A divergent approach for the total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids

Article abstract of DOI:10.1016/j.tet.2008.12.067

The divergent total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids are described. A common intermediate 5 for the two types of alkaloids was assembled practically from (+)-citronellal via organocatalytic α-amination, followed by th

Full text of DOI:10.1016/j.tet.2008.12.067

Tetrahedron 65 (2009) 1608–1617
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A divergent approach for the total syntheses of cernuane-type and
quinolizidine-type Lycopodium alkaloids
*
Yasuhiro Nishikawa, Mariko Kitajima, Noriyuki Kogure, Hiromitsu Takayama
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The divergent total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids are de-
scribed. A common intermediate 5 for the two types of alkaloids was assembled practically from
Received 20 November 2008
Received in revised form 15 December 2008
Accepted 16 December 2008
Available online 25 December 2008
(þ)-citronellal via organocatalytic
a-amination, followed by the construction of oxazolidinone that was
used for diastereoselective allylation. Key compound 5 was converted into cermizine C (3), and this in
turn was converted into senepodine G (4) by the regioselective Polonovsky–Potier reaction. The total
synthesis of representative cernuane-type alkaloids, (ꢀ)-cernuine (1) as well as (þ)-cermizine D (2), was
also accomplished from 5 by utilizing asymmetric transfer aminoallylation as a key step.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
alkaloids, (þ)-cermizine D (2), (þ)-cermizine C (3), and (ꢀ)-sen-
epodine G (4).
The genus Lycopodium (Lycopodiaceae) has long been studied
because it boasts of a number of alkaloids, the so-called Lycopodium
alkaloids,1 which have unique structures and biological activities,
such as acetylcholine esterase (AchE) inhibitory activity. It is pri-
marily because of this that Lycopodium alkaloids have been an at-
tractive target in synthetic organic chemistry2 and medicinal
chemistry. Cernuine (1), which was isolated by Marion and Manske
in 1948, is a representative of cernuane-type Lycopodium alka-
loids.3a Its structure featuring a fused tetracyclic ring system con-
taining an aminal moiety was elucidated by Ayer et al. in 1967.3b–e
Although the total syntheses of various types of Lycopodium alka-
loids have been achieved, that of cernuane-type alkaloids has not
been reported to date. In 2004, Kobayashi et al. reported the iso-
lation of cermizine D (2), cermizine C (3), and senepodine G (4), in
which cermizine D and senepodine G exhibited cytotoxicity to
2. Results and discussion
2.1. Retrosynthesis
Our synthetic plan is outlined in Scheme 1. As the target com-
pounds have the same quinolizidine structure, we envisioned that
both cernuane-type and quinolizidine-type Lycopodium alkaloids
could be provided from a key intermediate such as 5, which has the
common quinolizidine core bearing appropriate functional groups
for further transformation into the target compounds. Following the
divergent strategy, cermizine C (3) and senepodine G (4) would be
H
H
murine lymphoma L1210 cells with an IC50 of 7.5 mg/mL and 7.8 mg/
H
H
H
N
N
mL, respectively (Fig. 1).4 These compounds are new Lycopodium
alkaloids possessing a quinolizidine skeleton related to cernuine
(1). As part of our chemical research on Lycopodium alkaloids,5 we
attempted to establish an efficient synthetic route to these cer-
nuane-type and quinolizidine-type alkaloids, and our endeavor has
enabled us to confirm their structures and absolute configurations.
Recently, we completed the first total synthesis of (ꢀ)-cernuine (1)
and (þ)-cermizine D (2).5a In this article, we present the details of
the divergent syntheses of (ꢀ)-cernuine (1) and related Lycopodium
N
H
H
N
H
O
cernuine (1)
cermizine D (2)
H
N
H
N
cermizine C (3)
senepodine G (4)
* Corresponding author. Tel./fax: þ81 43 290 2901.
Figure 1. Cernuane-type and quinolizidine-type Lycopodium alkaloids isolated from
Lycopodium cernuum.
E-mail address: htakayam@p.chiba-u.ac.jp (H. Takayama).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.067

Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
1609
stereocontrolled
allylation
H
H
reductive
cyclization
H
H
N
H
H
N
H
N
H
N
H
H
N
H
H2N
aminoallylation
O
O
RCM
O
Wittig
O
OHC
HO
RCM
1
6
7
5: Key intermediate
H
N
H
N
H
N
H
H
H
N
3
4
2
Cbz
cyclization
OMe
O
O
HN
O
O
N
H
N
O
O
O
O
O
9
10
asymmetric
amination
8
Scheme 1. Divergent strategy for the total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids.
produced by the reductive removal of oxygen functionalities. On the
other hand, the construction of a cyclic system with an aminal
moiety in 1 was expected by reductive cyclization of aminolactam 6
that would be used as a common intermediate for the synthesis of
cermizine D (2). Aminolactam 6 would be derived by stereoselective
installation of allyl and amino groups onto aldehyde 7 that could be
prepared by Wittig homologation of key intermediate 5. The qui-
nolizidine core in 5 would be accessible through diastereoselective
allylation to aminoacetal 8 utilizing oxazolidinone as the directing
group, followed by the RCM reaction. The construction of oxazoli-
dinone in 9, which would lead to 8 by cyclization, could be per-
hydrazinoalcohol 13.8 The use of 12 was crucial since subsequent
N–N bond cleavage proved troublesome when other azodicarb-
oxylates, such as DEAD and DTAD, were used. Although cyclization
of 13 to form 9 was initially conducted by treatment with meth-
anolic NaOH in one pot,8a this procedure was not productive (Table
1, entries 1 and 2). It turned out that 13 could be cleanly converted
into oxazolidinone 9 under anhydrous conditions using K2CO3 in
refluxing toluene with good results (94%, 75% de, entry 3). Selec-
tivity could be improved by employing diphenylprolinol silyl ether
A29 as catalyst at room temperature (entry 5), whereas lowering
the temperature resulted in a decrease of selectivity (entry 6).
The next task was reductive N–N bond cleavage in hydrazine 9
(Table 2). We had expected that the reduction of 9 would lead to
oxazolidinone 15 directly, but the exposure of 9 to Raney Ni in
MeOH could not give 15 in satisfactory yield (entry 1).8b After ex-
amining the conditions (entry 2),8,10 we found that removal of the
Cbz group in advance is important. In fact, after hydrogenation
under mild conditions, the reduction of resultant hydrazine 14 with
Raney Ni was carried out successfully to furnish oxazolidinone 15
(entry 3).
formed via organocatalytic a-amination of the known aldehyde 10.
2.2. Synthesis of key intermediate 5
The preparation of oxazolidinone 9 commenced with the pro-
tection of aldehyde in (þ)-citronellal with ethylene glycol.6 The
protected citronellal 11 was converted to aldehyde 10 by Ru-cata-
lyzed oxidative cleavage of the olefin function (Scheme 2).7
Upon treatment of 15 with a catalytic amount of p-TsOH in
refluxing MeOH, cyclization involving elimination of ethylene gly-
col occurred to form aminoacetal 8 as an allylation precursor
(Scheme 3).11 The Hosomi–Sakurai allylation of aminoacetal 8 was
conducted by using allyltrimethylsilane with TiCl4 to give the de-
sired 16 exclusively.12 The stereoselectivity would be interpreted by
the axial attack of a nucleophile on the acyliminium intermediate
that had a rigid conformation defined by oxazolidinone. The ste-
reochemistry at C-7 and C-13 positions in 16 was unambiguously
proved by NOE measurements and the coupling constants of axial
proton on C-14 (ddd, J¼13.4, 12.2, 3.8), which indicated an all syn-
relationship among the two protons on C-7 and C-15 and the allyl
group on C-13. Hydrolysis of the oxazolidinone in 16 afforded
amino alcohol 17, which in turn was directly acylated with acryloyl
chloride to give acrylamide 18. At this stage, the desired di-
astereomer of 18 was obtained in pure form (56% in six steps) after
OH
HO
p-TsOH
O
O
OHC
PhH, reflux
O
O
11
(+)-citronellal
RuCl3, NaIO4
O
(CH2Cl)2, H2O
rt
87% (2 steps)
10
Scheme 2. Synthesis of aldehyde 10.
At this stage, organocatalytic
a-amination was investigated.
First, we carried out amination of 10 with dibenzyl azodicarb-
oxylate 12 in the presence of a catalytic amount of (S)-proline in
CH2Cl2 at room temperature followed by in situ reduction to give
single chromatographic separation from
a concomitant di-
astereomer derived from the organocatalytic reaction. The

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Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
Table 1
O
O
OMe
O
TMS
Organocatalytic oxazolidinone synthesis
O
HN
p-TsOH
N
Cbz
TiCl4, CH2Cl2
-78 to 0 °C
1) CbzN=NCbz 12,
MeOH
reflux
O
O
HN
catalyst (10 mol%)
solvent, condition
O
O
Cbz
OH
15
O
N
O
8
O
then NaBH4
O
10
MeOH
12.2 Hz
13
see Table
H
14
H
Me
15
H
7
14
Me
14
N
13
15
7
Cbz
N
H
N
Ar
Ar
OTMS
H
O
H
13
O
O
O
HN
7
O
Nu
O
N
H
H
O
N
O
16
2) K2CO3
NOE
toluene
reflux
O
A1: Ar = 3,5-(CF3)2C6H3
A2: Ar = Ph
9
H
H
acryloyl chloride
Et3N
CH2Cl2, -78 °C
56% over 6 steps
Entry
Catalyst
Solvent
Conditionsa
% Yield
% dec
8M NaOH aq.
