Asymmetric aza-Michael addition: synthesis of (-)-allosedridine and (-)-2-epi-ethylnorlobelol

Article abstract of DOI:10.1016/j.tetasy.2008.02.019

The combination of cross-metathesis and aza-Michael addition is an efficient method for generating piperidine alkaloids. Allosedridine and 2-epi-ethylnorlobelol were synthesized in six steps with ca. 25% overall yield. The aza-Michael addition is reversible for phenyl and alkyl ketones; however, the epimerization is not observed for the corresponding ester and amide.

Full text of DOI:10.1016/j.tetasy.2008.02.019

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 715–720
Asymmetric aza-Michael addition: synthesis of (ꢀ)-allosedridine
and (ꢀ)-2-epi-ethylnorlobelol
Li-Ju Chen and Duen-Ren Hou*
Department of Chemistry, National Central University, Jhong-Li City, Taoyuan 32001, Taiwan
Received 22 January 2008; accepted 14 February 2008
Abstract—The combination of cross-metathesis and aza-Michael addition is an efficient method for generating piperidine alkaloids.
Allosedridine and 2-epi-ethylnorlobelol were synthesized in six steps with ca. 25% overall yield. The aza-Michael addition is reversible
for phenyl and alkyl ketones; however, the epimerization is not observed for the corresponding ester and amide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
OH
Piperidine alkaloids,1 such as lobeline,2 coniine,3 and sed-
amine,4 represent a large, important family of natural
products. Many of these compounds are biologically ac-
tive, and the piperidine moiety is frequently found in the
structure of drug candidates.5 Therefore, the development
of an efficient, stereoselective access to the piperidine alka-
loids continues to attract the attention of organic chem-
ists.6 Recently, several research groups have shown that
asymmetric aza-Michael addition to generate b-amino-
ketones or esters is a good entry to alkaloids.7 For example,
O’Brien et al. have applied the tandem SN2 substitution
and intramolecular aza-Michael addition to prepare ethyl
2-piperidineacetate as a key intermediate in their synthesis
of (ꢀ)-sparteine.7d,8 We felt that this approach would be
applicable to our current studies in synthesizing piperidine
alkaloids. Thus, we applied the intramolecular aza-Michael
addition to the synthesis of (ꢀ)-allosedridine 1 and (ꢀ)-2-
epi-ethylnorlobelol 2, and report our results herein.
R
N
H
R = Me, (-)-allosedridine, 1
R = Et, (-)-2'-epi-ethylnorlobelol, 2
2. Results and discussion
Cross-metathesis (CM) of commercially available 6-chloro-
1-hexene and methyl acrylate quickly generates the 7-
chloro-hept-2-enoate 3 in good yield; the yield is lower
(47%) without p-cresol as the beneficial additive.9 Com-
pared to the reported method for preparing 7-chloro- and
7-iodo-hept-2-enoate,7f,10 our preparation utilizing CM
methodology decreases the number of synthetic steps. By
using phase transfer catalysis, substitution, and intramolec-
ular Michael addition of 3 and (R)-a-methylbenzylamine,
methyl 2-(piperidin-2-yl)acetates 4 and 5 were obtained in
a diastereomeric ratio of 2:1 (Scheme 1). This ratio is con-
sistent with O’Brien’s observation using 7-iodo-hept-2-eno-
ate.7d The diastereomers were separable by flash column
chromatography. Other chiral auxiliaries, (R)-1-(1-naph-
thyl)ethylamine and (R)-a-ethylbenzylamine, gave 4:5 in
the ratios of 3:1 and 1.5:1, respectively. However, the reac-
tions with these chiral amines were sluggish and the diaste-
reomers produced were more difficult to separate. The
reversibility of this intramolecular aza-Michael addition
was examined by re-subjecting 4 to the reaction conditions.
Under these conditions, we found that 4 does not epimerize
OH
N
H
Ph
N
Me
(-)-Conine
(+)-Sedamine
OH
O
Ph
N
Ph
Me
(-)-Lobeline
1
to 5, as shown by H NMR spectroscopy. This result sup-
*
ports the conclusion that the diastereomeric ratio of 4:5 is
determined at the cyclization step, which is in contrast to
Corresponding author. Tel.: +886 3 4227157; fax: +886 34227664;
e-mail: drhou@cc.ncu.edu.tw
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.019

716
L.-J. Chen, D.-R. Hou / Tetrahedron: Asymmetry 19 (2008) 715–720
Table 1. Reaction of 6 and organometallic reagents
Grubbs cat.
H3CO2C
2nd Generation
H3CO2C
Entry
Reagent
Temp. (°C)
Time (min)
Yield (%)
(CH2)4Cl
+
71a
65b
18
0
91
94
(CH2)4Cl
3
5 mol%, 80%
1
2
3
4
5
6
PhLi
PhLi
PhMgBr
Ph2CuLi
CH3MgCl
C2H5MgCl
ꢀ40
ꢀ40
ꢀ40
ꢀ40
25
30
60
60
60
90
90
(R)-α-Methylbenzylamine
H3CO2C
H3CO2C
N
N
NaI, Na2CO3, Bu4NBr,
CH3CN, 82%
4
5
Ph
Ph
25
2 : 1
a 11:12 = 4: 1.
b 11:12 = 2: 1.
O
(CH3O)CH3NH2Cl
4
N
O
N
AlMe3, CH2Cl2, 75%
6
Ph
reagents only gave poor yields or decomposed product
when used in place of phenyllithium (Table 1, entries 3
and 4).
Scheme 1.
