A facile synthetic route to (+)-allosedamine via hydrolytic kinetic resolution and olefin metathesis

Article abstract of DOI:10.1016/j.tet.2004.05.054

A concise synthesis of (+)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and ruthenium-catalyzed ring closing metathesis (RCM) as two key steps, in which HKR was used to introduce both stereogenic centers in the natural compound with a high degree of diastereomeric ratio and cyclization was carried out with the well developed RCM procedure.

Full text of DOI:10.1016/j.tet.2004.05.054

Tetrahedron 60 (2004) 7353–7359
A facile synthetic route to (1)-allosedamine via hydrolytic kinetic
resolution and olefin metathesis
*
Byungman Kang and Sukbok Chang
Department of Chemistry and School of Molecular Science (BK21), Center for Molecular Design and Synthesis (CMDS),
Korea Advanced Institute of Science and Technology (KAIST), 373-1, Kusong-dong, Yusong-gu, Daejeon 305-701, South Korea
Received 10 March 2004; revised 22 May 2004; accepted 24 May 2004
Available online 10 June 2004
This paper is dedicated to Professor Robert H. Grubbs of California Institute of Technology on the occasion of his receiving the Tetrahedron Prize
Abstract—A concise synthesis of (þ)-allosedamine has been achieved using cobalt-catalyzed hydrolytic kinetic resolution (HKR) and
ruthenium-catalyzed ring closing metathesis (RCM) as two key steps, in which HKR was used to introduce both stereogenic centers in the
natural compound with a high degree of diastereomeric ratio and cyclization was carried out with the well developed RCM procedure.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of sedamine alkaloid in racemic3 and optically
active form,4 facile and direct application of the approaches
on synthesis of allosedamine turned out to be difficult in
most cases.5 For example, whereas an elegant recent
strategy described by Cossy et al. for the synthesis of (þ)-
sedamine is based on the enantioselective allyltitanation of
an aldehyde precursor by chiral titanium complex followed
by ring-closing metathesis to provide a N-heterocyclic
system,4c Lebreton’s route for the preparation of (2)-
allosedamine relies on Brown’s asymmetric allylation and
subsequent electrophilic cyclization.5e
Lobelia inflata, also known as Indian tobacco, has been used
for the treatment of some respiratory illnesses by American
settlers. It was later found that a family of piperidine
alkaloids including lobeline, lobelanine, lobelanidine and
allosedamine are responsible for the therapeutic effects
(Fig. 1).1 Extracts of the plants have been also used for the
treatment of narcotic poisoning, coal gas asphyxia,
pneumonia and control of anxiety, and it has been revealed
that the continual doses of its extracts cause a various side
effects.2
2. Results and discussion
One of the most distinguishing structural features of (þ)-
allosedamine is the fact that it contains a secondary free
benzylic hydroxy group and a piperidine moiety. At the
outset of our studies, it was anticipated that both of two
stereogenic centers located at b-position each other could be
readily introduced by asymmetric catalysis. Our synthetic
approach for (þ)-allosedamine relies on two metal-
catalyzed reactions; hydrolytic kinetic resolution (HKR)
and ring-closing metathesis (RCM) (Scheme 1).6 Inversion
of a hydroxyl group-containing stereogenic center at
homoallylic position was envisioned to be another key
step for the success in this strategy. (þ)-Styrene oxide 1 was
chosen as a starting material for providing a stereogenic
center at benzylic position because it is readily available in
multi gram scale via a hydrolytic kinetic resolution of
racemic styrene oxide.7
Figure 1. Lobelia alkaloids.
We were particularly interested in the development of an
efficient asymmetric synthetic route of allosedamine and its
diastereomeric isomer (sedamine) among those alkaloids.
While numerous approaches have been reported for the
Keywords: Allosedamine; Total synthesis; Hydrolytic kinetic resolution;
Ring-closing metathesis.
*
Corresponding author. Tel.: þ82-428692841; fax: þ82-428692810;
e-mail address: sbchang@kaist.ac.kr
As shown in Scheme 2, regioselective ring opening of
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.054

7354
B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
Scheme 1. Retrosynthetic analysis of (þ)-allosedamine.
Scheme 2. Construction of two stereogenic centers.
