2O8S [M+H]+ 499.2114, found 499.2103.
(2S,4S)-2-(Allylaminocarbonyl)piperidin-4-yl acetate (12b). According to the same procedure
described for 12a, acetate 12b was synthesized from 11b in 0.0477 mmol scale (13.8 mg, quant., white
solid). [!]D20 +1.7 (c 0.41, CHCl3); IR (neat) 3318, 1722, 1660 cm–1; 1H NMR (500 MHz, CDCl3) " 6.91
(1H, br s), 5.87–5.79 (1H, m), 5.20–5.12 (2H, m), 5.09 (1H, quint, J = 4.0 Hz), 3.89–3.86 (2H, m), 3.59
(1H, dd, J = 10.0, 4.0 Hz), 2.99 (1H, dt, J = 12.0, 4.0 Hz), 2.89 (1H, dt, J = 12.0, 4.0 Hz), 2.08–2.04 (4H,
13
m), 1.82–1.68 (3H, m); C NMR (75 MHz, CDCl3) " 172.6, 169.9, 133.8, 116.2, 67.4, 55.5, 41.4, 40.6,
33.6, 30.2, 21.3; MS (EI) m/z 226 (M+); HRMS (EI) calcd for C11H18N2O3 (M+) 226.1318, found
226.1282.
(2S,4S)-2-Allylaminocarbonyl-4-hydroxypiperidine (13b). According to the same procedure described
20
for 13a, acetate 13b was synthesized from 12b in 0.034 mmol scale (6.3 mg, 97%, colorless oil). [!]D
–11.1 (c 0.330, CHCl3); IR (neat) 3410, 2927, 1644 cm–1; 1H NMR (500 MHz, CDCl3) " 7.13 (1H, br s),
5.86–5.79 (1H, m), 5.19–5.11 (2H, m), 4.04–4.00 (1H, m), 3.88 (2H, t, J = 6.0 Hz), 3.70–3.68 (1H, m),
3.11–3.06 (1H, m), 2.79–2.74 (1H, m), 2.04–2.00 (1H, m), 1.84–1.78 (1H, m), 1.75–1.69 (1H, m),
13
1.55–1.49 (1H, m); C NMR (75 MHz, CDCl3) " 173.2, 134.0, 116.2, 64.7, 55.3, 41.5, 40.6, 36.8, 33.7;
MS (EI) m/z 184 (M+); HRMS (EI) calcd for C9H16N2O2 (M+) 184.1212, found 184.1216.
REFERENCES
1. (a) C. Vézina, A. Kudelski, and S. N. Sehgal, J. Antibiot., 1975, 28, 721; (b) S. N. Sehgal, H. Baker,
and C. Vézina, J. Antibiot., 1975, 28, 727; (c) H. Baker, A. Sidorowicz, S. N. Sehgal, and C. Vézina,
J. Antibiot., 1978, 31, 539; (d) D. C. N. Swindells, P. S. White, and J. A. Findlay, Can. J. Chem.,
1978, 56, 2491; (e) K. Singh, S. Sun, and C. Vézina, J. Antibiot., 1979, 32, 630; (f) J. A. Findlay and
L. Radics, Can. J. Chem., 1980, 58, 579; (g) J. A. Findlay and L. Radics, Can. J. Chem., 1981, 59,
49; (h) J. B. McAlpine, S. J. Swanson, M. Jackson, and D. N. Whittern, J. Antibiot., 1991, 44, 688;
(i) J. B. McAlpine, S. J. Swanson, M. Jackson, and D. N. Whittern, J. Antibiot., 1991, 44, C-3.
2. H. Tanaka, A. Kuroda, H. Marusawa, H. Hatanaka, T. Kino, T. Goto, M. Hashimoto, and T. Taga, J.
Am. Chem. Soc., 1987, 109, 5031.

HETEROCYCLES, Vol. 90, No. 2, 2015
937
3. H. Vanderhaeghe, G. Janssen, and F. Compernolle, Tetrahedron Lett., 1971, 27, 2687.
4. M. A. Letavic, M. Z. Axt, J. T. Barberia, T. J. Carty, D. E. Danley, K. F. Geoghegan, N. S. Halim, L.
R. Hoth, A. V. Kamath, E. R. Laird, L. L. Lopresti-Morrow, K. F. McClure, P. G. Mitchell, V.
Natarajan, M. C. Noe, J. Pandit, L. Reeves, G. K. Shulte, S. L. Snow, F. J. Sweeney, D. H. Tan, and
C. H. Yu, Bioorg. Med. Chem. Lett., 2002, 12, 1387.
5. (a) D. Lamarre, G. Croteau, E. Wardrop, L. Bourgon, D. Thibeault, C. Clouette, M. Vaillancourt, E.
Cohen, C. Pargellis, C. Yoakim, and P. C. Anderson, Antimicrob. Agents Chemother., 1997, 965; (b)
V. Gorys, F. Soucy, C. Yoakim, and P. L. Beaulieu, U. S. Patent 5 552 405, 1996; (c) P. C. Anderson,
F. Soucy, C. Yoakim, P. Lavallée, and P. L. Beaulieu, U. S. Patent 5 545 640, 1997 and 5 807 870,
1998.
6. (a) T. D. Copeland, E. M. Wondrak, J. Tozser, M. M. Roberts, and S. Oroszlan, Biochem. Biophys.
Res. Comm., 1990, 169, 310; (b) A. G. S. Blommaert, J. H. Weng, A. Dorville, I. McCort, B. Ducos,
C. Durieux, and B. P. Roques, J. Med. Chem., 1993, 36, 2868; (c) B. Bellier, I. McCort-Tranchepain,
B. Ducos, S. Da Nascimento, H. Meudal, F. Noble, C. Garbay, and B. P. Roques, J. Med. Chem.,
1997, 40, 3947; (d) B. Bellier, S. Da Nascimento, H. Meudal, E. Gincel, B. P. Roques, and C. Garbay,
Bioorg. Med. Chem. Lett., 1998, 8, 1419.