Although the stereolability of 11 limits its suitability for
our purposes, methyl and ethyl ketones 13ab can be pre-
pared from 6 with retained stereochemistry and in good
yields (Table 1, entries 5 and 6). Epimerization of these
ketones 13ab is much slower. Thus, at room temperature,
four days was required for diastereomerically pure 13a
and 13b in CDCl3 to reach an equilibrium ratio of 2:1.
Therefore, isolation, purification, and further chemical
modification of ketones 13 are practical. The differences
in the rates of epimerization of 4, 6, 11, and 13 correlate
qualitatively with their relative acidities.13
the finding that the aza-Michael addition is reversible when
an a,b-unsaturated phenyl ketone is the acceptor (vide in-
fra). Compound 4 was further converted to the Weinreb
amide 6 at ꢀ10 °C.11
Alternatively, compound 6 was prepared from 6-chloro-1-
hexene by a sequence involving amination, ozonolysis,
Horner–Emmons olefination, and aza-Michael addition
(Scheme 2). This method was also applied to the prepara-
tion of phenyl ketone 9b and the corresponding b-ketopi-
peridines 11 and 12. Unfortunately, neither 9a nor 9b
provided an improved diastereomeric ratio for the intra-
molecular aza-Michael addition compared to that obtained
with 3. Nonetheless, the mixture of 6 and 10 was separable
by column chromatography. Pure 6 does not undergo epi-
merization to form 10 under the reaction conditions. Thus,
the formation of both compounds 4 and 6 is irreversible.
On the other hand, efforts to isolate pure 11 or 12 always
gave a 2:1 mixture even though these diastereomers have
distinct Rf values on TLC. This phenomenon suggests a
facile epimerization process for interconverting the two
phenyl ketones. This was confirmed when it was found that
the acyl substitution of pure 6 with phenyllithium at
ꢀ40 °C (Eq. 1 and entries 1 and 2, Table 1) generated both
11 and 12 in a ratio that approached 2:1 as the reaction
time increased. Thus, the behavior of 11 is analogous to
that of lobeline12 in that the epimerization occurs via a
retro-Michael addition. Phenyl Grignard and Gilman
O
O
RM
13a, R = Me
13b, R = Et
11 + 12, R = Ph
R
N
ð1Þ
N
O
N
THF
Ph
Ph
6
Ketones 13 were reduced to the corresponding alcohols
with sodium borohydride (Eq. 2 and Table 2). We found
that the addition of Lewis acids such as zinc chloride and
manganese(II) chloride improves the diastereoselectivity
up to 17:1 via chelation control.14 As seen in Eq. 3, hydro-
genolysis to remove the chiral auxiliary generated (ꢀ)-
allosedridine 1 and (ꢀ)-20-epi-ethylnorlobelol 2.
OH
O
NaBH4
MeOH
R
N
R
N
ð2Þ
(R)-α-Methylbenzylamine
(CH2)4Cl
Ph
Ph
NH
14a, R = Me
14b, R = Et
13a, R = Me
13b, R = Et
NaI, Na2CO3, Bu4NBr
7
Ph
H2O/MeCN, 61%
(i) (t-BuOCO)2O
CH2Cl2, 92%
Phosphorus ylids
NBoc
Table 2. Reduction of ketones 13
O
Entry
Compound
Additive
Temp.
(°C)
Time
(h)
dra
Yield
(%)
(ii) O3, CH2Cl2, 98%
Ph
8
O
O
+
O
1
2
3
4
5
6
13a
13a
13a
13a
13b
13b
—
—
MnCl2
ZnCl2
MnCl2
ZnCl2
25
0
0
0
0
2
3
3
16
3
16
3:1
4:1
7:1
17:1
5:1
14:1
62
71
66
95
46
99
(i) TFA, CH2Cl2
(ii) DBU, rt
R
(CH2)4NBoc
Ph
R
N
R
N
Ph
Ph
R = NCH3(OCH3), 6 + 10 (2 : 1), 95%
R = Ph, 11 + 12 (2 : 1), 96%
9a, R = NCH3(OCH3), 50%
9b, R = Ph, 73%
0
a Diastereomeric ratio, determined by 1H NMR spectroscopy.
Scheme 2.

L.-J. Chen, D.-R. Hou / Tetrahedron: Asymmetry 19 (2008) 715–720
717
25.59, 29.99, 31.98, 44.59, 51.55, 52.37, 59.29, 126.51,
127.28, 128.13, 146.13, 173.64; HRMS-FAB (m/z):
[M+H]+ calcd for (C16H24NO2) 262.1807; found
OH
H2, Pd/C
MeOH
OH
R
N
H
R
N
ð3Þ
262.1802. Diastereomer 5 (39 mg, 0.15 mmol, 26%) was
Ph
1, R = Me, 61%
2, R = Et, 62%
20
eluted later (Rf 0.45). ½aꢂ ¼ þ9:7 (c 1.5, CHCl3), 1H
D
14a, R = Me
14b, R = Et
NMR (200 MHz, CDCl3) d 2.25–2.35 (d, J = 6.7 Hz,
3H), 2.35–2.75 (m, 6H), 2.4–2.75 (m, 4H), 3.1–3.23 (m,
1H), 3.58 (s, 3H), 3.75–3.9 (q, J = 6.7 Hz, 1H), 7.15–7.4
(m, 5H); 13C NMR (50 MHz, CDCl3) d 20.2, 21.3, 24.9,
29.0, 32.7, 43.4, 51.4, 52.7, 59.1, 126.7, 127.3, 128.1,
144.7, 173.4.
