Enantioselective synthesis of (+)-sedamine and (-)-allosedamine

Article abstract of DOI:10.1055/s-2006-950331

Two different approaches to the enantioselective syntheses of (+)-sedamine and (-)-allosedamine are described, both using the Sharpless asymmetric epoxidation as the key step. Regioselective reduction of epoxides, chemoselective oxidation of alcohols, ring-closing metathesis, and nucleophilic displacements were the other key steps employed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950331

PAPER
4005
Enantioselective Synthesis of (+)-Sedamine and (–)-Allosedamine
E
J
nantiosel
.
e
ctive Synth
S
e
sis of (+)-Sed
.
a
mine and
(
Y
–)-Allosedamine adav,* M. Sridhar Reddy, P. Purushothama Rao, A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 7 July 2006; revised 20 July 2006
protected as a MOM ether 7 after reaction with chlo-
ro(methoxy)methane, N,N-diisopropylethylamine, and 4-
Abstract: Two different approaches to the enantioselective synthe-
ses of (+)-sedamine and (–)-allosedamine are described, both using
the Sharpless asymmetric epoxidation as the key step. Regioselec-
tive reduction of epoxides, chemoselective oxidation of alcohols,
(
N,N-dimethylamino)pyridine. Deprotection of the piv-
aloyl ester group was achieved with potassium carbonate
ring-closing metathesis, and nucleophilic displacements were the in methanol, resulting in primary alcohol 8, whose oxida-
other key steps employed.
tion under Swern conditions followed by the addition of
Key words: alkaloids, asymmetric synthesis, regioselective reduc- allylmagnesium bromide to the crude aldehyde in diethyl
tion, ring-closing metathesis
ether produced alcohol 9 as an inseparable 1:1 diastereo-
meric mixture. Alcohol 9 was treated with mesyl chloride,
triethylamine, and 4-(N,N-dimethylamino)pyridine to
Piperidine alkaloids make up a large family of com- yield the corresponding mesylate, which, without purifi-
pounds. Many of them exhibit a wide range of physiolog- cation, was subjected to nucleophilic substitution with so-
ical activities. Much activity has been devoted to the dium azide in N,N-dimethylformamide at 50 °C to furnish
azide 10, again as an inseparable diastereomeric mixture.
isolation and structure determination of such bases and to
the development of general methodologies and routes for
Chromatographically separable diastereomers 11 and 12
formed upon reduction of azide 10 with triphenylphos-
phine (TPP) in methanol followed by in situ protection of
1
their synthesis. (+)-Sedamine (1) (Figure 1) and its enan-
tiomer were the first alkaloids isolated from Sedum acre2
and were obtained later from a number of other Sedum
the resulting amine by the addition of Boc O to the mix-
2
3
species. (–)-Allosedamine (2) (Figure 1) was isolated
ture (Scheme 1). The stereochemistry of these diastereo-
mers was determined by converting them into the known
final targets. Diastereomer 11, the faster-running isomer
on TLC, was allylated with allyl bromide and sodium hy-
dride in N,N-dimethylformamide at 50 °C to give Grubbs’
ring-closing metathesis (RCM) precursor 13, which, on
exposure to the Grubbs-I catalyst in benzene at 50 °C,
gave cyclised product 14. Reduction of the olefinic bond
with platinum(IV) oxide under a hydrogen atmosphere
gave 15 which, on reduction of the Boc group with lithium
aluminum hydride in refluxing tetrahydrofuran resulted in
N-methylpiperidine derivative 16. Deprotection of the
MOM ether in 16 by use of concentrated hydrochloric
acid in acetonitrile and water gave (–)-allosedamine (2)
4
from Lobelia inflata, which furnished a crude extract
useful for the treatment of respiratory illnesses such as
5
asthma, bronchitis, and pneumonia. These alkaloids have
been the subject of much synthetic activity since their iso-
6
–9
lation.
OH
OH
N
N
Me
Me
(
+)-sedamine 1
(–)-allosedamine 2
Figure 1
(
in good agreement with the reported data).
Our own interest in the synthesis of enantiopure bioac-
tives prompted us to explore the possibility of synthesis-
ing (+)-sedamine (1) and (–)-allosedamine (2). This effort
has resulted in two different approaches for each target.
The other diastereomer 12, the slower-running isomer on
TLC, was converted into (+)-sedamine 1 via allylated
product 17, RCM product 18, and reduced products 19
and 20 under the same conditions as those described for
the conversion of 11 into 2 (Scheme 1). The analytical
data of compound 1 were in good agreement with the re-
ported data.
Our synthetic programme commenced from cinnamyl al-
cohol (3) (Scheme 1). Sharpless asymmetric epoxidation
of 3 by (+)-diethyl-D-tartrate, tert-butyl hydroperoxide,
and titanium(IV) isopropoxide at –30 °C gave epoxy alco-
hol 4, which was regioselectively reduced by Red-Al to
yield 1,3-diol 5. Protection of the primary hydroxy group
as a pivaloyl ester was achieved in the presence of piv-
aloyl chloride and pyridine at 0 °C, to give 6, which was
Having succeeded in a combined approach for the synthe-
sis of the target molecules, we explored the possibilities
for the alternative and specific approaches that are also
useful for the other diastereomers and structurally closely
related piperidine alkaloids.
Our alternative approach is outlined in Scheme 2. We
started with the chiral substrate 8, whose synthesis was al-
ready described in Scheme 1. Oxidation of alcohol 8 un-
SYNTHESIS 2006, No. 23, pp 4005–4012
x
x.
x
x
.
2
0
0
6
Advanced online publication: 20.10.2006
DOI: 10.1055/s-2006-950331; Art ID: Z14206SS
Georg Thieme Verlag Stuttgart · New York
©

4
006
J. S. Yadav et al.
PAPER
OR2
OMOM
O
i
ii
v
Ph
OH
OH
Ph
OR1
R = H, R = H
Ph
OH
Ph
4
3
8
1
2
5
6
7
iii
1
2
R = Piv, R = H
iv
1
2
MOMO
NHBoc
R = Piv, R = MOM
Ph
MOMO
Ph
OH
MOMO
Ph
N3
11
+
NHBoc
vi
vii
viii
MOMO
Ph
9
10
1
2
Boc
MOMO
Boc
MOMO
R3
N
N
MOMO
N
xiii
xiii
ix
ix
x
xi
1
1
2
Ph
Ph
Ph
xii
1
4
1
3
5 R3 = Boc
3
1
1
R3
6 R = Me
Boc
Boc
xi
MOMO
Ph
N
MOMO
N
MOMO
N
x
1
12
Ph
Ph
1
8
1
7
1
9 R3 = Boc
xii
3
2
0 R = Me
Scheme 1 Reagents and conditions: (i) (+)-DET, Ti(Oi-Pr) , t-BuOOH, –30 °C, 6 h, 84%; (ii) Red-Al, THF, 0 °C, 2 h, 88%; (iii) PvCl, py,
4
CH Cl , 0 °C to r.t., 90%; (iv) MOMCl, DIPEA, DMAP, CH Cl , 0 °C to r.t., 4 h, 98%; (v) K CO , MeOH, r.t., 2 h, 92%; (vi) (COCl) , DMSO,
2
2
2
2
2
3
2
DIPEA, CH Cl , –78 °C, then H C=CHCH MgBr, Et O, 0 °C, 74%; (vii) MsCl, Et N, DMAP, CH Cl , 0 °C, 1 h, then NaN , DMF, 60 °C, 6 h,
2
2
2
2
2
3
2
2
3
8
4% (2 steps); (viii) TPP, MeOH, H O, then (Boc) O, r.t., 86%; (ix) NaH, H C=CHCH Br, DMF, 50 °C, 12 h, 88%; (x) Grubbs-I catalyst, ben-
2 2 2 2
zene, 50 °C, 2 h, 90–92%; (xi) PtO , H , EtOAc, 1 atm, r.t., 2 h, 90–92%; (xii) LiAlH , THF, reflux, 6 h, 80–82%; (xiii) concd HCl, MeCN,
2
2
4
H O, r.t., 3 h, 88–92%.
