Protecting-Group-Directed Regio- and Stereoselective Oxymercuration-Demercuration: Synthesis of Piperidine Alkaloids Containing 1,2- and 1,3-Amino Alcohol Units

Article abstract of DOI:10.1055/s-0036-1589523

An efficient synthesis of naturally occurring 1,2- and 1,3-amino alcohol unit containing 2-substituted piperidine alkaloids and their analogues has been developed from l -pipecolinic acid. The protocol describes the regio- and stereoselective oxymercuration-demercuration of 2-alkenyl piperidines based on protecting groups to give piperidine alkaloids as a key step.

Full text of DOI:10.1055/s-0036-1589523

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, 1113–1122
paper
1113
en
S. T. Bugde et al.
Paper
Synthesis
Protecting-Group-Directed Regio- and Stereoselective
Oxymercuration–Demercuration: Synthesis of Piperidine
Alkaloids Containing 1,2- and 1,3-Amino Alcohol Units
Sandesh T. Bugdea
Prajesh S.Volvoikara
Santosh G. Tilve*a,b
PG = Cbz
R
PG = Boc
OH
H
H
H
N
R
N
N
R
regio- and
stereoselective
regio- and
stereoselective
H
H
OH
PG
a Department of Chemistry, Goa University, Taleigao Plateau,
Goa 403206, India
stilve@unigoa.ac.in
b Organic Chemistry Department, RUDN University,
6 Miklukcho-Maklaya str., Moscow 117198, Russian Federation
Received: 01.07.2017
Accepted after revision: 23.10.2017
Published online: 29.11.2017
DOI: 10.1055/s-0036-1589523; Art ID: ss-2017-t0436-op
H
H
N
N
H
H
OH
OH
(+)-α-conhydrine (2)
(–)-β-conhydrine (1)
Abstract An efficient synthesis of naturally occurring 1,2- and 1,3-
amino alcohol unit containing 2-substituted piperidine alkaloids and
their analogues has been developed from L-pipecolinic acid. The proto-
col describes the regio- and stereoselective oxymercuration–demercu-
ration of 2-alkenyl piperidines based on protecting groups to give
piperidine alkaloids as a key step.
OH
H
OH
H
N
R
N
R
H
H
3
4
R = Me; (+)-sedridine (3a)
R = Et; (+)-ethylnorlobelol (3b)
R = Pr; (+)-halosaline (3c)
R = Me; (–)-allosedridine (4a)
R = Et; (–)-2'-epi-ethylnorlobelol (4b)
R = Pr; (–)-8-epi-halosaline (4c)
Key words oxymercuration, stereoselectivity, oxazolidinone, piperi-
dines, pipecolinic acid
Figure 1 Natural 2-substituted piperidine alkaloids
Amino alcohols having 1,2- and 1,3-relationships are
compounds of special interest as ligands in various metal-
mediated reactions.1 This spatial relationship is also found
in several natural products.2 Conhydrines 1 and 2 are piper-
idine alkaloids of the hemlock family, isolated from the
plant Conium Maculatum L.3 (+)-Sedridine 3a, (–)-allosedri-
dine 4a, (+)-ethylnorlobelol 3b, (–)-2′-epi-ethylnorlobelol
4b, (+)-halosaline 3c, and (–)-8-epi-halosaline 4c have been
isolated from different sedum species and are therefore
called sedum alkaloids (Figure 1).4 Considerable attention
has focused on their synthesis during the last decade due to
their biological activities, which includes anti-Alzheimer,
anti-viral and anti-bacterial action.5 Although a plethora of
routes are reported for the synthesis of hydroxyalkyl piper-
idines,6 the development of new efficient strategies for the
synthesis of these alkaloids and their analogues remains
desirable.
taining a 1,3-oxyamino unit.7 Recently, we developed a
Henry–Nef reaction protocol for the synthesis of naturally
occurring 1,3-amino alcohols containing pyrrolidine as well
as piperidine rings.8 In a continuation of this work, we re-
port herein regioselective and stereoselective oxymercura-
tion–demercuration for the synthesis of hydroxyl piperi-
dine alkaloids containing the 1,3- and 1,2-amino alcohol
units.9 A regioselective functionalization by the oxy-mercu-
ration of β,γ-unsaturated urethanes was disclosed earlier by
Krow and Fan for the synthesis of γ-ketourethanes.9h Dia-
stereoselective intramolecular azamercurations for the syn-
thesis of (+)-pseudohygroline has been reported by Perlmutter
and co-workers.9i
We conceptualized that protecting group directed
regio- and stereoselective oxymercuration–demercuration
of olefins 5–7 (Scheme 1), which could be obtained from
commercially available L-pipecolinic acid (8), may give
access to both 1,3- and 1,2-amino alcohol unit containing
alkaloids 1–4. It was anticipated that Hg(OAc)2 would add
stereoselectively from the less hindered side of olefins 5–7
to form the mercurinium ion intermediates Y, which then
could be attacked by the water (nucleophile) regio-
Asymmetric synthesis using easily available chiral pre-
cursors has a great advantage of built-in chirality; however,
the challenge of regioselective and stereoselective genera-
tion of the next stereocenter still needs to be met. We had
earlier reported a regioselective Wacker oxidation for the
synthesis of naturally occurring pyrrolidine alkaloids con-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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S. T. Bugde et al.
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Synthesis
Table 1 Synthesis of 2-Alkenyl Piperidinesa
OH
OH
H
H
H
N
H
R
R
N
H
Entry
Protecting group Phosphonium salt
14a–c
R
Product Yield
(%)b
OH
4
1
1
2
3
4
5
6
7
8
9
-COOEt
-Cbz
-Cbz
-Cbz
-Cbz
-Boc
-Boc
-Boc
-Boc
C2H5PPh3+Br–
C2H5PPh3+Br–
C3H7PPh3+Br–
C4H9PPh3+Br–
C6H13PPh3+Br
C2H5PPh3+Br–
C3H7PPh3+Br–
C4H9PPh3+Br–
C6H13PPh3+Br–
Me
Me
Et
5
63
71
66
72
59
72
61
55
63
OAc
6a
6b
6c
6d
7a
7b
7c
7d
R
Hg
H
H
N
R
N
N
H
R
PG
O
PG
Pr
O
9–11
Y
12
Pent
Me
Et
R
H
H
N
H
COOH
N
Pr
PG
Pent
5 PG = COOEt
6 PG = Cbz
7 PG = Boc
8
a Reaction conditions: 14a (1.0 equiv), NaHCO3 (1.5 equiv), DMP (1.5 equiv)
in CH2Cl2 (20 mL), 0 °C, then to phosphonium salt (1 equiv) in THF (20 mL),
n-BuLi (1 equiv) at 0 °C, then, aldehyde (1 equiv).
b Isolated yield.
Scheme 1 Retrosynthetic approach
selectively, depending on the size of the protecting group,
leading to 1,3-aminoalcohols 9–11; if the protecting group
participates in an intramolecular fashion,10–12 it may lead to
oxazolidinones 12 regio- and stereosectively. Oxazolidi-
nones 12 then could be hydrolyzed to give 1,2-amino alco-
hols (–)-β-conhydrines 1 while alcohols 9–11 would pro-
vide natural alkaloids 4. The minor diastereomers could
then be similarly converted into other natural products 2
and 3.
