Synthesis of (R)-coniine and (S)-coinicine via organocatalytic-aminoxyl- ation of an aldehyde

Article abstract of DOI:10.1055/s-0030-1257869

A short and efficient synthesis of the indolizidine alkaloid (S)-coinicine has been achieved using organocatalytic sequential-aminoxylation and Horner-Wadsworth-Emmons olefination of an aldehyde catalyzed by l-proline. Similarly, a common organocatalytic-aminoxylation route has been developed for the asymmetric synthesis of both (R)-coniine and (S)-coinicine. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1257869

PAPER
3105
Synthesis of (R)-Coniine and (S)-Coinicine via Organocatalytic
a-Aminoxylation of an Aldehyde
Synthesis of
(
R
)-C
a
oniine and
g
(
S
)-Coinicine via Organ
n
ocatalytic
a
-
d
Aminoxylati
r
on a B. Kondekar, Pradeep Kumar*
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: pk.tripathi@ncl.res.in
Received 22 April 2010; revised 30 April 2010
protein catalysis and toxic metal catalysis,5 thus becoming
a fundamental tool in the catalysis toolbox available for
asymmetric synthesis.6 Proline in the recent past has been
defined as a ‘universal catalyst’ because of its utility in
Abstract: A short and efficient synthesis of the indolizidine alka-
loid (S)-coinicine has been achieved using organocatalytic sequen-
tial a-aminoxylation and Horner–Wadsworth–Emmons olefination
of an aldehyde catalyzed by L-proline. Similarly, a common orga-
nocatalytic a-aminoxylation route has been developed for the asym- different reactions providing rapid, catalytic, atom-
economical access to enantiomerically pure products.7
metric synthesis of both (R)-coniine and (S)-coinicine.
Similarly, organocatalytic tandem processes are provid-
ing an efficient means to construct complex target mole-
cules in an environmentally friendly and rapid way from
simple and readily available precursors, while minimizing
yield, time and energy losses.8
In continuation of our interest in organocatalysis9 and
asymmetric synthesis of piperidine and indolizidine alka-
loids,10 we wish to report a-aminoxylation and sequential
a-aminoxylation and Horner–Wadsworth–Emmons
(HWE) olefination approaches for the synthesis of (R)-
coniine and (S)-coinicine.
Key words: synthesis, organocatalysis, sequential reactions, pro-
line, hemlock alkaloids
Substituted piperidines and ring-fused piperidines such as
indolizidines are among the most ubiquitous heterocyclic
building blocks in both natural products and synthetic
compounds with important biological activities
(Figure 1).1,2 The interest in the piperidine and indolizi-
dine alkaloids, which display a wide array of structural di-
versity, is well displayed by the wealth of published
material detailing their sources and biological activities.3
(R)-Coniine (1) and (S)-coinicine (2), the simplest mem-
bers of the piperidine and indolizidine alkaloids, respec-
tively, have attracted a great deal of interest from chemists
as representative targets, resulting in numerous successful
asymmetric syntheses of these molecules.4
Our synthetic approach for the synthesis of (R)-coniine (1)
and (S)-coinicine (2) via a-aminoxylation was envisioned
through the retrosynthetic routes shown in Scheme 1.
Azide 12, which was thought to be a common intermedi-
ate for the synthesis of both compounds, could be easily
obtained from epoxide 9 which, in turn, could be prepared
from the diol derivative 7 obtained by a-aminoxylation of
the corresponding aldehyde 6.
Thus, the synthesis began with the aldehyde 611 which on
a-aminoxylation catalyzed by L-proline and in situ reduc-
tion with sodium borohydride gave the O-amino-substi-
tuted diol 7 in 71% yield and 95% ee12 (Scheme 2). This
O-amino-substituted diol 7 was then subjected to reduc-
tive hydrogenation conditions using palladium-on-carbon
to afford the diol 8 in 85% yield. Compound 8 on selective
monotosylation using p-toluenesulfonyl chloride with cat-
alytic dibutyltin oxide, followed by base treatment, fur-
nished the epoxide 9 in 79% yield (over two steps).
Regioselective opening of epoxide 9 with lithium acetyl-
ide afforded homopropargyl alcohol 10 in 82% yield,
which on partial reduction using hydrogen with Lindlar
catalyst gave the homoallylic alcohol 11 in 90% yield.
OH
OH
H
H
HO
HO
N
N
N
H
(R)-coniine (1)
(S)-coinicine (2)
(+)-castanospermine (3)
OH
OH
N
H2N
H
(–)-SS20846A
(5)
N
H
(+)-pseudodistomin D (4)
Figure 1 Some of the important piperidine- and indolizidine-
containing bioactive natural products
During the last decade it has been established that small The free hydroxy group was then converted into an azido
organic molecules can be highly selective and efficient group following a two-step process of mesylation using
catalysts, and the area of organocatalysis has emerged as methanesulfonyl chloride and triethylamine, and subse-
a promising strategy and as an alternative to expensive quent sodium azide treatment, to afford the azide 12 in
68% yield (over two steps). Compound 12 was used as a
common precursor for the synthesis of (R)-coniine (1) and
(S)-coinicine (2).
SYNTHESIS 2010, No. 18, pp 3105–3112
Advanced online publication: 22.07.2010
x
x.
x
x
.
2
0
1
0
DOI: 10.1055/s-0030-1257869; Art ID: Z10510SS
© Georg Thieme Verlag Stuttgart · New York

3106
N. B. Kondekar, P. Kumar
PAPER
NHBoc
NHCbz
N3
OH
HO
PMBO
HO
12
13
16
O
PMBO
H
9
ONHPh
OH
N
N
H•HCl
PMBO
PMBO
(S)-coinicine (2)
(R)-coniine (1)
7
O
6
Scheme 1 Retrosynthetic route to (R)-coniine (1) and (S)-coinicine (2) via a-aminoxylation of aldehyde 6
For the synthesis of (R)-coniine (1), double bond reduc- troscopic data of 1 were in full agreement with the
tion of 12 along with in situ conversion of azide into free literature data.