MeOH, reflux
(9)b
H
H
H
N
NH
1d
2d
3
4
5
(S)-Proline
(S)-Proline
(S)-Proline
A1
A2
A2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 ꢁC, 24 h
rt, 1.5 h
rt, 1.5 h
rt, 5 min
rt, 0.5 h
0 ꢁC, 3 h
53
74
94
99
94
82
78
75
75
75
84
65
O
HO
HO
HO
17
18
single diastereomer
6
H
N
H
a
Grubbs I
H2, Pd/C
EtOH, rt
99% (2 steps)
All reactions were carried out with 1.1 equiv of aldehyde and 1 equiv of dibenzyl
azodicarboxylate.
H
N
CH2Cl2
rt
b
Isolated yield.
c
O
O
The de values were determined by HPLC using CAPCELL-PAK C18 MG.
Cyclization was performed under aqueous condition in one pot (1 N aqueous
HO
d
19
5
NaOH in MeOH at rt).
Scheme 3. Practical synthesis of key intermediate 5.
synthesis of key intermediate 5 was accomplished in 99% yield by
RCM with first-generation Grubbs catalyst13a followed by hydro-
genation of olefin. It is noteworthy that the present procedure for
the preparation of 5, which is a pivotal intermediate in our di-
vergent synthesis, required only two purification steps throughout
the eight-step conversion from 9 to 5.
isolation procedure of the natural product, we elaborated cermizine
C as TFA salt while Snider’s group leads 3 to its HCl salt. The spectral
data of the TFA salt of synthetic 3 were identical with those
reported for the natural product including the optical property:
17
25
synthetic [
a
]
þ7.6 (c 1.0, MeOH); natural, [
a]
þ4 (c 0.8, MeOH),
D
D
though the [
a
] value is not reliable due to the small value of the
D
optical rotation.4 Next, we investigated the transformation of cer-
mizine C (3) into senepodine G (4). We anticipated that cermizine C
(3) having a cis-quinolizidine skeleton would be suitable for the
regioselective oxidation to senepodine G (4). Because, among the
protons on C-1, C-5, and C-9, only the proton (H-9) is situated at
anti-position to the N–O bond in the N-oxide derivative 22 (see the
reaction intermediate in Scheme 4). In fact, N-oxide 22 obtained by
m-CPBA oxidation was subjected to the Polonovsky–Potier re-
action14 by treatment with TFAA in CH2Cl2 to give regioselectively
2.3. Syntheses of (D)-cermizine C and (L)-senepodine G
Having developed a practical and large-scale route to key in-
termediate 5, we next turned our attention to the further trans-
formation of 5 into quinolizidine-type alkaloids (Scheme 4). After
reduction of the amido group with borane, the resulting hydroxyl
group of 20 was removed in two steps involving chlorination of 20
with SOCl2 and reductive dehalogenation of chloride 21 with LiAlH4
to yield cermizine C (3). As reported in the work of Snider and
Grabowski,2g the 1H NMR data of synthetic 3 were not identical to
those of the reported data for natural cermizine C. Considering the
H
N
H
N
H
N
BH3-THF
SOCl2
H
H
H
Table 2
THF
CHCl3
reflux
Investigation of N–N bond cleavage
reflux
O
Cbz
HO
HO
Cl
O
O
O
O
5
20
21
HN
H2N
O
O
O
N
N
H
N
H
see table
O
O
O
5
mCPBA
LiAlH4
THF, reflux
9
14
N
O
1
9
CH2Cl2, 0 °C
89%
52% in 3 steps
O
O
HN
(+)-cermizine (3)
22
O
H
15
Me
O
N
CF3
H
TFAA
CH2Cl2, 0 °C
quant.
Entry
Conditions
H2, Raney Ni, MeOH, 60 ꢁ
H2, Pd/C, EtOH, rt, then Zn, acetone, AcOH, rt
H2, Pd/C, EtOH, rt, then H2, Raney Ni, EtOH, rt, 1.5 h
Isolated yield.
% Yield (15)a
N
5
Me
9
1
1
2
3
C
40
Decomp.
94
CF3CO2
(-)-senepodine G (4)
H
CF3CO2
a
Scheme 4. Synthesis of (þ)-cermizine C (3) and (ꢀ)-senepodine G (4).

Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
1611
H
N
H
N
Scheme 5. Alcohol 5 was oxidized with IBX in DMSO to give the
aldehyde, which in turn was subjected to the Wittig reaction with
Ph3PCH2(OMe)Cl and KHMDS in THF, followed by mild acid hy-
drolysis to give carbon-elongated aldehyde 7 in 62% yield over
three steps. To install allyl and amino groups onto aldehyde 7, we
initially adopted the Ellman protocol.15 Condensation of aldehyde 7
and (R)-tert-butanesulfinamide 24 using CuSO4 afforded sulfinyl-
imine 25. The addition of allylmagnesium bromide followed by the
removal of sulfinyl auxiliary under acidic conditions furnished the
desired homoallylamine 6 in good yield (54%, two steps) but with
poor stereoselectivity (up to 60% de). After several attempts at the
stereoselective synthesis of homoallylamine 6, we found that
transfer aminoallylation developed by Kobayashi et al.16 gave the
best results. Thus, upon treatment of aldehyde 7 with reagent 26
derived from (1R)-camphor quinone, condensation, and aza-Cope
rearrangement resulted in the simultaneous and highly stereo-
selective installation of allyl and amine functions onto C-5 in 7 to
provide homoallylamine 6 in 92% yield and 94% de. The stereo-
chemistry of the newly generated chiral center was inferred from
the reaction mechanism shown in Scheme 5 and later confirmed by
using cyclic compound 27 (Scheme 6) (vide infra).
1) IBX, DMSO
rt
3 M HCl
H
H
THF
2) Ph3PCH2(OMe)Cl
KHMDS, THF
0 °C to rt
rt
O
H
MeO
O
HO
62%
(3 steps)
5
23
tBu
NH2
H
N
H
S
O
24
H
N
CuSO4, CH2Cl2, rt
93%
O
N
O
tBu
OHC
5
S
O
5
25
7
H
MgBr
1)
CH2Cl2, -78 °C
2) 3 M HCl
MeOH, rt
54% (2 steps)
up to 60% de
H
NH2
O
H
N
26
With aminolactam 6 in hand, we focused on the construction of
the aminal moiety (Scheme 6). We had envisioned that partial re-
duction of the amide group in 6 should provide the desired product
as seen in the syntheses of pyrrolidinoindolines.17 However, treat-
ment of aminolactam 6 with any reductant under various condi-
tions gave mostly the over-reduced product. Therefore, to elaborate
the aminal ring system, we thought that the cyclization of 6 was
necessary prior to reduction. To this end, amine 6 was treated with
TiCl4 in refluxing xylene to furnish amidine 27,18 whose stereo-
chemistry was confirmed by NOE experiment, as shown in Scheme
5. The conversion into aminal 28 was accomplished by stereo-
selective reduction with NaBH4 in the presence of AcOH and the
obtained aminal 28 was directly acylated with acryloyl chloride and
Et3N to provide acrylamide 29 in 62% yield (two steps). At this
stage, the stereochemistry at C-9 was confirmed by NOE experi-
ment in which significant NOE between H-9 and H-13 was ob-
served. This stereoselectivity can be expected by the attack of
hydride from the convex face of 27. Finally, formation of the
piperidone ring by RCM with second-generation Grubbs catalyst13b
and subsequent hydrogenation completed the total synthesis of
H
H2N
O
camphorsulfonic acid
(CH2Cl)2, rt
5
6
then NH2OH-AcOH
92%, 94% de
H
N
H
N
N
5
H
5
O
H
N
O
H
H
O
O
2-aza Cope rearrangement
Scheme 5. Stereoselective synthesis of homoallylamine.
senepodine G (4), which was identical with the natural senepodine
G in all respects.4
2.4. Stereoselective synthesis of cernuine (1)
and cermizine D (2)
(ꢀ)-cernuine (1) in good yield. The spectroscopic data were in
Our next effort on the further transformation of key in-
termediate 5 into cernuine (1) and cermizine D (2) is illustrated in
25
agreement with those of the natural product: synthetic, [
a
]
ꢀ23.2
D
NOE
H
H
N
H
H
H
NaBH4
AcOH
acryloyl chloride
13
N
H
TiCl4
H
H
H
Et3N
H
H
H
N
H
N
H
xylene, reflux
9
MeOH
rt
CH2Cl2
-78 °C
62% (2 steps)
H
80%
NOE
N
O
H2N
O
N
NH
5
5
27
28
29
6
acryloyl chloride
Et3N
1) Grubbs II, CH2Cl2
rt, 78%
CH2Cl2, -78 °C
2) H2, Pd/C, EtOH
rt, 96%
82%
H
H
N
H
H
1) Grubbs I
1) LiAlH4, THF
reflux, 60%
CH2Cl2, rt
H
H
H
H
H
N
N
N
N
H
2) H2, Pd/C
EtOH, rt
95% (2 steps)
2) TFA
H
N
H
H
N
H
H
H
O
O
O
N
O
O
TFA
30
31
(+)-cermizine D (2)
(-)-cernuine (1)
Scheme 6. Completion of the total syntheses.