3. Conclusion
In conclusion, the asymmetric synthesis of 1 and 2 was
achieved in six steps and 25–27% overall yield. The efficacy
of this sequence shows that the combination of cross-
metathesis and aza-Michael addition is a useful way to pre-
pare the piperidine alkaloids. We also demonstrated that
the reversibility of the intramolecular aza-Michael addition
is influenced by the carbonyl group, that is, the epimeriza-
tion rate of phenyl ketone 11 is faster than that of alkyl
ketones 13ab, while ester 4 and Weinreb amide 6 do not
epimerize under the reaction conditions. Consequently,
the diastereomeric ratios obtained from the intramolecular
aza-Michael additions of 3 and 9a were determined at the
stage of the initial cyclization.
4.3. N-Methoxy-N-methyl (2S)-1-[(1R)-1-phenylethyl]-
piperidineacetamide 6
Trimethylaluminum (2.0 M in toluene, 1.67 mL, 3.3 mmol)
was added dropwise to a solution of N,O-dimethyl-hydrox-
ylamine hydrochloride (325 mg, 3.3 mmol) and CH2Cl2
(4 mL) under nitrogen at ꢀ10 °C. The reaction mixture
was stirred at room temperature for another 30 min and
re-cooled to ꢀ10 °C. A solution of 4 (290 mg, 1.1 mmol)
in CH2Cl2 (2.0 mL) was added, and the mixture was stirred
for 2 h at ꢀ10 °C. It was then quenched with water (10 mL)
and extracted with CH2Cl2 (10 mL ꢁ 3). The combined
organic solution was dried over Na2SO4, filtered, and con-
centrated to give crude 6 (241.7 mg, 75%).
4. Experimental
Alternatively, to the solution of 9a (77 mg, 0.2 mmol) and
CH2Cl2 (0.7 mL) was added trifluoroacetic acid (114 mg,
1.0 mmol) at 0 °C, and the mixture was stirred for 1 h. It
was then concentrated under vacuum, redissolved in
CH2Cl2 (0.7 mL), after which DBU (500 lL, 0.33 mmol)
was added, and the solution was stirred at rt for 16 h. After
being concentrated, purification by column chromatogra-
phy (SiO2, CH3OH/CHCl3/Et3N, 1:1:0.02; Rf 0.50) affor-
ded 6 (36 mg, 0.12 mmol, 64%) as a colorless oil;
½aꢂD ¼ þ20:4 (c 1, CHCl3); H NMR (500 MHz, CDCl3)
d 1.28–1.32 (d, J = 6.6 Hz, 3H), 1.32–1.50 (m, 3H),
1.51–1.6 (m, 2H), 1.70–1.80 (m, 1H), 2.15–2.35 (m, 2H),
2.55–2.8 (m, 2H), 3.54–3.60 (m, 1H), 3.65–3.75 (m, 4H),
7.15–7.4 (m, 5H); 13C NMR (125 MHz, CDCl3) d 17.7,
20.8, 25.5, 29.3, 32.1, 45.2, 52.2, 59.5, 61.3, 126.8, 127.5,
128.3, 146.5, 173.5; HRMS-ESI (m/z): [M+H]+ calcd for
(C17H27N2O2), 291.2073; found, 291.2071.
4.1. (E)-Methyl 7-chloro-2-heptenoate 37f
To a solution of 6-chloro-1-hexene (100 mg, 0.84 mmol),
methyl acrylate (726 mg, 8.4 mmol), and p-cresol (46 mg,
0.42 mmol) was added the second generation Grubbs cata-
lyst15 (18 mg, 0.02 mmol) in toluene (0.5 mL). The reaction
mixture was heated in an oil bath (120 °C) for 3 h, and then
excess solvent was removed under vacuum. Purification by
column chromatography (SiO2: EtOAc/hexane 1:4; Rf
0.67) provided 3 (119 mg, 0.67 mmol, 80%) as a colorless
oil. 1H NMR (200 MHz, CDCl3) d 1.45–1.90 (m, 4H),
2.12–2.31 (m, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.70 (s, 3H),
5.81 (dt, J = 15.6 Hz and 1.4 Hz, 1H) 6.92 (dt,
J = 15.6 Hz and 7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 25.21, 31.30, 31.83, 44.54, 51.41, 121.44, 148.50, 166.94.
