An advanced intermediate for the synthesis of (±)-pumiliotoxin C and its analogues

Article abstract of DOI:10.1081/SCC-120037916

Compound 1 as a versatile intermediate for the synthesis of (±)-pumiliotoxin C and its analogues was prepared from commercially available cyclohexanone. The key step in the synthesis was the construction of octahydroquinoline ring by a stereoselective ami

Full text of DOI:10.1081/SCC-120037916

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 2031–2038, 2004
An Advanced Intermediate for the Synthesis
of (+)-Pumiliotoxin C and Its Analogues
Zhi-Hui Shao,1,2 Fang-Zhi Peng,2 Jing-Bo Chen,2
Chen-Ying Wang,2 Rong Huang,2 Yong-Qiang Tu,1
Liang Li,2 and Hong-Bin Zhang2,
*
1National Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou, P.R. China
2School of Pharmacy, Yunnan University, Kunming, P.R. China
ABSTRACT
Compound 1 as a versatile intermediate for the synthesis of (+)-pumiliotoxin
C and its analogues was prepared from commercially available cyclo-
hexanone. The key step in the synthesis was the construction of octa-
hydroquinoline ring by a stereoselective aminocyclization.
Key Words: (+)-Pumiliotoxin; Cyclohexanone; Octahydroquinoline;
Aminocyclization.
*
Correspondence: Hong-Bin Zhang, School of Pharmacy, Yunnan University,
Kunming 650091, P.R. China; E-mail: zhanghb@ynu.edu.cn.
2031
DOI: 10.1081/SCC-120037916
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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INTRODUCTION
Pumiliotoxin C, or decahydroquinoline cis-195A,[1] is a nontoxic alkaloid
originally isolated from the skin of Amphibians of the genus Dendrobates
pumilio. As a representative member of a wide class of decahydroquinoline
alkaloids isolated from neotropical dendrobatid frogs, pumiliotoxin C has
become a popular target for illustrating new methodologies for construction
of the decahydroquinoline ring system[2,3] (For recent syntheses of (+) pumi-
litoxin C, see Ref.[3a–d]. For enantiomerically pure pumilitoxin, see Ref.[3e–
i]). Although the syntheses of pumiliotoxin C have been the focus of more
than nine total syntheses,[3] from the medicinal chemistry point of view, ver-
satile precursors for the synthesis of pumiliotoxin C as well as decahydroqui-
noline analogues are still target of pursue.
We have recently developed a facile aminocyclization approach towards
the synthesis of the core N-heterocyclic center for a number of natural alka-
loids.[4] We describe herein its application towards the synthesis of a versatile
intermediate for (+)-pumiliotoxin C and its analogues. The retrosynthetic
analysis is shown in Sch. 1.
Starting with commercially available cyclohexanone, a Grinard reaction
with allylmagnesium bromide followed by hydroboration–oxidation afforded
compound 4. Selective protection of primary alcohol with acetic anhydride,
treatment of the resulting mixture with SOCl2 in pyridine and finally hydro-
lysis of the acetate with KOH in methanol/water (v/v ¼ 1/1) afforded
Scheme 1. Retrosynthetic analysis of (+)-pumiliotoxin C.