1612
Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
(c 0.46, MeOH); natural, [
a
]
ꢀ20.5 (c 1.0, MeOH).3c Hence, the
layers were washed with brine, dried over MgSO4, and evaporated.
The residue was purified by silica gel chromatography (EtOAc/n-
D
structure including the absolute configuration was confirmed.
Having succeeded in the synthesis of (ꢀ)-cernuine, we next in-
vestigated the synthesis of cermizine D (2). Synthetic intermediate
6 yielded piperidone 31 via a similar three-step sequence that in-
cluded acryloylation, RCM, and hydrogenation (78% in three steps).
hexane¼30:70) to give 3.04 g (87% over two steps) of 10 as a col-
25
orless oil. [
a]
þ3.55 (c 1.14, CHCl3); IR (ATR) nmax cmꢀ1: 2953,
D
2879, 2723, 1720, 1411, 1133, 1032, 945; 1H NMR (CDCl3, 400 MHz)
d
ppm: 9.78 (1H, t, J¼1.7 Hz), 4.90 (1H, dd, J¼5.3, 4.8 Hz), 3.97 (2H,
Target compound 2 was obtained by complete reduction of bis-
m), 3.84 (2H, m), 2.46 (2H, m), 1.63–1.79 (3H, m), 1.49–1.58 (2H, m),
25
amide in 31 with LiAlH4 in THF ([
a
]
þ80.3 (c 0.06, MeOH)).
0.97 (3H, d, J¼6.4 Hz); 13C NMR (CDCl3, 100 MHz)
d ppm: 202.6,
However, similar to cermizine C, the 1DH NMR data of synthetic 2
were not identical to those reported in the literature,4 particularly
the chemical shifts of protons on the carbon neighboring the ni-
trogen atom. The 1H and 13C NMR data of the prepared cermizine D
TFA salt were in agreement with the reported data. On the other
103.4, 64.71, 64.65, 41.5, 40.5, 30.0, 28.9, 19.7; FABMS (Gly) m/z: 173
[MþH]þ; HR-FABMS (Gly/PEG): calcd for C9H17O3 [MþH]þ:
173.1178, found: 173.1180.
4.3. Synthesis of hydradine 9 using catalyst A2
(Table 1, entry 5)
hand, its optical rotation showed an opposite sign to that of the
20
natural product: synthetic TFA salt, [
natural, [
a]
þ24.2 (c 0.50, MeOH);
D
a
]
ꢀ33 (c 0.6, MeOH). We cannot discuss further the
To a stirred solution of dibenzyl azodicarboxylate (31.0 mg,
D
absolute configuration of natural cermizine D because the conju-
gate acid of the natural product is not available in the literature.
97.7
CH2Cl2 (0.4 mL) was added (R)-2-(diphenyltrimethylsilyloxy-
methyl)pyrrolidine (A2) (20 L,10.4 mol, 0.5 M solution in CH2Cl2),
mmol, 94% purity) and aldehyde 10 (19.8 mg, 115 mmol) in
m
m
3. Conclusion
and the reaction mixture was stirred at room temperature for
30 min. Then, the mixture was treated with MeOH (0.4 mL) and
We have established an efficient synthetic route to cernuane-
type and quinolizidine-type Lycopodium alkaloids. Key in-
termediate 5 was successfully prepared from (þ)-citronellal over 12
steps involving organocatalytic reaction in a scalable manner.
Compound 5 proved to be a valuable intermediate in the total
syntheses of four Lycopodium alkaloids, (þ)-cermizine C (3),
(ꢀ)-senepodine G (4), (ꢀ)-cernuine (1), and (þ)-cermizine D (2).
The fact that the conversion of cermizine C (3) into senepodine G
(4) was enabled by the regioselective Polonovsky–Potier reaction
would be helpful in the future synthesis of other related alkaloids
under mild conditions.4,19 The critical stereoselective construction
of nitrogen-containing heterocycle could be effected by transfer
aminoallylation.
NaBH4 (4.7 mg, 124 m
mol) at 0 ꢁC and stirred at room temperature
for 30 min. The reaction was quenched by adding water and the
whole mixture was extracted two times with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure to afford a crude product that
was used for the next reaction without purification. The mixture of
the above crude product and K2CO3 (43 mg, 0.31 mmol) in toluene
was refluxed for 1 h. The reaction mixture was cooled to room
temperature and diluted with EtOAc. The mixture was washed with
water and then with brine, dried over MgSO4, and evaporated. The
crude product was purified by silica gel chromatography (EtOAc/n-
hexane¼1:1) to give 33.4 mg (94% over two steps, 84% de) of 9 as
a colorless oil. The de value was determined by HPLC analysis using
CAPCELL-PAK C18 MG [55% H2O, 45% MeOH, flow¼0.4 mL/min, tR
25
4. Experimental section
4.1. General
(major)¼88.5 min, tR (minor)¼93.0 min]. [
a
]
ꢀ16.1 (c 0.95, CHCl3);
D
IR (ATR) nmax cmꢀ1: 3277, 2957,1755,1731,1455,1118,1026, 753, 697;
1H NMR (CDCl3, 400 MHz, VT50)
d
ppm: 7.29–7.38 (5H, m), 6.67 (1H,
br s), 5.21 (1H, d, J¼12.2 Hz), 5.17 (1H, d, J¼12.4 Hz), 4.85 (1H, t,
J¼5.0 Hz), 4.50 (1H, t, J¼8.2 Hz), 4.08 (1H, br s), 3.86–3.99 (3H, m),
3.72–3.84 (2H, m), 1.92 (1H, ddd, J¼13.7, 6.6, 5.0 Hz), 1.80 (1H, sep,
J¼6.5 Hz),1.50–1.70 (2H, m),1.39 (1H, dt, J¼14.3, 7.1 Hz), 0.96 (3H, d,
IR: recorded on a JASCO FT/IR-230 spectrophotometer. 1H and
13C NMR spectra: recorded on a JEOL JNM A-400, JNM A-500, JNM
ECP-400 or JNM ECP-600 spectrometer, J values are given in hertz.
EIMS: direct probe insertion at 70 eV recorded on a JEOL JMS GC-
mate spectrometer. FABMS: recorded on a JEOL JMS-AX500 or JMS-
HX110 mass spectrometer. Optical rotation: measured with a JASCO
P-1020 polarimeter. Melting point: measured with a Yanagimoto
Micro Melting Point Apparatus 1631A. TLC: precoated Kieselgel 60
F254 plates (Merck, 0.25 mm thick). Column chromatography: Kie-
selgel 60 [Merck, 70–230 mesh (for open chromatography) and
230–400 mesh (for flash chromatography)]. Medium pressure
liquid chromatography (MPLC): C.I.G. prepacked column CPS-HS-
221-05 (Kusano Kagakukikai, SiO2). High performance liquid
chromatography (HPLC): CAPCELL-PAK C18 MG (SHISEIDO) and
Inertsil ODS-2 (GL sciences).
J¼6.6 Hz); 13C NMR (CDCl3, 100 MHz, VT50)
d ppm: 163.1, 143.4,
136.5, 136.3, 136.1, 111.0, 76.2, 76.0, 72.7, 72.6, 63.2, 48.5, 48.0, 34.0,
28.9; FABMS (NBA) m/z: 365 [MþH]þ; HR-FABMS (NBAþKI/PEG):
calcd for C18H24N2O6K [MþK]þ: 403.1271, found: 403.1260.
4.4. (R)-4-((R)-3-(1,3-Dioxolan-2-yl)-2-
methylpropyl)oxazolidin-2-one (15)
A mixture of 9 (5.25 g, 14.4 mmol, 75% de prepared from entry 3
in Table 1) and 10% Pd/C (766 mg) in THF (48 mL) was stirred at
room temperature for 3 h under hydrogen atmosphere. The re-
action mixture was filtered with Celite and the filtrate was evapo-
rated to give the crude product as a pale yellow oil, which was
subjected for the next reaction without purification. To a solution of
the above product in MeOH (53 mL) was added Raney Ni W1 (6.1 g,
wet weight). The reaction mixture was heated to 60 ꢁC for 7 h
under hydrogen atmosphere. The reaction mixture was filtered
with Celite and the filtrate was evaporated to give a crude product
(3.03 g) of 15 as a pale yellow oil, which was used for the next re-
action without purification. For analytical data, the crude product of
4.2. (R)-5-(1,3-Dioxolan-2-yl)-4-methylpentanal (10)
To a stirred solution of 2-((R)-2,6-dimethylhept-5-enyl)-1,3-
dioxolane (4.00 g, 20.2 mmol, prepared by following literature
procedure20) and RuCl3$nH2O (146 mg, 0.71 mmol) in (CH2Cl)2
(100 mL) and H2O (100 mL) was added in portions NaIO4 (8.60 g,
40.4 mmol) over a period of 5 min at room temperature. After
stirring vigorously for 2 h at the same temperature, the reaction
was quenched by adding saturated aqueous NaHCO3 and 1 M
aqueous Na2S2O3 and the two layers were separated. The aqueous
layer was extracted three times with EtOAc. The combined organic
15 was purified by silica gel chromatography (EtOAc) to afford 15 as
16
colorless oil (single diastereomer). [
a]
þ21.1 (c 0.37, CHCl3); IR
D
(ATR) nmax cmꢀ1: 3246, 2917, 1742, 1409, 1241, 1112, 1021, 942, 772;
1H NMR (CDCl3, 400 MHz)
ppm: 5.93 (1H, br s), 4.87 (1H, t,
d

Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
1613
J¼4.9 Hz), 4.50 (1H, m), 3.92–4.01 (4H, m), 3.80–3.89 (2H, m), 1.70–
1.82 (2H, m), 1.57–1.69 (2H, m), 1.40 (1H, m), 1.00 (3H, d, J¼6.8 Hz);
(32 mL) at room temperature. The mixture was heated to 100 ꢁC for
36 h under argon atmosphere. The reaction mixture was cooled to
room temperature and then H2O (32 mL) was added. The whole
mixture was extracted three times with CH2Cl2. The combined or-
ganic layers were dried over Na2SO4 and evaporated to afford crude
product (2.10 g) as a yellow oil, which was used for the next re-
action without purification. To a solution of the above product and
Et3N (1.9 mL, 13.7 mmol) in CH2Cl2 (40 mL) was added acryloyl
chloride (1.0 mL, 12.3 mmol) at ꢀ78 ꢁC under argon atmosphere.