To test the hypothesis we started with L-pipecolinic
acid, which was first reduced with LiAlH4 and then protect-
ed with a carboethoxy group (Scheme 2). Further oxidation
with Dess–Martin periodinane (DMP) and subsequent
Wittig olefination provided the required olefin 5 (Table 1,
entry 1). Wittig reaction of unstabilized ylides are known to
provide Z-olefins, and the geometry of the product ob-
tained 5 was found to be Z based on its 1H NMR data.
Once olefin 5a was in hand, it was first subjected to
oxymercuration using 1.1 equiv Hg(OAc)2 in THF/H2O (1:1)
until the yellow color persisted. Demercuration using NaOH
and NaBH4 afforded a mixture of two diastereomers in 1:1.7
ratio. The selectivity was marginally increased to 1:2 by the
use of the Cbz protecting group (Scheme 3). Hence for fur-
ther studies, the Cbz protecting group was chosen, because
it is much easier to remove than the COOEt group.
An optimal yield of 88% was obtained for 6a when 1.5
equiv Hg(OAc)2 was used (Table 2, entry 1). We elaborated
this methodology for a series of Z-alkenes 6b–d. It was ob-
served that as the size of the alkyl group increased, the
yield of the oxymercuration–demercuration reaction di-
minished while the stereoselectivity for the syn isomer
(Table 2) increased from 1:2 to 1:4.1. The configuration of
1. Hg(OAc)2 (1 equiv)
THF/H2O
OH
OH
H
H
H
+
N
N
N
2. NaOH, NaBH4
PG
PG
PG
5 PG = COOEt
6a PG = Cbz
15/9 1:1.7; 60%
16a/10a 1:2; 76%
Scheme 3 Oxymercuration–demercuration reaction of olefin 5 and 6a
Table 2 Oxymercuration–Demercuration of N-Cbz Protected Alkenesa
R
OH
1. Hg(OAc)2 (1.5 equiv)
THF/H2O
OH
H
H
H
+
R
N
N
R
N
2. NaOH, NaBH4
Cbz
Cbz
Cbz
LiAlH4
reduction
16a–d
N-protection
6a–d
10a–d
H
H
OH
ref. 2
N
ref. 2
N
COOH
H
Entry
6
Product
Time
Yield (%)
Ratio
H
13
16a–d/10a–d (h)
16a–d/10a–d
16a–d/10a–d
8
(combined)b
(S)-piperidine-2-carboxylic
acid
1
2
3
4
6a
6b
6c
6d
R = Me
R = Et
24
29/59 (88)
14/52 (66)
14/53 (67)
9/31 (55)
1:2
R
Table 1
Wittig reaction
H
H
24
24
24
1:3.7
1:3.8
1:4.1
OH
N
N
R = Pr
PG
5–7
PG
R= Pent
14a–c
a Reaction conditions: 6 (1 equiv), Hg(OAc)2 (1.5 equiv), H2O/THF (1:1, 12
mL) at r.t., then 3 N NaOH (2 mL), 0.5 N NaBH4 (3 mL) at 0 °C for 1 h.
b Isolated yield.
Scheme 2 Synthesis of 2-alkenyl piperidines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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S. T. Bugde et al.
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Synthesis
the products was assigned by comparison with published
NMR data, and the optical rotation of the antipodes, and
further confirmed by conversion into the natural products.
The targeted natural products and their analogues were
then synthesized from their respective starting compounds.
(+)-Sedridine 3a and (–)-allosedridine 4a were synthesized
by removal of the N-Cbz group through hydrogenation in 95
and 92% yield, respectively. (+)-Ethylnorlobelol 3b and (–)-
2′-epi-ethylnorlobelol 4b were similarly synthesized from
16b and 10b, respectively. (+)-Halosaline 3c, (–)-8-epi-halo-
saline 4c, 3d, and 4d were obtained from their respective
starting compounds (Table 3 and Table 4).
After accomplishing the synthesis of piperidine alka-
loids containing the 1,3-amino alcohol unit, we set out to
synthesize conhydrine 1, which is an alkaloid containing
the 1,2-amino alcohol unit. When 7a was subjected to
oxymercuration–demercuration using 1.5 equiv Hg(OAc)2,
oxazolidinone 12a was obtained regioselectively and with
complete diastereoselectivity in 33% yield. The yield in-
creased to 77% when 1 equiv Hg(OAc)2 was employed.
Similar Boc group participation has been utilized to obtain
oxazolidinones by halo-induced cyclization recently by
Paisuwan et al.,10a using SnCl4 catalysts by Alcaide et al.,10b
and earlier by Fisher and Overman.10c Brocherieux-Lanoy et
al.10d reported TiCl4 and Colombo et al.10e InCl3 for oxazi-
none formation. Comins et al. and Cipolla et al. reported the
participation of the Cbz group for iodolactonisation reac-
tions.11,12 Suga et al. have shown participation of the N-
methyl carbamate group in [2+4] cycloaddition reactions
for oxazinone synthesis.13
Similarly, oxymercuration–demercuration of alkenes
7b–d gave oxazolidinones 12b–d. Increasing the length of
the side-arm chain had no effect on the formation of oxazo-
lidinones and yields, which were consistently satisfactory
(Table 5). Basic hydrolysis of these oxazolidinones fur-
nished (–)-β-conhydrine 1a and its analogues in 73–78%
yield (Table 6).
Table 3 Synthesis of 1,3-Amino Alcohol Alkaloidsa
OH
OH
H2, Pd/C
H
H
Table 5 Oxymercuration of N-Boc Protected Alkenesa
N
R
N
R
EtOH, 6 h
H
Cbz
R
16a–d
3a–d
1. Hg(OAc)2 (1 equiv)
THF/H2O
R
H
H
N
N
Entry
16
16a
Product
3a; R = Me; (+)-sedridine
Yield (%)b
O
Boc
2. NaOH, NaBH4
O
7a–d
12a–d
1
2
3
4
95
84
92
92
16b
16c
16d
3b; R = Et; (+)-ethylnorlobelol
3c; R = Pr; (+)-halosaline
3d; R = Pent; (+)-3d
Entry
7
12
Time (h)
Yield (%)b
1
2
3
4
7a
7b
7c
7d
12a
12b
12c
12d
4
4
4
4
77
73
71
76
a Reaction conditions: 16 (1.0 equiv), Pd/C(10% w/w), EtOH (15 mL) at r.t.
under H2 pressure (40 psi) Parr hydrogenator for 6 h.
b Isolated yield.
a Reaction conditions: 7 (1 equiv), Hg(OAc)2 (1 equiv), H2O/THF (1:1,
12 mL) at r.t., then 3 N NaOH (2 mL), 0.5 N NaBH4 (3 mL) at 0 °C for 1 h.
b Isolated yield.
Table 4 Synthesis of 1,3-Amino Alcohol Alkaloidsa
OH
OH
H2, Pd/C
H
H
Table 6 Synthesis (–)-β-Conhydrine and Analoguesa
N
R
EtOH, 6 h
N
R
H
Cbz
4a–d
10a–d
R
H
H
KOH, reflux
N
N
MeOH/H2O (9:1)
H
Entry
10
10a
Product
4a; R = Me; (–)-allosedridine
Yield (%)b
O
OH
O
12a–d
1a–d
1
2
3
4
92
88
96
94
10b
10c
10d
4b; R = Et; (–)-2′-epi-ethylnorlobelol
4c; R = Pr; (–)-8-epi-halosaline
4d; R = Pent; (–)-4d
Entry
12
12a
Product
Yield (%)b
1
2
3
4
1a; (–)-β-conhydrine
1b; R = Et
71
83
76
71
12b
12c
12d
a Reaction conditions: 10 (1.0 equiv), Pd/C(10% w/w), EtOH (15 mL) at r.t.
under H2 pressure (40 psi) Parr hydrogenator for 6 h.
b Isolated yield.