amine and tert-butyl carbamate protection of the resulting
amine was achieved in one step using hydrogen with pal-
ladium-on-carbon and (Boc)2O. Subsequent p-methoxy-
benzyl (PMB) deprotection using 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) afforded the free hy-
droxy compound 13 in 80% yield (over two steps). The
free hydroxy group of 13 was converted into its methane-
sulfonyl ester using methanesulfonyl chloride and triethyl-
Similarly, for the synthesis of (S)-coinicine (2), the azide
12 was converted into amine using triphenylphosphane
under Staudinger reaction conditions, which was followed
by in situ protection of the free amine as its benzyl car-
bamate under basic conditions to afford compound 15 in
90% yield (Scheme 3). Olefin 15 was further subjected to
a hydroboration–oxidation reaction using borane–dimethyl-
sulfide complex and then hydrogen peroxide to afford the
amine in 85% yield. Subsequent base treatment of 14 us-
corresponding alcohol which, on subsequent PMB depro-
ing sodium hydride furnished Boc-protected (R)-coniine
tection using DDQ, gave the diol 16 in 74% yield. Both
in good yield. Finally, the hydrochloride salt of (R)-coni-
free hydroxy groups of diol 16 were then mesylated using
25
25
ine (1) {[a]D –8.64 (c 0.25, EtOH); Lit.4i [a]D –7.3 (c
0.33, EtOH)} was easily obtained by Boc deprotection us-
ing methanolic hydrochloric acid. The physical and spec-
methanesulfonyl chloride to provide dimesyl compound
17 in 84% yield. Finally, benzyl carbamate deprotection
and concomitant cyclization under hydrogenation condi-
tions using palladium hydroxide furnished (S)-coinicine
(2) {[a]D25 +9.5 (c 1.1, EtOH); Lit.4q [a]D25 +10.2 (c 1.76,
EtOH)} in excellent yield. The physical and spectroscopic
data of 2 were in full agreement with the literature data.4q
ONHPh
a
b
OH
PMBO
PMBO
PMBO
CHO
6
8
7
9
OH
O
c
d
OH
N3
NHCbz
PMBO
a
b
PMBO
HO
PMBO
OH
N3
OH
12
16
15
f
e
NHCbz
NHCbz
PMBO
PMBO
PMBO
c
11
OH
OMs
10
12
MsO
17
NHBoc
h
g
H
HO
i
d
13
N
NHBoc
2
MsO
Scheme 3 Asymmetric synthesis of (S)-coinicine. Reagents and
conditions: (a) Ph3P, THF, H2O; then CbzCl, Na2CO3, 1,4-dioxane,
H2O, 90%; (b) (i) BH3·SMe2, THF; then H2O2; (ii) DDQ, CH2Cl2,
H2O, 74% (over two steps); (c) MsCl, Et3N, CH2Cl2, 84%; (d) H2,
Pd(OH)2, EtOAc, 80%.
N
14
H•HCl
1
Scheme 2 Asymmetric synthesis of (R)-coniine. Reagents and con-
ditions: (a) (i) nitrosobenzene, L-proline, DMSO; (ii) NaBH4, MeOH,
71% (over two steps); (b) H2, Pd/C, EtOAc, 85%; (c) (i) TsCl,
Bu2SnO, Et3N, CH2Cl2; (ii) K2CO3, MeOH, 79% (over two steps); (d)
HC≡CLi, DMSO, 82%; (e) H2, Lindlar catalyst, EtOAc, 90%; (f) (i)
MsCl, Et3N, CH2Cl2; (ii) NaN3, DMF, 68% (over two steps); (g) (i)
H2, Pd/C, (Boc)2O, EtOAc; (ii) DDQ, CH2Cl2, H2O, 80% (over two
steps); (h) MsCl, Et3N, CH2Cl2, 85%; (i) NaH, DMF, 0 °C; then HCl,
MeOH, 90%.
We have recently developed a new methodology for enan-
tiopure syn/anti-1,3-polyols in an iterative manner using
g-hydroxy esters as a substrate by a proline-catalyzed se-
quential a-aminoxylation and HWE olefination reaction
of aldehydes.9 As an extension of our research interest in
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Coniine and (S)-Coinicine via Organocatalytic a-Aminoxylation
3107
H
OH
O
PMBO
PMBO
COOEt
N
3
3
6
(S)-coinicine (2)
18
Scheme 4 Retrosynthetic route to (S)-coinicine (2) via a-aminoxylation and HWE olefination of aldehyde 6
ONHPh
OH
b
a
PMBO
CHO
PMBO
COOEt
PMBO
COOEt
6
18
N3
NHBoc
c
d
PMBO
COOEt
PMBO
COOEt
OH
20
19
NHBoc
NHBoc
e
f
g
OH
2
PMBO
HO
22
21
Scheme 5 Sequential a-aminoxylation and HWE olefination route for the synthesis of (S)-coinicine. Reagents and conditions: (a) nitrosoben-
zene, L-proline, DMSO; then (EtO)2P(O)CH2CO2Et, DBU, LiCl, MeCN; (b) H2, Pd/C, EtOAc, 65% (over two steps); (c) (i) MsCl, Et3N,
CH2Cl2; (ii) NaN3, DMF, 71% (over two steps); (d) H2, Pd/C, (Boc)2O, EtOAc, 91%; (e) DIBAL-H, CH2Cl2, 0 °C, 87%; (f) DDQ, CH2Cl2,
H2O, 78%; (g) (i) MsCl, Et3N, CH2Cl2; (ii) HCl, MeOH; then NaH, DMF, 0 °C, 67%.
vents were dried and purified by conventional methods prior to use.
The progress of all reactions was monitored by TLC using glass
plates precoated with silica gel 60 F254 to a thickness of 0.25 mm
(Merck). Column chromatography was performed on silica gel (60
and 230 mesh) using EtOAc and petroleum ether (PE) as the elu-
ents. Optical rotations were measured with a JASCO DIP-360 digi-
tal polarimeter at 25 °C. IR spectra were recorded on a Perkin-
Elmer FT-IR spectrophotometer. 1H and 13C NMR spectra were re-
corded in CDCl3 on Bruker AC 200, AV 400 and DRX 500 spec-
trometers (1H at 200 or 500 MHz; 13C at 50, 100 or 125 MHz) with
TMS as internal standard. ESI-MS were obtained using an Applied
Biosystems API QSTAR mass spectrometer.
the area of organocatalysis and in order to reduce the over-
all number of steps for the synthesis of (S)-coinicine (2),
a different route via sequential a-aminoxylation and HWE
olefination of aldehyde 6 was envisioned, as shown in the
retrosynthetic analysis in Scheme 4.