2
der Swern conditions followed by in situ C2 Wittig Thus, we have reported two divergent approaches for the
olefination resulted in the formation of a,b-unsaturated synthesis of each of (+)-sedamine (1) and (–)-allo-
ester 21. Controlled reduction of compound 21 with di- sedamine (2) from the same starting material, cinnamyl
isobutylaluminum hydride in dichloromethane yielded alcohol (3). Both approaches generate the required stereo-
allyl alcohol 22, which, on Sharpless asymmetric epoxi- genic centres from Sharpless asymmetric epoxidation as
dation using (–)-diethyl-D-tartrate gave epoxy alcohol 23. the sole chiral source. The approaches are practically ap-
Regioselective reduction of epoxide 23 by Red-Al afford- plicable in the synthesis of other diastereomers and struc-
ed 1,3-diol 24. One-pot chemoselective oxidation and C2 turally closely related analogues when appropriate
elongation was carried out by reaction with TEMPO, starting materials and reagents are chosen for Sharpless
(diacetoxyiodo)benzene, and then the stable ylide (ethoxy- asymmetric epoxidation.
carbonylmethylene)triphenylphosphorane in dichloro-
1
0
methane to produce conjugated ester 25. Reduction of
ester 25 with lithium aluminum hydride yielded saturated
Commercial reagents were used without further purification. All
solvents were purified by standard techniques. Infrared (IR) spectra
diol 26, which, on dimesylation using mesyl chloride, tri- were recorded on a Perkin-Elmer 683 spectrometer. Optical rota-
ethylamine, and 4-(N,N-dimethylamino)pyridine in tions were obtained on a Jasco Dip 360 digital polarimeter. Melting
points are uncorrected. NMR spectra were recorded in CDCl as
dichloromethane followed by treatment of the corre-
sponding dimesylate with 40% methylamine in water and
N,N-dimethylformamide resulted in N-methylpiperidine
derivative 20 after sequential intermolecular and intramo-
lecular nucleophilic displacements.11 Hydrogen chloride
3
solvent on Varian Gemini 200, Bruker 300, or Varian Unity 400
NMR spectrometers. Chemical shifts (d) are quoted in ppm and are
referenced to TMS as internal standard. Coupling constants (J) are
quoted in Hz. Column chromatographic separations were carried
out on silica gel (60–120 mesh) and flash chromatographic separa-
mediated deprotection of the MOM ether furnished (+)- tions were carried out using 230–400 mesh size silica gel. Mass
sedamine (1) (Scheme 2).
spectra were obtained on a Finnegan MAT 1020B or a micro mass
VG 70-70H spectrometer operating at 70 eV and using a direct inlet
system.
In an alternative route (Scheme 2), Sharpless asymmetric
epoxidation of allyl alcohol 22 by (+)-diethyl-L-tartrate
resulted in the formation of epoxy alcohol 27, which was [(2R,3R)-3-Phenyloxiran-2-yl]methanol (4)
converted into (–)-allosedamine (2) via 1,3-diol 28, Wittig A mixture of Ti(Oi-Pr) (2.75 g, 9.68 mmol), (+)-DET (2.30 g,
1.16 mmol), and activated powdered 4-Å MS (5 g) was stirred in
anhyd CH Cl (200 mL) at –30 °C for 30 min. Cinnamyl alcohol 3
4
1
product 29, 1,5-diol 30, and piperidine derivative 16 by
use of the same reagents and conditions as those described
for the conversion of 23 into 1.
2
2
(
10.0 g, 74.62 mmol) in CH Cl (20 mL) was added at –30 °C, and
2 2
the resulting mixture was stirred at –30 °C for 30 min. The mixture
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (+)-Sedamine and (–)-Allosedamine
4007
OMOM
O
OMOM
OMOM
i
ii
iii
Ph
OEt
Ph
OH
Ph
Ph
OH
8
21
22
MOMO
Ph
OH
O
OMOM
MOMO
Ph
OH
O
iv
v
OEt
OH
OH
Me
2
5
2
4
2
3
MOMO
Ph
OH
( )3
MOMO
Ph
N
viii
vi
vii
iv
1
OH
26
20
OMOM
MOMO
Ph
OH
O
MOMO
Ph
OH
O
ix
v
22
OEt
Ph
OH
OH
OH
27
28
Me
29
MOMO
Ph
OH
( )3
MOMO
Ph
vii
N
viii
vi
2
3
0
16
Scheme 2 Reagents and conditions: (i) (COCl) , DMSO, CH Cl , –78 °C, Et N, then Ph PCHCO Et, 82% (2 steps); (ii) DIBAL-H, CH Cl ,
2
2
2
3
3
2
2
2
0
°C to r.t., 1 h, 88%; (iii) (–)-DET, Ti(Oi-Pr) , t-BuOOH, CH Cl , –30 °C, 6 h, 82%; (iv) Red-Al, THF, 0 °C to r.t., 2 h, 84–86%; (v) TEMPO,
4 2 2
Ph[I(OAc) ], CH Cl , then Ph PCHCO Et, 0 °C to r.t., 3 h, 61–65%; (vi) LiAlH , THF, 0 °C to r.t., 4 h, 90–92%; (vii) (a) Et N, MsCl, DMAP,
2
2
2
3
2
4
3
CH Cl , 0 °C to r.t., 1 h, (b) 40% MeNH in H O, DMF, 50 °C, 12 h, 76–78% (two steps); (viii) concd HCl, MeCN, H O, 3 h, 90%; (ix) (+)-
2
2
2
2
2
DET, Ti(Oi-Pr) , t-BuOOH, –30 °C, 6 h, 84%.
4
–
1
was treated with 3.0 M t-BuOOH in toluene (62.5 mL) and stirred
IR (neat): 3356, 2943, 1050, 700 cm .
for 4 h at –30 °C. It was then allowed to warm to 0 °C and poured
1
H NMR (200 MHz, CDCl ): d = 7.38–7.09 (m, 5 H), 4.86 (dd,
3
into a freshly prepared and cooled (0 °C) soln of FeSO (12 g) and
4
J = 7.8, 4.3 Hz, 1 H), 3.77 (t, J = 6.0 Hz, 2 H), 3.44–3.31 (br s, 1 H),
3
tartaric acid (3.5 g) in deionised H O (20 mL). The two-phase mix-
2
.11–2.88 (br s, 1 H), 1.99–1.74 (m, 2 H).
ture was stirred for 25–30 min, and the aqueous phase was separated
1
3
C NMR (75 MHz, CDCl ): d = 141.2, 128.2, 126.5, 125.5, 73.1,
and extracted with Et O (2 × 100 mL). The combined organic phas-
3
2
5
9.7, 40.1.
es were treated with a precooled (0 °C) 30% (w/v) soln of NaOH in
sat. brine (5 mL). The two-phase mixture was then stirred for 1 h at
+
LSIMS: m/z = 175.1 [M + Na].
r.t. and the aqueous layer was separated and treated with Et O (2 ×
2
5
0 mL). The combined organic extracts were dried (Na SO ) and
(3R)-3-Hydroxy-3-phenylpropyl Pivalate (6)
2
4
concentrated under reduced pressure. Purification of the resulting
crude product by flash column chromatography (silica gel, EtOAc–
hexanes, 1:4) afforded 4 as a liquid.
PvCl (4.4 mL, 35.9 mmol) was added very slowly at 0 °C to diol 5
(5.2 g, 34.2 mmol) and Et N (14.2 mL, 101.9 mmol) in CH Cl (70
3
2
2
mL). The mixture was allowed to warm to r.t. and stirred for 4 h. Af-
2
0
ter completion of the reaction, H O (100 mL) was added to the mix-
Yield: 9.4 g (84%); R = 0.5 (EtOAc–hexanes, 40:60); [a] –50.2
2
f
D
ture, and the organic layer was separated and washed with H O (2 ×
(
c 1.0, EtOH).
2
5
0 mL) and brine (2 × 50 mL). The organic layer was dried
–
1
IR (neat): 3580, 3450, 2980, 1600, 1450, 1380 cm .
(Na SO ), concentrated, and purified by column chromatography
2
4
1
H NMR (200 MHz, CDCl ): d = 2.20 (br s, 1 H), 3.25–3.33 (m, 1
H), 3.81 (dd, J = 5.1 Hz, 1 H), 3.95 (d, J = 3.0 Hz, 1 H), 4.18 (dd,
J = 3.1 Hz, 1 H), 7.20–7.50 (m, 5 H).
(silica gel, EtOAc–hexanes, 1:9).
3
Yield: 7.2 g (90%); colourless oil; R = 0.6 (EtOAc–hexanes,
f
20
2
0:80); [a]D +6.62 (c 1. 0, CHCl3).
1
3
C NMR (75 MHz, CDCl ): d = 136.5, 128.3, 128.1, 125.5, 62.5,
IR (neat): 3446, 2969, 1726, 1161, 700 cm–1.
3
6
1.4, 55.7.
1
H NMR (300 MHz, CDCl ): d = 7.31–7.27 (m, 5 H), 4.72 (dd, J =
3
+
HRMS (EI): m/z calcd for C H O [M ]: 150.0681; found:
9
10
2
7.5, 5.2 Hz, 1 H), 4.37–4.28 (m, 1 H), 4.12–4.04 (m, 1 H), 2.28–2.11
1
50.0687.
(br s, 1 H) 2.07–1.94 (m, 2 H), 1.20 (s, 9 H).