1c; R = Pr
1d; R = Pent
a Reaction conditions: 12 (1 equiv), KOH (20 equiv), MeOH/H2O (10 mL,
9:1) was heated at reflux for 24 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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S. T. Bugde et al.
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Synthesis
AcOHg
N
HgOAc
15, 16a
O
N
O
OR
OR
H2O
H2O
A
A'
Hg(OAc)2
THF/H2O
N
+
O
AcOHg
OR
5, 6a
HgOAc
9, 10a
N
O
N
O
OR
OR
H2O
H2O
B
B'
Scheme 4 Plausible mechanism for formation of 1,3-amino alcohols
A speculative mechanism to account for the formation
of the 1,3-amino alcohols is depicted in Scheme 4 and for
the 1,2-alcohols in Scheme 5. Alkenes 5 and 6a react with
Hg(OAc)2 to form reversibly mercurinium ions A(A′) and
B(B′). Nucleophilic attack by water on A(A′) and B(B′) then
provided 15, 16a, and 9, 10a after demercuration (Scheme
4). The low ratio of selectivity suggests that both A and B
mercurinium ion intermediates are formed in almost equal
proportions. In the case of alkene 7, the Boc protecting
group participates in an intramolecular fashion because of
its proximity, and loses isobutylene to form oxazolidinone
12a regioselectively after demercuration. The fact that for-
mation of the isomer 17a was not observed could be due to
the disfavored pathway because of significant steric inter-
actions in the transition state, as depicted in Scheme 5.
HgOAc
HgOAc
N
N
O
O
O
O
H
NaBH4
N
Hg(OAc)2
THF/H2O
N
H
O
AcOHg
O
O
O
AcOHg
N
12a
O
7a
N
O
O
O
HgOAc
HgOAc
N
O
N
O
O
X
O
NaBH4
H
Hg(OAc)2
THF/H2O
N
N
H
O
O
HgOAc
AcOHg
N
O
O
17a
not observed
X
O
O
O
7a
N
O
Scheme 5 Plausible mechanism for formation of 1,2-amino alcohols
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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S. T. Bugde et al.
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Synthesis
In summary, the oxymercuration–demercuration reac-
tion was successfully employed to synthesize natural 2-
substituted hydroxyl alkyl piperidines (+)-sedridine, (–)-al-
losedridine, (+)-ethylnorlobelol, (–)-2′-epi-ethylnorlobelol,
(+)-halosaline, (–)-8-epi-halosaline (–)-β-conhydrine and
their analogues. The synthesis of 1,3-amino alcohols was
achieved by employing N-benzyloxycarbamates of L-
pipecolinic acid, and 1,2-amino alcohols were prepared
from N-tert-butyloxycarbamates. The remarkable protect-
ing group directed switchable regio- and stereoselectivity
of oxymercuration–demercuration of the internal alkene is
noteworthy. Further studies for such protecting group di-
rected hydroboration will be undertaken soon.
IR (KBr): 2935, 1693, 1427, 1255 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H19NO2Na: 220.1314;
found: 220.1314.
(Z)-Benzyl 2-(Prop-1-enyl)piperidine-1-carboxylate (6a)14a
Yield: 1.02 g (71%); colorless liquid; [α]D27 +9.6 (c = 1.9, CHCl3) {ref.14a
[α]D +14.6 (c = 1.9, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.35 (m, 5 H), 5.72 (t, J = 10.4 Hz,
1 H), 5.54–5.58 (m, 1 H), 5.07 (d, J = 12.4 Hz, 1 H), 5.02 (d, J = 12.4 Hz,
1 H), 4.06 (d, J = 13.6 Hz, 1 H), 2.95 (dt, J = 13.6, 2.8 Hz, 1 H), 1.53–1.71
(m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 155.3, 137.0, 128.4, 127.8, 127.8,
127.5, 66.9, 52.2, 48.0, 40.0, 30.3, 25.5, 19.4, 13.2.
IR (KBr): 3024, 2937, 1693, 1427 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H21NO2Na: 282.1470;
found: 282.1470.
Chemicals and solvents were purchased from commercial suppliers
and purified where required. Column chromatography was per-
formed on silica gel (60–120 mesh) and on basic alumina. 1H (400
MHz) and 13C (100 MHz) NMR spectra were recorded with a Bruker
AVANCE III instrument. Chemical shifts are given in ppm relative to
residual solvent peak. DEPT experiments were used to find the multi-
plicities of carbon signals. Optical rotations were measured using so-
dium D line (589 nm) with a Rudolph Autopol IV. Infrared spectra
were recorded with a Shimadzu FTIR instrument. High-resolution
mass spectra (HRMS) were recorded with a Micro Mass ES-QTOF
mass spectrometer.
(Z)-Benzyl 2-(But-1-enyl)piperidine-1-carboxylate (6b)
Yield: 0.859 g (66%); colorless liquid; [α]D27 +6.8 (c = 2.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.19–7.27 (m, 5 H), 5.57–5.62 (m, 1 H),
5.36–5.41 (m, 1 H), 5.05 (d, J = 12.4 Hz, 1 H), 5.01 (d, J = 12.4 Hz, 1 H),
3.98 (dd, J = 14.0, 3.6 Hz, 1 H), 2.89 (dt, J = 12.8, 2.8 Hz, 1 H), 2.00 (t, J =
7.2 Hz, 2 H), 1.51–1.56 (m, 6 H), 1.36–1.39 (m, 1 H), 0.84 (t, J = 7.6 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 155.2, 137.0, 134.1, 128.4, 127.8,
125.9, 66.9, 48.2, 39.9, 30.6, 25.5, 20.9, 19.4, 14.1.
IR (KBr): 2935, 2864, 1693, 1421 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H23NO2Na: 296.1626;
.
I. Oxidation-Wittig Reaction; General Procedure
To a mixture of N-protected pipecolinol 14a–c (4.8 mmol, 1 equiv),
and NaHCO3 (7.2 mmol, 1.5 equiv) in CH2Cl2 (20 mL) at 0 °C under N2
atmosphere was added Dess–Martin periodinane (7.2 mmol, 1.5
equiv). The reaction mixture was stirred at r.t. for 30 min. The reac-
tion mixture was extracted with CH2Cl2 (3 × 10 mL) and washed with
saturated NaHCO3 solution (2 × 10 mL). The combined organic layer
was dried over anhydrous Na2SO4. The solvent was removed in vacuo
to give the crude pipecolinal, which was used for further reactions
without purification. To a three-neck round-bottom flask containing
the phosphonium salt (4.8 mmol, 1 equiv) in THF (20 mL) under N2
atmosphere, was added n-butyllithium (4.8 mmol, 1 equiv) dropwise
by syringe at 0 °C. A dark-orange color was obtained. The reaction
mixture was stirred for 10 min and pipecolinal (4.8 mmol, 1 equiv) in
THF (2 mL) was added by syringe and stirred further for 2 h. The reac-
tion was quenched with 2 N NH4Cl (20 mL) solution. The reaction
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organ-
ic layer was washed with brine (2 × 10 mL) and dried over anhydrous
Na2SO4. The solvent was removed in vacuo and the residue was puri-
fied by column chromatography on silica gel (60–120 mesh) using
EtOAc/hexanes to afford products 5–7.
found: 296.1626.
