Efficient, asymmetric synthesis of (-)-isooncinotine

Article abstract of DOI:10.1016/j.tet.2007.01.068

Asymmetric synthesis of (-)-isooncinotine, a 22-membered lactam of spermidine alkaloid, starting from resolution of 2-piperidineethanol with (S)-10-camphorsulfonic acid is reported. Michael addition, amidations, and aluminum hydride reduction were applied to form the moiety of spermidine. Retro-Michael addition was observed when β-amido- and β-amino-propionitriles were reduced by LAH. The effects of LAH versus AlH₃ were discussed. The synthesis of the skeleton of this macrolide is achieved with ring-closing metathesis of the?diene prepared from acylation of the spermidine.

Full text of DOI:10.1016/j.tet.2007.01.068

Tetrahedron 63 (2007) 3000–3005
Efficient, asymmetric synthesis of (L)-isooncinotine
*
Hsiu-Yi Cheng and Duen-Ren Hou
Department of Chemistry, National Central University, Jhongli City, Taoyuan 32001, Taiwan
Received 14 December 2006; revised 29 January 2007; accepted 31 January 2007
Available online 2 February 2007
Abstract—Asymmetric synthesis of (ꢀ)-isooncinotine, a 22-membered lactam of spermidine alkaloid, starting from resolution of 2-
piperidineethanol with (S)-10-camphorsulfonic acid is reported. Michael addition, amidations, and aluminum hydride reduction were applied
to form the moiety of spermidine. Retro-Michael addition was observed when b-amido- and b-amino-propionitriles were reduced by LAH.
The effects of LAH versus AlH3 were discussed. The synthesis of the skeleton of this macrolide is achieved with ring-closing metathesis of
the diene prepared from acylation of the spermidine.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
As shown in Scheme 1, our synthetic strategy toward (ꢀ)-
isooncinotine is based on ring-closing metathesis7 of the
Polyamines, such as putrescine, spermidine, and spermine,
are essential for the growth and function of normal cells.1
Studies on N-alkylated polyamines revealed that these com-
pounds possess antineoplastic activity against a number of
murine and human tumor lines in vitro and in vivo.2 There-
fore, polyamines and their inhibitors/analogues have drawn
certain attentions in recent years.3 Isooncinotine, isolated
from Oncinotisnitida (Apocynaceae),4 is a member of
oncinotines with spermidine skeleton. Recently, F€urstner’s
group reported the first enantioselective synthesis of this
22-membered lactam.5 In pursuit of efficient syntheses in-
volving ring-closing metathesis (RCM) and following our
previous work on oncinotines,6 we report our results in
preparing isooncinotine here.
diene 2, which could be obtained from diamidation of suc-
cinic anhydride with amines 4 and 5, reduction to triamine
3, and acylation of 3 with 9-decenoic acid.
O
H
H
7
RCM
10
NH
O
N
N
NH
3
N
4
3
N
4 H
Bn
(-)-isooncinotine (1)
CO2H
7
H
+
7
H
N
O
N
Bn
NH
N
NH2
3
4 NBn
2
4
3
H
N
H
N
NH2
3
H2N
H2N
NH2
3
3
4
H
Putrescine
H
Spermine
O
O
CN
O
BnNH
H
10
+
NH
+
O
5
4
H2N
N
NH2
N
N
NH2
3
m
4
n
OH
CN
+
BnNH2
Spermidine
Oncinotine, m = 3, n = 4
Neooncinotine, m = 4, n = 3
NH
Scheme 1. Retrosynthetic analysis of (ꢀ)-isooncinotine.
H
N
HN
O
2. Results and discussion
N
H
Isooncinotine (1)
Commercially available, racemic 2-piperidineethanol was
resolved by (S)-10-camphorsulfonic acid according to Toy
and Price’s procedure with some modifications.8 The optical
purity of the resulting (S,S)-ammonium salt 6 was further
* Corresponding author. Fax: +886 3 4227664; e-mail: drhou@cc.ncu.
edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.068

H.-Y. Cheng, D.-R. Hou / Tetrahedron 63 (2007) 3000–3005
3001
H
confirmed by preparing its camphorsulfonamide derivative 7
H
OH
ref. 11
(Scheme 2).9,10 Only one set of diastereotopic hydrogens,
assigned to a-methylene of sulfonamide 7, was observed
on 1H NMR (Fig. 1a); on the other hand, the diastereomeric
mixtures, prepared directly from racemic 2-piperidineetha-
nol and (S)-10-camphorsulfonic chloride, clearly show two
sets of those hydrogens (Fig. 1b). Compound 6 was then neu-
tralized and protected as a carbamate 8, which was converted
to 2-allylpiperidine 4 by Swern oxidation, Wittig olefination,
and deprotection following a procedure reported by Ikeda’s
group (Scheme 3).11
Boc2O, Et3N
CH2Cl2, 88%
6
CF3CO2
NBoc
8
NH2
4
H
N
5, Bz2O, Et3N
succinic anhydride
K2CO3, DMF, 99%
DMAP, 87%
9
O
CO2H
H
LiAlH4, concd H2SO4
87%
Bn
N
N
CN
2
2
10
O
O
H
N
OH
9-decenoic chloride
Et3N, 73%
H
Bn
N
H
NH OH
NH2
3
4
3
HO3SH2C
O
NH2
O3SH2C
resolution
O
6
H
N
7
OH
O
H
N
NH
4 N
Bn
3
2
O
ClO2SH2C
O
S
O
Scheme 3.
7
O
hand, the reductions with aluminum hydride15,16 are free
of the fragmented product 11 (entries 2–4). We also noticed
that excess amount of hydride is required to ensure complete
Scheme 2.
The acylation of piperidine 4 with succinic anhydride was
achieved in high yield. The resulting carboxylic acid 96
was coupled with amino nitrile 512 to give diamide 10.
Here, we found that benzoic anhydride is a better dehydrat-
ing reagent than conventional N,N0-diisopropylcarbodiimide
(DIC) for this coupling reaction. This is mainly due to the
product 10, which was difficult to separate from diisopropyl
urea, the byproduct from DIC. On the other hand, the usage
of benzoic anhydride greatly simplified the purification step
with a good yield.13
Table 1. Reduction of compound 10
H
N
H
10
Bn
N
+
3
(1)
25 °C
CN
N
NHBn
2
4
4
11
12
Entry Reagent
Yielda Product ratiob (%)
(%)
3
11
12
1
2
3
4
LiAlH4 (3 equiv)
LiAlH4/AlCl3 (2.7 equiv each)
LiAlH4/H2SO4 (3.8 equiv, 1.9 equiv) 73
LiAlH4/H2SO4 (7.7 equiv, 3.8 equiv) 87
82
43
41
0
71
100
59
0
0
0
Reduction of cyanoamide 10 requires more efforts (Eq. 1 and
Table 1). We found that reduction using lithium aluminum
hydride (LAH) gives a 2:3 mixture of the desired, fully
reduced product 3 and diamine 11, obviously derived from
retro-Michael addition of 10 (entry 1).14 On the other
100
29
0
0
a
Isolated yields.
Ratios were determined by 500 MHz 1H NMR of the crude product.
b
Figure 1. (a) 1H NMR (500 MHz) of 7 prepared from 6; (b) 1H NMR (500 MHz) of two diastereomers prepared from racemic 2-piperidineethanol.

3002
H.-Y. Cheng, D.-R. Hou / Tetrahedron 63 (2007) 3000–3005
reduction to give pure triamine 3 with 87% yield (entry 4).
The two byproducts 11 and 12 were independently synthe-
sized and confirmed by spectroscopic data (see Section 3).
Further studies on the reductions of b-amino- or b-amido-
propionitriles using model compounds 13 and 14 are summa-
rized in Table 2.17 All the products 15–17 are known and have
distinct absorptions on 1H NMR.18–20 When LAH was
applied, the fragmented product 16 was observed in both
substrates in spite of different ratios (entries 1, 2, and 5).
The fact that b-aminonitriles (12 and 14) were not found in
the LAH reduction of b-amidonitriles (10 and 14) and differ-
ent product ratios derived from 13 and 14 imply that 12 and
14 as the reaction intermediates are unlikely. Thus, LAH
preferentially reacts with the cyano group and has two
reaction pathways: reduction and retro-Michael addition. In
contrast, only amide reduced 12 and 15 as the byproducts/
intermediates in AlH3 reductions suggests that this reduction
occurs at amides first and free of retro-Michael addition.