After stirring at the same temperature for 3 h, the reaction mixture
was quenched by adding MeOH (2.0 mL) and warmed to room
temperature. The mixture was treated with H2O and the whole
mixture was extracted three times with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
evaporated. The residue was purified by silica gel chromatography
13C NMR (CDCl3, 100 MHz)
d ppm: 159.6, 103.1, 70.7, 64.8, 64.7, 50.8,
42.8, 40.8, 26.4, 20.3; FABMS (NBA) m/z: 216 [MþH]þ; HR-FABMS
(NBA/PEG): calcd for C10H18NO4 [MþH]þ: 216.1236, found:
216.1237.
4.5. (5S,7R,8aR)-Tetrahydro-5-methoxy-7-methyl-1H-
oxazolo[3,4-a]pyridin-3(5H)-one (8)
To a stirred solution of the above crude product of 15 (3.03 g,
ca. 14.1 mmol) in MeOH (53 mL) was added p-toluenesulfonic acid
monohydrate (254 mg, 1.34 mmol) at room temperature. The
mixture was heated to reflux for 2 h under argon atmosphere. The
reaction was quenched by adding saturated aqueous NaHCO3 at
room temperature. The whole mixture was evaporated to half
volume and extracted three times with EtOAc. The combined or-
ganic layers were washed with brine, dried over MgSO4, and
evaporated to afford a crude product (2.44g) of 8 as a pale yellow
oil, which was used for the next reaction without purification. For
analytical data, the crude product of 8 was purified by silica gel
(EtOAc/n-hexane¼1:1) to afford 1.816 g (56% in six steps, single
23
diastereomer) of 18 as a colorless oil. [
a]
þ91 (c 2.6, CHCl3); IR
D
(neat) nmax cmꢀ1: 3386, 3076, 2952, 2870, 1643, 1601, 1454, 1255,
1055, 991; 1H NMR (CDCl3, 400 MHz)
d
ppm: 6.53 (1H, dd, J¼16.8,
10.6 Hz), 6.17 (1H, dd, J¼16.8, 1.6 Hz), 5.71 (1H, ddt, J¼15.7, 10.0,
7.1 Hz), 5.64 (1H, dd, J¼10.6, 1.7 Hz), 5.09 (1H, m), 5.04 (1H, br s),
4.13 (1H, q, J¼6.5 Hz), 3.88 (1H, ddd, J¼12.6, 5.7, 2.2 Hz), 3.80 (1H,
ddd, J¼12.5, 8.7, 6.0 Hz), 3.41 (1H, m), 2.55 (1H, dt, J¼14.5, 7.4 Hz),
2.33 (1H, dt, J¼14.4, 7.2 Hz), 1.93 (1H, m), 1.71 (2H, m), 1.35 (1H, q,
J¼12.3 Hz), 1.24 (1H, ddd, J¼13.7, 12.4, 5.4 Hz), 0.94 (3H, d,
chromatography (EtOAc/n-hexane¼30:70) to afford 8 as a colorless
23
oil. [
a]
ꢀ26.0 (c 0.49, CHCl3); IR (neat) nmax cmꢀ1: 2954, 2873,
D
2831, 1751, 1410, 1271, 1080, 825, 762; 1H NMR (CDCl3, 400 MHz)
d
ppm: 5.04 (1H, dd, J¼3.7, 1.7 Hz), 4.48 (1H, m), 3.90–3.98 (1H, m),
3.90 (1H, t, J¼7.6 Hz), 3.33 (3H, s), 1.99 (1H, m),1.90 (1H, ddt, J¼13.6,
3.6, 1.8 Hz), 1.85 (1H, m), 1.24 (1H, ddd, J¼13.7, 12.3, 3.8 Hz), 1.02
(1H, q, J¼12.0 Hz), 0.96 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3,100 MHz)
J¼6.6 Hz); 13C NMR (CDCl3, 100 MHz)
d ppm: 168.0, 133.9, 130.8,
126.7, 118.0, 64.3, 56.9, 55.7, 37.1, 36.4, 35.3, 25.8, 22.0; EIMS m/z
(%): 223 (4, Mþ), 192 (30), 182 (bp); HR-EIMS m/z: calcd for
C13H21NO2 [M]þ: 223.1572, found: 223.1584.
d
ppm: 156.9, 80.8, 68.6, 55.3, 50.1, 38.7, 38.0, 24.3, 21.6; EIMS m/z
(%): 185 (8, Mþ), 154 (bp); HR-EIMS m/z: calcd for C9H15NO3 [M]þ:
185.1052, found: 185.1045.
4.8. (6R,8S,9aS)-Hexahydro-6-(hydroxymethyl)-8-methyl-1H-
quinolizin-4(6H)-one (5)
4.6. (5S,7S,8aR)-5-Allyl-tetrahydro-7-methyl-1H-oxazolo[3,4-
a]pyridin-3(5H)-one (16)
To acrylamide 18 (52 mg, 0.23 mmol) and first-generation
Grubbs catalyst (1.9 mg, 2.3 mmol) was added degassed CH2Cl2
To a stirred solution of the above crude product of 8 (2.44 g, ca.
13.2 mmol) and allyltrimethylsilane (4.2 mL, 26.4 mmol) in CH2Cl2
(53 mL) was added TiCl4 (26.3 mL, 26.3 mmol, 1 M solution in
CH2Cl2) at ꢀ78 ꢁC under argon atmosphere. After stirring at the
same temperature for 1 h, the mixture was warmed to room tem-
perature and stirred for 1 h. The reaction mixture was cooled in ice
bath and then quenched by adding 8 M aqueous NaOH and the
basified mixture was extracted three times with EtOAc. The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated under reduced pressure to afford a crude product
(2.48 g) of 16 as a pale yellow oil, which was used for the next re-
action without purification. For analytical data, the crude product of
(3.1 mL) at room temperature under N2 atmosphere. After stirring
for 30 h at the same temperature, the mixture was concentrated
under reduced pressure. The residue and 10% Pd/C (12 mg) were
suspended in EtOH (1.2 mL) and the mixture was stirred at room
temperature for 6 h under H2 atmosphere. The reaction mixture
was filtered with Celite and the filtrate was evaporated. The residue
was dissolved in CH2Cl2 and triphenylphosphine oxide (32 mg,
0.11 mmol)21 was added, which was stirred at room temperature
for 20 h and then evaporated. The obtained residue was purified by
silica gel chromatography (MeOH/EtOAc¼5:95) to afford 46 mg
22
(99% in two steps) of 5 as a colorless oil. [
a
]
þ197 (c 2.10, CHCl3);
D
IR (neat) nmax cmꢀ1: 3356, 2947, 2868, 1614, 1471, 1335, 1186, 1066;
16 was purified by silica gel chromatography (EtOAc/n-
1H NMR (CDCl3, 400 MHz)
d
ppm: 4.62 (1H, dq, J¼11.6, 5.9 Hz), 4.09
23
hexane¼1:1) to afford 16 as a colorless oil. [
a]
þ16.9 (c 0.54,
(1H, t, J¼4.4 Hz), 3.67 (1H, m), 3.64 (2H, dd, J¼5.9, 4.6 Hz), 2.43 (1H,
dddd, J¼18.0, 5.5, 3.8, 1.7 Hz), 2.34 (1H, ddd, J¼17.8, 9.8, 6.4 Hz),
1.82–1.93 (2H, m), 1.58–1.81 (4H, m), 1.11–1.23 (3H, m), 1.00 (3H, d,
D
CHCl3); IR (neat) nmax cmꢀ1: 3076, 2951,1743,1641,1414,1273,1055,
916, 762; 1H NMR (CDCl3, 400 MHz)
ppm: 5.78 (1H, ddt, J¼17.0,
d
10.8, 6.8 Hz, H-11), 5.09 (1H, m, H-17), 5.06 (1H, t, J¼1.3 Hz, H-17),
4.38 (1H, t, J¼8.2 Hz, H-6), 4.06 (1H, q, J¼7.0 Hz, H-13), 3.87 (1H, dd,
J¼8.3, 5.9 Hz, H-6), 3.79 (1H, m, H-7), 2.40 (1H, m, H-12), 2.26 (1H,
m, H-12), 1.73–1.86 (2H, m, H-15 and H-8a), 1.66 (1H, ddt, J¼13.6,
3.3, 1.7 Hz, H-14a), 1.26 (1H, ddd, J¼13.4, 12.2, 5.9 Hz, H-14b), 0.99
(1H, q, J¼12.3 Hz, H-8b), 0.96 (3H, d, J¼6.4 Hz, H-16); 13C NMR
J¼6.6 Hz); 13C NMR (CDCl3, 100 MHz)
d ppm: 173.1, 66.4, 55.0, 47.4,
38.2, 32.3, 31.2, 27.5, 25.8, 21.6, 16.4; EIMS m/z (%): 197 (19, Mþ), 167
(78), 166 (bp), 98 (72); HR-EIMS m/z: calcd for C11H19NO2 [M]þ:
197.1416, found: 197.1418.