20
1
4.2. Methyl (2S)-1-[(1R)-1-phenylethyl]piperidineacetate 4
and (R,R)-diastereomer 5
4.4. (R)-N-(1-Phenylethyl)-5-hexenyl amine 716
A solution of 3 (100 mg, 0.57 mmol), tetrabutylammonium
bromide (50% in water, 255 mg), sodium iodide (255 mg,
1.7 mmol), sodium carbonate (300 mg, 2.9 mmol), and
(R)-a-methylbenzylamine (68.6 mg, 0.57 mmol) in acetoni-
trile (10 mL) was heated at reflux for 16 h. The reaction
mixture was diluted with water (10 mL) and extracted with
ether (15 mL ꢁ 3). The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The crude prod-
uct was purified by column chromatography (SiO2:
(R)-a-Methylbenzylamine (2.04 g, 16.9 mmol) was added
to a solution of 6-chloro-1-hexene (1.0 g, 8.4 mmol), tetra-
butylammonium bromide, 50% in water, 544 mg,
0.84 mmol, sodium iodide (2.53 g, 16.9 mmol), sodium car-
bonate (2.68 g, 25.3 mmol), and acetonitrile (15 mL). After
being heated at reflux for 16 h, the reaction mixture was di-
luted with water (20 mL), extracted with ether (15 mL ꢁ 3),
and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Purification by column chromato-
graphy (SiO2, EtOAc/hexanes/Et3N, 2:3:0.05; Rf 0.45) gave
EtOAc/hexane/Et3N, 1:4:0.05; Rf 0.67) to give 4 (81 mg,
20
0.31 mmol, 55%) as a colorless oil; ½aꢂD ¼ þ39:2 (c 1,
7 (1.04 g, 5.1 mmol, 61%) as a light yellow oil;
20
CHCl3), 1H NMR (200 MHz, CDCl3) d 1.25–1.32 (d,
J = 6.7 Hz, 3H), 1.35–1.85 (m, 6H), 2.1–2.4 (m, 2H), 2.5–
2.63 (m, 2H), 3.38–3.55 (m, 1H), 3.6–3.75 (m, 4H), 7.15–
7.4 (m, 5H); 13C NMR (50 MHz, CDCl3) d 17.87, 20.80,
½aꢂD ¼ þ46:8 (c 1, CHCl3); H NMR (500 MHz, CDCl3)
d 1.30–1.32 (d, J = 6.6 Hz, 3H), 1.32–1.55 (m, 5H), 1.95–
2.05 (q, J = 7.05 Hz, 2H), 2.35–2.55 (m, 2H), 3.70–3.80
(q, J = 6.6 Hz, 1H), 4.98–5.02 (m, 2H), 5.70–5.85 (m,
1

718
L.-J. Chen, D.-R. Hou / Tetrahedron: Asymmetry 19 (2008) 715–720
1H), 7.20–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3) d
24.3, 26.6, 29.8, 33.6, 47.7, 58.4, 114.4, 126.5, 126.8,
128.4, 138.8, 145.9; HRMS-FAB (m/z): [M+H]+ calcd
for (C14H22N), 204.1752; found, 204.1747.
32.0, 32.3, 43.3, 52.8, 61.5, 79.4, 118.7, 126.9, 127.9,
128.2, 141.9, 147.2, 155.7, 166.9; HRMS-ESI (m/z):
[M+H]+ calcd for (C22H35N2O4), 391.2597; found,
391.2599; IR(cmꢀ1): 3063, 3028, 2973, 2936, 1686, 1666,
1635, 1157, 1024.
4.5. tert-Butyl 5-oxopentyl (R)-(1-phenylethyl)carbamate 8
4.7. tert-Butyl (7-oxo-7-phenyl-(5,E)-heptenyl)-(R)-(1-phen-
ylethyl)carbamate 9b
Di-tert-butyl dicarbonate (1.23 g, 5.6 mmol) was added to
a solution of 7 (1.04 g, 5.1 mmol) and CH2Cl2 (20 mL).
The solution was stirred at rt for 16 h, and excess reagent
and by-product were removed by washing with water
(10 mL ꢁ 3). The organic layer was dried over Na2SO4, fil-
tered, and concentrated to give the Boc-protected 7 as a
To a solution of 8 (388 mg, 1.27 mmol) and benzene (5 mL)
was added 1-phenyl-2-(triphenylphosphoranylidene)etha-
none18 (483 mg, 1.27 mmol). The solution was heated at
reflux for 16 h. The solvent was removed under vacuum,
and purification by column chromatography (SiO2,
EtOAc/hexanes, 1:4; Rf 0.40) gave 9b (378 mg, 0.93 mmol,
20
light-yellow oil (1.43 g, 4.7 mmol). ½aꢂD ¼ þ71:1 (c 1,
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.18–1.25 (m,
2H), 1.41 (s, br, 9H), 1.49–1.52 (m, 5H), 1.90–2.00 (m,
2H), 2.70–3.40 (m, br, 2H), 4.85–5.00 (m, 2H), 5.60–5.80
(m, 1H), 7.15–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3)
d 26.43, 27.39, 28.48, 33.30, 79.37, 85.15, 114.37, 126.95,
128.21, 138.66, 146.73; HRMS-FAB (m/z): [M+H]+ calcd
for (C19H30NO2), 304.2277; found, 304.2274.
20
1
73%) as a light-yellow oil. ½aꢂ ¼ þ49:0 (c 1, CHCl3); H
NMR (200 MHz, CDCl3) d D1.30–1.60 (m, 16H), 2.10–
2.30 (q, J = 6.8 Hz, 2H), 2.70–3.20 (m, br, 2H), 5.10–5.65
(m, br, 1H), 6.70–7.10 (m, 2H), 7.15–7.30 (m, 5H), 7.35–
7.6 (m, 3H), 7.85–7.95 (dd, J = 1.36 Hz, 7.96 Hz, 2H);
13C NMR (50 MHz, CDCl3) d 17.5, 25.7, 28.5, 29.4, 32.3,
43.5, 79.5, 126.0, 127.0, 128.2, 128.5, 132.5, 137.9, 141.9,
149.3, 155.7, 190.8; HRMS-FAB (m/z): [M+H]+ calcd
for (C26H34NO3), 408.2539; found, 408.2534; IR(cmꢀ1):
3063, 3030, 2973, 2933, 1683, 1671, 1636, 1156, 1024.