As illustrated in Scheme 5, the sequential a-aminoxyla-
tion and HWE olefination of aldehyde 6 and subsequent
reduction of the resulting O-amino-substituted allylic al-
cohol furnished the g-hydroxy ester 18 in 65% yield and
95% ee.13 The free hydroxy group of 18 was reacted with
methanesulfonyl chloride, which was followed by treat-
ment with sodium azide, to furnish the azido ester 19 in
71% yield (over two steps). In situ conversion of azide 19
into Boc-protected amine 20 was achieved in one step in
excellent yield using hydrogen with palladium-on-carbon
and (Boc)2O. The ester 20 on DIBAL-H reduction gave
the alcohol 21 in 87% yield which, on subsequent PMB
deprotection using DDQ, afforded diol 22 in 78% yield.
Treatment of diol 22 with methanesulfonyl chloride gave
dimesyl compound. Finally, Boc deprotection using acid
treatment (methanolic HCl) followed by reaction with ex-
cess sodium hydride afforded the target molecule (S)-
coinicine (2). The physical and spectroscopic data of 2
were in accord with those described in the literature.4q
(R)-6-(4-Methoxybenzyloxy)-2-(phenylaminooxy)hexan-1-ol (7)
To a stirred soln of 6-(4-methoxybenzyloxy)hexanal (6; 1.00 g, 4.24
mmol) and nitrosobenzene (0.379 g, 3.53 mmol) in DMSO (9 mL)
was added L-proline (0.097 g, 0.84 mmol, 20 mol%) in one portion
at 25 °C. After 1 h, the temperature was lowered to 0 °C, which was
followed by dilution of the mixture with anhyd MeOH (10 mL) and
careful addition of excess NaBH4 (0.643 g, 17.0 mmol). The reac-
tion was quenched after 10 min by pouring the mixture into a vigor-
ously stirred, biphasic solution of Et2O and aq 1 M HCl. The organic
layer was separated, and the aqueous phase was extracted with
EtOAc (3 × 20 mL). The combined organic phases were dried
(Na2SO4), concentrated and purified by column chromatography
over silica gel (EtOAc–PE, 4:6) to give pure aminooxy alcohol 7;
yield: 1.03 g (71%).
[a]D25 +1.14 (c 1.8, CHCl3).
In conclusion, proline-catalyzed a-aminoxylation and
sequential a-aminoxylation and Horner–Wadsworth–
Emmons olefination approaches have been successfully
applied to the synthesis of (R)-coniine and (S)-coinicine.
The present method is easily amenable for the synthesis of
a variety of piperidine and indolizidine alkaloids. Current-
ly, studies in this direction are in progress.
IR (CHCl3): 3028, 2979, 2358, 1600, 1494, 1454, 1029 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.44–1.68 (m, 8 H), 3.44–3.52 (m,
3 H), 3.63–3.69 (m, 1 H), 3.83 (s, 3 H), 3.93–4.00 (m, 1 H), 4.46 (s,
2 H), 6.88–6.93 (m, 2 H), 6.98–7.04 (m, 2 H), 7.22–7.38 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 22.4, 29.6, 29.7, 55.2, 65.0, 69.7,
72.5, 83.8, 113.7, 114.7, 122.3, 122.8, 128.9, 129.2, 130.5, 148.4,
159.1.
Anal. Calcd for C20H27NO4: C, 69.54; H, 7.88; N, 4.05. Found: C,
69.67; H, 7.71; N, 4.17.
All reactions were carried out under inert atmosphere, unless other-
wise mentioned, following standard syringe septa techniques. Sol-
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

3108
N. B. Kondekar, P. Kumar
PAPER
(R)-6-(4-Methoxybenzyloxy)hexane-1,2-diol (8)
2 H), 3.71–3.74 (m, 1 H), 3.81 (s, 3 H), 4.44 (s, 2 H), 6.88 (d, J = 8.7
Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 22.3, 27.3, 29.5, 35.9, 55.3, 69.8,
70.8, 72.6, 80.9, 113.8, 129.2, 130.6, 131.5, 159.1.
The aminooxy alcohol 7 (1.00 g, 2.89 mmol) was dissolved in
EtOAc (10 mL); to the solution was added 10% Pd/C (0.050 g) and
the mixture was stirred in a H2 atmosphere (1 atm, balloon pressure)
for 12 h. After completion of the reaction (monitored by TLC), the
mixture was filtered through a Celite® pad, the filtrate was concen-
trated and the crude product was purified by silica gel chromatogra-
phy (EtOAc–PE, 4:6) to give pure diol 8; yield: 0.625 g (85%).
[a]D25 +0.84 (c 0.5, CHCl3).
IR (CHCl3): 3412, 3018, 2938, 1612, 1513, 1248, 1215 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33–1.56 (m, 6 H), 2.81 (br s, 2
H), 3.27–3.40 (m, 3 H), 3.49–3.56 (m, 1 H), 3.59–3.63 (m, 1 H),
3.72 (s, 3 H), 4.35 (s, 2 H), 6.80 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7
Hz, 2 H).
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.38; H,
8.31.
(R)-8-(4-Methoxybenzyloxy)oct-1-en-4-ol (11)
To a soln of homopropargyl alcohol 10 (1.0 g, 3.81 mmol) in EtOAc
(10 mL) was added Lindlar catalyst (0.08 g). The mixture was
stirred for 0.5 h under a balloon of H2 at r.t. and was then filtered
through a Celite® pad. The filtrate was concentrated and the residue
was purified by silica gel column chromatography (PE–EtOAc, 9:1)
to give homoallylic alcohol 11 as a pale yellow oil; yield: 0.90 g
(90%).
[a]D25 +3.60 (c 1.35, CHCl3).
IR (CHCl3): 3464, 2983, 1614, 1587, 1514, 1447, 1098 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.32–1.43 (m, 5 H), 1.52–1.59 (m,
2 H), 2.01–2.24 (m, 2 H), 3.37 (t, J = 2.6 Hz, 2 H), 3.48–3.61 (m, 1
H), 3.72 (s, 3 H), 4.35 (s, 2 H), 5.00–5.02 (m, 1 H), 5.06–5.10 (m, 1
H), 5.64–6.85 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 7.18 (d, J = 8.7
Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 22.1, 29.5, 32.7, 55.2, 66.5, 69.8,
72.0, 72.4, 113.7, 129.2, 130.4, 159.1.
Anal. Calcd for C14H22O4: C, 66.12; H, 8.72. Found: C, 66.02; H,
8.84.