(Z)-Benzyl 2-(Pent-1-enyl)piperidine-1-carboxylate (6c)
Yield: 0.861 g (72%); colorless liquid; [α]D27 +14.3 (c = 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.24–7.28 (m, 5 H), 5.63 (tt, J = 5.6,
1.6 Hz, 1 H), 5.38–5.41 (m, 1 H), 5.06 (d, J = 12.4 Hz, 1 H), 5.03 (d, J =
12.4 Hz, 1 H), 3.98 (d, J = 13.2 Hz, 1 H), 2.88 (dt, J = 12.8, 3.2 Hz, 1 H),
1.97 (q, J = 7.2 Hz, 2 H), 1.52–1.59 (m, 6 H), 1.36–1.38 (m, 1 H), 1.26
(q, J = 7.2 Hz, 2 H), 0.77 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.2, 136.9, 132.3, 128.4, 127.8,
126.5, 66.9, 48.2, 39.9, 30.6, 29.6, 25.5, 22.6, 19.4, 13.8.
IR (KBr): 2935, 1693, 1421, 1263 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H25NO2Na: 310.1783;
.
found: 310.1783.
(Z)-Benzyl 2-(Hept-1-enyl)piperidine-1-carboxylate (6d)14b
Yield: 0.902 g (59%); colorless liquid; [α]D27 +17.2 (c = 2.07, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.27–7.28 (m, 5 H), 5.59–5.64 (m, 1 H),
5.38–5.41 (m, 1 H), 5.03 (s, 2 H), 3.98 (d, J = 10.4 Hz, 1 H), 2.89 (dt, J =
13.2, 2.8 Hz, 1 H), 1.98 (d, J = 6.0 Hz, 2 H), 1.51–1.63 (m, 6 H), 1.13–
1.24 (m, 7 H), 0.79 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.2, 137.0, 128.4, 127.8, 126.3, 66.9,
48.2, 39.9, 31.5, 30.6, 29.2, 27.5, 25.5, 22.5, 19.4, 14.0.
IR (KBr): 2931, 1697, 1421, 1255 cm–1
(Z)-Ethyl 2-(Prop-1-enyl)piperidine-1-carboxylate (5)
Yield: 0.92 g (58%); colorless liquid; [α]D27 +4.1 (c = 0.68, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 5.72 (t, J = 9.2, 1.2 Hz, 1 H), 5.54–5.59
(m, 1 H), 5.09 (t, J = 6.4 Hz, 1 H), 4.09–4.16 (m, 2 H), 4.00 (d, J =
14.0 Hz, 1 H), 2.90 (dt, J = 11.2, 2.4 Hz, 1 H), 1.56–1.70 (m, 9 H), 1.25
(t, J = 7.2 Hz, 3 H).
.
13C NMR (100 MHz, CDCl3): δ = 155.5, 127.6, 126.3, 61.0, 47.7, 39.8,
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H29NO2Na: 338.2096;
30.2, 25.5, 19.4, 14.6, 13.1.
found: 338.2096.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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Synthesis
(Z)-tert-Butyl 2-(Prop-1-enyl)piperidine-1-carboxylate (7a)14c,14d
tracted with EtOAc (3 × 10 mL). The combined organic layer was dried
over anhydrous Na2SO4. The solvent was removed in vacuum and the
residue was purified by column chromatography on silica gel (60–120
mesh) using EtOAc/hexanes to afford products 9, 15, 10a–d or 16a–d.
Yield: 0.89 g (72%); colorless liquid; [α]D27 +7.3 (c = 0.3, CHCl3) {ref.14d
[α]D26 +13.7 (c = 0.3, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 5.70 (t, J = 9.2 Hz, 1 H), 5.52–5.56 (m,
1 H), 5.03 (t, J = 5.2 Hz, 1 H), 3.95 (d, J = 15.2 Hz, 1 H), 2.85 (dt, J = 13.2,
2.0 Hz, 1 H), 1.53–1.71 (m, 9 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 154.8, 128.0, 125.8, 79.1, 47.7, 39.6,
30.3, 28.4, 25.6, 19.5, 13.2.
Ethyl (S)-2-((S)-2-Hydroxypropyl)piperidine-1-carboxylate (9)8
28
Yield: 0.125 g (19%); colorless liquid; [α]D –16.0 (c = 0.04, CHCl3)
{ref.8 [α]D28 –16.0 (c = 0.04, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 4.47 (br s, 1 H), 4.14–4.22 (m, 3 H),
4.00 (d J = 12.0 Hz, 1 H), 3.55 (br s, 1 H), 2.73 (t, J = 13.2 Hz, 1 H), 2.00
(t, J = 12.8 Hz, 1 H), 1.38–1.73 (m, 7 H), 1.25–1.28 (m, 4 H), 1.19 (t, J =
4.4 Hz, 3 H).
IR (KBr): 2976, 1693, 1415 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H23NO2Na: 248.1626;
found: 248.1626.
13C NMR (100 MHz, CDCl3): δ = 157.1, 63.2, 61.6, 47.0, 39.2, 39.1, 29.2,
25.4, 19.1, 14.5.
(Z)-tert-Butyl 2-(But-1-enyl)piperidine-1-carboxylate (7b)
Yield: 0.805 g (61%); colorless liquid; [α]D27 +3.7 (c = 1.72, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 5.83 (dt, J = 10.8, 2.0 Hz, 1 H), 5.34–
5.41 (m, 1 H), 4.94 (t, J = 7.2 Hz, 1 H), 3.87 (dd, J = 12.8, 3.6 Hz, 1 H),
2.79 (dt, J = 13.2, 2.8 Hz, 1 H), 2.01–2.11 (m, 2 H), 1.48–1.61 (m, 6 H),
1.38 (s, 9 H), 0.91 (t, J = 7.6 Hz, 3 H).
IR (KBr): 3455, 2900, 1690 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H21NO3Na: 238.1419;
found: 238.1419.
Ethyl (S)-2-((R)-2-Hydroxypropyl)piperidine-1-carboxylate (15)8
13C NMR (100 MHz, CDCl3): δ = 154.7, 133.5, 126.3, 79.1, 47.9, 39.5,
30.7, 28.5, 25.6, 20.9, 19.5, 14.2.
Yield: 0.262 g (40%); colorless liquid; [α]D28 –56.4 (c = 0.2, CHCl3) {ref.8
[α]D28 –56.8 (c = 0.2, CHCl3)}.
IR (KBr): 2974, 1693, 1415, 1166 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.38 (br s, 1 H), 4.13 (q, J = 6.8 Hz, 2 H),
4.00 (d, J = 8.8 Hz, 1 H), 3.81 (d, J = 4.8 Hz, 1 H), 2.87 (t, J = 12.8 Hz,
1 H), 1.85 (br s, 1 H), 1.55–1.60 (m, 6 H), 1.40 (d, J = 12.4 Hz, 1 H),
1.21–1.27 (m, 6 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H25NO2Na: 262.1783;
found: 262.1783.
(Z)-tert-Butyl 2-(Pent-1-enyl)piperidine-1-carboxylate (7c)
Yield: 0.773 g (55%); colorless liquid; [α]D27 +14.4 (c = 1.9, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 156.0, 65.9, 61.3, 48.5, 39.6, 39.2, 29.2,
25.4, 23.4, 18.9, 14.6.