H
N
N
N
7
Cl
Ru
O
Cl
Ph
NH
PCy3
N
3
4
concd HCl(aq)
Bn
2
CH2Cl2, reflux, 65%
18
O
H
N
(i) H2, 5% Pd/C
concd HCl, MeOH
10
NH
3
(ii) H2, PdCl2, AcOH
53%; 2 steps
N
4
H
(-)-isooncinotine (1)
Scheme 4.
2-piperidineethanol, the title compound was prepared in 11
steps with 9% total yield. There are several advantages in
this synthesis. All the chemical reagents used here are com-
mercially available and inexpensive. Only two protective
groups (Boc and Bn) were applied; therefore, the whole syn-
thesis is straightforward and concise. It should provide an
easy access to (ꢀ)-isooncinotine and opportunity for further
studying its functions in biological systems.
Acylation of triamine 3 with 9-decenoic chloride6,21 pro-
vided the diene 2, the essential synthetic intermediate for
RCM.
Ring-closing metathesis of 2 was carried out with the
Grubbs’ second-generation catalyst under an acidic con-
dition to afford the cyclized lactam 18 in 65% yield. Hydro-
genation and then debenzylation of lactam 18 gave
isooncinotine (Scheme 4). We found that our previous de-
benzylation method for oncinotines, using Pearlman’s
catalyst (palladium hydroxide in charcoal) and ammonium
formate did not complete the deprotection and the amount
of impurities gradually raised as the reaction time in-
creased.6,22 However, the procedure reported by Bergeron
et al., H2/PdCl2 in acetic acid, proves to be effective and
gives clean product 1.23 One-pot reduction and deprotection
of 18 using Bergeron’s condition led to incomplete deprotec-
tion (50%) even when the reaction time was prolonged to
24 h. The optical rotation of our synthetic (ꢀ)-isooncinotine
is consistent with that previously reported.4c,5
3. Experimental section
3.1. Resolution of 2-piperidineethanol
A solution of (1S)-(+)-10-camphorsulfonic acid (31.0 g,
0.13 mmol) in ethanol (45 mL) was added dropwise to a
solution of 2-piperidineethanol (33.0 g, 0.25 mmol) in etha-
nol (50 mL) with stirring. The reaction mixture was cooled
in a refrigerator overnight and the needle- to lath-like crys-
tals (compound 6, 17.7 g, mp 130–151 ꢁC) were collected
by filtration, washed with ether, and dried under vacuum.
The first crop crystals were redissolved in warm ethanol
(20 mL) and cooled in a refrigerator. The formed crystals
(15.2 g, mp 162–165 ꢁC) were collected, and the recrystalli-
zation procedure was repeated with warm ethanol (15 mL)
to have the lath-like crystal (11.3 g, mp 165–167 ꢁC,
24%). This product was used for the following synthesis.
In summary, we have developed an efficient method to
prepare (ꢀ)-isooncinotine. Starting from resolution of
3.2. Sulfonamide 7
Table 2. Reduction of compounds 13 and 14
(1S)-(+)-10-Camphorsulfonyl chloride (36 mg, 0.11 mmol)
in CH2Cl2 (1 mL) was added to the solution of (S,S)-ammo-
nium salt 6 (40 mg, 0.10 mmol) and triethylamine (46 mL,
0.33 mmol) in dry CH2Cl2 (1 mL) at 0 ꢁC. After stirring at
room temperature for 24 h, the reaction mixture was diluted
with CH2Cl2 (20 mL), washed with water (5 mLꢂ2) and
saturated NaCl(aq) (10 mL), dried over sodium sulfate, fil-
tered, and concentrated to give 7 as a yellow oil (20 mg,
X
O
Et
Et
N
(CH2)3NH2
NBn
H
N(CH2)2CN
Bn
(2)
NBn
H
Bn
THF
16
17
15
13, X = O
14, X = H, H
Entry Substrate Reagent
Yielda (%) Product ratiob (%)
1
15
16
17
0.058 mmol, 53%). H NMR (500 MHz, CDCl3) d 4.45
(1H, m), 4.43 (1H, m), 3.57 (1H, d, J¼15.1 Hz), 3.20 (1H,
m), 2.99 (1H, d, J¼15.1 Hz), 2.90 (1H, m), 2.71 (1H, dt, J¼
12.2, 2.3 Hz), 2.45–2.39 (2H, m), 2.12 (1H, m), 2.10–1.98
(2H, m), 1.97–1.89 (2H, m), 1.88–1.72 (2H, m), 1.70–1.50
(4H, m), 1.49–1.29 (4H, m), 1.06 (3H, s), 0.85 (3H, s); 13C
NMR (125 MHz, CDCl3) d (rotamers) 216.8, 214.6, 66.8,
58.3, 57.9, 53.6, 48.1, 47.9, 47.4, 46.7, 45.3, 42.8, 42.7, 42.6,
42.5, 33.5, 29.0, 26.9, 26.8, 24.9, 24.5, 22.8, 22.7, 21.3, 19.7,
19.6; HRMS (FAB) calcd for [M+H]+ (C17H30O4NS):
344.1896, found: 344.1894.