(R)-2-[4-(4-Methoxybenzyloxy)butyl]oxirane (9)
To a soln of diol 8 (0.21 g, 0.825 mmol) in anhyd CH2Cl2 (5 mL)
was added dibutyltin oxide (0.004 g, 0.016 mmol), followed by the
addition of TsCl (0.157 g, 0.825 mmol) and Et3N (0.115 mL, 0.83
mmol), and the mixture was stirred at r.t. under N2. After comple-
tion of the reaction (15 min, monitored by TLC), it was quenched
by the addition of H2O. The solution was extracted with CH2Cl2
(3 × 10 mL), and the combined organic phases were washed with
H2O (20 mL), dried (Na2SO4) and concentrated.
13C NMR (50 MHz, CDCl3): d = 22.1, 29.4, 36.2, 41.7, 54.8, 69.7,
70.3, 70.9, 72.2, 113.5, 117.3, 129.0, 134.8, 158.8.
Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found: C, 72.80; H,
9.29.
(S)-1-[(5-Azidooct-7-enyloxy)methyl]-4-methoxybenzene (12)
To an ice-cold, stirred soln of homoallylic alcohol 11 (1.0 g, 3.78
mmol) and Et3N (0.948 mL, 6.8 mmol) in anhyd CH2Cl2 (75 mL)
was added dropwise MsCl (0.322 mL, 4.16 mmol) over 15 min. The
resulting mixture was allowed to warm to r.t. and was stirred for 2
h. After dilution with CH2Cl2 (100 mL), the solution was washed
with H2O (3 × 50 mL) and brine, dried (Na2SO4) and concentrated
to give the crude mesylated product. This was used for the next step
without further purification.
To this crude mixture in MeOH (10 mL) at 0 °C was added K2CO3
(0.215 g, 1.56 mmol) and the resulting mixture was stirred for 1 h at
that temperature. After completion of the reaction (as indicated by
TLC), it was quenched by the addition of ice pieces and MeOH, and
the mixture was concentrated on a rotatory evaporator. The concen-
trated mixture was then extracted with EtOAc (3 × 20 mL), and the
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated. Column chromatography (PE–EtOAc, 9:1) gave
the epoxide 9 as a colorless liquid; yield: 0.15 g (79%).
To a soln of the mesylated product in anhyd DMF (15 mL) was add-
ed portionwise NaN3 (1.47 g, 22.69 mmol) and the resulting suspen-
sion was stirred at 45 °C for 24 h. After cooling the orange solution
to r.t., Et2O (50 mL) and H2O (50 mL) were added and the aqueous
layer was extracted with Et2O (3 × 40 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed under re-
duced pressure. Purification of the crude product by silica gel col-
umn chromatography (PE) gave azide 12 as a yellowish liquid;
yield: 0.744 g (68%).
[a]D25 –21.41 (c 1.25, CHCl3).
IR (CHCl3): 2931, 2104, 1607, 1512, 1465, 1258 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.48–1.66 (m, 6 H), 2.27–2.34 (m,
2 H), 3.31–3.36 (m, 1 H), 3.46 (t, J = 6.2 Hz, 2 H), 3.81 (s, 3 H),
4.44 (s, 2 H), 5.10–5.12 (m, 1 H), 5.15–5.21 (m, 1 H), 5.72–5.92 (m,
1 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).
[a]D25 +4.18 (c 1.00, CHCl3).
IR (CHCl3): 2934, 2858, 1615, 1586, 1513, 1463, 1248 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.52–1.67 (m, 6 H), 2.45–2.49 (m,
1 H), 2.73–2.77 (m, 1 H), 2.87–2.94 (m, 1 H), 3.46 (t, J = 6.3 Hz, 2
H), 3.81 (s, 3 H), 4.44 (s, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.27 (d,
J = 8.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 22.6, 29.4, 32.2, 46.9, 52.1, 55.1,
69.7, 72.5, 113.7, 129.1, 130.6, 159.1.
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.04; H,
8.65.
(R)-8-(4-Methoxybenzyloxy)oct-1-yn-4-ol (10)
To a soln of epoxide 9 (0.5 g, 2.11 mmol) in DMSO (2 mL) at 0 °C
was added lithium acetylide–ethylenediamine complex (0.292 g,
3.16 mmol) in one portion. The mixture was stirred at 0 °C for 30
min and at r.t. for 12 h. The excess reagent was quenched with 0.3
N H2SO4, the mixture was extracted with Et2O (3 × 20 mL), and the
extracts were washed with H2O (2 × 20 mL) and brine, dried
(Na2SO4) and concentrated. The residue was purified by silica gel
chromatography (PE–EtOAc, 9:1) to afford homopropargyl alcohol
10 as a colorless liquid; yield: 0.455 g (82%).
[a]D25 +1.07 (c 1.02, CHCl3).
IR (CHCl3): 3438, 2937, 2250, 1608, 1463, 1249 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43–1.68 (m, 6 H), 1.79 (br s, 1
H), 2.06 (t, J = 2.6 Hz, 1 H), 2.33–2.42 (m, 2 H), 3.46 (t, J = 6.3 Hz,
13C NMR (125 MHz, CDCl3): d = 22.8, 29.4, 33.7, 38.7, 55.2, 62.2,
69.7, 72.5, 113.7, 118.0, 129.2, 130.6, 133.9, 159.1.
Anal. Calcd for C16H23N3O2: C, 66.41; H, 8.01; N, 14.52. Found: C,
66.56; H, 8.17; N, 14.65.
tert-Butyl (R)-8-Hydroxyoctan-4-ylcarbamate (13)
To a soln of azide 12 (0.8 g, 2.76 mmol) in EtOAc (8 mL) was added
10% Pd/C (0.05 g) and (Boc)2O (0.7 mL, 3.04 mmol). The resulting
solution was stirred under H2 atmosphere at r.t. for 12 h until disap-
pearance of the azide (as monitored by TLC). The mixture was fil-
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Coniine and (S)-Coinicine via Organocatalytic a-Aminoxylation
3109
tered through a Celite® pad to remove the catalyst and the filtrate
was concentrated under reduced pressure.
IR (CHCl3): 3020, 2962, 1215 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3 H), 1.46 (br
s, 4 H), 1.93 (br s, 5 H), 2.85–2.92 (m, 2 H), 3.45–3.50 (m, 1 H),
9.14–9.39 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 13.8, 18.7, 22.3, 22.4, 28.2, 35.4,
45.0, 57.3.