1H NMR (400 MHz, CDCl3): δ = 5.61 (dt, J = 8.4, 1.6 Hz, 1 H), 5.36–5.40
(m, 1 H), 4.95 (br s, 1 H), 3.87 (dd, J = 13.2, 2.4 Hz, 1 H), 2.79 (dt, J =
13.6, 3.2 Hz, 1 H), 2.01 (q, J = 8.4 Hz, 2 H), 1.51–1.53 (m, 4 H), 1.30–
1.38 (m, 13 H), 0.84 (t, J = 7.6 Hz, 3 H).
IR (KBr): 3502, 2985, 1690, 1670 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H21NO3Na: 238.1419;
.
found: 238.1419.
13C NMR (100 MHz, CDCl3): δ = 154.7, 131.8, 127.0, 79.1, 47.9, 39.5,
30.6, 29.6, 28.4, 25.6, 22.7, 19.5, 13.8.
(S)-Benzyl 2-((S)-2-Hydroxypropyl)piperidine-1-carboxylate (16a)8
23
Yield: 0.188 g (29%); colorless liquid; [α]D –19.3 (c = 0.21, CHCl3)
IR (KBr): 2960, 1693, 1417, 1166 cm–1
.
{ref.8 [α]D26 –28.5 (c = 2.920, CHCl3)}.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H27NO2Na: 276.1939;
found: 276.1939.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.36 (m, 5 H), 5.17 (d, J = 12.4 Hz,
1 H), 5.12 (d, J = 12.4 Hz, 1 H), 4.53 (d, J = 6.8 Hz, 1 H), 4.14 (br s, 1 H),
4.03 (d, J = 13.6 Hz, 1 H), 3.53 (br s, 1 H), 2.75 (t, J = 13.2 Hz, 1 H), 2.00
(t, J = 13.6 Hz, 1 H), 1.50–1.75 (m, 7 H), 1.19 (d, J = 5.6 Hz, 3 H).
(Z)-tert-Butyl 2-(Hept-1-enyl)piperidine-1-carboxylate (7d)
Yield: 0.99 g (63%); colorless liquid; [α]D27 +17.1 (c = 1.67, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 156.8, 136.6, 128.5, 128.4, 128.1,
1H NMR (400 MHz, CDCl3): δ = 5.60 (dt, J = 10.8, 2.0 Hz, 1 H), 5.34–
5.41 (m, 1 H), 4.94 (t, J = 6.8 Hz, 1 H), 3.87 (dd, J = 16.4, 2.8 Hz, 1 H),
2.79 (dt, J = 13.6, 2.8 Hz, 1 H), 2.03 (dq, J = 7.2, 2.0 Hz, 2 H), 1.45–1.61
(m, 6 H), 1.38 (s, 9 H), 1.38–1.21 (m, 6 H), 0.81 (t, J = 6.8 Hz, 3 H).
127.9, 68.6, 67.5, 47.3, 39.3, 37.1, 29.4, 29.2, 25.5, 19.2, 10.5.
IR (KBr): 3456, 2933, 2864, 1693, 1425 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H23NO3Na: 300.1576;
found: 300.1576.
13C NMR (100 MHz, CDCl3): δ = 154.7, 132.1, 126.1, 79.1, 47.9, 39.5,
31.5, 30.6, 29.3, 28.5, 27.6, 25.6, 22.5, 19.5, 14.0.
(S)-Benzyl 2-((S)-2-Hydroxybutyl)piperidine-1-carboxylate (16b)8
IR (KBr): 2931, 1693, 1454, 1166 cm–1
.
25
Yield: 0.073 g (14%); colorless liquid; [α]D –23.3 (c = 0.21, CHCl3)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H31NO2Na: 304.2252;
{ref.8 [α]D26 –27.9 (c = 0.8, CHCl3)}.
found: 304.2252.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.31 (m, 5 H), 5.12 (d, J = 12.4 Hz,
1 H), 5.05 (d, J = 12.0 Hz, 1 H), 4.45 (br s, 1 H), 3.98 (d, J = 12.4 Hz, 1 H),
3.14 (br s, 1 H), 2.67 (dt, J = 13.6, 2.4 Hz, 1 H), 1.94 (dt, J = 14.0, 2.0 Hz,
1 H), 1.33–1.59 (m, 8 H), 1.09–1.21 (m, 1 H), 0.86 (t, J = 6.8 Hz, 3 H).
II. Oxymercuration–Demercuration for Preparation of 9, 15, 10a–d
and 16a–d; General Procedure
13C NMR (100 MHz, CDCl3): δ = 156.9, 136.6, 128.1, 127.9, 68.5, 67.4,
47.2, 39.2, 37.1, 29.4, 25.4, 19.1, 10.4.
To a solution of Hg(OAc)2 (3.5 mmol, 1.5 equiv) in H2O/THF (1:1, 12
mL), was added a solution of alkenes 5, 6a–d or 7a–d (2.3 mmol, 1
equiv) in THF (2 mL) at r.t. and the mixture was stirred until the
yellow color disappeared. The reaction mixture was cooled to 0 °C. Aq
NaOH (3 N, 3 equiv) and aq. NaBH4 (0.5 M, 2 equiv) were added and
the mixture was stirred for 1 h. The reaction mixture was then ex-
IR (KBr): 3455, 2922, 2861, 1696 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H25NO3Na: 314.1732;
found: 314.1732.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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Synthesis
(S)-Benzyl 2-((S)-2-Hydroxypentyl)piperidine-1-carboxylate (16c)
Yield: 0.096 g (14%); colorless liquid; [α]D20 –28.4 (c = 0.76, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.28–7.30 (m, 5 H), 5.13 (d, J = 12.4 Hz,
1 H), 5.04 (d, J = 12.0 Hz, 1 H), 4.46 (d, J = 10.8 Hz, 1 H), 3.97 (d, J =
10.8 Hz, 1 H), 3.22 (br s, 1 H), 2.68 (dt, J = 13.2, 2.4 Hz, 1 H), 1.93 (dt,
J = 14.0, 1.6 Hz, 1 H), 1.36–1.58 (m, 10 H), 1.27 (t, J = 8.8 Hz, 2 H), 1.13
(dt, J = 11.2, 3.2 Hz, 1 H), 0.82 (t, J = 6.8 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.19–7.28 (m, 5 H), 5.07 (d, J = 12.4 Hz,
1 H), 5.04 (d, J = 12.4 Hz, 1 H), 4.37 (q, J = 5.6 Hz, 1 H), 3.97 (d, J =
13.2 Hz, 1 H), 3.56 (br s, 1 H), 2.82 (dt, J = 13.2, 4.4 Hz, 1 H), 1.81 (br s,
1 H), 1.54–1.59 (m, 6 H), 1.32–1.36 (m, 4 H), 0.82 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.8, 136.7, 128.4, 127.9, 127.8, 69.6,
67.1, 48.8, 39.7, 39.6, 37.8, 28.9, 25.4, 18.9, 18.8, 14.0.
IR (KBr): 3450, 2933, 1693, 1425, 1265 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 156.8, 136.6, 128.5, 128.0, 127.8, 67.4,
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H27NO3Na: 328.1889;
66.9, 47.3, 39.3, 38.9, 37.5, 29.4, 25.4, 19.2, 19.1, 14.1.
found: 328.1889.
IR (KBr): 3468, 2935, 1693, 1427 cm–1
.