1
3
C NMR (75 MHz, CDCl ): d = 178.6, 143.8, 128.4, 127.5, 125.6,
(
1R)-1-Phenylpropane-1,3-diol (5)
3
7
1.2, 61.4, 38.6, 38.0, 27.0.
A 70 wt% mixture of Red-Al in toluene (24.7 mL, 122.2 mmol) was
added dropwise to a cold (0 °C) soln of epoxide 4 (9.2 g, 61.3
mmol) in THF (200 mL). After 4 h at 0 °C, the mixture was
quenched carefully by dropwise addition of sat. aq sodium potassi-
um tartrate (Rochelle’s salt). EtOAc (200 mL) was added and the
mixture was allowed to warm to r.t. The organic layer was washed
with brine (2 × 50 mL) and the combined aqueous layers were ex-
tracted several times with EtOAc (2 × 100 mL). The combined ex-
tracts were dried (Na SO ), filtered, and concentrated under reduced
+
LSIMS: m/z = 259.1 [M + Na].
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 259.1310; found:
2
1
4
20
3
59.1313.
(
3R)-3-(Methoxymethoxy)-3-phenylpropyl Pivalate (7)
To alcohol 6 (5.6 g, 23.7 mmol) in anhyd CH Cl (50 mL) at 0 °C,
2
2
DMAP, DIPEA (12.4 mL, 71.1 mmol), and MOMCl (3.5 mL, 47.3
mmol) were added successively, and the mixture was stirred for 4 h
at r.t. After completion of the reaction, the mixture was quenched
by addition of H O and extracted with CH Cl (2 × 100 mL). The
organic extracts were washed with brine (2 × 50 mL), dried
(Na SO ), and concentrated under vacuum to remove the solvent,
2
4
pressure. The residue was purified by chromatography (silica gel,
EtOAc–hexanes, 1:2).
2
2
2
Yield: 8.2 g (88%); colourless oil; R = 0.4 (EtOAc–hexanes,
6
f
2
0
0:40); [a]D +34.8 (c 1.5, MeOH).
2
4
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

4
008
J. S. Yadav et al.
PAPER
–
1
and the crude product was purified by column chromatography (sil-
IR (neat): 3446, 2925, 1639, 760 cm .
ica gel, EtOAc–hexanes, 1:19) to afford pure product 7.
1
H NMR (300 MHz, CDCl ): d = 7.37–7.17 (m, 5 H), 5.88–5.70 (m,
3
Yield: 6.52 g (98%); colourless oil; R = 0.7 (silica gel, EtOAc–hex-
1 H), 5.11–5.00 (m, 2 H), 4.87 (dd, J = 9.8, 3.7 Hz, 0.5 H), 4.80 (dd,
J = 9.8, 5.2 Hz, 0.5 H), 4.51 (d, J = 6.7 Hz, 0.5 H), 4.48 (d, J = 6.7
Hz, 0.5 H), 4.46 (s, 1 H), 4.30–4.28 (m, 0.5 H), 3.99–3.87 (m, 1 H),
f
20
anes, 20:80); [a]D +95.4 (c 1.75, CHCl3).
–
1
IR (neat): 2963, 1730, 1156, 701 cm .
3
.84–3.73 (m, 0.5 H), 3.38 (s, 3 H), 3.14–3.11 (br s, 0.5 H), 2.30–
2.29 (br s, 0.5 H), 2.26–2.16 (m, 2 H), 1.96–1.85 (m, 1 H), 1.80–
.65 (m, 1 H).
1
H NMR (300 MHz, CDCl ): d = 7.37–7.21 (m, 5 H), 4.72 (dd,
3
J = 7.5, 5.2 Hz, 1 H), 4.46 (d, J = 6.7, 1 H), 4.45 (d, J = 6.7 Hz, 1
1
H), 4.36–4.28 (m, 1 H), 4.13–4.04 (m, 1 H), 3.32 (s, 3 H), 2.05–1.97
+
LSIMS: m/z = 259.1 [M + Na].
(
m, 2 H), 1.20 (s, 9 H).
1
3
C NMR (75 MHz, CDCl ): d = 178.3, 141.3, 128.5, 127.8, 126.7,
[(1S)-3-Azido-1-(methoxymethoxy)hex-5-en-1-yl]benzene (10)
MsCl (870 mg, 7.63 mmol) was added dropwise to a soln of com-
3
9
4.1, 74.6, 61.0, 55.5, 38.6, 37.0, 27.1.
+
pound 9 (1.20 g, 5.08 mmol), DMAP (90 mg, 0.73 mmol), and Et N
LSIMS: m/z = 303.1 [M + Na].
3
(
2.12 mL, 15.24 mmol) in CH Cl (12 mL) at 0 °C. After 0.5 h at
2 2
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 303.1572; found:
1
6
24
4
0
°C and 0.5 h at r.t., the mixture was diluted with CH Cl (20 mL)
2 2
3
03.1572.
and washed with H O (2 × 10 mL) and brine (2 × 10 mL). The or-
2
ganic phase was dried (Na SO ) and concentrated under reduced
2
4
(
3R)-3-(Methoxymethoxy)-3-phenylpropan-1-ol (8)
Pivalate 7 (7.2 g, 25.7 mmol) was dissolved in MeOH (60 ml),
K CO (3.5 g, 25.7 mmol) was added at r.t., and the mixture was
stirred for 2 h. Then the MeOH was removed under reduced pres-
sure and H O (100 mL) was added. The mixture was extracted with
CH Cl (2 × 100 mL) and the combined organic layers were dried
Na SO ) and the solvent was removed under reduced pressure. The
pressure. The mesylate was used in the next step without purifica-
tion.
2
3
A mixture of the above mesylate and NaN (1.65 g, 25.38 mmol) in
3
DMF (15 mL) was heated at 50 °C for 16 h. The mixture was cooled
2
to r.t. and diluted with Et O (30 mL) and washed with H O (2 × 10
2
2
2
2
mL) and brine (2 × 10 mL). The organic phase was concentrated un-
der reduced pressure and the crude was purified by column chroma-
tography (silica gel, EtOAc–hexanes, 1:19).
(
2 4
crude was purified by column chromatography (silica gel, EtOAc–
hexanes, 1:4).
Yield: 1.10 g (84%); colourless oil; R = 0.5 (silica gel, EtOAc–hex-
anes, 10:90).
Yield: 4.63 g (92%); colourless liquid; R = 0.4 (silica gel, EtOAc–
hexanes, 40:60); [a]D +179.5 (c 1.0, CHCl3).
f
f
20
–
1
–
1
IR (neat): 2946, 2102, 1027, 701 cm .
IR (neat): 3426, 2926, 1029, 701 cm .
1
1
H NMR (200 MHz, CDCl ): d = 7.39–7.13 (m, 5 H), 5.95–5.62 (m,
H NMR (200 MHz, CDCl ): d = 7.33–7.22 (m, 5 H), 4.80 (dd,
3
3
1
1
H), 5.25–5.05 (m, 2 H), 4.82–4.64 (m, 1 H), 4.48 (s, 1 H), 4.45 (s,
H), 3.82–3.63 (m, 1 H), 3.36 (s, 1.5 H), 3.34 (s, 1.5 H), 3.26–3.11
J = 9.5, 4.3 Hz, 1 H), 4.49 (s, 2 H), 3.81–3.68 (m, 2 H), 3.38 (s, 3
H), 2.21–1.8 (br s, 1 H), 2.07–1.99 (m, 1 H), 1.93–1.83 (m, 1 H).
(m, 1 H), 2.42–2.25 (m, 2 H), 2.14–1.74 (m, 1.5 H), 1.66–1.50 (m,
1
3
C NMR (75 MHz, CDCl ): d = 141.5, 128.5, 127.7, 126.7, 94.2,
3
0
.5 H).
7
6.4, 59.9, 55.6, 40.4.
+
LSIMS: m/z = 262.1 [M + H].
+
LSIMS: m/z = 219.1 [M + Na].
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 219.0997; found:
tert-Butyl Carbamates 11 and 12
1
1
16
3
2
19.0990.
To a soln of 10 (800 mg, 3.06 mmol) in MeOH–H O (8:2, 10 mL)
2
was added TPP (1.12 g, 4.27 mmol), and the mixture was stirred at
(
1R)-1-(Methoxymethoxy)-1-phenylhex-5-en-3-ol (9)
r.t. for 4 h. Then Boc O (800 mg, 3.66 mmol) was added to the mix-
2
DMSO (1.79 g, 19.1 mmol) in CH Cl (4 mL) was added by cannula
ture, which was stirred for another 4 h. The MeOH was removed un-
2
2
to oxalyl chloride (1.92 g, 15.3 mmol) in CH Cl (30 mL) cooled to
der reduced pressure, and the mixture was diluted with H O (10 mL)
2
2
2
–
78 °C. The mixture was stirred at –78 °C for 1 h before a soln of
and extracted with Et O (2 × 20 mL). The combined extracts were
2
the alcohol 8 (1.5 g, 7.65 mmol) in CH Cl (4 mL) was added drop-
washed with brine (2 × 10 mL), dried (Na SO ), and concentrated
2
2
2
4
wise by cannula. The mixture was stirred for 30 min and then DI-
PEA (9.33 mL, 53.5 mmol) was added dropwise over 10 min. The
mixture was stirred at –78 °C for 15 min and then warmed to 0 °C.