To a crude soln of the ester (0.960 g, 2.61 mmol) in CH2Cl2 (9.5
mL) and H2O (0.5 mL) was added DDQ (0.655 g, 2.88 mmol), and
the mixture was stirred at r.t. for 30 min. After completion of the re-
action (monitored by TLC), it was quenched by the addition of ice-
cooled aq NaHCO3 soln and the mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic fractions were washed with sat.
NaHCO3 soln (15 mL) followed by brine, then dried (Na2SO4) and
concentrated. Silica gel column chromatography of the crude prod-
uct (PE–EtOAc, 8:2) gave alcohol 13 as an oily liquid; yield: 0.542
g (80%).
[a]D25 +4.32 (c 1.72, CHCl3).
IR (CHCl3): 3464, 2984, 1740, 1518, 1478, 1465, 1243 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88–0.99 (m, 3 H), 1.25–1.35 (m,
4 H), 1.43 (s, 9 H), 1.52–1.79 (m, 4 H), 1.94–2.04 (m, 2 H), 2.26–
2.44 (m, 1 H), 3.63 (t, J = 6.4 Hz, 2 H), 4.30 (t, J = 6.7 Hz, 1 H).
ESI-MS: m/z = 128.2709 [M + H+].
Benzyl (S)-8-(4-Methoxybenzyloxy)oct-1-en-4-ylcarbamate
(15)
To a soln of azide 12 (2.0 g, 6.91 mmol) in THF (30 mL) and H2O
(4.5 mL) was added Ph3P (2.71 g, 10.36 mmol) and the mixture was
stirred at r.t. for 12 h. The mixture was concentrated, then 1,4-diox-
ane (25 mL), H2O (25 mL) and Na2CO3 (1.6 g, 15.20 mmol) were
added, and this mixture was stirred for another 10 min at 0 °C. To
this ice-cold solution, CbzCl (1.28 mL, 8.98 mmol) was added and
the mixture was allowed to warm to r.t. and was stirred overnight.
On completion of the reaction, the solvent was evaporated under re-
duced pressure and the residue was extracted with EtOAc (3 × 25
mL). The combined organic layers were washed with H2O (50 mL)
and brine, dried (Na2SO4) and concentrated. Silica gel column chro-
matography of the crude product (PE–EtOAc, 19:1) gave olefin 15
as a colorless liquid; yield: 2.47 g (90%).
13C NMR (100 MHz, CDCl3): d = 13.7, 14.0, 19.1, 22.0, 27.4, 28.4,
30.5, 32.5, 35.4, 38.0, 62.7, 65.5, 167.7.
Anal. Calcd for C13H27NO3: C, 63.64; H, 11.09; N, 5.71. Found: C,
63.80; H, 11.21; N, 5.58.
[a]D25 –5.22 (c 1.8, CHCl3).
IR (CHCl3): 3438, 2928, 1716, 1510, 1215 cm–1.
(R)-5-(tert-Butoxycarbonylamino)octyl Methanesulfonate (14)
To an ice-cold, stirred soln of alcohol 13 (0.3 g, 1.22 mmol) and
Et3N (0.306 mL, 2.2 mmol) in anhyd CH2Cl2 (7 mL) was added
dropwise MsCl (0.104 mL, 1.34 mmol) over 15 min. The resulting
mixture was allowed to warm to r.t. and was stirred for 2 h. After
dilution with CH2Cl2 (15 mL), the solution was washed with H2O
(3 × 25 mL) and brine, dried (Na2SO4) and concentrated. Silica gel
column chromatography of the crude mesylated product (PE–
EtOAc, 8:2) gave mesyl ester 14 as an oily liquid; yield: 0.336 g
(85%).
1H NMR (200 MHz, CDCl3): d = 1.43–1.53 (m, 4 H), 1.54–1.64 (m,
2 H), 1.94 (br s, 1 H), 2.21–2.30 (m, 1 H), 3.46 (t, J = 6.3 Hz, 2 H),
3.65–3.74 (m, 1 H), 3.83 (s, 3 H), 4.45 (s, 2 H), 4.53–4.65 (m, 1 H),
5.06–5.12 (m, 4 H), 5.69–5.89 (m, 1 H), 6.91 (d, J = 8.7 Hz, 2 H),
7.30 (d, J = 8.7 Hz, 2 H), 7.35–7.41 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 22.5, 29.4, 34.2, 39.3, 50.5, 55.1,
69.6, 72.3, 113.6, 117.6, 127.8, 128.3, 129.1, 130.5, 134.1, 136.6,
155.9, 159.0.
[a]D25 +2.80 (c 1.16, CHCl3).
IR (CHCl3): 2985, 1742, 1242, 1047 cm–1.
Anal. Calcd for C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C,
72.39; H, 7.98; N, 3.61.
1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 6.7 Hz, 3 H), 1.32–
1.43 (m, 18 H), 1.68–1.85 (m, 2 H), 3.00 (s, 3 H), 3.53 (br s, 1 H),
4.22 (t, J = 6.5 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 13.8, 18.9, 21.7, 28.2, 28.8, 34.8,
37.1, 37.6, 49.9, 69.9, 78.7, 155.7.
Benzyl (S)-1-Hydroxy-8-(4-methoxybenzyloxy)octan-4-ylcar-
bamate
To a soln of olefin 15 (0.54 g, 1.36 mmol) in anhyd THF (10 mL) at
0 °C under argon atmosphere was added 2 M BH3·SMe2 in THF
(0.103 g, 0.68 mL, 1.36 mmol) and the mixture was allowed to
warm to r.t. and was stirred for 3 h. The reaction flask was cooled
to 0 °C and then a soln of NaOH (0.108 g, 2.72 mmol) in EtOH–
H2O (2:1, 10 mL), followed by a 30% w/v soln of H2O2 in H2O (0.5
mL, 4.08 mmol), were added dropwise over 15 min. The mixture
was then stirred at r.t. for 6 h. The product was taken up in EtOAc
(20 mL) and the aqueous layer was extracted with EtOAc (3 × 15
mL). The combined organic layers were washed with H2O (30 mL)
and brine, dried (Na2SO4) and concentrated to give the crude alco-
hol product, benzyl (S)-1-hydroxy-8-(4-methoxybenzyloxy)octan-
4-ylcarbamate, which was used in the next step without purifica-
tion; yield: 0.485 g (86%).
Anal. Calcd for C14H29NO5S: C, 51.99; H, 9.04; N, 4.33; S, 9.91.