4.9. (2S,4R,9aS)-4-(Chloromethyl)-octahydro-2-methyl-1H-
quinolizine (21)
(CDCl3, 100 MHz)
d
ppm: 157.0, 134.6, 117.4, 68.1, 50.7, 49.1, 39.1,
35.4, 24.6, 22.0; FABMS (NBA) m/z: 196 [MþH]þ; HR-FABMS (NBA/
PEG): calcd for C11H18NO2 [MþH]þ: 196.1338, found: 196.1338.
To a stirred solution of alcohol 5 (46 mg, 0.23 mmol) in dry THF
was added dropwise a BH3 solution (0.71 mL, 1.0 M in THF,
0.71 mmol) at 0 ꢁC under argon atmosphere. The mixture was
heated at 70 ꢁC for 6 h. Aqueous 1 M NaOH solution (1.2 mL) and
MeOH (0.38 mL) were added to the mixture at 0 ꢁC, which was then
heated at 100 ꢁC for 2 h. The reaction mixture was treated with
water and the whole mixture was extracted three times with
4.7. 1-((2S,4S,6R)-2-Allyl-6-(hydroxymethyl)-4-
methylpiperidin-1-yl)prop-2-en-1-one (18)
To a stirred solution of the above crude product of 16 (2.48 g,
ca. 12.7 mmol) in MeOH (64 mL) was added 8 M aqueous NaOH

1614
Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
CH2Cl2. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to afford a crude product
(44 mg) that was used for the next reaction without purification. To
a solution of the above crude product (44 mg) in CHCl3 was added
J¼13.7 Hz), 1.24 (3H, d, J¼6.4 Hz), 0.94 (3H, d, J¼6.4 Hz); 13C NMR
(CDCl3, 100 MHz) d ppm: 73.8, 65.5, 57.7, 36.8, 33.6, 27.5, 24.7, 23.2,
22.8, 21.3, 13.9; FABMS (NBA) m/z: 184 [MþH]þ; HR-FABMS (NBA/
PEG): calcd for C11H22NO [MþH]þ: 184.1701, found: 184.1713.
thionyl chloride (44 mL, 0.61 mmol) at room temperature and the
reaction mixture was warmed to 70 ꢁC for 1 h under argon atmo-
sphere. The reaction mixture was cooled to room temperature and
then quenched by adding saturated aqueous Na2CO3 and the whole
mixture was extracted three times with CH2Cl2. The combined or-
ganic layers were dried over Na2SO4 and evaporated to afford crude
product (45 mg) as a yellow oil, which was unstable under silica gel
chromatography and so used for the next reaction without purifi-
cation. For analytical data, the crude product of 21 was purified by
4.12. Senepodine G (4)
To a stirred solution of cermizine C N-oxide (22) (9.3 mg,
51 mmol) in CH2Cl2 (0.85 mL) was added TFAA (35 mL, 0.25 mmol) at
0 ꢁC. After stirring for 4 h at the same temperature, the solvent was
evaporated. The obtained residue was dissolved in CH2Cl2 (0.85 mL)
and TFAA was added at 0 ꢁC again. After stirring for 4 h at the same
temperature, the reaction mixture was concentrated under reduced
19
silica gel chromatography (EtOAc/n-hexane¼35:65) to afford 21 as
pressure to afford 18 mg (quant.) of 4 as a yellow oil. [
a
]
ꢀ23.0 (c
D
22
a yellow oil. [
a
]
(as TFA salt) þ8.80 (c 1.01, MeOH); IR (neat)
0.66, MeOH); IR (ATR) nmax cmꢀ1: 3840, 2938, 2877,1668,1448,1174,
D
nmax cmꢀ1: 2929, 2870, 1456, 1093, 754; 1H NMR (CDCl3, 400 MHz)
ppm: 3.59–3.67 (2H, m), 3.30 (1H, m), 3.25 (1H, m), 3.12 (1H,
1130, 799; 1H NMR (CD3OD, 600 MHz)
d
ppm: 4.51 (1H, br d,
d
J¼12.9 Hz), 3.96 (1H, br s), 3.53 (1H, br t, J¼13.1 Hz), 3.00 (1H, dd,
J¼4.7,1.9 Hz), 2.46 (1H, m), 2.45 (3H, s),1.98–2.08 (2H, m),1.84–1.98
(4H, m),1.83 (1H, m),1.79 (1H, m),1.76 (1H, m),1.05 (3H, d, J¼6.6 Hz);
dddd, J¼12.2, 3.2, 3.2, 3.2 Hz), 2.79 (1H, ddd, J¼15.0, 12.2, 2.8 Hz),
1.70–1.90 (4H, m), 1.40–1.65 (4H, m), 1.12–1.31 (3H, m), 0.92 (3H, d,
J¼6.3 Hz); 13C NMR (CDCl3, 100 MHz)
d
ppm: 57.6, 52.2, 49.4, 47.2,
13C NMR (CDCl3, 150 MHz)
d ppm: 187.1, 64.8, 56.0, 43.7, 35.5, 34.7,
39.4, 38.7, 25.59, 25.55, 24.4, 22.2, 18; FABMS (NBA) m/z: 202
[MþH]þ; HR-FABMS (NBA/PEG): calcd for C11H21NCl [MþH]þ:
202.1363, found: 202.1375.
27.5, 24.6, 23.6, 21.9, 20.3; FABMS (NBA) m/z: 166 [M]þ; HR-FABMS
(NBA/PEG): calcd for C11H20N [M]þ: 166.1596, found: 166.1590.
4.13. 2-((2S,4R,9aS)-Octahydro-2-methyl-6-oxo-1H-
4.10. Cermizine C TFA salt (3)
quinolizin-4-yl)acetaldehyde (7)
To a solution of the above crude product (45 mg) in dry THF
(2.1 mL) was added LiAlH4 (91 mg, 2.4 mmol) at 0 ꢁC under argon
atmosphere. The mixture was heated to reflux for 3 h. After dilution
with Et2O and careful addition of water at 0 ꢁC, 1 M aqueous NaOH
was added to the mixture. The mixture was stirred overnight at
room temperature and then filtered with Celite. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (CHCl3/MeOH/NH4OH¼90:9:1) to afford
cermizine C (3) as a pale yellow oil. To a solution of the cermizine C
(3) in MeOH (0.5 mL) was added TFA (five drops, excess). The
mixture was concentrated under reduced pressure to afford 33 mg
To a stirred solution of alcohol 5 (2.00 g, 10.1 mmol) in DMSO
(30 mL) was added o-iodoxybenzoic acid (IBX) at room tempera-
ture. After stirring at the same temperature for 1 h under argon
atmosphere, H2O (30 mL) was carefully added to precipitate a white
solid, which was removed by filtration. The filtrate was extracted
three times with EtOAc. The combined organic layers were washed
two times with a mixture of saturated aqueous Na2S2O3 and satu-
rated aqueous NaHCO3, dried over MgSO4, and concentrated under
reduced pressure to afford a crude product (1.89 g) as a yellow oil,
which was used in the next reaction without purification. To
a suspension of methoxymethyltriphenylphosphonium chloride
(6.95 g, 20.3 mmol) in THF (25 mL) was added KHMDS (27 mL,
20.3 mmol, 15% solution in toluene) at 0 ꢁC under argon atmo-
sphere. After stirring at the same temperature for 0.5 h, the solution
of the above crude product (1.89 g) in THF (9 mL) was added
dropwise. The reaction mixture was stirred at 0 ꢁC for 1 h and at
room temperature for 1 h. It was quenched by adding propio-
naldehyde (1.5 mL, 20.3 mmol). After stirring for 0.5 h at room
temperature, saturated aqueous NH4Cl was added. The whole
mixture was extracted three times with EtOAc and the combined
organic extracts were washed with brine, dried over MgSO4, and
evaporated. The residue was purified by silica gel chromatography
(EtOAc) to obtain a mixture of E/Z isomers of 23 and triphenyl-
phosphine oxide, which was difficult to separate. To a solution of
the mixture in THF (65 mL) was added 3 M aqueous HCl (13 mL) at
0 ꢁC under argon atmosphere. After stirring at room temperature
for 2 h, the reaction mixture was neutralized with saturated
aqueous Na2CO3. The whole mixture was extracted three times
with EtOAc and the combined organic layers were washed with
brine, dried over MgSO4, and evaporated. The residue was purified
(52% in three steps) of TFA salt of 3 as a yellow oil. The spectral data
17
were identical with those reported for the natural product: [
a]
D
þ7.64 (c 1.00, MeOH); IR (ATR) nmax cmꢀ1: 2957, 1668, 1457, 1133,
796; 1H NMR (CD3OD, 600 MHz)
d ppm: 3.82 (1H, m), 3.65 (1H,
dddd, J¼13.6, 3.8, 1.9, 1.9 Hz), 3.59 (1H, br d, J¼12.9 Hz), 3.08 (1H,
ddd, J¼13.6, 13.6, 3.2 Hz), 2.17 (1H, m), 1.91–2.02 (3H, m), 1.76–1.84
(2H, m), 1.69 (1H, m), 1.60–1.68 (2H, m), 1.55 (1H, ddd, J¼14.4, 12.4,
5.3 Hz), 1.31 (3H, d, J¼6.3 Hz), 1.19 (1H, ddd, J¼14.7, 12.5, 12.5 Hz),
0.95 (3H, d, J¼6.3 Hz); 13C NMR (CD3OD,150 MHz)
d ppm: 61.5, 51.2,
50.0, 41.9, 38.5, 25.4, 24.6, 23.8, 21.6, 18.4, 17.7; EIMS m/z (%): 167
([M]þ, 12), 166 (8), 152 (bp); HR-EIMS m/z: calcd for C11H19NO2
[M]þ: 167.1674, found: 167.1673.