(þ)-styrene oxide 18 was most efficiently achieved by using
cuprate reagents derived from tetravinyltin in THF among a
variety of conditions examined leading to a homoallylic
alcohol 2a.9 Employment of other sources of vinyl group or
use of different solvents resulted in much lower selectivities
for the desired secondary alcohol. For example, when
vinylmagnesium bromide was used in the presence of Cu(I)
salt,10 almost equal ratio of primary versus secondary
alcohol isomer was generated albeit with higher combined
yields. In addition, when vinyl bromide was utilized in
combination with t-BuLi and CuCN, no desired product was
obtained from the reaction.
certain transition metal species provide high degree of
directing effects in the epoxidation of homoallylic
alcohols.11 This directed epoxidation is presumed to be
operated mainly via hydrogen bonding interactions between
the hydroxyl group of substrates and peroxy acids or
peracids leading to syn epoxy alcohols. As shown in Table 1,
a directed epoxidation of 2a was examined under various
conditions on the basis of the reported procedures.
In reality, no measurable diastereoselective induction was
observed when the epoxidation of 2a was carried out with
peracid or peroxide in the absence of metal species (entries
1–4). While almost no selectivity was also observed in the
presence of a Mo catalyst (entry 5), slightly improved
selectivity was induced with the use of a vanadium catalyst
albeit in lower yield (entry 6). The unexpectedly low
diastereoselectivity would be probably derived from weak
hydrogen bonding interactions between peracid oxygen and
homoallylic alcohol 2a. This result led us to employ a two-
step pathway for the preparation of an optically active epoxy
alcohol 3a from 2a: non-selective epoxidation of 2a with
m-CPBA and subsequent kinetic resolution of the resulting
epoxy alcohol moiety.
It was expected at the beginning that a directed epoxidation
of homoallylic alcohol 2a would be possible giving
practically acceptable diastereoselectivity under certain
conditions. Some precedent examples demonstrate that
either peroxy acids alone or peracids in combination with
Table 1. Attempts of directed epoxidation of homoallylic alcohol 2a
Protection of free hydroxyl group of 3a/3b was carried out
in high yield (95%) with chloromethyl methyl ether in
CH2Cl2 at 0 8C giving the corresponding MOM ethers 4a/4b
in the same ratio.12 In order to perform a kinetic resolution
of the diastereomeric epoxide mixture 4a/4b, Jacobsen’s
(R,R)-(2)-Co(salen) catalyst (5) was employed under the
optimized conditions.7 Treatment of a mixture of 4a/4b
(,1:1) with 5 (1 mol%), acetic acid (4 mol%), and H2O
(0.55 equiv.) in THF at room temperature provided 4a in
44% yield with .98% de. In the resolution reaction, diol 6
was isolated in 47% yield as a single diastereomer
Entry
Reaction conditionsa
Yield (%, 3a:3b)b
1
2
3
4
5
6
MPPA, NaOH (1 M), rt
MPPA, CH2Cl2, 0 8C to rt
MPPA, THF, 0 8C to rt
m-CPBA, CH2Cl2, 0 8C to rt
Mo(CO)6, TBHP, C6H6, rt
VO(acac)2, TBHP, C6H6, rt
NR
80 (1:1)
63 (1:1)
94 (1.1:1)
51 (1.2:1)
42 (2.8:1)
a
MPPA: monoperoxyphthalic acid, m-CPBA: 3-chloroperbenzoic acid,
TBHP: t-butyl hydroperoxide.
b
Combined yields, and ratios were determined by 1H NMR integration of
the crude reaction mixture.

B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
7355
1
determined by H NMR. It is noteworthy that synthetic
the secondary amino moiety 8 was carried out efficiently
under normal conditions to afford a dienyl compound 9, a
precursor for ring-closing metathesis.
utility of the ring-opened diol 6 could be readily found in
other syntheses because it is highly functionalized com-
pound with well-defined stereochemistry. Designation of
the absolute stereochemistry in the resolved epoxide,
(1S,3R)-4a, was ensured by comparing it with that of an
authentic sample which was prepared independently by a
literature procedure.4d Residual amounts of the used cobalt
catalyst in the product was completely removed by the use
of pyridinium p-toluene sulfonate (PPTS) during workup
processes.7c It should be particularly mentioned that the
present synthetic route can be also applied to the synthesis
of optically active sedamine, a diastereomer of alloseda-
mine by the choice of the Jacobsen’s Co catalyst. With the
use of (S,S)-(þ)-Co(salen) catalyst instead of (R,R)-isomer,
a diastereomeric epoxide 4b would be obtained with the
same efficiency and selectivity eventually leading to (2)-
sedamine. It should be mentioned that this synthetic route
uses two resolution reactions to obtain the key epoxide
intermediate 4a starting from a readily available racemic
styrene epoxide. Both resolutions proceed with an excellent
selectivity under mild conditions making the present
synthesis highly efficient and practical.