Ozone was bubbled into a solution of 7 the Boc-protected
(500 mg, 1.65 mmol) and methanol (50 mL) at ꢀ78 °C until
a light-blue color was observed. Dimethyl sulfide (0.61 mL,
8.24 mmol) was added at ꢀ78 °C. The solution was stirred
overnight and warmed to rt during this period. After the
removal of methanol under vacuum, the reaction mixture
was diluted with CH2Cl2 (20 mL) and washed with water
(10 mL ꢁ 3). The organic solution was dried over Na2SO4,
4.8. (2S)-(1-(R)-Phenylethyl-2-piperidyl)acetophenone 11
and the (R,R)-diastereomer 12
Trifluoroacetic acid (1.4 mL, 1.85 mmol) was added to a
solution of 9b (150 mg, 0.37 mmol) and CH2Cl2 (1.2 mL)
at 0 °C. After being stirred at 0 °C for 1 h, the reaction mix-
ture was concentrated and combined with a solution of
DBU (0.9 mL, 0.62 mmol) in CH2Cl2 (1.2 mL). The reaction
was stirred at rt for another 16 h, concentrated, and DBU
was removed by flash column chromatography (SiO2,
EtOAc/hexanes, 3:7) to give the two inseparable diastereo-
mers 11 and 12 (2:1, 109 mg, 0.35 mmol, 96%) as a yellow
oil (Rf 0.6 and 0.5, respectively, on SiO2-TLC plate eluted
filtered, and concentrated to give 8 (493 mg, 98%) as a light
20
yellow oil. ½aꢂD ¼ þ71:7 (c 1, CHCl3); 1H NMR(500 MHz,
CDCl3) d 1.35–1.55 (m, 16H), 2.27–3.05 (m, 2H), 2.75–3.1
(m, br, 2H), 5.2–5.7 (m, br, 1H), 7.20–7.40 (m, 5H), 9.65 (t,
J = 1.63 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 17.4, 19.5,
27.4, 28.5, 29.3, 43.4, 79.6, 85.2, 127.0, 128.3, 141.9, 155.7,
202.2; HRMS-FAB (m/z): [M+H]+ calcd for (C18H28NO3),
306.2069; found, 306.2067; IR(cmꢀ1): 3063, 3030, 2975,
2938, 2805, 2719, 1725, 1686, 1603, 1454, 1159, 1131.
1
by EtOAc/hexanes/Et3N, 1:4:0.05). Diastereomer 11: H
NMR (200 MHz, CDCl3) d 1.15–1.85 (m, 9H), 2.30–2.45
4.6. tert-Butyl 7-[methoxy(methyl)amino]-7-oxo-(5,E)-hep-
ten-yl-(R)-(1-phenylethyl) carbamate 9a
(m, 2H), 3.10–3.30 (m, 2H), 3.65–3.77 (m, 2H), 7.15–8.15
1
(m, 5H); diastereomer 12: H NMR (200 MHz, CDCl3) d
1.15–1.85 (m, 4.5H), 2.5–2.65 (m, 0.5H), 2.75–2.85 (m,
0.5H), 2.95–3.3 (m, 1H), 3.77–3.85 (m, 0.5H), 7.15–8.15
(m, 2.5H); HRMS-FAB (m/z): [M+H]+ calcd for
(C21H26NO), 308.2014; found, 308.2011. 13C NMR (mix-
ture of 11 and 12, 75 MHz, CDCl3) d 18.2, 19.7, 21.1, 22.2,
25.4, 25.6, 29.0, 30.2, 35.7, 35.9, 43.7, 45.2, 52.1, 52.7,
59.5, 60.2, 126.6, 126.9, 127.3, 127.5, 128.1, 128.2, 128.5,
128.7, 132.8, 133.0, 137.0, 137.7, 145.0, 146.2, 200.3, 200.7.
To a solution of dimethyl [2-(methoxymethylamino)-2-
oxoethyl]phosphonate17 (510 mg, 2.1 mmol) and THF
(3 mL) was added n-butyllithium (1.6 M in hexanes,
1.4 mL, 2.1 mmol) at 0 °C. The ylid solution was stirred
for 15 min, and 8 (650 mg, 2.1 mmol) dissolved in THF
(1.6 mL) was added at 0 °C. The reaction mixture was stir-
red at rt for 16 h, quenched with water (5 mL), and ex-
tracted with diethyl ether (5 mL ꢁ 3). The combined
organic layers were washed with satd NaCl(aq) (10 mL),
dried over Na2SO4, filtered, and concentrated. Purification
by column chromatography (SiO2, EtOAc/hexanes/Et3N,
4.9. N-Methoxy-N-methyl (2R)-1-[(1R)-1-phenylethyl]-pipe-
ridineacetamide 10
1:1:0.02; Rf 0.50) yielded 9a (416 mg, 1.1 mmol, 50%) as a
Trifluoroacetic acid (750 lL, 1 mmol) was added to a solu-
tion of 9a (77 mg, 0.20 mmol) and CH2Cl2 (0.7 mL) at
0 °C. After being stirred at 0 °C for 1 h, the reaction mix-
ture was concentrated and combined with a solution of
DBU (500 lL, 0.3 mmol) in CH2Cl2 (0.7 mL). The mixture
was stirred at rt for 16 h and concentrated. Purification by
column chromatography (SiO2, CH3OH/CHCl3/Et3N,
20
light-yellow oil. ½aꢂD ¼ þ54:0 (c 1, CHCl3); 1H NMR
(200 MHz, CDCl3) d 1.20–1.60 (m, 16H), 2.10–2.20 (m,
2H), 2.70–3.10 (m, br, 2H), 3.19 (s, 3H), 3.64 (s, 3H),
5.00–5.50 (m, br, 1H), 6.25–6.35 (d, J = 15.4 Hz, 1H),
6.80–6.95 (dt, J = 6.95 Hz, 15.4 Hz, 1H), 7.2–7.35 (m,
5H); 13C NMR (50 MHz, CDCl3) d 17.5, 25.8, 28.4, 29.5,

L.-J. Chen, D.-R. Hou / Tetrahedron: Asymmetry 19 (2008) 715–720
719
1:4:0.05) provided diastereomers
6
(Rf 0.5, 36 mg,
and concentrated. Purification by column chromatography
(SiO2, CH3OH/CHCl3/Et3N, 1:9:0.01; Rf 0.50) gave im-
pure alcohol (47.5 mg, 0.19 mmol, 95%). Repeating the col-
umn chromatography provided diastereomerically pure
0.1 mmol, 64%) and 10 (Rf 0.3, 18 mg, 0.06 mmol, 32%)
1
as colorless oils. H NMR (500 MHz, CDCl3) d 1.30–1.35
(d, J = 6.5 Hz, 3H), 1.35–1.45 (m, 2H), 1.50–1.70 (m,
4H), 2.50–2.65 (m, 3H), 2.70–2.80 (m, 1H), 3.08 (s, 3H),
3.18–3.25 (q, J = 4.6 Hz, 1H), 3.50 (s, 3H), 3.80–3.91 (q,
J = 6.5 Hz, 1H), 7.15–7.4 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 20.5, 21.3, 25.4, 29.5, 30.4, 32.0, 43.8, 52.4,
59.2, 61.1, 126.6, 127.4, 128.1, 144.7, 173.9.