1
2
3
4
5
13
13
13
13
14
LiAlH4 (1.9 equiv)c 71
LiAlH4 (1.9 equiv)d 85
AlH3 (2.5 equiv)c,e 87
34
14
63
0
0
17
49
0
0
0
—
37
41f
100
83
AlH3 (5 equiv)c,e
72
LiAlH4 (1 equiv)c 56
a
b
c
d
e
f
Isolated yields.
Ratios were determined by 500 MHz 1H NMR of the crude product.
25 ꢁC.
65 ꢁC.
Generated from LiAlH4/H2SO4 (2:1).
With 59% of 14.

H.-Y. Cheng, D.-R. Hou / Tetrahedron 63 (2007) 3000–3005
3003
3.3. 4-((S)-2-Allyl-piperidin-1-yl)-N-benzyl-N-(2-cyano-
ethyl)-4-oxo-butyramide (10)
reaction mixture was stirred for 20 h at room temperature, di-
luted with CH2Cl2 (20 mL), washed with saturated NH4Cl(aq)
(10 mLꢂ2), NaHCO3(aq) (10 mLꢂ3), and the organic layer
was dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2:
EtOAc/hexane 1:1; Rf 0.26) to provide the diamide (46 mg,
0.15 mmol, 10%). 1H NMR (500 MHz, CDCl3) d (rotamer)
1.31 (m, 1H), 1.40–1.59 (m, 4H), 1.65 (m, 2H), 2.15–2.20
(m), 2.24–2.32 (m) and 2.39–2.45 (m, 2H), 2.52–2.61 (m,
3H), 2.62–2.72 (m, 1H), 2.52–2.61 (m) and 3.01 (m, 1H),
3.64 (d, J¼13.3 Hz) and 4.44 (br, 1H), 3.97 (m) and 4.69–
4.73 (m, 1H), 4.38 (d, J¼5.7 Hz, 2H), 4.90–5.06 (m, 2H),
5.62 (m, 1H), 6.88 (br, 1H), 7.18–7.27 (m, 5H); 13C NMR
(125 MHz, CDCl3) d (rotamer) 18.7, 25.2, 25.8, 27.1, 28.2,
28.9, 29.2, 31.5, 34.0, 34.4, 36.6, 40.7, 43.3, 47.6, 52.4,
116.6, 117.9, 127.0, 127.4, 128.4, 134.1, 135.0, 138.5, 170.4,
172.5. The diamide (30 mg, 0.1 mmol) in THF (1 mL) was
added with LAH (18 mg, 0.48 mmol) and refluxed for 1 h.