Efficiency of the ring-closing metathesis reaction of 9 was
examined with the use of several catalyst systems under
various conditions.14 The best result was obtained when
diene 9 was reacted with the Grubbs’ second generation
catalyst (Im)Cl2PCy3RuCHPh 10 (10 mol%) in benzene
under N2 atmosphere to generate an olefinic piperidine
moiety in 54% yield. Other ruthenium carbene catalysts
gave a rather reduced activity and lower yields under
otherwise same conditions; Cl2(PCy3)2RuCHPh (40%) and
(3-bromopyridine)2Cl2(Im)RuCHPh (47%).15 No signifi-
cant improvement was observed when the cyclization was
carried out under ethylene atmosphere instead of N2. In
addition, when ammonium salts of diolefinic amine 9 were
subjected to the metathesis conditions, noticeable improve-
ments in chemical yields were not observed compared to
free amino substrate 9. For example, RCM of ammonium
salts of 9 of trifluoroacetic acid, p-toluenesulfonic acid, and
10-camphorsulfonic acid afforded the cyclized product in
54, 43, and 43% isolated yields under identical conditions,
respectively.16 While tandem hydrogenation of the olefinic
intermediate into a saturated piperidine adduct 11 was
initially tried in the absence of additional metal catalysts,17
no desired activity of the ruthenium carbene precursor was
observed for the reduction step. This led us to use another
one-pot procedure: addition of platinum oxide catalyst
(0.1 equiv.) after the metathesis reaction for the subsequent
hydrogenation.18 Hydrogenation underwent almost quanti-
tatively in the presence of PtO2 catalyst giving a protected
allosedamine 11 in 52% yield (two steps starting from 9). To
remove the residual ruthenium by products from the
product, various known purification procedures were
examined.19 Whereas simple silica gel column chromato-
graphy left significant amounts of residual ruthenium in the
desired product, treatment of the crude reaction mixture
with either lead tetraacetate (1.5 equiv. to catalyst)19a or
tris(hydroxymethylphosphine) (100 equiv. to catalyst)19b
Epoxide opening of an oxirane 4a with vinyl Grignard
reagent underwent smoothly in the presence of copper
additives in THF affording another homoallylic alcohol 7 in
70% yield (Scheme 3). Initially, the Mitsunobu’s inversion
protocol was investigated to introduce the required amino
group at the homoallylic position using allylamine and its
derivatives as a nucleophile.13 However, a variety of
attempts with several amino groups were unsuccessful
presumably because of steric hindrance around the alcohol
substrate. This led us to employ a two-step alternative:
conversion of the homoallyl alcohol 7 into its corresponding
mesylate followed by amination with methylamine to
provide an amino ether adduct 8 (43% over two steps).
The fact that configuration of the free hydroxyl containing
carbon in 7 was completely inverted in the substituted
product 8 was readily confirmed by 1H NMR. Allylation of
Scheme 3. Final stages in the synthesis of (þ)-allosedamine.

7356
B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
resulted in only marginal improvement in purity and brown
color was still seen from the isolated product. Most effective
removal of ruthenium residues from the reaction mixture
was achieved according to a recently published protocol, in
which the reaction mixture was treated with activated
charcoal (50 equiv. to the crude product in wt)19c for 12 h
followed by a silica gel column chromatography. Sub-
sequent deprotection of MOM group by conc. HCl in
acetonitrile12 provided (þ)-allosedamine 12 in high yield,
spectral data of which are identical to those of the reported
literature ones.5
cannula at 278 8C. The mixture was allowed to warm
slowly to 230 8C with stirring and then a heterogeneous
solution changed into a homogeneous yellow solution. After
cooling to 278 8C, a solution of (þ)-styrene oxide
(0.20 mL, 1.75 mmol) in THF (1 mL) was added dropwise
to the above solution. After stirring for 2 h at 230 8C, the
mixture was allowed to warm slowly to room temperature.