Found: C, 52.11; H, 9.11; N, 4.21; S, 9.81.
(R)-2-Propylpiperidine [(R)-Coniine, 1]
To a soln of mesyl ester 14 (0.1 g, 0.309 mmol) in DMF at 0 °C was
added NaH (60% dispersion in oil, 0.008 g). The reaction was al-
lowed to stir at r.t. On completion of the reaction (3 h, as indicated
by TLC), it was quenched by the addition of ice pieces. The result-
ing mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with H2O (20 mL) and brine, then dried
(Na2SO4). Silica gel column chromatography (EtOAc–PE, 9:1) fur-
nished the Boc-protected product as a colorless liquid.
IR (CHCl3): 3318, 2922, 1685, 1540, 1463, 1216 cm–1.
To this product (0.05 g, 0.22 mmol) in anhyd CH2Cl2 (2 mL) was
added methanolic HCl (2 mL) in a catalytic amount. The mixture
was stirred at r.t. for 2 h, then sat. aq NaHCO3 (30 mL) was added
and the mixture was extracted with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4) and
concentrated. The crude product was purified by silica gel column
chromatography (MeOH–CH2Cl2, 1:10) to give 1 as a solid com-
pound; yield: 0.032 g (90%). The physical and spectroscopic data of
1 were in full agreement with the literature data.
1H NMR (200 MHz, CDCl3): d = 1.42–1.46 (m, 4 H), 1.54–1.60 (m,
6 H), 1.90 (br s, 2 H), 3.42 (t, J = 6.3 Hz, 2 H), 3.64 (t, J = 5.5 Hz,
3 H), 3.80 (s, 3 H), 4.42 (s, 2 H), 5.09 (s, 2 H), 6.89 (d, J = 8.7 Hz,
2 H), 7.27 (d, J = 8.7 Hz, 2 H), 7.33–7.36 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 22.4, 28.6, 29.4, 31.6, 35.0, 50.9,
55.1, 62.2, 66.4, 69.7, 72.3, 113.6, 127.8, 128.3, 129.2, 130.4,
136.5, 156.3, 159.0.
ESI-MS: m/z = 438.2811 [M + Na+].
[a]D25 –8.64 (c 0.25, EtOH) {Lit.4i [a]D25 –7.3 (c 0.33, EtOH)}.
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

3110
N. B. Kondekar, P. Kumar
PAPER
Benzyl (S)-1,8-Dihydroxyoctan-4-ylcarbamate (16)
was added L-proline (0.395 g, 3.42 mmol) at 20 °C. The mixture
was vigorously stirred for 25 min under argon (the color of the re-
action mixture changed from green to yellow during this time), then
cooled to 0 °C. Thereafter, a premixed and cooled (0 °C) soln of tri-
ethyl phosphonoacetate (5.12 mL, 25.7 mmol), DBU (3.83 mL,
25.7 mmol) and LiCl (1.09 g, 25.7 mmol) in MeCN (18 mL) was
added quickly (1–2 min) at 0 °C. The resulting mixture was allowed
to warm to r.t. over 1 h, and the reaction was quenched by the addi-
tion of ice pieces. The MeCN was evaporated under reduced pres-
sure. The remaining mixture was then poured into H2O (50 mL) and
the resulting mixture was extracted with Et2O (5 × 100 mL). The
combined organic layers were washed with H2O (300 mL) and
brine, dried (Na2SO4) and concentrated under reduced pressure to
give crude product which was directly subjected to the next step
without purification.
To a soln of benzyl (S)-1-hydroxy-8-(4-methoxybenzyloxy)octan-
4-ylcarbamate (0.23 g, 0.55 mmol) in CH2Cl2 (9.5 mL) and H2O
(0.5 mL) was added DDQ (0.15 g, 0.663 mmol), and the mixture
was stirred at r.t. for 30 min. After completion of the reaction (mon-
itored by TLC), the mixture was extracted with EtOAc (3 × 20 mL).
The combined organic fractions were washed with sat. NaHCO3
soln (2 × 25 mL) followed by brine, then dried (Na2SO4) and con-
centrated. Silica gel column chromatography of the crude product
(PE–EtOAc, 6:4) gave diol 16 as an oily liquid; yield: 0.14 g (86%).
[a]D25 +2.53 (c 0.32, CHCl3).
IR (CHCl3): 3300, 2858, 1740, 1603, 1495, 1454, 1256 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.39–1.59 (m, 10 H), 2.58 (br s, 2
H), 3.57–3.63 (m, 4 H), 3.81–3.85 (m, 1 H), 4.77–4.85 (br s, 1 H),
5.08 (s, 2 H), 7.34 (m, 5 H).
To the crude O-amino-substituted allylic alcohol in EtOAc (25 mL)
was added 10% Pd/C (cat.) under hydrogenation conditions and the
mixture was stirred overnight. On completion of the reaction (until
1H NMR analysis of the crude mixture indicated complete conver-
sion), the mixture was filtered through a Celite® pad and the filtrate
was concentrated under reduced pressure. The crude product was
purified by flash column chromatography (PE–EtOAc, 85:15) to
give g-hydroxy ester 18 as a colorless liquid; yield: 1.78 g (65%).
[a]D25 +1.81 (c 1.16, CHCl3).
IR (CHCl3): 3452, 2928, 1731, 1613, 1586, 1462, 1248 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.29 (t, J = 7.0 Hz, 3 H), 1.37–
1.51 (m, 4 H), 1.54–1.78 (m, 4 H), 2.33–2.56 (m, 2 H), 3.48 (t,
J = 6.3 Hz, 2 H), 3.62–3.69 (m, 1 H), 3.84 (s, 3 H), 4.18 (q, J = 7.0
Hz, 2 H), 4.46 (s, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.7 Hz,
2 H).
13C NMR (100 MHz, CDCl3): d = 22.0, 28.7, 31.8, 32.3, 35.2, 51.0,
62.3, 62.4, 66.3, 128.0, 128.1, 128.5, 136.6, 156.6.
ESI-MS: m/z = 296.2657 [M + H+], 318.2326 [M + Na+].
Anal. Calcd for C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found: C,
65.19; H, 8.41; N, 4.88.