The reaction mixture was diluted with ether (5 mL),
quenched with saturated NaHCO3(aq) (0.3 mL), filtered, and
concentrated to have diamine 11 (25 mg, 0.09 mmol, 93%)
To a solution of triethylamine (210 mL, 1.5 mmol), DMAP
(6 mg, 0.04 mmol), and benzoic anhydride (116 mg,
0.44 mmol) in dry CH2Cl2 (2 mL) was added a solution of
acid 9 (100 mg, 0.44 mmol) in dry dichloromethane
(1.5 mL). After stirring at room temperature for 10 min, the
resulting mixture was added with amino nitrile 5 (60 mg,
0.37 mmol) in dry CH2Cl2 (3.5 mL) and stirred for another
25 h at room temperature. The reaction mixture was washed
with saturated NH4Cl(aq) (4 mLꢂ2), and the organic layer
was dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2:
EtOAc/hexane 1:1; Rf 0.67) to provide the compound 10
(120 mg, 0.33 mmol, 87%) as a yellow oil. [a]2D0 ꢀ28.1 (c
1.2, CHCl3); 1H NMR (500 MHz, CDCl3) d (rotamer) 1.38
(br, 1H), 1.48–1.71 (m, 5H), 2.18–2.40 (m) and 2.40–2.52
(m, 2H), 2.54–2.60 (m, 3H), 2.60–2.72 (m, 3H), 2.62–2.72
(m) and 3.07 (dt, J¼13.3 Hz, J¼2.7 Hz, 1H), 3.53 (m, 1H),
3.53 (m) and 4.45 (d, J¼13.5 Hz, 1H), 3.66 (m, 1H), 4.15
(br) and 4.80 (dd, J¼13.0 Hz, J¼7.1 Hz, 1H), 4.63 (s) and
4.69 (s, 2H), 4.88–5.10 (m, 2H), 5.67 (m, 1H), 7.17–7.34
(m, 5H). 13C NMR (125 MHz, CDCl3) d (rotamer) 16.0,
18.7, 25.2, 25.8, 27.0, 27.8, 28.1, 28.2, 28.4, 28.7, 34.0,
34.4, 36.6, 40.7, 42.7, 43.0, 47.5, 52.2, 52.3, 116.5, 116.6,
117.3, 117.8, 118.1, 126.5, 127.5, 127.7, 128.6, 128.9,
129.7, 134.2, 135.1, 135.2, 135.9, 170.0, 169.9, 170.0,
172.3, 173.0; IR (neat) 704, 735, 918, 1009, 1434, 1636,
2247, 2936, 3067, 3480 cmꢀ1; HRMS (FAB) calcd for
[M+H]+ (C22H30N3O2): 368.2338, found: 368.2342.
1
as a colorless oil. H NMR (500 MHz, CDCl3) d 1.22 (m,
1H), 1.30 (m, 1H), 1.35–1.50 (m, 5H), 1.50–1.67 (m, 4H),
2.17 (m, 1H), 2.27 (m, 1H), 2.35 (m, 1H), 2.61 (m, 3H),
2.76 (m, 1H), 3.75 (s, 2H), 4.98–5.02 (m, 2H), 5.72–5.77
(m, 1H), 7.20–7.31 (m, 5H); 13C NMR (125 MHz, CDCl3)
d 23.2, 25.6, 28.1, 30.2, 35.6, 49.2, 51.7, 53.4, 53.9, 59.4,
116.2, 126.7, 128.0, 128.2, 135.9, 140.3; HRMS (FAB) calcd
for [M+H]+ (C19H31N2): 287.2482, found: 287.2491.
3.6. Nitrile 12
3.4. N1-[4-((S)-2-Allyl-piperidin-1-yl)-butyl]-N1-benzyl-
propane-1,3-diamine (3)
Diamine 11 (25 mg, 0.087 mmol) in acrylonitrile (1 mL,
15 mmol) was refluxed for 48 h. The excess acrylonitrile
was removed under vacuum to give nitrile 12 as a light yellow
oil (24 mg, 0.07 mmol, 80%). 1H NMR (500 MHz, CDCl3)
d 1.25 (m, 1H), 1.36 (m, 1H), 1.39–1.58 (m, 5H), 1.58–
1.71 (m, 3H), 2.19–2.21 (m, 2H), 2.21–2.33 (m, 2H), 2.33–
2.42 (m, 3H), 2.42–2.55 (m, 2H), 2.65 (m, 1H), 2.74–2.77 (m,
3H), 3.60 (s, 2H), 4.99–5.02 (m, 2H), 5.72–5.80 (m, 1H),
7.21–7.30 (m, 5H); 13C NMR (125 MHz, CDCl3) d 16.3,
23.2, 25.3, 25.5, 30.2, 35.6, 49.2, 51.7, 53.4, 53.7, 58.4, 59.5,
116.34,118.9,127.1,128.3,128.6,136.0,138.8;HRMS(FAB)
calcd for [M+H]+ (C22H34N3): 340.2747, found: 340.2756.