The reaction was quenched by addition of saturated NH4Cl
and filtered through celite. The organic phase was washed
with brine, dried over MgSO4 and concentrated in vacuo.
The crude residue was purified on silica gel (EtOAc/
n-hexane, 1:5) to afford 2a as a colorless oil (137 mg, 53%):
Rf¼0.52 (EtOAc/n-hexane, 1:3); [a]D¼250.2 (c 1.45,
1
C6H6); IR (KBr) 3386, 1640, 1603, 1493, 1453 cm21; H
3. Conclusion
NMR (400 MHz, CDCl3) d 2.09 (d, 1H, J¼3.3 Hz), 2.51 (m,
2H), 4.72 (m, 1H), 5.11–5.17 (m, 2H), 5.80 (m, 1H), 7.24–
7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) d 43.7, 73.2,
118.4, 125.8, 127.5, 128.4, 134.4, 143.8; HRMS (EI) calcd
for C10H12O [Mþ] 148.0888, found 148.0899.
A concise synthesis of (þ)-allosedamine has been achieved
using cobalt-catalyzed hydrolytic kinetic resolution (HKR)
and ruthenium-catalyzed ring closing metathesis (RCM) as
two key steps. HKR was used to introduce both stereogenic
centers in the natural compound with a high degree of
diastereomeric ratio. Cyclization was carried out with the
well-developed RCM procedure and the desired piperidine
moiety was isolated after tandem hydrogenation in one-pot.
With the present synthetic approach, optically active
sedamine, a diastereomeric isomer of allosedamine, could
be also readily accessed by a simple choice of enantiomeric
cobalt catalyst via HKR.
4.1.2. (1S)-2-Oxiranyl-1-phenylethanol (3a, 3b). The
mixture of olefin 2a (500 mg, 3.37 mmol), m-chloro-
perbenzoic acid20 (983 mg, 4.38 mmol) in CH2Cl2
(12 mL) was stirred at 0 8C for 30 min. The mixture was
stirred for 12 h at room temperature and was then diluted
with dichloromethane. The organic phase was extracted
with saturated NaHCO3 twice. The organic phase was
washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude residue was purified on silica gel
(EtOAc/n-hexane, starting from 1/6 to 1/1) to afford product
as a colorless oil (521 mg, 94%) with a diastereomeric ratio
4. Experimental
1
of 1:1 (3a:3b, determined by H NMR): Rf¼0.20 (EtOAc/
4.1. General methods
n-hexane, 1:3); IR (KBr) 3423, 1494, 1454, 1410 cm21
.
Oxygen or moisture sensitive reactions were conducted in
oven- or flame-dried glassware under nitrogen. Unless
otherwise specified, materials were purchased from com-
mercial supplier and used without further purification.
Solvents were dried and purified prior to use. Benzene,
acetonitrile, and dichloromethane were distilled from
calcium hydride under argon or nitrogen atmosphere. THF
was distilled from sodium metal and benzophenone.
Analytical thin layer chromatography (TLC) was performed
on Merck precoated silica gel 60 F254 plates. Purification
by column chromatography was carried out using silica gel
60 (230–400 mesh, ASTM, Merck). Proton nuclear
magnetic resonance spectra were recorded on a Bruker
AVANCE 400 (400 MHz) spectrometer. Chemical shifts
are reported in delta (d) units, parts per million (ppm)
downfield from internal standard (tetramethylsilane), or in
ppm relative to the singlet at 7.26 ppm of chloroform-d1.
Splitting patterns are designated as follows: s; singlet, d;
doublet, t; triplet, q; quintet, m; multiplet, dd; doublet of
doublet, ddd; doublet of doublet of doublet, bs; broad
singlet. HRMS spectra were recorded on a VG AUTOSPEC
ULTIMA spectrometer.
1
3a: H NMR (400 MHz, CDCl3) d 1.90 (dd, 1H, J¼14.1,
6.5 Hz), 2.02 (dd, 1H, J¼9.5, 4.4 Hz), 2.48 (dd, 1H, J¼4.8,
2.8 Hz), 2.74 (t, 1H, J¼4.1 Hz), 2.99 (m, 1H), 4.89–4.96
(m, 1H), 7.25–7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 41.3, 46.7, 49.8, 71.8, 125.5, 127.6, 128.5, 143.8.