(S)-4-(Benzyloxycarbonylamino)octane-1,8-diyl Dimethane-
sulfonate (17)
To an ice-cold, stirred soln of diol 16 (0.5 g, 1.69 mmol) and Et3N
(0.943 mL, 6.8 mmol) in anhyd CH2Cl2 (10 mL) was added drop-
wise MsCl (0.314 mL, 4.06 mmol) over 15 min. The resulting mix-
ture was allowed to warm to r.t. and was stirred for 2 h. After
dilution with CH2Cl2 (25 mL), the solution was washed with H2O
(3 × 15 mL) and brine, dried (Na2SO4) and concentrated. Silica gel
column chromatography of the crude mesylated product (PE–
EtOAc, 7:3) gave dimesyl compound 17 as an oily liquid; yield:
0.64 g (84%).
[a]D25 +0.82 (c 1.0, CHCl3).
IR (CHCl3): 3022, 1710, 1512, 1217 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.39–1.54 (m, 5 H), 1.67–1.86 (m,
5 H), 2.77–2.89 (m, 1 H), 2.99 (s, 6 H), 4.10–4.27 (m, 4 H), 4.60–
4.70 (m, 1 H), 5.09 (s, 2 H), 7.35 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 22.1, 29.4, 30.6, 32.0, 37.0,
55.0, 60.3, 69.8, 70.7, 72.4, 113.6, 129.1, 130.4, 158.9, 174.6.
ESI-MS: m/z = 325.3509 [M + H+], 347.3415 [M + Na+], 363.3388
[M + K+].
Anal. Calcd for C18H28O5: C, 66.64; H, 8.70. Found: C, 66.52; H,
8.86.
Ethyl (S)-4-Azido-8-(4-methoxybenzyloxy)octanoate (19)
To an ice-cold, stirred soln of alcohol 18 (1.0 g, 3.08 mmol) and
Et3N (0.86 mL, 6.16 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise MsCl (0.266 mL, 3.44 mmol) over 15 min. The resulting
mixture was allowed to warm to r.t. and was stirred for 2 h. After
dilution with CH2Cl2 (15 mL), the solution was washed with H2O
(3 × 50 mL) and brine, dried (Na2SO4) and concentrated to give the
crude mesylated product. This was used for the next step without
further purification.
13C NMR (50 MHz, CDCl3): d = 21.8, 25.7, 28.7, 31.5, 34.9, 37.3,
50.4, 66.7, 69.6, 128.0, 128.2, 128.5, 136.4, 156.2.
Anal. Calcd for C18H29NO8S2: C, 47.88; H, 6.47; N, 3.10; S, 14.20.
Found: C, 47.98; H, 6.31; N, 3.17; S, 14.04.
(S)-Octahydroindolizine [(S)-Coinicine, 2]
To the dimesyl compound 17 (0.05 g, 0.11 mmol) in EtOAc (5 mL)
was added Pd(OH)2 (0.015 g) and the mixture was stirred under hy-
drogenation conditions for 12 h, until disappearance of the dimesyl
compound (as monitored by TLC). The mixture was filtered
through a Celite® pad to remove the catalyst and the filtrate was
concentrated under reduced pressure. Silica gel column chromatog-
raphy (MeOH–CH2Cl2, 1:10) gave 2 as a solid compound; yield:
0.011 g (80%). The physical and spectroscopic data of 2 were in full
agreement with the literature data.
[a]D25 +9.5 (c 1.1, EtOH) {Lit.4q [a]D25 +10.2 (c 1.76, EtOH)}.
IR (CHCl3): 2952, 2920, 1461, 1454, 1320, 1255, 1096 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.12–1.87 (m, 11 H), 1.95 (dt,
J = 3.6, 11.2 Hz, 1 H), 2.07 (q, J = 9.0 Hz, 1 H), 3.02–3.12 (m, 2 H).
To a soln of the mesylated product in anhyd DMF (10 mL) was add-
ed portionwise NaN3 (1.20 g, 18.5 mmol) and the resulting suspen-
sion was stirred at 45 °C for 24 h. After cooling the orange solution
to r.t., Et2O (25 mL) and H2O (25 mL) were added and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
layers were dried (Na2SO4) and the solvent was removed under re-
duced pressure. Silica gel column chromatography of the crude
product (PE–EtOAc, 95:5) gave azide 19 as a yellowish liquid;
yield: 0.764 g (71%).
[a]D25 +10.37 (c 1.54, CHCl3).
IR (CHCl3): 2937, 2099, 1732, 1613, 1586, 1247 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H), 1.55–
1.81 (m, 8 H), 2.39–2.49 (m, 2 H), 3.29–3.38 (m, 1 H), 3.48 (t,
J = 6.0 Hz, 2 H), 3.83 (s, 3 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.46 (s, 2
H), 6.91 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 20.5, 24.5, 25.4, 30.4, 31.0, 53.0,
54.2, 64.3.
Ethyl (R)-4-Hydroxy-8-(4-methoxybenzyloxy)octanoate (18)
To a soln of 6-(4-methoxybenzyloxy)hexanal (6; 2.0 g, 8.57 mmol)
and nitrosobenzene (0.92 g, 8.57 mmol) in anhyd DMSO (18 mL)
13C NMR (50 MHz, CDCl3): d = 14.0, 22.7, 29.3, 30.7, 34.0, 55.1,
60.4, 62.0, 69.5, 72.4, 113.6, 129.1, 130.4, 159.0, 172.8.
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

PAPER
Synthesis of (R)-Coniine and (S)-Coinicine via Organocatalytic a-Aminoxylation
3111
ESI-MS: m/z = 372.3995 [M + Na+], 388.1639 [M + K+].
uct (PE–EtOAc, 4:6) gave diol 22 as an oily liquid; yield: 0.053 g
(78%).
Anal. Calcd for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03. Found: C,
61.65; H, 7.63; N, 12.17.
[a]D25 –1.96 (c 0.8, CHCl3).
IR (CHCl3): 3310, 3081, 2850, 1740, 1216, 1035 cm–1.
Ethyl (S)-4-(tert-Butoxycarbonylamino)-8-(4-methoxybenzyl-
oxy)octanoate (20)
1H NMR (200 MHz, CDCl3): d = 1.20–1.31 (m, 4 H), 1.42 (s, 9 H),
1.50–1.58 (m, 6 H), 2.74 (br s, 2 H), 3.58–3.63 (m, 4 H), 4.52–4.56
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.0, 28.4, 28.8, 29.6, 32.0, 32.4,
35.3, 40.8, 50.2, 62.4, 155.8.