To a solution of LiAlH4 (43 mg, 1.13 mmol) in dry THF
(1 mL) was added concentrated H2SO4 (30 mL, 0.56 mmol)
under N2 at 0 ꢁC and stirred for 10 min. A solution of amide
10 (50 mg, 0.14 mmol) in dry THF (1 mL) was added to the
solution of aluminum hydride by syringe and stirred at room
temperature for another 3 h. The reaction mixture was
diluted with ether (10 mL) and quenched with NaOH(aq)
(1 N, 2 mLꢂ2). The organic layer was separated, dried
over Na2SO4, filtered, and concentrated to give triamine
3 (41 mg, 0.12 mmol, 87%) as a yellow oil. [a]2D0 ꢀ25.5
(c 2.2, CHCl3); 1H NMR (500 MHz, CDCl3) d 1.15–1.38 (m,
2H), 1.38–1.50 (m, 6H), 1.50–1.68 (m, 5H), 2.20–2.09 (m,
2H), 2.30–2.20 (m, 2H), 2.44–2.30 (m, 5H), 2.60 (m, 1H),
2.82–2.69 (m, 2H), 2.77 (br, 1H), 3.50 (s, 2H), 4.98–5.02
(m, 2H), 5.76 (m, 1H), 7.19 (m, 1H), 7.24–7.29 (m, 4H);
13C NMR (125 MHz, CDCl3) d 23.3, 24.8, 25.1, 25.5,
30.2, 30.9, 35.6, 40.4, 51.2, 51.7, 53.5, 53.7, 58.6, 59.4,
116.1, 126.6, 128.0, 128.6, 136.0, 139.9; IR (neat) 737, 910,
3.7. Nitrile 13
Acetyl chloride (0.6 mL, 0.84 mmol) was added to the solu-
tion of nitrile 5 (0.9 g, 5.6 mmol), triethylamine (2.5 mL,
17.9 mmol), and CH2Cl2 (10 mL) at 0 ꢁC. The reaction mix-
ture was stirred at room temperature for 2 h, washed with
water (5 mLꢂ2), saturated NaCl(aq) (10 mL), and the or-
ganic layer was dried over Na2SO4, filtered, and concen-
995, 1452, 1494, 1638, 2857, 2933, 3026, 3062, 3417 cmꢀ1
;
trated to give nitrile 13 (0.91 g, 4.5 mmol, 80%). H NMR
1
HRMS (FAB) calcd for [M+H]+ (C22H38N3): 344.3066,
found: 344.3063.
(500 MHz, CDCl3) d 2.15 (s, 3H), 2.63 (t, J¼6.6 Hz), 3.56
(t, J¼6.6 Hz), 4.66 (s, 2H), 7.15 (d, J¼7.3 Hz), 7.30–7.36
(m, 3H); 13C NMR (75 MHz, CDCl3) d 16.1, 21.5, 42.6,
53.2, 118.2, 126.2, 127.9, 128.7, 135.8, 171.4.
3.5. Diamine 11
To a solution of acid 9 (350 mg, 1.55 mmol) in dry CH2Cl2
(10 mL) wasaddedtriethylamine(0.6 mL, 4.3 mmol), DMAP
(8 mg, 0.07 mmol), benzoic anhydride (407 mg, 1.55 mmol),
and benzylamine (138 mg, 1.29 mmol), sequentially. The
3.8. Diene 2
A mixture of 9-decenoic acid (155 mg, 0.91 mmol) and
thionyl chloride (0.5 mL) was heated at 60 ꢁC for 30 min.

3004
H.-Y. Cheng, D.-R. Hou / Tetrahedron 63 (2007) 3000–3005
Excess thionyl chloride was removed under vacuum and
CH2Cl2 (1 mL) was added. The resulting solution of 9-dec-
enoyl chloride was added to a solution of triamine 3 and tri-
ethylamine (0.5 mL) in dry CH2Cl2 (10 mL) by syringe at
0 ꢁC and stirred for another 2 h. The reaction mixture was
washed with water (5 mLꢂ2), saturated NaCl(aq) (10 mL),
dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2:
MeOH/CH3Cl 1:9; Rf 0.5) to give diene 2 (276 mg,
0.56 mmol, 73%) as a yellow oil. [a]2D0 ꢀ13.7 (c 0.6,
was further purified by column chromatography (SiO2:
MeOH/CH3Cl 1:10 and then MeOH/CH3Cl/Et3N 1:4:0.5;
Rf 0.5) to give isooncinotine (8 mg, 0.021 mmol, 53%) as
a yellow oil. [a]D20 ꢀ32.3 (c 0.07, MeOH); 1H NMR
(500 MHz, CDCl3) d 1.18–1.39 (m, 17H), 1.39–1.50 (m,
6H), 1.50–1.69 (m, 8H), 2.13 (t, 4H), 2.32 (br, 1H), 2.50–
2.68 (m, 3H), 2.75 (br, 2H), 2.86 (m, 1H), 3.33–3.35 (m,
2H), 7.55 (br, 1H); 13C NMR (125 MHz, CDCl3) d 23.4,
23.8, 24.0, 25.7, 27.6, 28.0, 28.4, 28.5, 28.7, 28.9, 30.5, 30.8,
36.9, 39.8, 49.4, 50.3, 52.4, 53.4, 60.0, 173.0; IR (neat) 729,
1461, 1549, 1643, 2853, 2926, 3078, 3284 cmꢀ1; HRMS
(FAB) calcd for [M+H]+ (C23H46N3O): 380.3641, found:
380.3655.