1
3b: H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.4,
6.7, 3.5 Hz), 2.13 (ddd, 1H, J¼17.0, 9.0, 4.0 Hz), 2.59 (dd,
1H, J¼5.5, 3.5 Hz), 2.81 (t, 1H, J¼4.4 Hz), 3.16 (m, 1H),
4.89–4.96 (m, 1H), 7.25–7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 41.8, 46.9, 50.1, 72.7, 125.7, 127.7,
128.5, 144.1; HRMS (EI) calcd for C10H12O2 [Mþ]
164.0837, found 164.0836.
4.1.3. (1S)-Methoxymethyl-(2-oxiranyl-1-phenylethyl)-
ether (4a, 4b). To a solution of a mixture of alcohol 3a
and 3b (506 mg, 3.08 mmol) in CH2Cl2 (8 mL) at 0 8C were
added diisopropylethylamine (2.15 mL, 12.3 mmol),
chloromethyl methyl ether (0.70 mL, 9.24 mmol). After
being stirred at room temperature for 6 h, the resulting
mixture was diluted with dichloromethane and quenched
with water. The aqueous phase was extracted with
dichloromethane. The combined extracts were washed
with brine, dried over MgSO4, and filtered. Removal of
solvent left an oil which was purified by column
chromatography (EtOAc/n-hexane, 1:9), affording product
(604 mg, 95%) as a colorless oil: Rf¼0.55 (EtOAc/
n-hexane, 1:3); IR (KBr) 2925, 2887, 1494, 1454,
4.1.1. (1S)-1-Phenylbut-3-en-1-ol (2a). A solution of
tetravinyltin (0.46 mL, 2.45 mmol) in THF (7 mL) was
cooled to 0 8C and methyllithium (1.4 M in Et2O, 6.1 mL,
8.57 mmol) was added. The colorless solution was stirred
for 1 h and cooled to 278 8C. To a stirred heterogeneous
solution of CuCN (392 mg, 4.37 mmol) in THF (2 mL), the
colorless vinyllithium solution was added dropwise via
1408 cm21
.

B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
7357
1
4a: H NMR (400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0,
4.1.6. (1S,3R)-(1-(2-(Methoxymethoxy)-2-phenylethyl)-
but-3-enyl)methylamine (8). To a solution of alcohol 7
(188 mg, 0.79 mmol) in CH2Cl2 (5 mL) at 0 8C were added
triethylamine (0.22 mL, 1.59 mmol), methanesulfonyl-
chloride (0.12 mL, 1.59 mmol). After 30 min, the mixture
was diluted with dichloromethane, washed with brine, dried
over MgSO4, and concentrated to afford the crude mesylate.
The crude mesylate was taken up in a methanolic solution of
methylamine (14.6 mL, 39.2 mmol, 2.0 M in MeOH). The
resulting solution was heated to 70 8C for 12 h. After
cooling to room temperature, the solution was concentrated.
Then it was diluted with Et2O, washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified on silica gel (starting from EtOAc/n-hexane, 1:3 to
MeOH/CH2Cl2, 1:12) to afford 8 as a yellow oil (86 mg, two
steps 43%): Rf¼0.67 (MeOH/CH2Cl2, 1:8); [a]D¼2123.0
(c 1.0, MeOH); IR (KBr) 3354, 2936, 1638, 1493,
6.5, 5.0 Hz), 2.09 (m, 1H), 2.44 (dd, 1H, J¼5.0, 2.7 Hz),
2.70 (t, 1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s,
2H), 4.79 (t, 1H, J¼6.8 Hz), 7.25–7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9,
126.8, 127.8, 128.5, 141.0.
1
4b: H NMR (400 MHz, CDCl3) d 1.80 (ddd, 1H, J¼14.1,
7.1, 3.9 Hz), 2.13 (m, 1H), 2.59 (dd, 1H, J¼5.0, 2.7 Hz),
2.81 (t, 1H, J¼4.0 Hz), 3.16 (m, 1H),3.38 (s, 3H), 4.56 (s,
2H), 4.84 (dd, 1H, J¼9.4, 3.8 Hz), 7.25–7.39 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 41.4, 47.5, 49.6, 55.6, 75.2,
94.0, 126.6, 127.9, 128.5, 141.4.