(S)-Benzyl 2-((R)-2-Hydroxyheptyl)piperidine-1-carboxylate (10d)
Yield: 0.188 g (31%); colorless liquid; [α]D22 –36.7 (c = 0.78, CHCl3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H27NO3Na: 328.1889;
found: 328.1889.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.29 (m, 5 H), 5.07 (d, J = 12.4 Hz,
1 H), 5.03 (d, J = 12.4 Hz, 1 H), 4.37 (t, J = 5.2 Hz, 1 H), 3.97 (d, J =
12.0 Hz, 1 H), 3.55 (br s, 1 H), 2.83 (dt, J = 13.2, 2.0 Hz, 1 H), 2.1 (br s,
2 H), 1.64–1.69 (m, 1 H), 1.53–1.59 (m, 5 H), 1.35–1.38 (m, 4 H), 1.19–
1.25 (m, 5 H), 0.81 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.8, 136.8, 128.4, 127.8, 70.1, 67.1,
48.9, 39.6, 37.9, 37.6, 31.8, 29.2, 25.3, 25.4, 22.6, 18.9, 14.0.
(S)-Benzyl 2-((S)-2-Hydroxyheptyl)piperidine-1-carboxylate (16d)
Yield: 0.056 g (9%); colorless liquid; [α]D25 –23.0 (c = 0.60, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.19–7.29 (m, 5 H), 5.12 (d, J = 10.8 Hz,
1 H), 5.05 (d, J = 10.8 Hz, 1 H), 4.44 (br s, 1 H), 2.64 (dt, J = 13.6, 2.4 Hz,
1 H), 3.99 (d, J = 12.4 Hz, 1 H), 3.21 (br s, 1 H), 1.92 (dt, J = 14.0, 2.0 Hz,
1 H), 1.13–1.57 (m, 15 H), 0.81 (t, J = 7.2 Hz, 3 H).
IR (KBr): 3439, 2931, 1693, 1427 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 182.4, 156.8, 128.5, 128.1, 67.4, 67.2,
47.3, 39.3, 37.6, 36.7, 32.0, 29.4, 25.8, 25.4, 22.6, 19.1, 14.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H31NO3Na: 356.2202;
IR (KBr): 3462, 2934, 1693, 1425 cm–1
.
found: 356.2202.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H31NO3Na: 356.2202;
found: 356.2202.
III. Oxymercuration–Demercuration for Preparation of 12a–d;
General Procedure
To a solution of Hg(OAc)2 (2.3 mmol, 1 equiv) in H2O/THF (1:1, 12 mL),
were added a solution of alkenes 7a–d (2.3 mmol, 1 equiv) in THF (2
mL) at r.t. and the mixture was stirred until the yellow color disap-
peared. The reaction mixture was cooled to 0 °C. Aq NaOH (3 N, 3
equiv) and aq NaBH4 (0.5 M, 2 equiv) was added and the mixture was
stirred for 1 h. The reaction mixture was extracted with EtOAc (3 × 10
mL). The combined organic layer was dried over anhydrous Na2SO4.
The solvent was removed in vacuum and the residue was purified by
column chromatography on silica gel (60–120 mesh) using EtOAc/
hexanes to afford products 12a–d.
(S)-Benzyl 2-((R)-2-Hydroxypropyll)piperidine-1-carboxylate
(10a)8,14e
25
Yield: 0.37 g (59%); colorless liquid; [α]D –49.7 (c = 0.65, CHCl3)
{ref.14e [α]D22 –52.3 (c = 1.275, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.36 (m, 5 H), 5.15 (d, J = 12.4 Hz,
1 H), 5.10 (d, J = 12.4 Hz, 1 H), 4.41 (d, J = 5.6 Hz, 1 H), 4.04 (d, J =
10.4 Hz, 1 H), 3.82 (br s, 1 H), 2.90 (t, J = 12.8 Hz, 1 H), 1.81–1.88 (m,
1 H), 1.25–1.67 (m, 8 H), 1.18 (d, J = 4.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.9, 136.8, 128.3, 128.2, 128.1,
128.0, 127.9, 71.4, 67.1, 48.9, 39.6, 37.6, 30.3, 29.2, 25.5, 18.9, 10.0.
1-Ethyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (12a)6i,14f
IR (KBr): 3441, 2933, 2864, 1693, 1425 cm–1
.
20
Yield: 0.172 g (77%); colorless liquid; [α]D –29.4 (c = 0.31, CHCl3)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H23NO3Na: 300.1576;
found: 300.1576.
{ref.14f [α]D20 –33.2 (c = 0.4, CHCl3)}.
1H NMR (400 MHz, CDCl3): δ = 4.00 (q, J = 6.8 Hz, 1 H), 3.85 (dd, J =
10.8, 2.8 Hz, 1 H), 3.23–3.26 (m, 1 H), 2.79 (t, J = 12.4 Hz, 1 H), 1.71–
1.92 (m, 5 H), 1.25–1.45 (m, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).
(S)-Benzyl 2-((R)-2-Hydroxybutyl)piperidine-1-carboxylate (10b)8
Yield: 0.279 g (52%); light-yellow liquid; [α]D22 –45.2 (c = 0.21, CHCl3)
13C NMR (100 MHz, CDCl3): δ = 156.7, 81.9, 59.4, 41.1, 30.5, 27.0, 24.2,
{ref.8 [α]D26 –46.8 (c = 0.13, CHCl3)}.
22.6, 9.0.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.29 (m, 5 H), 5.07 (d, J = 12.4 Hz,
1 H), 5.03 (d, J = 12.4 Hz, 1 H), 4.36–4.39 (m, 1 H), 3.96 (d, J = 12.0 Hz,
1 H), 3.46 (br s, 1 H), 2.83 (t, J = 12.8 Hz, 1 H), 2.19 (br s, 1 H), 1.32–
1.71 (m, 10 H), 0.83 (t, J = 6.8 Hz, 3 H).
IR (KBr): 2939, 2879, 1745, 1427 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H15NO2Na: 192.1000;
.
found: 192.1000.
13C NMR (100 MHz, CDCl3): δ = 155.8, 136.8, 128.4, 127.9, 127.9, 71.4,
67.1, 48.9, 39.6, 37.6, 30.3, 29.1, 25.4, 18.9, 10.0.
1-Propyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (12b)
Yield: 0.257 g (73%); colorless liquid; [α]D20 –34.0 (c = 0.22, CHCl3).
IR (KBr): 3450, 3933, 1693, 1423 cm–1
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H25NO3Na: 314.1732;
found: 314.1732.
1H NMR (400 MHz, CDCl3): δ = 3.95–3.99 (m, 1 H), 3.78 (td, J = 13.2,
2.4 Hz, 1 H), 3.10–3.15 (m, 1 H), 2.72 (dt, J = 12.4, 3.2 Hz, 1 H), 1.61–
1.85 (m, 4 H), 1.18–1.57 (m, 6 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.7, 80.6, 59.8, 41.1, 36.1, 30.4, 24.2,
22.6, 18.1, 13.8.
(S)-Benzyl 2-((R)-2-Hydroxypentyl)piperidine-1-carboxylate (10c)
Yield: 0.363 g (53%); colorless liquid; [α]D22 –42.4 (c = 1.27, CHCl3).
IR (KBr): 2937, 1753, 1444, 1244 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122

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Synthesis
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H17NO2Na: 206.1157;
13C NMR (100 MHz, CDCl3): δ = 69.6, 54.8, 46.2, 40.6, 30.4, 30.4, 24.6,
found: 206.1157.
23.9, 10.1.
IR (KBr): 3329, 2934, 1460, 1265 cm–1
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H19NOH: 158.1545; found:
.