4.11. Cermizine C N-oxide (22)
To a stirred solution of cermizine C (3) TFA salt (20 mg, 71 mmol)
in CH2Cl2 (0.5 mL) were added K2CO3 (29 mg, 0.21 mmol) and m-
CPBA (24 mg, 0.11 mmol, 77% in H2O) at 0 ꢁC. After stirring for 1.5 h
at the same temperature, the mixture was filtered through a short
pad of silica gel. The filtrate was concentrated under reduced
pressure and the residue was purified by silica gel chromatography
by silica gel chromatography (EtOAc/CHCl3¼1:1) to afford 1.32 g
17
(62% in three steps) of 7 as a pale yellow oil: [
a]
þ162 (c 0.90,
D
(MeOH/CHCl3¼5:95 to MeOH/CHCl3/NH4OH¼9/90/1) to afford
CHCl3); IR (ATR) nmax cmꢀ1: 2948, 2870, 1717, 1624, 1460, 1416, 749;
9.3 mg (71%) of 22 as a yellow oil. [
a]
ꢀ1.97 (c 0.375, CHCl3); IR
1H NMR (CDCl3, 400 MHz)
d
ppm: 9.72 (1H, dd, J¼3.3, 2.0 Hz), 4.83
25
D
(ATR) nmax cmꢀ1: 3379, 2949, 2918, 2870, 1451, 1373, 979, 923; 1H
NMR (CDCl3, 400 MHz)
(1H, dq, J¼9.8, 6.8 Hz), 3.61 (1H, m), 2.63 (1H, ddd, J¼15.3, 7.1,
3.2 Hz), 2.53 (1H, ddd, J¼15.2, 6.2, 2.1 Hz), 2.33 (1H, dddd, J¼17.5,
5.1, 5.1, 1.5 Hz), 2.24 (1H, ddd, J¼17.5, 9.5, 5.9 Hz) 1.65–1.95 (6H, m),
1.59 (1H, m), 1.20–1.32 (2H, m), 0.98 (3H, d, J¼6.8 Hz); 13C NMR
d
ppm: 3.74 (1H, br d, J¼13.2 Hz), 3.63 (1H,
m), 3.36 (1H, br d, J¼13.2 Hz), 3.07 (1H, ddd, J¼13.6, 13.6, 3.2 Hz),
2.49 (1H, ddd, J¼13.2, 13.2, 5.1 Hz), 2.05 (1H, m), 1.96 (1H, q,
J¼12.6 Hz), 1.87 (1H, m), 1.64–1.83 (3H, m), 1.62 (1H, m), 1.57 (1H,
ddd, J¼12.6, 4.4, 4.4 Hz), 1.41 (1H, br d, J¼13.4 Hz), 1.31 (1H, br d,
(CDCl3, 100 MHz)
d ppm: 200.5, 170.1, 48.5, 47.3, 46.9, 38.6, 35.0,
32.6, 28.1, 26.0, 21.4, 17.0; EIMS m/z (%): 209 ([M]þ, 14), 180 (16), 166

Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
1615
18
(bp); HR-EIMS m/z: calcd for C11H19NO2 [M]þ: 209.1416, found:
NH4OH¼70:27:3) gave 186 mg (80%) of 27 as a brown oil. [
a
]
D
209.1414.
þ20.3 (c 1.11, CHCl3); IR (neat) nmax cmꢀ1: 3070, 2925, 2856, 1600,
1411, 1310, 1086, 906, 746; 1H NMR (CDCl3, 400 MHz)
d ppm: 5.85
4.14. Sulfinyl aldimine (25)
(1H, ddt, J¼17.2, 10.1, 7.1 Hz, H-3), 5.07 (1H, d, J¼17.3 Hz, H-17), 5.02
(1H, d, J¼10.1 Hz, H-17), 3.47 (1H, m, H-7), 3.41 (1H, tt, J¼11.7,
2.7 Hz, H-13), 3.31 (1H, m, H-5), 2.59 (2H, m), 2.48 (1H, m, H-4), 2.13
(1H, dt, J¼13.9, 8.2 Hz), 1.98 (1H, m, H-15), 1.82–1.90 (2H, m), 1.70–
1.82 (3H, m), 1.64 (1H, m), 1.30–1.40 (2H, m), 1.24 (1H, br q,
J¼12.5 Hz, H-14b), 1.13 (1H, q, J¼11.8 Hz, H-8b), 0.98 (3H, d,
To a stirred solution of aldehyde (7) (55 mg, 0.26 mmol) in dry
CH2Cl2 (0.9 mL) were added (R)-tert-butylsulfinamide (35 mg,
0.29 mmol) and anhydrous CuSO4 (84 mg, 0.53 mmol) successively
at room temperature. After stirring for 24 h at the same tempera-
ture, the reaction mixture was filtered through a pad of Celite and
the filter cake was washed with CH2Cl2. The filtrate was evaporated
and the obtained residue was purified by silica gel chromatography
J¼6.8 Hz, H-7); 13C NMR (CDCl3, 100 MHz)
d ppm: 156.6, 135.5,
116.9, 51.6, 51.5, 49.3, 41.2, 37.5, 36.9, 34.1, 30.9, 30.5, 24.3, 22.4,
19.5; EIMS m/z (%): 232 (39, Mþ), 191 (bp), 91 (42); HR-EIMS m/z:
calcd for C15H24N2 [M]þ: 232.1939, found: 232.1932.
(EtOAc/CHCl3¼1:1) to afford 76 mg (93%) of 25 as a pale yellow oil.
24
[
a]
ꢀ53 (c 0.28, CHCl3); IR (ATR) nmax cmꢀ1: 3450, 2950, 2870,
D
1615, 1459, 1416, 1080, 681; 1H NMR (CDCl3, 400 MHz)
d
ppm: 8.05
4.17. 1-((2S,3aR,5S,6aS,9aS)-2-Allyl-decahydro-5-
methylpyrimido[6,1,2-de]quinolizin-1(2H)-yl)prop-
2-en-1-one (29)
(1H, t, J¼5.1 Hz), 4.78 (1H, m), 3.61 (1H, m), 2.83 (1H, dt, J¼14.9,
5.2 Hz), 2.76 (1H, ddd, J¼14.8, 7.7, 5.3 Hz), 2.37 (1H, dtd, J¼17.5, 5.2,
1.3 Hz), 2.29 (1H, ddd, J¼17.5, 9.4, 5.9 Hz), 1.54–1.95 (8H, m), 1.20–
1.32 (1H, m), 1.20 (9H, s), 1.00 (3H, d, J¼6.8 Hz); 13C NMR (CDCl3,
To a stirred solution of amidine 27 (12 mg, 52
(0.8 mL) was added AcOH (3.0 L, 52 mol) at room temperature
under argon atmosphere. After cooling in an ice bath, NaBH4
(3.9 mg, 104 mol) was added and the reaction mixture was stirred
mmol) in EtOH
100 MHz)
d
ppm: 170.0, 166.9, 56.7, 48.8, 47.7, 40.3, 38.6, 34.6, 32.7,
m
m
28.2, 26.0, 22.4, 21.5, 17.1; FABMS (NBA) m/z: 313 [MþH]þ; HR-
FABMS (NBA/PEG): calcd for C16H29N2O2S [MþH]þ: 313.1950,
found: 313.1953.
m
at room temperature for 1 h. H2O was added to the reaction mix-
ture and the whole mixture was diluted with CH2Cl2, dried over
Na2SO4, filtered, and evaporated. To a solution of the residue and
4.15. (6R,8S,9aS)-6-((S)-2-Aminopent-4-enyl)-hexahydro-8-
methyl-1H-quinolizin-4(6H)-one (6)
Et3N (14
chloride (103
m
L, 104
mmol) in CH2Cl2 (0.8 mL) was added acryloyl
m
mL, 52
mol, 0.5 M solution in CH2Cl2) at ꢀ78 ꢁC un-
To a stirred solution of aldehyde 7 (325 mg, 1.55 mmol) and
(1R,3R,4S)-3-allyl-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
one (26) (354 mg, 1.71 mmol, prepared according to literature pro-
cedure13) in (CH2Cl)2 (3.9 mL) was added camphorsulfonic acid
(36 mg, 0.155 mmol) at room temperature. After stirring at the same
temperature for 24 h under argon atmosphere, a 0.5 M solution of
NH2OH/AcOH (6.2 mL, 3.1 mmol) in MeOH was added and the re-
action mixture was warmed at 50 ꢁC for 2.5 h. The mixture was
acidified with 1 M aqueous HCl (pH ca.1) and thenwashed twotimes
with CH2Cl2. The combined organic layers were extracted two
times with 1 M aqueous HCl. The combined aqueous layers were
basified with 8 M aqueous NaOH (pH ca.10) and then extracted four
times with CH2Cl2. The latter CH2Cl2 layers were dried over Na2SO4
and evaporated. The crude product was purified by silica gel
chromatography (CHCl3/MeOH/NH4OH¼90:9:1) to afford 357 mg
(92%, 94% de) of 6 as a yellow oil. The de value as a benzoylated
product was determined by HPLC analysis using Inertsil ODS-2 [40%
der argon atmosphere. After stirring at the same temperature for
3 h, the reaction mixture was quenched by adding MeOH (0.4 mL)
and warmed to room temperature. The mixture was treated with
H2O and the whole mixture was extracted three times with CH2Cl2.