14a (25 mg, 0.1 mmol, 50%) as
a light-yellow oil.
20
1
½aꢂD ¼ þ13:5 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3)
d 0.90–1.00 (m, 2H), 1.04–1.08 (d, J = 6.1 Hz, 3H), 1.22–
1.28 (m, 1H), 1.30–1.35 (d, J = 6.5 Hz, 3H), 1.55–1.70
(m, 3H), 1.82–1.92 (m, 1H), 2.01–2.11 (m, 1H), 2.75–2.85
(m, br, 2H), 3.02–3.20 (m, 2H), 3.52–3.6 (m, 1H), 4.06–
4.14 (q, J = 6.5 Hz, 1H), 6.55–7.05 (s, br, 1H), 7.16–7.37
(m, 5H); 13C NMR (125 MHz, CDCl3) d 19.13, 20.04,
22.05, 23.48, 23.65, 37.44, 41.07, 54.64, 57.94, 68.72,
127.13, 127.29, 128.69, 145.29; HRMS-ESI (m/z):
[M+H]+ calcd for (C16H26NO), 248.2014; found, 248.2009.
4.10. 1-[(2S)-1-[(1R)-1-Phenylethyl]-2-piperidinyl]-2-
propanone 13a
Methylmagnesium chloride (3 M in THF, 175 lL,
0.52 mmol) was added to a solution of 6 (50 mg,
0.17 mmol) and THF (0.5 mL) at 25 °C. After being stirred
for 1.5 h at 25 °C, the reaction mixture was cooled in an
ice-water bath, satd NH4Cl(aq) and 1 M HCl(aq) (1:1,
0.6 mL) were added, and the mixture was diluted with
water (5 mL) Following extraction with CH2Cl2
(5 mL ꢁ 3), the combined organic solution was dried over
4.13. (R)-1-((S)-1-((R)-1-Phenylethyl)-2-piperidinyl)butan-2-
ol 14b
Sodium borohydride (29 mg, 0.77 mmol) was added to a
solution of 13b (50 mg, 0.19 mmol), zinc chloride (13 mg,
0.1 mmol), and methanol (0.5 mL) at 0 °C. The reaction
mixture was stirred at rt for 16 h, quenched with water
(5 mL), and extracted with CH2Cl2 (5 mL ꢁ 3). The com-
bined organic solution was dried over Na2SO4, filtered,
and concentrated. Purification by column chromatography
(SiO2, CH3OH/CHCl3/Et3N, 1:9:0.01; Rf 0.45) gave
impure alcohol (49.4 mg, 0.2 mmol, 99%). Repeating the
column chromatography provided diastereomerically pure
14b (30 mg, 0.11 mmol, 60%) as a light-yellow oil.
Na2SO4, filtered, and concentrated to give 13a (38.4 mg,
20
0.15 mmol, 91%) as a light-yellow oil. ½aꢂD ¼ þ41:4 (c
1
1.1, CHCl3); H NMR (300 MHz, CDCl3) d 1.20–1.30 (d,
J = 6.6 Hz, 3H), 1.30–1.60 (m, 5H), 1.68–1.72 (m, 1H),
2.15 (s, 3H), 2.18–2.40 (m, 2H), 2.60–2.70 (m, 2H), 3.45–
3.55 (m, 1H), 3.55–3.68 (q, J = 6.6 Hz, 1H), 7.15–7.4 (m,
5H); 13C NMR (125 MHz, CDCl3) d 18.0, 20.9, 25.5,
30.0, 30.9, 41.3, 44.9, 51.4, 59.3, 126.5, 127.3, 128.2,
146.1, 208.7; HRMS-ESI (m/z): [M+H]+ calcd for
(C16H24NO), 246.1858; found, 246.1863; IR(cmꢀ1): 3060,
3024, 2970, 2932, 1710, 1601,1453.
20
1
½aꢂD ¼ þ5:8 (c 0.35, CHCl3); H NMR (500 MHz, CDCl3)
d 0.80–0.87 (t, J = 7.5 Hz, 3H), 0.92–1.03 (m, 1H), 1.20–
1.30 (m, 2H), 1.30–1.35 (d, J = 6.3 Hz, 3H), 1.40–1.50
(m, 1H), 1.60–1.75 (m, 2H), 1.82–1.93 (m, 1H), 1.96–2.1
(m, 1H), 2.75–2.9 (m, br, 1H), 3.02–3.21 (m, 2H), 3.27–
3.4 (m, 1H), 4.05–4.20 (q, J = 6.3 Hz, 1H), 6.70–7.05 (s,
br, 1H), 7.2–7.45 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 9.8, 19.1, 20.0, 22.1, 23.8, 30.6, 35.1, 41.1, 54.6, 57.9,
73.9, 127.1, 127.4, 128.7, 145.2; HRMS-ESI (m/z):
[M+H]+ calcd for (C17H28NO), 262.2171; found, 262.2172.