1
CHCl3); H NMR (500 MHz, CDCl3) d (rotamer) 1.15–
1.30 (br, 8H), 1.30–1.38 (m, 2H), 1.38–1.45 (br, 4H),
1.45–1.50 (m, 3H), 1.50–1.60 (5H), 3.46, 4.86–4.91 (m,
2H), 4.95–5.00 (m, 2H), 5.71–5.75 (m, 2H), 6.24 and 6.29
(br, 1H), 7.20 (m, 1H), 7.23–7.26 (m, 4H); 13C NMR
(125 MHz, CDCl3) d (rotamer) 22.9, 23.2, 24.7, 24.9, 25.1,
25.6, 25.9, 26.1, 28.7, 28.8, 29.0, 29.1, 29.7, 33.6, 35.3, 36.6,
38.1, 51.4, 51.6, 51.7, 53.2, 53.6, 58.7, 59.5, 114.0, 116.4,
126.9, 128.1, 128.8, 135.5, 138.9, 139.4, 172.7, 172.8; IR
(neat) 699, 734, 909, 995, 1452, 1465, 1494, 1551, 1643,
2928, 3028, 3076, 3303, 3424 cmꢀ1; HRMS (FAB) calcd
for [M+H]+ (C32H54N3O): 496.4267, found: 496.4271.
Acknowledgements
This research was supported by National Central University
and the National Science Council (NSC 94-2113-M-008-
007), Taiwan.
Supplementary data
3.9. Lactam 18
1H and 13C NMR spectra of all new compounds. Supplemen-
tary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2007.01.068.
Concentrated HCl(aq) (10 drops) was added to a solution of
diene 2 (20 mg, 0.04 mmol) in CH2Cl2 (10 mL) and stirred
for 5 min. The solvent was removed under vacuum and
a solution of Grubbs’ second-generation catalyst (4 mg,
0.0047 mmol) in CH2Cl2 (30 mL) was added to the flask.
The reaction mixture was heated to reflux for 14 h. The so-
lution was poured into a separation funnel, washed with sat-
urated NaHCO3(aq) (10 mLꢂ2), saturated NaCl(aq) (10 mL),
dried over NaSO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2:
MeOH/CH3Cl, 1:9; Rf 0.23 and then SiO2: MeOH/CH3Cl/
Et3N, 1:10:0.5; Rf 0.71) to give lactam 18 (12 mg,
0.026 mmol, 65%) as a yellow oil. [a]2D0 ꢀ23.5 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.34–1.14 (m, 10H),
1.49–1.34 (br, 5H), 1.60–1.49 (m, 4H), 1.70–1.60 (m, 3H),
2.14–1.88 (m, 5H), 2.30–2.14 (m, 2H), 2.48–2.30 (m, 4H),
2.60–2.48 (m, 2H), 2.75–2.60 (br, 1H), 2.88–2.75 (br, 1H),
3.15–3.32 (m, 2H), 3.51–3.46 (m, 2H), 5.39–5.35 (m, 2H),
6.92 (br, 1H), 7.30–7.21 (m, 5H); 13C NMR (125 MHz,
CDCl3) d 23.2, 23.3, 24.8, 25.1, 25.4, 25.5, 27.4, 27.9, 28.0,
28.6, 30.6, 31.5, 34.3, 36.8, 39.2, 51.7, 53.0, 53.2, 53.7, 58.8,
60.0, 127.0, 127.4, 128.2, 128.9, 131.8, 138.9, 172.8; IR
(neat) 699, 734, 969, 1452, 1644, 2854, 2928, 3025,
3434 cmꢀ1; HRMS (FAB) calcd for [M+H]+ (C30H50N3O):
468.3954, found: 468.3947.
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