It was stirred for 5 min at 0 °C and then quenched by the addition of
in vacuo. The crude residue was purified by column chromatogra-
phy (silica gel, EtOAc–hexanes, 1:10); this afforded 11 and 12 as
white solids.
0
.5 M NaHSO . The organic extracts were washed with H O (25
tert-Butyl {(1S)-1-[(2R)-2-(Methoxymethoxy)-2-phenyleth-
4
2
mL) and brine (2 × 30 mL), dried (Na SO ), and concentrated; this
yl]but-3-enyl}carbamate (11)
2
4
gave the crude aldehyde that was used in the next reaction without
purification.
Yield: 430 mg (43%); R
f
= 0.6 (EtOAc–hexanes, 20:80); mp 51–
2
0
53 °C; [a]
+98.9 (c = 1.0, CHCl ).
D
3
–
1
To the above aldehyde in anhyd Et O (15 mL) was added freshly
IR (neat): 3351, 1697, 1641, 1518, 700 cm .
2
prepared 2 M H C=CHCH MgBr in Et O (7.6 mL, 15.3 mmol)
1
2
2
2
H NMR (300 MHz, CDCl ): d = 7.31–7.19 (m, 5 H), 5.84–5.70 (m,
3
[
prepared from H C=CHCH Br (1.85 g, 15.30 mmol) and Mg (0.36
2 2
1
(
3
1
H), 5.09–5.04 (m, 2 H), 4.69 (dd, J = 10.5, 3.0 Hz, 1 H), 4.63–4.53
g, 15.30 mmol) in Et O (7.5 mL)] dropwise at 0 °C over 10 min. Af-
2
m, 1 H), 4.47 (d, J = 6.7 Hz, 1 H), 4.44 (d, J = 6.7 Hz, 1 H), 3.99–
.86 (m, 1 H), 3.32 (s, 3 H), 2.29 (t, J = 6.7 Hz, 2 H), 2.02–1.92 (m,
H), 1.61–1.52 (m, 1 H), 1.44 (s, 9 H).
ter stirring at r.t. for 0.5 h, the mixture was quenched with sat.
NH Cl soln. The organic layer was separated and washed with brine
4
(
2 × 20 mL). After removal of the solvent, the resulting crude prod-
1
3
C NMR (75 MHz, CDCl ): d = 155.5, 142.0, 134.5, 128.6, 127.8,
uct was purified by flash column chromatography (silica gel,
EtOAc–hexanes, 1:9).
3
1
26.7, 117.8, 94.5, 79.1, 74.9, 56.0, 47.6, 42.7, 40.1, 28.5.
+
MS–FAB: m/z = 336 [M + H].
Yield: 1.33 g (74%); colourless liquid; R = 0.4 (silica gel, EtOAc–
f
+
hexane, 20:80).
ESI-HRMS: m/z calcd for C H NO Na [M + Na]: 358.1994;
19 29 4
found: 358.2010.
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (+)-Sedamine and (–)-Allosedamine
4009
tert-Butyl {(1R)-1-[(2R)-2-(Methoxymethoxy)-2-phenyleth-
yl]but-3-enyl}carbamate (12)
trated in vacuo. The crude residue was purified by column
chromatography (silica gel, EtOAc–hexanes, 1:9).
Yield: 430 mg (43%); R = 0.52 (EtOAc–hexanes, 20:80); mp 62–
f
Yield: 270 mg (90%); colourless oil; R = 0.55 (silica gel, EtOAc–
hexanes, 20:80); [a]D +72.9 (c 0.5, CHCl3).
IR (neat): 2930, 1690, 1160, 701 cm–1.
20
f
6
4 °C; [a]D +120.5 (c = 1.0, CHCl3).
20
–
1
IR (neat): 3366, 1683, 1515, 700 cm .
1
H NMR (300 MHz, CDCl ): d = 7.35–7.21 (m, 5 H), 5.80–5.64 (m,
1
3
H NMR (300 MHz, CDCl ): d = 7.32–7.19 (m, 5 H), 4.56–4.37 (m,
3
1
3
1
H), 5.07–5.03 (m, 2 H), 4.68–4.55 (m, 2 H), 4.44 (s, 2 H), 3.71–
.66 (m, 1 H), 3.34 (s, 3 H), 2.38–2.26 (m, 2 H), 2.02–1.89 (m, 1 H),
.78–1.70 (m, 1 H), 1.43 (s, 9 H).
4
1
H), 3.99–3.84 (m, 1 H), 3.25 (s, 3 H), 2.74–2.62 (m, 1 H), 1.93–
.87 (m, 2 H), 1.61–1.44 (m, 6 H), 1.43 (s, 9 H).
1
3
C NMR (75 MHz, CDCl ): d = 155.0, 142.4, 128.3, 127.5, 126.6,
1
3
3
C NMR (75 MHz, CDCl ): d = 155.2, 141.3, 134.0, 128.4, 127.7,
3
9
5.1, 79.1, 75.6, 55.6, 48.1, 39.0, 38.4, 28.8, 28.3, 25.5, 19.0.
1
26.8, 117.8, 93.9, 78.9, 75.7, 55.7, 47.8, 42.2, 39.1, 28.3.
+
LSIMS: m/z = 272.2 [M + Na].
+
ESI-HRMS: m/z calcd for C H NO Na [M + Na]: 358.1994;
1
9
29
4
+
ESI-HRMS: m/z calcd for C H NO Na [M + Na] 372.2150;
found: 358.2003.
20 31
4
found: 372.2165.
tert-Butyl Allyl{(1S)-1-[(2R)-2-(methoxymethoxy)-2-phenyleth-
yl]but-3-enyl}carbamate (13)
(
2S)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]-1-methylpip-
eridine (16)
Compound 11 (400 mg, 1.19 mmol) in DMF (1 mL), followed by
H C=CHCH Br (215 mg, 1.77 mmol) were added dropwise at 0 °C
To a suspension of LiAlH (136 mg, 3.57 mmol) in anhyd THF (10
mL) was added dropwise a soln of 15 (250 mg, 0.71 mmol) in THF
4
2
2
to a suspension of 60% NaH (85 mg, 3.54 mmol) in DMF (7 mL).
The mixture was slowly warmed to 50 °C and stirred for 12 h at the
(2 mL). After 6 h under reflux, the mixture was quenched by addi-
tion of H O (0.2 mL), followed by the addition of a 15% aq NaOH
soln (0.2 mL) and H O (0.4 mL). The mixture was filtered through
Celite and the filtrate was dried (Na SO ) and concentrated in vac-
uo. The crude residue was purified by column chromatography (sil-
ica gel, MeOH–CH Cl , 1:20).
same temperature. It was then quenched with NH Cl soln at 0 °C
2
4
and extracted with Et O (2 × 10 mL). The combined extracts were
2
2
washed with brine (2 × 10 mL), dried (Na SO ), and concentrated
2
4
2
4
in vacuo. The crude residue was purified by column chromatogra-
phy (silica gel, EtOAc–hexanes, 1:19).
2
2
Yield: 150 mg (80%); colourless oil; R = 0.44 (silica gel, MeOH–
Yield: 390 mg (88%); colourless oil; R = 0.4 (EtOAc–hexanes,
f
f
2
0
2
0
CH Cl , 10:90); [a] +99.6 (c 1.0, MeOH).
1
0:90); [a]D +61.7 (c 1.0, CHCl3).
2 2 D
–
1
–
1
IR (neat): 2933, 1630, 1383, 1033, 702 cm .
IR (neat): 2976, 2929, 1692, 702 cm .
1
1
H NMR (300 MHz, CDCl ): d = 7.35–7.26 (m, 5 H), 4.66 (t, J = 6.7
H NMR (300 MHz, CDCl ): d = 7.30–7.16 (m, 5 H), 5.97–5.62 (m,
3
3
Hz, 1 H), 4.46 (d, J = 6.7 Hz, 1 H), 4.43 (d, J = 6.7 Hz, 1 H), 3.30
2
3
2
H), 5.10–4.94 (m, 4 H), 4.57–4.37 (m, 3 H), 3.95–3.78 (m, 1 H),
.72–3.42 (m, 2 H), 3.25 (s, 3 H), 2.38–2.13 (m, 2 H), 1.96–1.66 (m,
H), 1.45 (s, 9 H).
(
s, 3 H), 3.20–3.15 (m, 1 H), 2.66–2.58 (m, 5 H), 2.27–2.24 (m, 1
H), 2.11–1.56 (m, 6 H), 1.44–1.31 (m, 1 H).