4.11. 1-[(2S)-1-[(1R)-1-Phenylethyl]-2-piperidinyl]-2-
butanone 13b
Ethylmagnesium chloride (1 M in THF, 525 lL,
0.52 mmol) was added to a solution of 6 (50 mg,
0.17 mmol) and THF (0.5 mL) at 25 °C. Following the
same procedure as with 13a, compound 13b (38.4 mg,
0.16 mmol, 94%) was obtained as a light-yellow oil.
20
1
½aꢂD ¼ þ32:6 (c 0.8, CHCl3); H NMR (500 MHz, CDCl3)
d 1.00–1.10 (t, J = 7.3 Hz, 3H), 1.22–1.28 (d, J = 6.7 Hz,
3H), 1.3–1.55 (m, 5H), 1.68–1.78 (m, 1H), 2.18–2.37 (m,
2H), 2.37–2.50 (m, 2H), 2.6–2.65 (d, J = 6.5 Hz, 2H),
3.46–3.55 (m, 1H), 3.58–3.65 (q, J = 6.7 Hz, 1H), 7.15–
7.20 (m, 1H), 7.22–7.29 (m, 2H), 7.31–7.35 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 7.8, 17.9, 20.9, 25.6, 30.2,
37.0, 39.9, 45.0, 51.5, 59.3, 126.5, 127.3, 128.1, 146.2,
211.2; HRMS-ESI (m/z): [M+H]+ calcd for (C17H26NO),
260.2014; found, 260.2011; IR(cmꢀ1): 3060, 3024, 2970,
2932, 1709, 1601, 1453.
4.14. (ꢀ)-Allosedridine 1
A suspension of 14a (25 mg, 0.1 mmol), palladium (5% on
activated carbon, 5 mg) in methanol (2 mL) was stirred at
25 °C for 3 h under a hydrogen atmosphere (1 atm). The
suspension was filtered and concentrated to give 1
(8.8 mg, 0.06 mmol, 61%). Mp 61.5–63.0 °C (crystallized
20
from diethyl ether); ½aꢂD ¼ þ20:7 (c 0.22, MeOH);6c 1H
NMR (500 MHz, CDCl3) d 1.11–1.15 (d, J = 6.16 Hz,
3H), 1.30–1.70 (m, 7H), 1.75–1.85 (m, 1H), 2.65–2.75 (m,
1H), 2.85–2.96 (m, 1H), 3.15–3.21 (m, br, 1H), 3.95–4.06
(m, 1H), 4.58 (s, br, 2H); 13C NMR (125 MHz, CDCl3) d
23.45, 24.03, 24.86, 32.06, 43.08, 45.39, 57.87, 68.11;
HRMS-FAB (m/z): [M+H]+ calcd for (C8H18NO),
144.1388; found, 144.1389.
4.12. (R)-1-((S)-1-((R)-1-Phenylethyl)-2-piperidinyl)propan-
2-ol 14a
Sodium borohydride (31 mg, 0.8 mmol) was added to a
solution of 13a (50 mg, 0.2 mmol), zinc chloride (14 mg,
0.1 mmol), and methanol (0.5 mL) at 0 °C. The reaction
mixture was stirred at rt for 16 h, quenched with water
(5 mL), and extracted with CH2Cl2 (5 mL ꢁ 3). The com-
bined organic solution was dried over Na2SO4, filtered,
4.15. (ꢀ)-20-epi-Ethylnorlobelol 2
A suspension of 14b (30 mg, 0.1 mmol), palladium (5% on
activated carbon, 5 mg) in methanol (2 mL) was stirred at
25 °C for 3 h under a hydrogen atmosphere (1 atm). The

720
L.-J. Chen, D.-R. Hou / Tetrahedron: Asymmetry 19 (2008) 715–720
5, 70; (c) Takahata, H.; Kubota, M.; Ikota, N. J. Org. Chem.
1999, 64, 8594; (d) Passarella, D.; Barilli, A.; Belinghieri, F.;
Fassi, P.; Riva, S.; Sacchetti, A.; Silvania, A.; Danielia, B.
Tetrahedron: Asymmetry 2005, 16, 2225.
suspension was filtered and concentrated to give 2
20
(11.0 mg, 0.07 mmol, 62%). ½aꢂD ¼ ꢀ6:8 (c 0.24, EtOH);6c
1H NMR (500 MHz, CDCl3) d 0.84–0.90 (t, J = 7.47 Hz,
3H), 1.12–1.25 (m, 1H), 1.30–1.52 (m, 6H), 1.55–1.70 (m,
2H), 1.75–1.85 (m, 1H), 2.56–2.65 (m, 1H), 2.72–2.80 (m,
1H), 3.05–3.13 (m, 1H), 3.65–3.75 (m, 1H), 4.04 (s, br,
2H); 13C NMR (125 MHz, CDCl3) d 9.8, 24.1, 26.3, 30.9,
33.4, 41.5, 45.7, 58.1, 74.0; HRMS-ESI (m/z): [M+H]+
calcd for (C9H20NO), 158.1545; found, 158.1547.
7. (a) Yamada, M.; Nagashima, N.; Hasegawa, J.; Takahashi, S.