The combined organic layers were dried over Na2SO4 and evapo-
rated. The residue was purified by silica gel chromatography
(MeOH/CHCl3¼5:95) to afford 9.2 mg (62% in two steps) of 29 as
23
a colorless oil. [
a
]
ꢀ100 (c 0.86, CHCl3); IR (ATR) nmax cmꢀ1: 3075,
D
2924, 2866, 1643, 1606, 1421, 1142, 975, 912, 795; 1H NMR (CDCl3,
400 MHz, VT50)
d
ppm: 6.51 (1H, dd, J¼16.7, 10.4 Hz), 6.29 (1H, dd,
J¼16.8, 2.2 Hz), 5.76 (1H, m), 5.61 (1H, dd, J¼10.4, 2.1 Hz), 5.02–5.10
(2H, m), 4.77 (1H, br s, H-9), 3.88 (1H, dq, J¼9.1, 4.6 Hz), 3.19 (1H,
m), 3.09 (1H, m, H-13), 2.78 (1H, dt, J¼14.0, 8.7 Hz, H-4), 2.57–2.62
(1H, m, H-4), 1.82–1.99 (3H, m), 1.56–1.74 (6H, m), 1.48 (1H, dt,
J¼4.2, 2.1 Hz), 1.41 (1H, td, J¼12.6, 5.3 Hz), 1.11 (1H, q, J¼11.9 Hz),
1.01 (1H, br d, J¼12.4 Hz), 0.88 (3H, d, J¼6.3 Hz, H-16); 13C NMR
(CDCl3, 100 MHz, VT50) d ppm: 165.6, 135.8, 129.0, 126.9, 117.1, 72.9,
H2O/60% MeOH, flow¼0.5 mL/min, tR (major)¼39.0 min, tR
58.1, 51.2, 44.4, 44.2, 41.1, 39.1, 30.9, 26.9, 24.3, 23.2, 22.2, 21.2; EIMS
m/z (%): 288 (50, Mþ), 273 (16), 259 (78), 245 (bp); HR-EIMS m/z:
calcd for C18H28N2O [M]þ: 288.2201, found: 288.2201.
23
(minor)¼31.0 min]. [
a
]
þ128 (c 1.41, CHCl3); IR (neat) nmax cmꢀ1
:
D
3234, 3076, 3008, 2841,1618, 752; 1H NMR (CDCl3, 400 MHz)
d ppm:
5.78 (1H, m), 5.08 (2H, d, J¼13.5 Hz), 4.66 (1H, quin, J¼7.5 Hz), 3.61
(1H, m), 2.82 (1H, tt, J¼8.5, 4.3 Hz), 2.36 (1H, dt, J¼17.6, 4.9 Hz), 2.22–
2.32 (2H, m), 2.03 (1H, dt, J¼14.6, 7.3 Hz),1.56–1.93 (8H, m),1.50 (1H,
ddd, J¼13.2, 7.9, 4.9 Hz),1.10–1.24 (2H, m), 0.99 (3H, d, J¼7.0 Hz); 13C
4.18. Dehydrocernuine (S1)
To aminal 29 (20 mg, 69
mmol) and second-generation Grubbs
NMR (CDCl3, 100 MHz)
d
ppm: 169.5, 135.7, 117.4, 48.5, 48.4, 46.9,
catalyst (2.9 mg, 3.4 mol) was added degassed CH2Cl2 (3.1 mL) at
m
43.5, 41.6, 38.9, 35.1, 32.7, 28.1, 26.0, 21.3,17.1; FABMS (NBA) m/z: 251
[MþH]þ; HR-FABMS (NBA/PEG): calcd for C15H27N2O [MþH]þ:
251.2123, found: 251.2125.
room temperature under N2 atmosphere. After 12 h and 18 h, the
mixture was treated twice with an additional amount of second-
generation Grubbs catalyst (2.9 mg, 3.4 mmol). After 24 h,
triphenylphosphine oxide (142 mg, 0.51 mmol)21 was added and
the reaction mixture was stirred at room temperature for 12 h and
then evaporated. The obtained residue was purified by MPLC
(MeOH/CHCl3¼5:95) twice to yield 14 mg (78%) of S1 as trans-
4.16. (2S,3aR,5S,6aS)-2-Allyl-2,3,3a,4,5,6,6a,7,8,9-decahydro-5-
methylpyrimido[6,1,2-de]quinolizine (27)
To a stirred solution of homoallylamine 6 (250 mg, 1.00 mmol)
in xylene (16 mL) was added TiCl4 (2.0 mL, 2.0 mmol, 1.0 M solution
in toluene) at room temperature. The reaction mixture was heated
at 150 ꢁC for 1 h under argon atmosphere. It was then cooled to
0 ꢁC and quenched by adding a methanolic solution (14 mL) of
NaOH (400 mg). Filtration, washing of the residue with CHCl3, and
purification by silica gel chromatography (CHCl3/MeOH/
parent needles still contaminated with a minuscule amount of the
16
ruthenium catalyst. [
a
]
D
ꢀ45 (c 0.59, CHCl3); IR (ATR) nmax cmꢀ1
:
2920, 2859, 1664, 1612, 1419, 1097, 824, 790; 1H NMR (CDCl3,
400 MHz)
d
ppm: 6.46 (1H, ddd, J¼9.8, 6.0, 2.6 Hz), 5.88 (1H, dd,
J¼9.8, 2.9 Hz), 5.29 (1H, dd, J¼11.5, 2.7 Hz), 3.70 (1H, tdd, J¼12.0,
5.7, 3.7 Hz), 3.16 (1H, m), 3.11 (1H, tt, J¼11.1, 2.6 Hz), 2.40 (1H, dt,
J¼17.9, 5.9 Hz), 2.22 (1H, ddt, J¼17.9, 12.4, 2.8 Hz), 1.69–1.92 (6H,

1616
Y. Nishikawa et al. / Tetrahedron 65 (2009) 1608–1617
m), 1.66 (1H, m), 1.55 (1H, dt, J¼4.0, 2.0 Hz), 1.48 (1H, dd, J¼12.6,
5.0 Hz), 1.31–1.42 (2H, m), 1.07 (1H, br d, J¼11.7 Hz), 0.89 (3H, d,
J¼6.3 Hz), 0.88 (1H, q, J¼12.0 Hz); 13C NMR (CDCl3, 100 MHz)
reaction mixture was filtered with Celite and the filtrate was
evaporated. The residue was dissolved in CH2Cl2 and triphenyl-
phosphine oxide (122 mg, 0.22 mmol)21 was added, which was
stirred at room temperature for 15 h and then evaporated. The
obtained residue was purified by silica gel chromatography (MeOH/
d
ppm: 163.8, 137.8, 125.1, 68.6, 57.6, 48.4, 45.4, 42.1, 41.0, 39.3, 31.2,
25.2, 24.4, 22.5, 22.3, 18.9; EIMS m/z (%): 260 (88, Mþ), 231 (94, Mþ),
218 (bp); mp: 145–146 ꢁC; HR-EIMS m/z: calcd for C16H24N2O [M]þ:
260.1889, found: 260.1889.
CHCl3¼10:90) to afford 39 mg (95% in two steps) of 31 as a colorless
23
oil. [
a
]
D
þ53.3 (c 1.96, CHCl3); IR (ATR) nmax cmꢀ1: 2947, 2871, 1655,
1614, 1462, 1416, 1330, 1173, 745; 1H NMR (CDCl3, 400 MHz)
d ppm:
4.19. Cernuine (1)
6.36 (1H, br s, –NH–), 4.59 (1H, qd, J¼7.9, 4.9 Hz), 3.60 (1H, dddd,
J¼10.6, 5.7, 5.7, 3.7 Hz), 3.39 (1H, m), 2.25–2.42 (3H, m), 2.25 (1H,
ddd, J¼17.6, 10.7, 6.6 Hz), 2.09 (1H, m), 1.75–1.95 (5H, m), 1.58–1.75
(5H, m), 1.56 (1H, ddd, J¼14.0, 6.1, 5.0 Hz), 1.35 (1H, m), 1.12–1.26
(2H, m), 1.00 (3H, d, J¼6.8 Hz, H-16); 13C NMR (CDCl3, 100 MHz)
A mixture of S1 (11 mg, 42 mmol) and 10% Pd/C (6.0 mg) in EtOH
was stirred at room temperature for 2 h under H2 atmosphere. The
reaction mixture was filtered with Celite and the filtrate was
evaporated. The residue was purified by silica gel chromatography
d
ppm: 172.0, 170.2, 51.4, 47.9, 46.8, 42.8, 38.6, 36.1, 32.5, 31.2, 28.9,
(MeOH/EtOAc¼5:95) to afford 11 mg (96%) of 1 as a white solid.