4.1.4. (1S,3R)-Methoxymethyl-(2-oxiranyl-1-phenyl-
ethyl)ether (4a). A 25 ml round bottom flask equipped
with a stirring bar was charged with (R,R)-Co(salen)
catalyst (5, 16.8 mg, 27.8 mmol). The catalyst was treated
1
1454 cm21; H NMR (400 MHz, CDCl3) d 1.76 (ddd, 1H,
with
a
solution of 4a/4b mixture (,1:1, 580 mg,
J¼14.0, 8.1, 4.5 Hz), 1.91 (ddd, 1H, J¼13.3, 8.9, 4.4 Hz),
2.11 (bs, 1H), 2.28 (m, 1H), 2.41 (s, 3H), 2.75 (m, 1H), 3.39
(s, 3H), 4.54 (s, 2H), 4.82 (dd, 1H, J¼8.8, 4.4 Hz), 5.11 (d,
1H, J¼11.9 Hz), 5.77 (m, 1H), 7.28–7.35 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 32.8, 37.6, 41.9, 55.1, 55.7,
75.4, 94.2, 117.4, 126.6, 127.5, 128.4, 134.9, 142.0; HRMS
(EI) calcd for C15H23NO2 [Mþ] 249.1729, found 249.1716.
2.78 mmol), acetic acid (6.4 mL, 111 mmol) in THF
(0.2 mL). The solution was cooled to 0 8C, and H2O
(27 mL, 1.53 mmol) was added. The reaction mixture was
allowed to warm to room temperature and stirred for 16 h.
Pyridinium p-toluenesulfonate (28 mg, 4.0 equiv. based on
catalyst) and 1 mL of CH3CN/CH2Cl2 (1:1, v/v) were
added, and the reaction mixture was applied to a pad of
silica gel. The pad was washed with EtOAc. After the
mixture was concentrated under reduced pressure, the
residue was purified on silica gel (EtOAc/n-hexane, 1:6)
to afford 4a as a colorless oil (255 mg, 44%, 98% de based
on the H NMR): [a]D¼2121.1 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) d 1.91 (ddd, 1H, J¼14.0, 6.5, 5.0 Hz),
2.09 (q, 1H, 7.0 Hz), 2.44 (dd, 1H, J¼4.9, 2.6 Hz), 2.70 (t,
1H, J¼4.1 Hz), 2.90 (m, 1H), 3.37 (s, 3H), 4.54 (s, 2H), 4.79
(t, 1H, J¼6.8 Hz), 7.25–7.35 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 40.9, 46.7, 49.6, 55.5, 75.7, 93.9, 126.8, 127.9,
128.5, 141.0; HRMS (EI) calcd for C12H16O3 [Mþ]
208.1099, found 208.1097.
4.1.7. (1S,3R)-N-Allyl-(1-(2-(methoxymethoxy)-2-
phenylethyl)but-3-enyl)methylamine (9). To a solution
of amine 8 (63 mg, 0.25 mmol) in acetonitrile (3 mL) was
added powder K2CO3 (105 mg, 0.76 mmol). The mixture
was stirred for 30 min at room temperature, and then
allylbromide (32.8 mL, 0.38 mmol) was added. After
stirring for 4 h at room temperature, the resulting mixture
was diluted with Et2O and quenched with water. The
aqueous phase was extracted with Et2O. The extracts were
washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude residue was purified on silica gel (EtOAc/
n-hexane, 1:5) to afford 9 as a pale yellow oil (66 mg, 90%):
Rf¼0.57 (EtOAc/n-hexane, 1:3); [a]D¼2104.2 (c 1.0,
1
1
4.1.5. (1S,3S)-1-Methoxymethoxy-1-phenylhex-5-en-3-ol
(7). To a solution of CuBr/Me2S (246 mg, 1.2 mmol) in
THF (4 mL) cooled to 230 8C was added vinyl magnesium
bromide (3.6 mL, 3.6 mmol, 1.0 M in THF). The resulting
mixture was allowed to warm slowly to 20 8C and a
solution of epoxide 4a (250 mg, 1.2 mmol) in THF (2 mL)
was added at 260 8C. After being stirred at 230 8C for 1 h,
the mixture was allowed to warm slowly to room
temperature. The reaction was quenched with saturated
NH4Cl solution and extracted with Et2O. The combined
extracts were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The crude residue was
purified on silica gel (EtOAc/n-hexane, 1:6) to afford 7 as a
colorless oil (198 mg, 70%): Rf¼0.42 (EtOAc/n-hexane,
1:3); [a]D¼2159.5 (c 1.0, CHCl3); IR (KBr) 3447,
CHCl3); IR (KBr) 2942, 1639, 1493, 1452 cm21 1H
;
NMR (400 MHz, CDCl3) d 1.64 (ddd, 1H, J¼14.4, 9.6,
3.4 Hz), 1.80–1.93 (m, 2H), 2.19 (s, 3H), 2.90 (m, 1H), 3.01
(dd, 1H, J¼13.7, 6.1 Hz), 3.11 (dd, 1H, J¼13.8, 6.1 Hz),
3.32 (s, 3H), 4.53 (dd, 2H, J¼14.8, 6.6 Hz), 4.85 (dd, 1H,
J¼9.6, 3.3 Hz), 5.02 (d, 2H, J¼14.2 Hz), 5.04 (d, 1H,
J¼17.2 Hz), 5.15 (dd, 2H, J¼12.9, 1.3 Hz), 5.79 (m, 2H),
7.28–7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 33.1,
36.1, 39.8, 55.5, 56.5, 59.1, 75.3, 94.5, 116.1, 126.6, 127.2,
128.3, 137.0, 137.1, 143.1; HRMS (EI) calcd for
C18H27NO2 [Mþ] 289.2042, found 289.2036.