´
Tetrahedron Lett. 1998, 39, 9019; (b) Fustero, S.; Jimenez, D.;
´
´
Sanchez-Rosello, M.; del Pozo, C. J. Am. Chem. Soc. 2007,
129, 6700; (c) Chippindale, A. M.; Davies, S. G.; Iwamoto,
K.; Parkin, R. M.; Smethurst, C. A. P.; Smith, A. D.;
Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253; (d) Hermet,
J.-P. R.; McGrath, M. J.; O’Brien, P.; Portera, D. W.; Gilday,
J. Chem. Commun. 2004, 1830; (e) Yu, L.-T.; Huang, J.-L.;
Chang, C.-Y.; Yang, T.-K. Molecules 2006, 11, 641; (f) Al-
Sarabi, A. E.; Bariau, A.; Gabant, M.; Wypych, J.-C.;
Chalard, P.; Troin, Y. ARKIVOC 2007, 119.
Acknowledgments
This research was supported by the National Science
Council (NSC 95-2113-M-008-007), Taiwan. The authors
thank Prof. John C. Gilbert, Santa Clara University for
helpful comments. We are grateful to Ms. Ping-Yu Lin at
the Institute of Chemistry, Academia Sinica, and Valuable
Instrument Center in National Central University for
obtaining mass spectral analyses. Thanks are also due to
the National Center for High-performance Computing
for computer time and facilities.
8. Bunce, R. A.; Peeples, C. J.; Jones, P. B. J. Org. Chem. 1992,
57, 1727.
9. (a) Forman, G. S.; McConnell, A. E.; Tooze, R. P.; van
Rensburg, W. J.; Meyer, W. H.; Kirk, M. M.; Dwyer, C. L.;
Serfontein, D. Organometallics 2005, 24, 4528; (b) Chou,
C.-Y.; Hou, D.-R. J. Org. Chem. 2006, 71, 9887.
10. Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62,
7418.
11. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815; (b) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.;
Ha, H.-J. J. Org. Chem. 2003, 68, 7675; (c) Bariau, A.; Canet,
J.-L.; Chalard, P.; Troin, Y. Tetrahedron: Asymmetry 2005,
16, 3650.
References
`
12. Compere, D.; Marazano, C.; Das, B. C. J. Org. Chem. 1999,
1. (a) Eibein, A. D.; Molyneux, R. In Alkaloids; Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; John Wiley and
Sons: New York, 1987; Vol. 57, p 1; (b) Bisai, A.; Singh, V.
K. Tetrahedron Lett. 2007, 48, 1907.
2. Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237; A
recent review on lobeline: McCurdy, C. R.; Miller, R. L.;
Beach, J. W. In Biologically Active Natural Products; Cutler,
S. J., Cutler, H. G., Eds.; CRC: Boca Raton, Fla, 2000; pp
151–162.
3. A recent review on Hemlock alkaloids: Reynolds, T. Phyto-
chemistry 2005, 66, 1399 and references cited therein.
4. (a) Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del
Pozo, C. Org. Lett. 2007, 9, 5283; (b) Yadav, J. S.; Reddy, M.
S.; Rao, P. P.; Prasad, A. R. Synthesis 2006, 23, 4005; (c)
Zheng, G.; Dwoskin, L. P.; Crooks, P. A. J. Org. Chem. 2004,
69, 8514.
5. Examples: (a) Gilligan, P. J.; Cain, G. A.; Christos, T. E.;
Cook, L.; Drummond, S.; Johnson, A. L.; Kergaye, A. A.;
McElroy, J. F.; Rohrbach, K. W.; Schmidt, W. K.; Tam, S.
W. J. Med. Chem. 1992, 35, 4344; (b) Yang, S. S.; Cragg, G.
M.; Newman, D. J.; Bader, J. P. J. Nat. Prod. 2001, 64, 265;
(c) Kennelly, E. J.; Flynn, T. J.; Mazzola, E. P.; Roach, J. A.;
McCloud, T. G.; Danford, D. E.; Betz, J. M. J. Nat. Prod.
64, 4528 and references cited therein.
13. The pKa-values of compounds 11, 13, 4, and 6 should be
analogous to acetophenone, acetone, ethyl acetate, and N,N-
diethylacetamide, whose pKa-values in DMSO are 24.7, 26.5,
30.5, and 34.5, respectively: Matthews, W. S.; Bares, J. E.;
Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker,
G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.;
Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006; Bordwell, F.
G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
14. (a) Berkesˇ, D.; Kolarovicˇ, A.; Povazˇanec, F. Tetrahedron
Lett. 2000, 41, 5257; (b) Berkesˇ, D.; Kolarovicˇ, A.; Manduch,
R.; Baran, P.; Povazˇanec, F. Tetrahedron: Asymmetry 2005,
16, 1927; (c) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 16178; (d) Yun, J. M.; Sim, T. B.;
Hahm, H. S.; Lee, W. K.; Ha, H.-J. J. Org. Chem. 2003, 68,
7675–7680.
15. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
16. Craig, D. C.; Edwards, G. L.; Muldoon, C. A. Synlett 1997,
1441.
17. Frame, R. R.; Faulconer, W. J. Org. Chem. 1971, 36,
2048.
18. Babu, K. S.; Li, X.-C.; Jacob, M. R.; Zhang, Q.; Khan, S. I.;
Ferreira, D.; Clark, A. M. J. Med. Chem. 2006, 49, 7877–
7886.
´
1999, 62, 1385; (d) Mill, S.; Hootele, C. J. Nat. Prod. 2000, 63,
762.
6. Reviews on piperidine synthesis: (a) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701; (b) Cossy, J. Chem. Rec. 2005,