1-Butyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one(12c)
Yield: 0.27 g (71%); colorless liquid; [α]D20 –34.0 (c = 0.31, CHCl3).
158.1545.
1H NMR (400 MHz, CDCl3): δ = 4.04 (dq, J = 5.6, 2.0 Hz, 1 H), 3.85 (dd,
J = 13.2, 4.8 Hz, 1 H), 3.19–3.23 (m, 1 H), 2.78 (dt, J = 12.8, 3.6 Hz, 1 H),
1.91 (d, J = 11.2 Hz, 1 H), 1.83 (d, J = 13.2 Hz, 1 H), 1.61–1.74 (m, 4 H),
1.35–1.46 (m, 6 H), 0.93 (t, J = 7.2 Hz, 3 H).
(+)-Halosaline (3c)
Yield: 0.030 g (92%); white solid; mp 79–80 °C; [α]D25 +20.5 (c = 0.05,
25
EtOH) {ref.15b for R,R-isomer, (–)-halosaline [α]D –24.5 (c = 0.86,
13C NMR (100 MHz, CDCl3): δ = 156.6, 80.7, 59.8, 41.1, 33.7, 30.4, 26.8,
EtOH)}.
24.2, 22.3, 22.3, 13.8.
IR (KBr): 2935, 1759, 1446, 1244 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H19NO2Na: 220.1313;
found: 220.1313.
1H NMR (400 MHz, CDCl3): δ = 3.89–3.93 (m, 1 H), 3.35 (d, J = 12.4 Hz,
1 H), 3.18–3.23 (m, 1 H), 2.76 (dt, J = 12.0, 4.4 Hz, 1 H), 1.25–1.86 (m,
12 H), 0.84 (t, J = 6.8 Hz, 3 H).
.
13C NMR (100 MHz, CDCl3): δ = 66.5, 54.7, 44.9, 39.5, 39.4, 28.8, 22.7,
22.2, 18.9, 14.0.
IR (KBr): 3273, 2933, 1454, 1126 cm–1
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H21NOH: 172.1701; found:
.
1-Hexyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one (12d)
Yield: 0.302 g (76%); colorless liquid; [α]D20 –31.9 (c = 0.83, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 4.03 (q, J = 7.2 Hz, 1 H), 3.85 (d, J =
14.4 Hz, 1 H), 3.20 (dt, J = 11.2, 2.8 Hz, 1 H), 2.78 (dt, J = 12.8, 3.2 Hz,
1 H), 1.90 (d, J = 9.6 Hz, 1 H), 1.83 (d, J = 12.8 Hz, 1 H), 1.61–1.71 (m,
3 H), 1.28–1.47 (m, 11 H), 0.88 (t, J = 6.8 Hz, 3 H).
172.1701.
(S)-1-((S)-Piperidin-2-yl)heptan-2-ol (3d)15c
23
Yield: 0.024 g (92%); white solid; mp 64–65 °C; [α]D +6.9 (c = 0.14,
13C NMR (100 MHz, CDCl3): δ = 156.7, 80.8, 59.8, 41.1, 34.1, 31.6, 30.5,
EtOH) {ref.15c [α]D22 +9.0 (c = 0.7, EtOH)}.
28.9, 24.7, 24.2, 22.6, 22.2, 14.0.
IR (KBr): 2931, 1759, 1444, 1244 cm–1
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H23NO2Na: 248.1626;
found: 248.1626.
1H NMR (400 MHz, CDCl3): δ = 3.95 (br s, 1 H), 3.39 (d, J = 12.4 Hz,
1 H), 3.23 (d, J = 9.6 Hz, 1 H), 2.78–2.81 (m, 1 H), 2.37 (br s, 2 H), 1.74–
1.89 (m, 6 H), 1.37–1.44 (m, 4 H), 1.18–1.23 (m, 6 H), 0.82 (t, J =
6.4 Hz, 3 H).
.
13C NMR (100 MHz, CDCl3): δ = 67.0, 54.7, 45.3, 40.1, 37.5, 31.8, 29.3,
25.4, 23.0, 22.9, 22.6, 14.0.
IR (KBr): 3441, 2929, 1460, 1263 cm–1
IV. Deprotection of Benzyl Carbamates by Hydrogenation; General
Procedure
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H25NOH: 200.2014; found:
200.2014.
Compounds 10a–d and 16a–d in EtOH (15 mL) were stirred with 10%
Pd/C (10% w/w) under H2 atmosphere (40 psi) for 6 h using a Parr hy-
drogenator at r.t. The reaction mixture was filtered, washed with
EtOH and then concentrated to give compounds 3a–d and 4a–d.
(–)-Allo-sedridine (4a)15a
Yield: 0.072 g (92%); yellow solid; mp 62–63 °C (ref.6j mp 61.5–63 °C);
(+)-Sedridine (3a)15a
[α]D25 –21.6 (c = 0.32, MeOH) {ref.8 [α]D –16.4 (c = 0.80, MeOH)}.
Yield: 0.074 g (95%); yellow solid; mp 82–83 °C (ref.6j 82–83 °C);
1H NMR (400 MHz, CDCl3): δ = 4.07–4.11 (m, 2 H), 3.32 (d, J = 13.2 Hz,
1 H), 3.06 (t, J = 10.4 Hz, 1 H), 2.78–2.83 (m, 1 H), 1.73–1.88 (m, 5 H),
1.50–1.59 (m, 3 H), 1.20 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 67.5, 57.8, 45.1, 42.4, 30.7, 24.3, 23.4,
22.9.
[α]D25 +26.3 (c = 0.57, EtOH) {ref.15a [α]D +26.2 (c = 0.85, EtOH)}.
1H NMR (400 MHz, CDCl3): δ = 5.00 (br s, 1 H), 4.50 (br s, 1 H), 4.15–
4.18 (m, 1 H), 3.26 (d, J = 12.4 Hz, 1 H), 3.06–3.11 (m, 1 H), 2.72 (dt, J =
12.0, 3.2 Hz, 1 H), 1.58–1.69 (m, 7 H), 1.41–1.45 (m, 1 H), 1.21 (d, J =
6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 63.9, 54.5, 45.9, 42.6, 30.1, 24.1, 23.6,
23.5.
IR (KBr): 3350, 2945, 1604, 1436 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H17NOH: 144.1388; found:
144.1388.
IR (KBr): 3381, 2964, 1556, 1404 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H17NOH: 144.1388; found:
144.1388.
(–)-2′-epi-Ethylnorlobelol (4b)15a
25
Yield: 0.076 g (96%); white crystalline solid; mp 52–53 °C; [α]D
–10.2 (c = 0.98, EtOH) {ref.15a [α]D –6.6 (c = 0.8, EtOH)}.
(+)-Ethylnorlobelol (3b)15a
1H NMR (400 MHz, CDCl3): δ = 3.76–3.82 (m, 1 H), 3.39 (d, J = 12.8 Hz,
1 H), 3.15 (br s, 1 H), 2.86 (t, J = 10.8 Hz, 1 H), 1.73–1.95 (m, 8 H),
1.40–1.45 (m, 3 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 73.4, 58.0, 45.3, 40.8, 32.0, 31.0, 24.6,
23.4, 9.9.
IR (KBr): 3334, 2931, 1612, 1452 cm–1
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H19NOH: 158.1545; found:
Yield: 0.023 g (84%); light-yellow crystalline solid; mp 61–62 °C
26
(ref.15a 61 °C); [α]D +16.1 (c 0.23, EtOH) {ref.15a [α]D +17.5 (0.80,
EtOH)}.