4.1.8. (2R)-2-((22)-2-(Methoxymethoxy)-2-phenylethyl)-
N-methylpiperidine (11). To a solution of diene 9 (178 mg,
0.61 mmol) in anhydrous benzene (28 mL) was added a
solution of the Grubbs ruthenium catalyst (Im)Cl2PCy3-
RuCHPh (10, 52 mg, 0.06 mmol) in benzene (2 mL) at
room temperature. The mixture was refluxed at 70 8C for
12 h. It was cooled to room temperature and was
concentrated in vacuo. Then, to a solution of crude
metathesis product in EtOAc (8 mL) was added PtO2
(14 mg, 0.06 mmol). After 1 h under H2 (1 atm), the mixture
was filtered through celite and concentrated in vacuo. The
crude residue in CH2Cl2 (5 mL) was added to a solution of
2943, 1638 cm21 1H NMR (400 MHz, CDCl3) d 1.81
;
(ddd, 1H, J¼14.4, 4.6, 2.4 Hz), 1.97 (m, 1H), 2.24 (m, 1H),
3.25 (d, 1H, J¼1.7 Hz), 3.39 (s, 3H), 3.83 (m, 1H), 4.45
(s, 2H), 4.84 (dd, 1H, J¼9.5, 4.7 Hz), 5.06 (d, 1H, J¼
2.3 Hz), 5.10 (d, 1H, J¼7.0 Hz), 5.82 (m, 1H), 7.25–7.35
(m, 5H); 13C NMR (100 MHz, CDCl3) d 41.9, 44.1, 55.9,
70.3, 78.0, 93.7, 117.6, 126.8, 127.9, 128.5, 134.5, 140.9;
HRMS (EI) calcd for C14H20O3 [Mþ] 236.1412, found
236.1462.

7358
B. Kang, S. Chang / Tetrahedron 60 (2004) 7353–7359
Lett. 1977, 223–228. (b) Liguori, A.; Ottana, R.; Romeo, G.;
Sindona, G.; Uccellla, N. Chem. Ber. 1989, 122, 2019–2020.
(c) Oppolzer, W.; Deerberg, J.; Tamura, O. Helv. Chim. Acta
1994, 77, 554–560. (d) Meth-Cohn, O.; Yau, C. C.; Yu, C.-Y.
J. Heterocyclic Chem. 1999, 36, 1549–1554. (e) Felpin, F.-X.;
Lebreton, J. Tetrahedron Lett. 2002, 43, 225–227.
activated charcoal (10.0 g, 50 equiv. wt of the crude
product) in CH2Cl2 (95 mL) and stirred for 12 h. After the
carbon was filtered, the filtrate was concentrated in vacuo
and purified on a silica gel column chromatography (MeOH/
CH2Cl2, starting from 1:8 to 1:3) to provide 11 as a colorless
oil (84 mg, two steps 52%): Rf¼0.37 (MeOH/CH2Cl2,
1:12); [a]D¼2101.1 (c 0.5, MeOH); IR (KBr) 2943, 1631,
6. For recent examples of metathesis-based synthesis from this
laboratory, see: (a) Jo, E.; Na, Y.; Chang, S. Tetrahedron Lett.