7. For reviews, see (a) F. Couty, Amino Acids, 1999, 16, 297; (b) C. Kadouri-Puchot and S. Comesse,
Amino Acids, 2005, 29, 101; (c) A. A. Cant and A. Sutherland, Synthesis, 2012, 1935.
8. Recent examples, see (a) A. Golubev, N. Sewald, and K. Burger, Tetrahedron Lett., 1995, 36, 2037;
(b) J. W. Skiles, P. P. Giannousis, and K. R. Fales, Bioorg. Med. Chem. Lett., 1996, 6, 963; (c) J.
Gillard, A. Abraham, P. C. Anderson, P. L. Beaulieu, T. Bogri, Y. Bousquet, L. Grenier, I. Guse, and P.
Lavallée, J. Org. Chem., 1996, 61, 2226; (d) F. Machetti, F. M. Cordero, F. De Sarlo, A. Guarna, and
A. Brandi, Tetrahedron Lett., 1996, 37, 4205; (e) P. L. Beaulieu, P. Lavallée, A. Abraham, P. C.
Anderson, C. Boucher, Y. Bousquet, J.-S. Duceppe, J. Gillard, V. Gorys, C. Grand-Maître, L. Grenier,
Y. Guindon, I. Guse, L. Plamondon, F. Soucy, S. Valois, D. Wernic, and C. Yoakim, J. Org. Chem.,
1997, 62, 3440; (f) C. D. Nardo and O. Varela, J. Org. Chem., 1999, 64, 6119; (g) M. Haddad and M.
Larchevêque, Tetrahedron: Asymmetry, 1999, 10, 4231; (h) F. Machetti, F. M. Cordero, F. De Sarlo,
and A. Brandi, Tetrahedron Lett., 2001, 57, 4995; (i) P. Celestini, B. Danieli, G. Lesma, A. Sacchetti,
A. Silvani, D. Passarella, and A. Virdis, Org. Lett., 2002, 4, 1367; (j) F. M. Cordero, S. Bonollo, F.
Machetti, and A. Brandi, Eur. J. Org. Chem., 2006, 3235; (k) E. G. Occhiato, D. Scarpi, and A.
Guarna, Eur. J. Org. Chem., 2008, 524; (l) C. Alegret, X. Ginesta, and A. Riera, Eur. J. Org. Chem.,
2008, 1789; (m) P. Merino, V. Mannucci, and T. Tejero, Eur. J. Org. Chem., 2008, 3943; (n) C.-S.
Sun, Y.-S. Lin, and D.-R. Hou, J. Org. Chem., 2008, 73, 6877; (o) E. G. Occhiato, D. Scarpi, A.
Guarna, S. Tabasso, A. Deagostino, and C. Prandi, Synthesis, 2009, 3611; (p) N. Purkayastha, D. M.

938
HETEROCYCLES, Vol. 90, No. 2, 2015
Shendage, R. Fröhlich, and G. Haufe, J. Org. Chem., 2010, 75, 222; (q) N. Purkayastha and G.
Haufe, Synlett, 2010, 1501; (r) L. Bartali, A. Casini, A. Guarna, and D. Scarpi, Eur. J. Org. Chem.,
2010, 5831; (s) E. G. Occhiato, A. Casini, A. Guarna, and D. Scarpi, Eur. J. Org. Chem., 2011, 6544;
(t) L. S. Fowler, L. H. Thomas, D. Ellis, and A. Sutherland, Chem. Commun., 2011, 47, 6569; (u)
H.-D. Vu, J. Renault, L. Toupet, P. Uriac, and N. Gouault, Eur. J. Org. Chem., 2013, 6677.
9. F. Machetti, F. M. Cordero, F. De Sarlo, A. M. Papini, M. C. Alcaro, and A. Brandi, Eur. J. Org.
Chem., 2004, 2928.
10. A. S. Golubev, H. Schedel, G. Radics, J. Sieler, and K. Burger, Tetrahedron Lett., 2001, 42, 7941.
11. (a) P. L. Ornstein, M. B. Arnold, W. H. W. Lunn, L. J. Heinz, J. D. Leander, D. Lodge, and D. D.
Schoepp, Bioorg. Med. Chem. Lett., 1998, 8, 389; (b) P. L. Beaulieu, P. C. Anderson, D. R. Cameron,
G. Croteau, V. Gorys, C. Grand-Maître, D. Lamarre, F. Liard, W. Paris, L. Plamondon, F. Soucy, D.
Thibeault, D. Wernic, and C. Yoakim, J. Med. Chem., 2000, 43, 1094.
12. (a) D. Diaz and V. Martin, Org. Lett., 2000, 2, 335; (b) I. Shiina, J. Shibata, R. Ibuka, Y. Imai, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 2001, 74, 113; (c) O. Flögel, M. G. Okala Amombo, H.-U.
Reißig, G. Zahn, I. Brüdgam, and H. Hartl, Chem. Eur. J., 2003, 9, 1405.
13. (a) H. Azuma, K. Okano, T. Fukuyama, and H. Tokuyama, Org. Synth., 2011, 88, 152; (b) U. Zoller
and D. Ben-Ishai, Tetrahedron, 1975, 31, 863; (c) U. Schmidt, A. Lieberknecht, and J. Wild,
Synthesis, 1984, 53.
14. A. P. Nin, O. Varela, and R. M. de Lederkremer, Tetrahedron, 1993, 49, 9459.