To a soln of azide 19 (0.14 g, 0.40 mmol) in EtOAc (2 mL) was add-
ed 10% Pd/C (cat.) and (Boc)2O (0.101 mL, 0.44 mmol). The result-
ing solution was stirred under H2 atmosphere at r.t. for 12 h until
disappearance of the azide (as monitored by TLC). The mixture was
filtered through a Celite® pad to remove the catalyst and the filtrate
was concentrated under reduced pressure. Silica gel column chro-
matography of the crude product (PE–EtOAc, 8:2) gave Boc-pro-
tected amine 20 as a colorless liquid; yield: 0.154 g (91%).
ESI-MS: m/z = 284.368 [M + Na+].
Anal. Calcd for C13H27NO4: C, 59.74; H, 10.41; N, 5.36. Found: C,
59.87; H, 10.32; N, 5.48.
[a]D25 –1.37 (c 1.6, CHCl3).
IR (CHCl3): 2978, 1743, 1716, 1612, 1514, 1247, 1097 cm–1.
(S)-Octahydroindolizine [(S)-Coinicine, 2]
To an ice-cold, stirred soln of diol 22 (0.5 g, 1.91 mmol) and Et3N
(1.06 mL, 7.65 mmol) in anhyd CH2Cl2 (7 mL) was added dropwise
MsCl (0.36 mL, 4.6 mmol) over 15 min. The resulting mixture was
allowed to warm to r.t. and was stirred for 2 h. After dilution with
CH2Cl2 (25 mL), the solution was washed with H2O (3 × 15 mL)
and brine, dried (Na2SO4) and concentrated to give the crude di-
mesylated product as an oily liquid.
1H NMR (200 MHz, CDCl3): d = 1.29 (t, J = 7.6 Hz, 3 H), 1.47 (s,
9 H), 1.49–1.52 (m, 2 H), 1.58–1.69 (m, 4 H), 1.81–1.95 (m, 2 H),
2.39 (t, J = 7.6 Hz, 2 H), 3.43–3.49 (m, 2 H), 3.55–3.60 (m, 1 H),
3.84 (s, 3 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.45 (s, 2 H), 6.91 (d, J = 9.0
Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 22.4, 28.2, 29.4, 30.3, 30.9,
35.4, 50.2, 55.0, 60.2, 69.6, 72.3, 78.8, 113.6, 129.1, 130.5, 155.6,
158.9, 173.5.
To the crude dimesylated product (0.10 g, 0.24 mmol) in anhyd
CH2Cl2 (2 mL) was added methanolic HCl (2 mL) in a catalytic
amount. The mixture was stirred at r.t. for 2 h and was then concen-
trated on a rotatory evaporator to remove CH2Cl2 and MeOH. To
this crude reaction mixture was then added DMF (2 mL) and NaH
(60% dispersion in oil, 0.04 g) at 0 °C and the mixture was stirred
overnight. On completion of the reaction, it was quenched by the
addition of ice pieces, and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed with H2O
(2 × 15 mL) and brine, then dried (Na2SO4). Silica gel column chro-
matography (MeOH–CH2Cl2, 1:10) furnished (S)-octahydroin-
dolizine (2) as a solid compound; yield: 0.02 g (67%). The physical
and spectroscopic data of 2 were in full agreement with the litera-
ture data.4q
ESI-MS: m/z = 446.335 [M + Na+].
Anal. Calcd for C23H37NO6: C, 65.22; H, 8.81; N, 3.31. Found: C,
65.29; H, 8.69; N, 3.24.
tert-Butyl (S)-1-Hydroxy-8-(4-methoxybenzyloxy)octan-4-yl-
carbamate (21)
To a soln of ester 20 (1.0 g, 2.36 mmol) in CH2Cl2 (10 mL) was add-
ed 2.27 M DIBAL-H in toluene (2.52 mL, 5.72 mmol) at 0 °C under
argon atmosphere. The mixture was stirred at this temperature for 1
h, then sat. aq tartaric acid (4 mL) was added. The resulting mixture
was stirred for 15 min and the organic layer was separated. The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure to give crude product which, on silica gel col-
umn chromatography (PE–EtOAc, 8:2), gave alcohol 21 as a
colorless liquid; yield: 0.783 g (87%).
Acknowledgment
N.B.K. thanks CSIR, New Delhi for the award of a research fel-
lowship. Financial support in the form of a research grant (Grant
No. SR/S1/OC-40/2003) from DST, New Delhi is gratefully
acknowledged.
[a]D25 –0.99 (c 1.8, CHCl3).
IR (CHCl3): 3308, 2922, 1741, 1685, 1554, 1453, 1216 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.29–1.40 (m, 4 H), 1.47 (s, 9 H),
1.54–1.66 (m, 8 H), 3.46 (t, J = 6.3 Hz, 2 H), 3.59–3.71 (m, 3 H),
3.84 (s, 3 H), 4.45 (s, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.30 (d, J = 8.6
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 22.5, 28.3, 28.8, 29.5, 32.0, 35.3,
50.3, 55.2, 62.5, 69.8, 72.4, 79.0, 113.7, 129.2, 130.6, 155.9, 159.0.
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Anal. Calcd for C21H35NO5: C, 66.11; H, 9.25; N, 3.67. Found: C,
66.25; H, 9.14; N, 3.81.
tert-Butyl (S)-1,8-Dihydroxyoctan-4-ylcarbamate (22)
To a soln of alcohol 21 (0.1 g, 0.262 mmol) in CH2Cl2 (9.5 mL) and
H2O (0.5 mL) was added DDQ (0.065 g, 0.288 mmol), and the mix-
ture was stirred at r.t. for 30 min. After completion of the reaction
(monitored by TLC), the mixture was extracted with EtOAc (3 × 20
mL). The combined organic fractions were washed with sat.
NaHCO3 soln (25 mL) followed by brine, then dried (Na2SO4) and
concentrated. Silica gel column chromatography of the crude prod-
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York

3112
N. B. Kondekar, P. Kumar
PAPER
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(12) The enantiomeric excess (95% ee) was calculated using
Mosher analysis by converting alcohol 8 into the
monobenzylated alcohol 23 (Figure 2) and then derivatizing
alcohol 23 as its Mosher ester.
OH
OBn
PMBO
23
Figure 2
(13) The enantiomeric excess of 18 (95% ee) was calculated
using Mosher analysis by derivatizing alcohol 18 as its
Mosher ester.
Synthesis 2010, No. 18, 3105–3112 © Thieme Stuttgart · New York