1
3
1
3
C NMR (75 MHz, CDCl ): d = 141.1, 128.4, 127.3, 125.5, 68.7,
C NMR (75 MHz, CDCl ) (rotamers): d = 155.7, 142.4, 142.2,
3
3
6
2.0, 55.7, 40.7, 38.7, 27.6, 22.4, 21.3.
1
1
4
36.1, 135.6, 135.4, 135.1, 128.3, 128.2, 127.6, 127.5, 126.5, 126.4,
17.0, 116.8, 116.2, 115.9, 94.9, 94.6, 76.0, 75.4, 55.8, 52.5, 45.8,
1.8, 41.0, 38.5, 28.4, 28.2.
+
LSIMS: m/z = 264.1 [M + H].
+
ESI-HRMS: m/z calcd for C H NO [M + H] 264.1963; found:
1
6
26
2
+
MS–FAB: m/z = 376 [M + H].
2
64.1957.
tert-Butyl (2S)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]-
(
1R)-2-[(2S)-1-Methyl-2-piperidyl]-1-phenylethanol [(–)-Allo-
1
,2,3,6-tetrahydropyridine-1-carboxylate (14)
sedamine] (2)
To a soln of 13 (380 mg, 1.01 mmol) in anhyd benzene (50 mL) was
added over 10 min a soln of the Grubbs-I catalyst [benzylidene-
dichlorobis(tricyclohexylphosphine)ruthenium] (35 mg, 0.2 mmol)
in benzene (2 mL). The mixture was stirred for 2 h at 50 °C and was
then concentrated in vacuo. The crude residue was purified by col-
umn chromatography (silica gel, EtOAc–hexanes, 1:10).
A soln of piperidine 16 (100 mg, 0.38 mmol) in MeCN (5 mL) was
treated with concd HCl (0.04 mL). After being stirred at r.t. for 4 h,
the soln was diluted with an EtOAc–i-PrOH mixture (1:1, 10 mL)
and made basic with aq NaHCO soln until pH 9–10. The aqueous
3
layer was extracted with EtOAc (2 × 8 mL). The organic extracts
were dried (Na SO ), filtered and evaporated under reduced pres-
2
4
sure. The crude residue was purified by column chromatography
(silica gel, MeOH–CH Cl , 1:9).
Yield: 313 mg (90%); colourless oil; R = 0.6 (EtOAc–hexanes,
f
2
0
2
0:80); [a]D +49.8 (c 0.5, CHCl3).
2
2
–
1
Yield: 73 mg (88%); white solid; R = 0.5 (silica gel, MeOH–
f
IR (neat): 2933, 2780, 1383, 702 cm .
2
0
9b
CH Cl , 20:80); mp 78–80 °C; [a] –29.1 (c 0.9, MeOH) {Lit.
1
2
2
D
H NMR (200 MHz, CDCl ): d = 7.35–7.18 (m, 5 H), 5.75–5.45 (m,
H), 4.78–4.12 (m, 5 H), 3.44–3.29 (m, 1 H), 3.25 (s, 3 H), 2.55–
.27 (m, 1 H), 2.07–1.73 (m, 3 H), 1.43 (s, 9 H).
20
3
[
a]D –29.8 (c 0.2, MeOH)}.
2
2
–
1
IR (neat): 3358, 2936, 2864, 1448, 1052 cm .
1
1
3
H NMR (200 MHz, CDCl ): d = 7.40–7.11 (m, 5 H), 5.07 (dd,
C NMR (75 MHz, CDCl ): d = 154.8, 142.2, 128.4, 127.6, 126.9,
26.6, 123.5, 95.1, 79.5, 76.7, 55.7, 55.5, 40.0, 39.4, 28.4, 28.0.
3
3
J = 10.4, 3.4 Hz, 1 H), 3.27–3.17 (m, 1 H), 2.64 (s, 3 H), 2.56–2.42
1
(
m, 1 H), 2.18–2.05 (m, 1 H), 1.88–1.57 (m, 6 H), 1.33–1.20 (m, 2
+
LSIMS: m/z = 370.2 [M + Na].
H).
13C NMR (75 MHz, CDCl
62.5, 55.9, 39.9, 39.5, 27.9, 22.2, 21.7.
ESI-HRMS: m/z calcd for C H NO [M+H] : 220.1701; found:
): d = 143.8, 128.5, 127.5, 125.4, 69.5,
tert-Butyl (2S)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]pip-
eridine-1-carboxylate (15)
To a soln of 14 (300 mg, 0.86 mmol) in EtOAc (10 mL) was added
3
+
1
4
22
PtO (10 mg, 0.04 mmol). After stirring for 1 h under a H atmo-
2
2
220.1691.
sphere (1 atm), the mixture was filtered through Celite and concen-
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

4
010
J. S. Yadav et al.
PAPER
+
tert-Butyl Allyl{(1R)-1-[(2R)-2-(methoxymethoxy)-2-phenyleth-
yl]but-3-enyl}carbamate (17)
Compound 17 was prepared from 12 (400 mg, 1.19 mmol) follow-
ing the same procedure as that described for the synthesis of 13.
ESI-MS: m/z = 264 [M + H].
+
ESI-HRMS: m/z calcd for C H NO [M + H]: 264.1963; found:
1
6
26
2
2
64.1952.
Yield: 390 mg (88%); colourless oil; R = 0.35 (silica gel, EtOAc–
hexanes, 10:90); [a]D +74.88 (c 1.0, CHCl3).
(1R)-2-[(2R)-1-Methyl-2-piperidyl]-1-phenylethanol
[(+)-Sedamine] (1)
Compound 1 was prepared from 20 (100 mg, 0.38 mmol) following
the same procedure as that described for the synthesis of 2.
f
20
–
1
IR (neat): 2975, 1692,1172, 1027,702 cm .
1
H NMR (300 MHz, CDCl ): d = 7.39–7.17 (m, 5 H), 6.03–5.48 (m,
3
Yield: 76 mg (92%); white solid; R = 0.5 (silica gel, MeOH–
f
2
3
H), 5.23–4.89 (m, 4 H), 4.61–4.36 (m, 3 H), 4.13–3.48 (m, 3 H),
.32 (s, 3 H), 2.41–1.98 (m, 3 H), 1.96–1.71 (m, 1 H), 1.42 (s, 9 H).
2
0
CH Cl , 20:80); mp 57–58 °C; [a] –86.8 (c 1.0, EtOH).
2
2
D
–
1
IR (neat): 3357, 2932, 2855, 1451,1363, 1061, 756, 701 cm .
1H NMR (300 MHz, CDCl
): d = 7.20–7.42 (m, 5 H), 4.89 (dd,
J = 10.6, 2.6 Hz, 1 H), 4.70 (br s, 1 H), 3.1 (m, 1 H), 2.9 (m, 1 H),
.57 (m, 1 H), 2.51 (s, 3 H), 2.12 (m, 1 H), 1.20–1.81 (m, 7 H).
13C NMR (75 MHz, CDCl
): d = 144.7, 128.3, 127.2, 125.4, 73.4,
1.2, 52.4, 39.8, 39.3, 25.9, 22.2, 20.7.
1
3
C NMR (75 MHz, CDCl ) (rotamers): d = 155.4, 141.2, 136.0,
3
1
7
35.2, 135.1, 128.3, 127.8, 127.2, 126.6, 116.8, 115.8, 94.0, 75.7,
5.4, 55.5, 53.0, 46.8, 41.0, 40.7, 38.1, 37.5, 28.3, 28.2.
3
2
+
ESI-HRMS: m/z calcd for C H NO Na [M + Na]: 398.2307;
2
2
33
4
found: 398.2320.
3
6
tert-Butyl (2R)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]-
,2,3,6-tetrahydropyridine-1-carboxylate (18)
Compound 18 was prepared from 17 (380 mg, 1.01 mmol) follow-
ing the same procedure as that described for the synthesis of 14.
+
ESI-MS: m/z = 220 [M + 1].
1
+
ESI-HRMS: m/z calcd for C H NO [M + H]: 220.1701; found:
14 22
2
20.1738.