1H NMR (400 MHz, CDCl3): δ = 3.87 (br s, 1 H), 3.56–3.67 (m, 2 H),
3.40–3.43 (m, 1 H), 3.23–3.24 (m, 1 H), 2.80–2.83 (m, 1 H), 1.17–1.93
(m, 10 H), 0.90 (t, J = 7.2 Hz, 3 H).
.
158.1545.
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1121
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Synthesis
(–)-8-epi-Halosaline (4c)15b
13C NMR (100 MHz, CDCl3): δ = 73.5, 61.3, 46.4, 35.8, 29.0, 26.0, 24.3,
25
19.0, 14.1.
IR (KBr): 3323, 3070, 2937, 1442 cm–1
Yield: 0.024 g (96%); white solid; mp 37–38 °C; [α]D –11.4 (c = 1.1,
MeOH) {ref.15b [α]D25 –12.1 (c = 0.45, MeOH)}.
.
1H NMR (400 MHz, CDCl3): δ = 3.75–3.77 (m, 1 H), 3.67 (br s, 2 H),
3.00 (dd, J = 14.8, 1.2 Hz, 1 H), 2.71 (t, J = 9.2 Hz, 1 H), 2.55 (dt, J = 12.0,
1.6 Hz, 1 H), 1.74–1.77 (m, 1 H), 1.58 (dt, J = 13.6, 2.0 Hz, 2 H), 1.11–
1.46 (m, 9 H), 0.84 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 72.5, 58.1, 45.9, 42.3, 40.3, 34.0, 26.9,
24.3, 18.6, 14.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H19NOH: 158.1545; found:
158.1545.
(S)-1-((S)-Piperidin-2-yl)pentan-1-ol (1c)
Yield: 0.197 g (76%); yellow thick liquid; [α]D21 –13.8 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 3.21 (dt, J = 7.6, 2.8 Hz, 1 H), 3.03 (dd,
J = 12.0, 2.8 Hz, 1 H), 2.51 (dt, J = 12.0, 3.2 Hz, 1 H), 2.28 (dt, J = 7.2,
2.8 Hz, 1 H), 1.24–1.76 (m, 12 H), 1.06 (dq, J = 10.8, 4.0 Hz, 1 H), 0.84
(t, J = 11.2 Hz, 3 H).
IR (KBr): 3311, 2929, 1444, 1124 cm–1
.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H21NOH: 172.1701; found:
172.1701.
13C NMR (100 MHz, CDCl3): δ = 73.9, 61.3, 46.4, 33.3, 29.1, 27.9, 26.2,
(R)-1-((S)-Piperidin-2-yl)heptan-2-ol (4d)
24.4, 22.8, 14.0.
25
IR (KBr): 3315, 3170, 2931, 1454 cm–1
.
Yield: 0.059 g (94%); white solid; mp 56–57 °C; [α]D –14.9 (c = 0.8,
EtOH).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H21NOH: 172.1701; found:
172.1701.
1H NMR (400 MHz, CDCl3): δ = 3.87 (br s, 2 H), 3.76 (d, J = 4.4 Hz, 1 H),
3.02 (d, J = 12.8 Hz, 1 H), 2.71 (t, J = 10.0 Hz, 1 H), 2.56 (t, J = 12.8 Hz,
1 H), 1.76 (d, J = 12.0 Hz, 1 H), 1.58 (t, J = 13.6 Hz, 2 H), 1.15–1.46 (m,
13 H), 0.81 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 70.6, 57.4, 44.8, 40.1, 38.2, 31.6, 29.3,
25.1, 22.3, 21.9, 13.9.
(S)-1-((S)-Piperidin-2-yl)heptan-1-ol (1d)
Yield: 0.189 g (71%); yellow thick liquid; [α]D21 –14.0 (c = 0.52, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 3.21 (t, J = 12.8 Hz, 1 H), 3.01 (dd, J =
13.6, 2.4 Hz, 1 H), 2.52 (dt, J = 12.0, 2.8 Hz, 1 H), 2.28 (dt, J = 9.6,
3.2 Hz, 1 H), 1.21–1.74 (m, 16 H), 1.05 (dq, J = 12.0, 4.0 Hz, 1 H), 0.81
(t, J = 6.4 Hz, 3 H).
IR (KBr): 3394, 2949, 2858, 1454, 1128 cm–1
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H25NOH: 200.2014; found:
.
13C NMR (100 MHz, CDCl3): δ = 73.8, 61.3, 46.4, 33.6, 31.8, 29.4, 29.0,
200.2014.
26.1, 25.7, 24.4, 22.6, 14.1.
V. Hydrolysis of Oxazolidinones; General Procedure
IR (KBr): 3315, 3169, 2929, 1442 cm–1
.
KOH (20 equiv) was added to a stirred solution of oxazolidinones
12a–d (1 equiv) in MeOH/H2O (9:1, 10 mL) and the mixture was heat-
ed at reflux for 12 h. The reaction mixture was then cooled and con-
centrated under reduced pressure. The residue was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layer was dried over anhy-
drous Na2SO4. The solvent was removed in vacuo and the residue was
purified by column chromatography on basic alumina using CHCl3/
MeOH to afford products 1a–d.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H25NOH: 200.2014; found:
200.2014.
Funding Information
This publication was supported by the Ministry of Education and
Science of the Russian Federation (Agreement No. 02.А03.21.0008)
and Council of Science and Research, New Delhi, project No.
(–)-β-Conhydrine (1a)15d
02(252)/16/EMR-II.
M
n
isitry
of
E
d
u
coaitn
a
n
d
S
ecin
c
e
of
hte
Ruasni
F
e
d
e
oarint
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.
0
32.10.0
0
8
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o
u
n
lc
i
of
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a
n
d
R
eseacrh
,
N
e
w
D
he
l
i
0(
2
2(
5
2
1/)
6
E/
M
R)I-
Yield: 0.12 g (71%); mp 67–68 °C (ref.15d mp 68–70 °C); [α]D –32.4
25
(c = 0.68, CHCl3) {ref.15d [α]D25 –34.5 (c = 1, CHCl3)}.
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 3.17 (dt, J = 8.0, 3.2 Hz, 1 H), 3.04 (d, J =
11.2 Hz, 1 H), 2.53 (dt, J = 9.2, 2.8 Hz, 1 H), 2.26- 2.34 (m, 3 H), 1.78
(dt, J = 4.8, 3.2 Hz, 1 H), 1.75 (br s, 1 H), 1.49–1.60 (m, 2 H), 1.26–1.33
(m, 3 H), 1.06–1.10 (m, 1 H), 0.91 (t, J = 7.6 Hz, 3 H).
We thank IISc (Bangalore) for HRMS facility. S.T.B. is thankful to UGC
New Delhi for the award of senior research fellowship and P.S.V. is
thankful to CSIR New Delhi for a senior research fellowship.
13C NMR (100 MHz, CDCl3): δ = 75.5, 60.8, 46.3, 28.9, 26.5, 26.3, 24.3,
9.9.
IR (KBr): 3298, 2931, 2854, 1450 cm–1
.
Supporting Information
HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H17NOH: 144.1388; found:
144.1388.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589137.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(S)-1-((S)-Piperidin-2-yl)butan-1-ol (1b)
Yield: 0.12 g (83%); white crystalline solid; mp 63–64 °C; [α]D22 –19.2
(c = 0.5, CHCl3).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 1113–1122