1999, 40, 5581–5582. (b) Lee, W.-W.; Chang, S.
Tetrahedron: Asymmetry 1999, 10, 4473–4475. (c) Lee,
W.-W.; Shin, H. J.; Chang, S. Tetrahedron: Asymmetry
2001, 12, 29–31. (d) Park, S.-H.; Kang, H. J.; Ko, S.; Park,
S. Y.; Chang, S. Tetrahedron: Asymmetry 2001, 12,
2621–2624. (e) Chang, S.; Na, Y.; Shin, H. J.; Choi, E.;
Jeong, L. S. Tetrahedron Lett. 2002, 43, 7445–7448. (f) Kang,
B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5,
3041–3043.
1
1454, 1376 cm21; H NMR (400 MHz, CDCl3) d 1.36 (m,
1H), 1.73 (m, 3H), 1.93 (m, 2H), 2.09 (m, 1H), 2.26 (m, 1H),
2.56 (s, 3H), 2.62 (m, 2H), 3.13 (m, 1H), 3.31 (s, 3H), 4.47
(dd, 2H, J¼9.7, 6.6 Hz), 4.68 (t, 1H, J¼6.9 Hz), 7.23–7.35
(m, 5H); 13C NMR (100 MHz, CDCl3) d 21.6, 22.5, 29.2,
38.2, 40.3, 54.9, 55.8, 61.5, 75.7, 94.1, 126.7, 128.3, 128.7,
139.9; HRMS (EI) calcd for C16H25NO2 [Mþ] 263.1885,
found 263.1848.
4.1.9. (2R)-2-((22)-2-Hydroxy-2-phenylethyl)-N-methyl-
piperidine (12). A solution of piperidine 11 (50 mg,
0.19 mmol) in CH3CN (2 mL) was treated with conc. HCl
(0.02 mL). After being stirred at room temperature for 4 h,
the solution was diluted with EtOAc/isopropanol mixture
and basified with aqueous NaHCO3 until pH 9–10. The
aqueous layer was extracted with ethyl acetate. The organic
extracts were dried over MgSO4, filtered, and evaporated
under reduced pressure. The crude residue was purified on
silica gel (MeOH/CH2Cl2, 1:6) to afford 12 (38 mg, 93%):
Rf¼0.37 (MeOH/CH2Cl2, 1:6); IR (KBr) 3363, 2943, 2692,
7. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936–938. (b) Jacobsen, E. N. Acc. Chem.
Res. 2000, 33, 421–431. (c) Ready, J. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2001, 123, 2687–2688. (d) Schaus, S. E.;
Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.;
Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307–1315.
8. It was obtained in high enantiomeric purity (.98% ee) using
the Jacobsen’s protocol (Ref. 7) in multi gram scales from
racemic epoxide.
1
1453 cm21; H NMR (400 MHz, CDCl3) d 1.47 (m, 1H),
9. (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. J. Org.
Chem. 1984, 49, 3938–3942. (b) Lipshutz, B. H.; Wilhelm,
R. S. J. Am. Chem. Soc. 1981, 103, 7672–7674.
1.73–1.78 (m, 2H), 1.85 (m, 1H), 1.93–2.01 (m, 3H), 2.11
(m, 1H), 2.77 (s, 3H), 2.84 (m, 1H), 3.16 (br, 1H), 3.30 (m,
1H), 5.11 (dd, 1H, J¼9.5, 3.2 Hz), 7.18–7.35 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 21.3, 22.4, 27.6, 38.7, 40.7,
55.7, 62.0, 68.7, 125.5, 127.3, 128.4, 144.1; HRMS (EI)
calcd for C14H21NO [Mþ] 219.1623, found 219.1624.
10. Smith, J. G. Synthesis 1984, 629–656.
11. (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307–1370. (b) Mihelich, E. D.; Daniels, K.; Eickhoff,
D. J. J. Am. Chem. Soc. 1981, 103, 7690–7692. (c) Fringuelli,
F.; Germani, R.; Pizzo, F.; Santinelli, F.; Savelli, G. J. Org.
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Acknowledgements
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This work was supported by a grant of the Korea Health 21
R and D Project, Ministry of Health and Welfare, Republic
of Korea (01-PJ1-PG1-01CH12-0002).
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