Yield: 320 mg (92%); colourless oil; R = 0.55 (silica gel, EtOAc–
hexane, 20:80); [a]D +102.8 (c 0.5, CHCl3).
f
Ethyl (2E,5R)-5-(Methoxymethoxy)-5-phenylpent-2-enoate (21)
20
Oxalyl chloride (5.4 g, 42.8 mmol) in CH Cl (60 mL) was cooled
2
2
–
1
IR (neat): 2930, 1696, 1031, 702 cm .
to –78 °C, and DMSO (5.03 g, 53.5 mmol) in CH Cl (10 mL) was
2 2
added by cannula. The mixture was stirred at –78 °C for 1 h before
1
H NMR (300 MHz, CDCl ): d = 7.35–7.21 (m, 5 H), 5.73–5.54 (m,
3
a soln of alcohol 8 (4.2 g, 21.42 mmol) in CH Cl (10 mL) was add-
2
2
2
3
1
H), 4.51–4.40 (m, 3 H), 4.38–4.06 (m, 2 H), 3.59–3.38 (m, 1 H),
.33 (s, 3 H), 2.44–2.28 (m, 1 H), 2.10–1.90 (m, 2 H), 1.87–1.62 (m,
H), 1.45 (s, 9 H).
ed dropwise by cannula. The mixture was stirred for 30 min, and
then Et N (20.8 mL, 150.0 mmol) was added dropwise over 10 min.
3
The mixture was stirred at –78 °C for 15 min and then warmed to
0 °C. It was stirred for 5 min at 0 °C and then quenched by the ad-
1
3
C NMR (75 MHz, CDCl ): d = 154.7, 141.8, 128.3, 127.7, 127.0,
3
1
26.6, 122.7, 94.1, 79.5, 75.6, 55.7, 55.5, 39.4, 38.2, 28.4, 28.0.
dition of H O (100 mL). The organic extracts were washed with
2
+
H O (2 × 50 mL) and brine (2 × 50 mL), dried, and concentrated.
ESI-HRMS: m/z calcd for C H NO Na [M + Na]: 370.1994;
found: 370.2003.
2
2
0
29
4
This gave the crude aldehyde, which was dissolved in dry benzene
(
100 mL). (Ethoxycarbonylmethylene)triphenylphosphorane (8.17
g, 23.50 mmol) was added to the soln, and the mixture was stirred
for 4 h at r.t. After removal of the solvent, the resulting crude prod-
uct was purified by flash column chromatography (silica gel,
EtOAc–hexanes, 1:10).
tert-Butyl (2R)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]pi-
peridine-1-carboxylate (19)
Compound 19 was prepared from 18 (300 mg, 0.86 mmol) follow-
ing the same procedure as that described for the synthesis of 15.
Yield: 4.6 g (82%); colourless liquid; R = 0.6 (silica gel, EtOAc–
hexane, 20:80); [a]D +94.2 (c 1.0, CHCl3).
Yield: 280 mg (92%); colourless oil; R = 0.5 (silica gel, EtOAc–
hexanes, 20:80); [a]D +129.9 (c 1.0, CHCl3).
f
f
2
0
20
–
1
–
1
IR (neat): 2938, 1719, 1033, 701 cm .
IR (neat): 2932, 1690, 1161, 701 cm .
1
1
H NMR (200 MHz, CDCl ): d = 7.35–7.18 (m, 5 H), 7.03–6.85 (m,
H NMR (300 MHz, CDCl ): d = 7.30–7.20 (m, 5 H), 4.49 (dd,
3
3
1
H), 5.83 (d, J = 15.6 Hz, 1 H), 4.68 (dd, J = 7.8, 4.6 Hz, 1 H), 4.47
J = 7.5, 6.0 Hz, 1 H), 4.43 (s, 2 H), 4.38–4.33 (m, 1 H), 3.96–3.92
(
s, 2 H), 4.14 (q, J = 7.0 Hz, 2 H), 3.33 (s, 3 H), 2.79–2.44 (m, 2 H),
(
m, 1 H), 3.32 (s, 3 H), 2.82–2.74 (m, 1 H), 2.14–2.01 (m, 1 H),
1
.28 (t, J = 7.0 Hz, 3 H).
1
.94–1.80 (m, 1 H), 1.67–1.49 (m, 4 H), 1.44–1.33 (m, 11 H).
1
3
1
3
C NMR (75 MHz, CDCl ): d = 166.2, 144.8, 140.9, 128.5, 127.9,
C NMR (75 MHz, CDCl ): d = 154.9, 141.8, 128.3, 127.7, 127.1,
3
3
1
26.7, 123.6, 94.1, 76.6, 60.1, 55.6, 40.6, 14.2.
9
4.0, 79.1, 75.6, 55.5, 47.6, 39.2, 38.0, 28.4, 27.4, 25.5, 18.9.
+
+
LSIMS: m/z = 287.1 [M + Na].
LSIMS: m/z = 372.2 [M + Na].
+
ESI-HRMS: m/z calcd for C H O Na [M
+ Na]: 287.1259;
1
5
20
4
(
2R)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl-1-methylpip-
found: 287.1258.
eridine (20)
Compound 20 was prepared from 19 (250 mg, 0.71 mmol) follow-
ing the same procedure as that described for the synthesis of 16.
(
2E,5R)-5-(Methoxymethoxy)-5-phenylpent-2-en-1-ol (22)
To a soln of 21 (3.5 g, 13.2 mmol) in CH Cl (40 mL) at 0 °C, a 1.4
2
2
M soln of DIBAL-H in toluene (18.8 mL, 26.4 mmol) was added
dropwise and the mixture was stirred for 1 h at this temperature. The
reaction was quenched by the addition of MeOH (5 mL) followed
by sat. aq sodium potassium tartrate soln (30 mL). It was warmed to
r.t. and stirred for 1 h. The aqueous layer was extracted with EtOAc
(2 × 50 mL) and washed with brine (2 × 30 mL), dried (Na SO ),
Yield: 154 mg (82%); colourless oil; R = 0.44 (silica gel, MeOH–
f
20
CH Cl , 10:90); [a] +87.7 (c 1.0, MeOH).
2
2
D
–
1
IR (neat): 2923, 1449, 1361, 1028, 702 cm .
1
H NMR (300 MHz, CDCl ): d = 7.34–7.25 (m, 5 H), 4.64 (dd,
3
J = 10.5, 3.0 Hz, 1 H), 4.43 (s, 2 H), 3.34 (s, 3 H), 3.13–3.06 (m, 1
2
4
H), 2.74–2.67 (m, 1 H), 2.51 (s, 3 H), 2.29–2.19 (m, 1 H), 2.07–1.98
and concentrated in vacuo. Purification of the crude by column
(
m, 1 H), 1.84–1.37 (m, 7 H).
chromatography (silica gel, EtOAc–hexanes, 1:4) afforded 22 as an
1
3
oil.
C NMR (75 MHz, CDCl ): d = 140.6, 128.7, 128.2, 126.5, 94.1,
3
7
4.3, 62.4, 56.0, 40.9, 38.5, 29.8, 27.7, 23.1, 21.8.
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (+)-Sedamine and (–)-Allosedamine
4011
Yield: 2.6 g (88%); R = 0.2 (silica gel, EtOAc–hexanes, 30:70);
H), 2.63 (br s, 1 H), 2.37 (t, J = 6.2 Hz, 2 H), 2.00–1.67 (m, 2 H),
1.29 (t, J = 7.0 Hz, 3 H).
f
20
[
a]D +114.3 (c 1.0, CHCl3).
–
1
13
IR (neat): 3418, 2933, 1030, 701 cm .
C NMR (75 MHz, CDCl ): d = 166.3, 145.1, 141.4, 128.5, 127.7,
3
1
126.4, 123.7, 94.7, 75.4, 66.9, 60.2, 55.9, 44.8, 40.1, 14.2.
H NMR (200 MHz, CDCl ): d = 7.37–7.17 (m, 5 H), 5.66–5.62 (m,
H), 4.57 (dd, J = 7.8, 6.2 Hz, 1 H), 4.47 (s, 2 H), 4.11–4.03 (m, 2
3
+
2
LSIMS: m/z = 331.1 [M + Na].
H), 3.31 (s, 3 H), 2.72–2.31 (m, 2 H).
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 331.1521; found:
331.1515.
1
7
24
5
1
3
C NMR (75 MHz, CDCl ): d = 141.3, 131.9, 128.3, 127.7, 126.8,
3
9
4.1, 77.7, 63.3, 55.5, 40.6.
(
5S,7R)-7-(Methoxymethoxy)-7-phenylheptane-1,5-diol (26)
To a suspension of LiAlH (296 mg, 7.78 mmol) in dry THF (10
mL) at 0 °C was added dropwise a soln of ester 25 (800 mg, 2.59
mmol) in dry THF (3 mL). The mixture was allowed to warm to r.t.
and was stirred for 2 h. It was then cooled to 0 °C and quenched by
dropwise addition of sat. aq NH Cl (2 mL). The precipitate was col-
lected by filtration and washed with EtOAc. The combined organic
extracts were dried (Na SO ) and the solvent was removed in vacuo.
Column chromatography (silica gel, EtOAc–hexanes, 1:1) afforded
6 as a viscous liquid.
+
LSIMS: m/z = 245.1 [M + Na].
4
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 245.1153; found:
1
3
18
3
2
45.1160.