28.0, 25.9, 21.2, 16.9 (C-16); EIMS m/z (%): 278 ([M]þ, 25), 180 (36),
167 (bp), 152 (89); HR-EIMS m/z: calcd for C16H26N2O2 [M]þ:
278.1994, found: 278.1985.
20
[
a]
ꢀ23 (c 0.46, MeOH); IR (ATR) nmax cmꢀ1: 2918, 2861, 1635,
D
1435, 1416, 1227, 854; 1H NMR (CD3OD, 600 MHz)
d ppm: 5.44 (1H,
dd, J¼12.2, 3.2 Hz), 3.64 (1H, m), 3.24 (1H, tt, J¼11.2, 2.9 Hz), 3.08
(1H, ddt, J¼12.4, 5.1, 2.6 Hz), 2.31–2.39 (2H, m), 2.12 (1H, qd, J¼12.7,
4.1 Hz), 2.02 (1H, m),1.95 (1H, m),1.89 (1H, qd, J¼13.1, 4.0 Hz),1.75–
1.86 (2H, m), 1.73 (1H, dt, J¼13.0, 3.0 Hz), 1.61–1.70 (3H, m), 1.58
(1H, ddt, J¼13.3, 3.8, 1.9 Hz), 1.49 (1H, tdd, J¼12.8, 9.6, 3.0 Hz), 1.40
(1H, td, J¼12.9, 5.2 Hz), 1.20 (1H, q, J¼12.1 Hz), 1.12 (1H, br d,
J¼13.5 Hz), 0.89 (3H, d, J¼6.6 Hz), 0.81 (1H, q, J¼12.1 Hz); 13C NMR
4.22. (D)-Cermizine D (2) and its TFA salt
To a solution of bis-amide 31 (16 mg, 57 mmol) in THF (1.1 mL)
was added LiAlH4 (22 mg, 0.57 mmol) at 0 ꢁC under argon atmo-
sphere. The mixture was heated to reflux for 5 h. After dilution with
Et2O and careful addition of water at 0 ꢁC, 1 M aqueous NaOH was
added to the mixture. The mixture was stirred overnight at room
temperature and then filtered with Celite. The filtrate was dried
over Na2SO4, and then concentrated under reduced pressure. The
residue was purified by silca gel chromatography (CHCl3/MeOH/
NH4OH¼80:18:2) to afford 8.6 mg (60%) of cermizine D (2) as a pale
yellow oil. To a solution of the cermizine D (2) (4.3 mg) in MeOH
(0.5 mL) was added TFA (one drop, excess). The mixture was con-
(CD3OD,150 MHz) d ppm: 171.1, 68.7, 59.2, 52.1, 47.6, 42.5, 41.7, 40.0,
33.7, 31.2, 26.3, 25.6, 23.5, 22.5, 21.5, 19.9; EIMS m/z (%): 262 (57,
Mþ), 233 (93, Mþ), 220 (bp); mp: 104–106 ꢁC; HR-EIMS m/z: calcd
for C16H26N2O [M]þ: 260.2045, found: 260.2052. The spectral data
were identical to those of the natural product.3c,4
4.20. N-((S)-1-((2S,4R,9aS)-Octahydro-2-methyl-6-oxo-1H-
quinolizin-4-yl)pent-4-en-2-yl)acrylamide (30)
centrated under reduced pressure to afford 9.9 mg (quant.) of cer-
25
mizine D TFA salt as a yellow oil. Compound 2: [
a]
þ80 (c 0.06,
D
MeOH); IR (ATR) nmax cmꢀ1: 3305, 2921, 1442, 1371, 725; 1H NMR
(CD3OD, 600 MHz)
To a solution of amine 6 (50 mg, 0.20 mmol) and Et3N (55
0.40 mmol) in CH2Cl2 (2.0 mL) was added acryloyl chloride (20
m
m
L,
L,
d
ppm: 3.40 (1H, br d, J¼14.0 Hz), 3.25 (1H, m),
0.25 mmol) at ꢀ78 ꢁC under argon atmosphere. After stirring at the
same temperature for 2 h, the reaction mixture was quenched by
adding MeOH (0.4 mL) and warmed to room temperature. The
mixture was treated with H2O and the whole mixture was extrac-
ted three times with CH2Cl2. The combined organic layers were
dried over Na2SO4 and evaporated. The residue was purified by
3.13 (1H, m), 3.06 (1H, br d, J¼10.7 Hz), 2.71 (1H, td, J¼13.5, 2.5 Hz),
2.67 (1H, m), 2.64 (1H, td, J¼12.1, 2.8 Hz), 2.00 (1H, qd, J¼12.8,
4.1 Hz), 1.76–1.92 (3H, m), 1.62–1.73 (3H, m), 1.52–1.62 (2H, m),
1.43–1.51 (2H, m), 1.39 (1H, td, J¼12.6, 5.0 Hz), 1.24–1.33 (3H, m),
1.14–1.24 (2H, m), 0.92 (3H, d, J¼6.3 Hz), 0.87 (1H, q, J¼12.0 Hz); 13C
NMR (CD3OD, 125 MHz)
d ppm: 59.2, 54.9, 50.2, 47.3, 40.6, 40.4,
silica gel chromatography (MeOH/EtOAc¼5:95) to afford 50 mg
39.7, 34.1, 26.4, 26.2, 25.8, 25.42, 25.37, 22.6, 19.7; EIMS m/z (%): 250
23
(39, Mþ), 178 (21), 166 (21), 166 (52), 152 (bp); HR-EIMS m/z: calcd
(82%) of 30 as pale yellow oil. [
a
]
þ77.9 (c 2.50, CHCl3); IR (neat)
D
nmax cmꢀ1: 3275, 3076, 2954, 1666, 1614, 754; 1H NMR (CDCl3,
400 MHz)
for C16H30N2 [M]þ: 250.2409, found: 250.2407.
20
(þ)-Cermizine D TFA salt:4
[a
]
þ24 (c 0.50, MeOH); IR (ATR)
d
ppm: 7.01 (1H, br d, J¼8.2 Hz), 6.29 (1H, dd, J¼17.0,
D
nmax cmꢀ1: 2954, 2871, 2719, 1665, 1457, 1429, 1125, 719; 1H NMR
1.8 Hz), 6.19 (1H, dd, J¼17.1, 10.0 Hz, H-2), 5.76 (1H, m, H-3), 5.61
(1H, dd, J¼10.1, 1.8 Hz, H-17), 5.01–5.06 (2H, m, H-18), 4.25 (1H, m),
4.02 (1H, m), 3.63 (1H, m), 2.17–2.42 (4H, m, H-10 and H-4), 1.56–
1.94 (9H, m), 1.13–1.27 (2H, m), 0.98 (3H, d, J¼6.8 Hz, H-16); 13C
(CD3OD, 600 MHz)
d
ppm: 3.96 (1H, br t, J¼11.0 Hz), 3.65–3.73 (2H,
m), 3.42 (1H, m), 3.31 (1H, m), 3.15 (1H, td, J¼13.7, 3.1 Hz), 3.05 (1H,
td, J¼12.7, 2.9 Hz), 2.31 (1H, ddd, J¼14.6, 8.7, 3.5 Hz), 2.21 (1H, m),
2.16 (1H, m), 2.01 (1H, m), 1.88–1.98 (4H, m), 1.52–1.82 (10H, m),
1.16 (1H, q, J¼12.7 Hz), 0.98 (3H, d, J¼6.3 Hz); 13C NMR (CD3OD,
NMR (CDCl3, 100 MHz) d ppm: 170.2, 165.7, 134.6, 131.5, 125.6, 117.5,
49.1, 47.5, 46.8, 39.7, 38.7, 38.0, 34.9, 32.8, 28.1, 25.9, 21.5, 17.0 (C-
16); FABMS (NBA) m/z: 305 [MþH]þ; HR-FABMS (NBA/PEG): calcd
for C18H29N2O2 [MþH]þ: 305.2229, found: 305.2224.
100 MHz)
d ppm: 62.4, 54.2, 51.4, 50.0, 45.9, 38.9, 38.0, 36.3, 31.0,
24.9, 24.6, 23.7, 23.2, 23.1, 21.6, 18.6; EIMS m/z (%): 250 (10, Mþ), 166
(12), 152 (95), 83 (bp); HR-EIMS m/z: calcd for C16H30N2 [M]þ:
250.2409, found: 250.2408.
4.21. (6R,8S,9aS)-Hexahydro-8-methyl-6-(((S)-6-oxopiperidin-
2-yl)methyl)-1H-quinolizin-4(6H)-one (31)
Acknowledgements
To acrylamide 30 (45 mg, 0.15 mmol) and first-generation
Grubbs catalyst (3.6 mg, 4.4 mmol) was added degassed CH2Cl2
(3.0 mL) at room temperature under N2 atmosphere. After stirring
for 7 h at the same temperature, an additional amount of first-
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
generation Grubbs catalyst (3.6 mg, 4.4 mmol) was added to the
mixture. After further stirring for 9 h, the reaction mixture was
concentrated under reduced pressure. The residue and 10% Pd/C
(22 mg) were suspended in EtOH (1.5 mL) and the mixture was
stirred at room temperature for 3 h under H2 atmosphere. The
References and notes
1. For recent reviews, see: (a) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G.
A., Ed.; Academic: New York, NY, 2005; Vol. 61, pp 1–57; (b) Ayer, W. A.;

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