{
(2R,3R)-3-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]oxiran-2-
4
yl}methanol (23)
Compound 23 was prepared from 22 (2.3 g, 10.36 mmol) and (–)-
DET (0.32 g, 1.55 mmol) following the same procedure as that de-
scribed for the synthesis of 4.
2
4
2
Yield: 2.02 g (82%); colourless oil; R = 0.5 (silica gel, EtOAc–hex-
anes, 60:40); [a]D +131.3 (c 1.5, CHCl3).
f
Yield: 626 mg (90%); R = 0.2 (silica gel, EtOAc–hexane, 60:40);
[a]D +103.3 (c 1.0, MeOH).
IR (neat): 3411, 2938, 1452, 1032 cm–1.
f
20
20
–
1
IR (neat): 3446, 2944, 1028, 702 cm .
1
H NMR (200 MHz, CDCl ): d = 7.29–7.24 (m, 5 H), 4.81 (dd,
1
3
H NMR (300 MHz, CDCl ): d = 7.35–7.20 (m, 5 H), 4.88 (dd,
3
J = 9.5, 4.3 Hz, 1 H), 4.5 (s, 2 H), 3.86–3.80 (m, 1 H), 3.63–3.53 (m,
J = 9.0, 3.0 Hz, 1 H), 4.52 (s, 2 H), 3.89–3.79 (m, 1 H), 3.61 (t,
J = 6.0 Hz, 2 H), 3.39 (s, 3 H), 2.79–2.41 (br s, 2 H), 1.92–1.79 (m,
1
1
H), 3.36 (s, 3 H), 3.20–3.14 (m, 1 H), 2.93–2.76 (m, 1 H), 2.10–
.94 (m, 1 H), 1.88–1.73 (m, 1 H), 1.68–1.52 (br s, 1 H).
1
H), 1.78–1.36 (m, 7 H).
1
3
C NMR (100 MHz, CDCl ): d = 141.1, 128.4, 127.8, 126.5, 94.0,
13
3
C NMR (75 MHz, CDCl ): d = 141.8, 128.3, 127.5, 126.4, 94.7,
3
7
5.0, 61.6, 59.1, 55.5, 53.2, 40.3.
7
5.8, 68.0, 62.4, 55.7, 45.1, 36.9, 32.4, 21.7.
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 261.1102; found:
+
1
3
18
4
LSIMS: m/z = 291.1 [M + Na].
2
61.1108.
(
2R)-2-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]-1-methylpip-
(
3S,5R)-5-(Methoxymethoxy)-5-phenylpentane-1,3-diol (24)
eridine (20)
Compound 24 was prepared from 23 (1.6 g, 6.72 mmol) following
the same procedure as that described for the synthesis of 5.
To a soln of diol 26 (500 mg, 1.86 mmol) and Et N (1.03 mL, 7.42
mmol) in CH Cl (20 mL) at 0 °C was added MsCl (530.0 mg, 4.64
3
2
2
mmol). After 15 min, the mixture was poured into ice water (15
mL). The layers were separated and the organic phase was washed
with 1 M aq HCl (10 mL), a sat. NaHCO soln (10 mL), and H O
Yield: 1.35 g (84%); colourless oil; R = 0.2 (silica gel, EtOAc–hex-
anes, 60:40); [a]D +109.9 (c 1.5, MeOH).
f
20
–
1
3
2
IR (neat): 3410, 2944, 1033, 702 cm .
(
10 mL). The organic layer was dried (Na SO ) and evaporated and
2 4
1
H NMR (200 MHz, CDCl ): d = 7.36–7.17 (m, 5 H), 4.90 (dd,
the crude dimesylate was used in the next step without further puri-
fication.
3
J = 7.8, 5.2 Hz, 1 H), 4.55 (d, J = 6.0 Hz, 1 H), 4.50 (d, J = 6.0 Hz,
1
2
H), 4.25–4.05 (m, 1 H), 3.83 (t, J = 5.2 Hz, 2 H), 3.41 (s, 3 H),
.73–2.54 (br s, 1 H), 1.89–1.61 (m, 4 H), 1.48–1.40 (br s, 1 H).
A mixture of the above dimesylate and a 40% soln of MeNH in
2
H O (2.87 mL, 37.0 mmol) in DMF (10 mL) were maintained at
2
1
3
C NMR (100 MHz, CDCl ): d = 141.7, 128.5, 127.6, 126.5, 94.8,
60 °C for 12 h. After dilution with EtOAc (20 mL), the mixture was
3
7
5.6, 68.1, 61.2, 55.8, 45.4, 38.6.
washed with brine (5 mL) and H O (5 mL), dried, and evaporated.
2
+
The product was purified by column chromatography (silica gel,
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 263.1259; found:
1
3
20
4
MeOH–CH Cl , 1:19). The compound 20 prepared from 26 was
2
2
2
63.1249.
identical in all respects with the one prepared from 19.
Ethyl (2E,5S,7R)-5-Hydroxy-7-(methoxymethoxy)-7-phenyl-
hept-2-enoate (25)
Yield: 372 mg (76%); colourless oil; R = 0.44 (silica gel, MeOH–
f
CH Cl , 10:90).
2
2
To a stirred soln of diol 24 (1.1 g, 4.58 mmol) in CH Cl (12 mL)
2
2
were added Ph[I(OAc) ] (1.77 g, 5.5 mmol) and TEMPO (0.07 g,
{(2S,3S)-3-[(2R)-2-(Methoxymethoxy)-2-phenylethyl]oxiran-2-
yl}methanol (27)
2
0
.45 mmol). The yellow soln was stirred for 1.5 h, cooled to 0 °C,
and (ethoxycarbonylmethylene)triphenylphosphorane (2.38 g, 6.85
mmol) was added. The mixture was allowed to warm to r.t., stirred
for 1 h, and then filtered through a Celite pad. The residue was
Compound 27 was prepared from 22 (2.3 g, 10.36 mmol) following
the same procedure as that described for the synthesis of 4.
Yield: 2.07 g (84%); colourless oil; R = 0.5 (silica gel, EtOAc–hex-
f
washed with Et O and the filtrate was concentrated and purified by
20
2
anes, 60:40); [a]D +94.10 (c 1.5, CHCl3).
column chromatography (silica gel, EtOAc–hexanes, 1:6).
–
1
IR (neat): 3446, 2942, 1745, 1027, 702 cm .
Yield: 861 mg (61%); colourless liquid; R = 0.2 (silica gel, EtOAc–
f
1
20
H NMR (200 MHz, CDCl ): d = 7.43–7.24 (m, 5 H), 4.72 (dd,
hexane, 20:80); [a]D +30.28 (c 0.5, CHCl3).
3
J = 7.8, 6.2 Hz, 1 H), 4.49 (s, 2 H), 3.83–3.67 (m, 1 H), 3.57–3.44
–
1
IR (neat): 3474, 2942, 1716, 1652, 1034 cm .
(m, 1 H), 3.36 (s, 3 H), 2.93–2.85 (m, 1 H), 2.81–2.72 (m, 1 H),
1
H NMR (200 MHz, CDCl ): d = 7.35–7.18 (m, 5 H), 7.06–6.84 (m,
2.30–2.15 (m, 1 H), 1.90–1.74 (m, 1 H).
3
1
H), 5.84 (d, J = 15.6 Hz, 1 H), 4.86 (dd, J = 9.3, 3.9 Hz, 1 H), 4.51
13
C NMR (75 MHz, CDCl ): d = 140.9, 128.5, 128.0, 126.8, 94.1,
3
(
s, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 4.11–3.91 (m, 1 H), 3.39 (m, 3
7
5.8, 61.6, 58.0, 55.5, 53.2, 39.9.
+
LSIMS: m/z = 261.0 [M + Na].
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York

4
012
J. S. Yadav et al.
PAPER
(
3R,5R)-5-(Methoxymethoxy)-5-phenylpentane-1,3-diol (28)
References
Compound 28 was prepared from 27 (1.6 g, 6.72 mmol) following
the same procedure as that described for the synthesis of 5.
(
1) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids, Vol. 26;
Brossi, A., Ed.; Academic Press: New York, 1985, 89–174.
Yield: 1.38 g (86%); colourless oil; R = 0.2 (silica gel, EtOAc–hex-
anes, 60:40); [a]D +98.8 (c 1.5, MeOH).
f
(b) Numata, A.; Ibuka, T. In The Alkaloids, Vol. 31; Brossi,
20
A., Ed.; Academic Press: New York, 1987.
IR (neat): 3413, 2944, 1449,1035, 702.
(2) (a) Marion, L.; Lavigne, R.; Lemay, L. Can. J. Chem. 1951,
29, 347. (b) Granck, B. Chem. Ber. 1958, 91, 2803.
1
H NMR (300 MHz, CDCl ): d = 7.37–7.18 (m, 5 H), 4.85 (dd,
3
(
3) (a) Logar, S.; Mesicek, M.; Perpar, M.; Seles, E. Farm.
Vestn. 1974, 21; Chem. Abstr. 1975, 82, 82916h.
J = 10.5, 3.7 Hz, 1 H), 4.50 (s, 2 H), 4.20–4.09 (m, 1 H), 3.86–3.75
(
1
m, 2 H), 3.42 (s, 3 H), 2.82–2.62 (br s, 1 H), 2.17–2.03 (m, 1 H),
.82–1.66 (m, 3 H), 1.58–1.47 (br s, 1 H).
(b) Krasnov, E. A.; Petrova, L. V.; Bekker, E. F. Khim. Prir.
Soedin. 1977, 585; Chem. Abstr. 1977, 87, 164249k.
1
3
C NMR (75 MHz, CDCl ): d = 140.9, 128.5, 127.9, 126.8, 93.9,
3
(4) Schoff, C.; Kauffmann, T.; Berth, P.; Bundschuh, W.;
Dummer, G.; Fett, H.; Habermehl, G.; Wieters, E.; Wust, W.
Liebigs Ann. Chem. 1957, 608, 88.
7
8.0, 70.7, 60.9, 55.8, 45.1, 38.8.
+
LSIMS: m/z = 263.1 [M + Na].
(
5) Gershwin, M. E.; Terr, A. Clin. Rev. Allergy Immunol. 1996,
Ethyl (2E,5R,7R)-5-Hydroxy-7-(methoxymethoxy)-7-phenyl-
hept-2-enoate (29)
Compound 29 was prepared from 28 (1.1 g, 4.58 mmol) following
14, 241.
(6) For the synthesis of (±)-sedamine, see: (a) Tufariello, J. J.;
Ali, S. A. Tetrahedron Lett. 1978, 47, 4647. (b) Shono, T.;
Matsumura, Y.; Tsubatta, K. J. Am. Chem. Soc. 1981, 103,
the same procedure as that described for the synthesis of 25.
1172. (c) Tirel, P. J.; Vaultier, M.; Carrie, R. Tetrahedron
Yield: 917 mg (65%); colourless oil; R = 0.2 (silica gel, EtOAc–
f
Lett. 1989, 30, 1947. (d) Pilli, R. A.; Dias, L. C. Synth.
Commun. 1991, 21, 2213. (e) Ozawa, N.; Nakajima, S.;
Zzoya, K.; Hamaguchi, F.; Nagasaka, T. Heterocycles 1991,
32, 889. (f) Driessens, F.; Hootele, C. Can. J. Chem. 1991,
20
hexanes, 20:80); [a]D +107.3 (c 1.0, CHCl3).
–
1
IR (neat): 3491, 2942, 1717, 1037, 701 cm .
1
H NMR (300 MHz, CDCl ): d = 7.37–7.23 (m, 5 H), 7.01–6.88 (m,
3
69, 211. (g) Ghiaci, M.; Adibi, M. Org. Prep. Proced. Int.
1
4
3
1
H), 5.84 (d, J = 15.8 Hz, 1 H), 4.84 (dd, J = 10.5, 4.5 Hz, 1 H),
.49 (s, 2 H), 4.18 (q, J = 7.5 Hz, 2 H), 4.05–3.94 (m, 1 H), 3.41 (s,
H), 2.46–2.31 (m, 2 H), 2.05–1.92 (m, 1 H), 1.83–1.72 (m, 1 H),
.31 (t, J = 7.5 Hz, 3 H).
1996, 38, 474.
(
7) For the synthesis of (+)- and (–)-sedamine, see:
(a) Beyerman, H. C.; Eveleens, W.; Muller, Y. M. F. Recl.
Trav. Chim. Pays-Bas 1956, 75, 63. (b) Beyerman, H. C.;
Eenshuistra, J.; Eveleens, W.; Zweistra, A. Recl. Trav. Chim.
Pays-Bas 1959, 78, 43. (c) Schopf, C.; Cummer, G.; Wust,
W. Liebigs Ann. Chem. 1959, 626, 134. (d) Wakabayachi,
T.; Watanabe, K.; Kato, Y.; Saito, M. Chem. Lett. 1977,
223. (e) Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J. Chem. Soc.,
Chem. Commun. 1985, 633. (f) Pyne, S. G.; Bloem, P.;
Chapman, S. L.; Dixon, C. E.; Griffith, R. J. Org. Chem.
1
3
C NMR (75 MHz, CDCl ): d = 166.8, 145.4, 141.1, 129.9, 128.6,
3
1
27.4, 124.3, 94.2, 78.5, 70.5, 60.8, 56.5, 44.9, 40.7, 14.8.
+
LSIMS: m/z = 331.1 [M + Na].
(
5R,7R)-7-(Methoxymethoxy)-7-phenylheptane-1,5-diol (30)
Compound 30 was prepared from 29 (800 mg, 2.59 mmol) follow-
ing the same procedure as that described for the synthesis of 26.
1
990, 55, 1086. (g) Kiguchi, T.; Nakazono, Y.; Kotera, S.;
Yield: 640 mg (92%); colourless oil; R = 0.2 (silica gel, EtOAc–
hexanes, 60:40); [a]D +80.3 (c 1.0, MeOH).
f
20
Ninomiya, I.; Naito, T. Heterocycles 1990, 31, 1525.
(h) Comins, D. L.; Hong, H. J. Org. Chem. 1993, 58, 5035.
–
1
IR (neat): 3391, 2938, 1453, 1034, 702 cm .
(
i) Poerwono, H.; Higashiyama, K.; Takahashi, H.
1
H NMR (200 MHz, CDCl ): d = 7.34–7.18 (m, 5 H), 4.81 (dd,
Heterocycles 1998, 47, 263. (j) Yu, C. Y.; Meth-Cohn, O.
Tetrahedron Lett. 1999, 40, 6665. (k) Compere, C.;
Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 4528.
3
J = 9.8, 3.7 Hz, 1 H), 4.47 (s, 2 H), 3.83–3.78 (m, 1 H), 3.6 (t,
J = 6.0 Hz, 2 H), 3.39 (s, 3 H), 2.03–1.83 (m, 1 H), 1.76–1.65 (m, 1
H), 1.57–1.38 (m, 6 H).
(
l) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org.
Chem. 2002, 67, 1982. (m) Felpin, F. X.; Lebreton, J. J.
Org. Chem. 2002, 67, 9192. (n) Angoli, M.; Barilli, A.;
Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B.
J. Org. Chem. 2003, 68, 9525. (o) Zheng, G.; Dwoskin, L.
P.; Crooks, P. A. J. Org. Chem. 2004, 69, 8514. (p) Yadav,
J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron
Lett. 2006, 47, 4397.
1
3
C NMR (75 MHz, CDCl ): d = 141.0, 128.5, 127.9, 126.8, 93.8,
3
7
8.2, 70.9, 62.4, 55.8, 44.9, 32.5, 21.5.
+
ESI-HRMS: m/z calcd for C H O Na [M + Na]: 291.1572; found:
2
1
5
24
4
91.1576.
(
2R)-2-[(2S)-2-(Methoxymethoxy)-2-phenylethyl]-1-methylpip-
eridine (16)
(
(
8) For the synthesis of (±)-allosedamine, see: (a) Ozawa, N.;
Nakajima, K.; Zaoya, K.; Hamaguchi, F.; Nagasaka, T.
Heterocycles 1991, 32, 989. (b) Liguori, A.; Ottana, R.;
Romeo, G.; Sindona, S.; Uccella, N. Chem. Ber. 1989, 122,
Compound 16 was prepared from 30 (500 mg, 1.86 mmol) follow-
ing the same procedure as that described for the synthesis of 20 from
2
6. The compound 16 prepared here from 30 was identical in all re-
spects with the one prepared from 15.
2
089; and references cited therein.
9) For the synthesis of (+)- and (–)-allosedamine, see:
a) Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2002, 43,
25. (b) Oppolzer, W.; Deeberg, J.; Tamura, O. Helv. Chim.
Yield: 381 mg (78%); colourless oil; R = 0.44 (silica gel, MeOH–
CH Cl , 10:90).
f
(
2
2
2
Acta 1994, 77, 554. (c) Kang, B.; Chang, S. Tetrahedron
2004, 60, 7353. (d) Raghavan, S.; Rajender, A. Tetrahedron
Lett. 2004, 45, 1919.
Acknowledgment
M.S.R. thanks CSIR, New Delhi for the award of a fellowship.
(
(
10) Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715.
11) (a) Mehta, G.; Reddy, M. S.; Thomas, A. Tetrahedron 1998,
54, 7865. (b) Masaki, Y.; Oda, H.; Kozuta, K.; Usui, A.;
Itoh, A.; Xu, F. Tetrahedron Lett. 1992, 33, 5089.
Synthesis 2006, No. 23, 4005–4012 © Thieme Stuttgart · New York