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compound 5 in 95% yield over the three steps. Alcohol 5 was then oxidized by
PCC to aldehyde 6, which was immediately converted to alcohol 7 by addition
of propylmagnesium chloride. After oxidation with Collins reagent and reduc-
tive amidation, the secondary amine 2 was obtained in 80% yield. The key
ring-forming product was obtained in 63% yield by following our reported
procedure.[4] To our delight, the syn-isomer (9 : 1) was predominantly formed
in the bromo-aminocyclization step. The double bond position of compound 1
was established based on spectrum analysis of COSY, HMQC and HMBC
spectra. The spatial proximity of H-8a (3.12 ppm) towards H-2 (2.54 ppm)
was confirmed by a NOSEY experiment (Sch. 2).
In conclusion, a versatile immediate for the synthesis of (+)-pumilitoxin C
and its analogues has been prepared with high stereoselectivity. The amino-
cyclization demonstrated herein represents a highly efficient while flexible
method for the construction of decahydroquinoline ring system. Manipulation
of the immediate 1 to (+)-pumilitoxin C and its analogues is currently under-
way in our laboratory.
EXPERIMENTAL
Proton nuclear magnetic resonance (1H-NMR) spectra were recorded on a
Bruker Avance 300 spectrometer at 300 MHz. Carbon-13 nuclear magnetic
resonance (13C-NMR) spectra were recorded on a Bruker Avance 300 spec-
trometer at 75MHz. Chemical shifts are reported as d values in parts per million
(ppm) relative to tetramethylsilane (TMS) for all recorded NMR spectra. Low
resolution mass spectra were recorded on Finnigan Trance 2000 GC-MS spec-
trometer. High resolution mass spectra were recorded on Autospec 3000 instru-
ment. IR spectra were recorded onAVATAR 360 spectrometer. Starting material
and reagents used in reactions were obtained commercially from Acros, Aldrich,
and Fluka, and used without purification, unless otherwise indicated.
1-(3-Hydroxy-propyl-cyclohexanol (4). A solution of cyclohexanone
(9.8 g, 100 mmol) in Et2O (20 mL) was added dropwise to a solution of 1 M
allylmagnesium bromide in Et2O (100 mL) at 08C. The resulting mixture
was stirred at room temperature for 1 hr, and then quenched by addition of
10% NH4Cl aqueous solution (50 mL). The mixture was extracted with
Et2O (100 mL ꢀ 3). After removal of the solvents, the residue was chromato-
graphed on silica gel (petroleum ether–EtOAc ¼ 30/1 ! 20/1) to give the
1
product (9.1 g, 65%) as colorless oil. H NMR (300 MHz, CDCl3): d 1.14–
1.70 (m, 10H), 1.76–1.94 (br s, 1H), 2.15 (dd, J ¼ 0.9, 7.5 Hz, 2H), 4.97–
5.10 (m, 2H), 5.82 (m, 1H); 13C NMR (75 MHz, CDCl3): d 132.9, 117.4,
70.0, 45.8, 36.3, 24.8 21.2; GC-MS, m/z (%) 98.9 (Mþ 2 C3H6, 100), 96.9
(12), 80.8 (100). The data was in agreement with those reported in Ref.[5]
.

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Scheme 2. Synthesis of the advanced intermediate for (+)-pumiliotoxin C and
.
its analogues. (a) Allylmagnesium bromide, Et2O, 65%; (b) BH3 Me2S, THF, 70%;
(c) Ac2O, pyridine, CH2Cl2; (d) SOCl2, pyridine, 2158C; (e) KOH, methanol/H2O
(1/1), 95% (three steps); (f) PCC, CH2Cl2; (g) propylmagnesium chloride, THF,
85% (two steps); (h) CrO3-Py2, CH2Cl2, 100%; (i) benzylamine, benzene, reflux,
then NaBH4, ethanol, 80%; (j) Br2, CH2Cl2, 2788C then K2CO3, DMF, 608C, 63%.

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.
To the solution of the oil (1.4 g, 10 mmol) in THF was added BH3 Me2S
(12 mmol) at 08C. After stirring at room temperature for 10 hr, the reaction
mixture was quenched by sequential addition of water (5 mL), 3 M NaOH
(4 mL), and 30% H2O2 (4 mL). The mixture was extracted with Et2O
(5 mL ꢀ 3) and the combined extracts were concentrated. The residue was
chromatographed on silica gel (petroleum ether–EtOAc ¼ 3/1 ! 2/1) to
1
yield product 4 (1.1 g, 70%) as colorless oil. H NMR (300 MHz, CDCl3):
d 1.13–1.78 (m, 14H), 3.54 (t, J ¼ 6.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d 71.4, 63.3, 39.0, 37.8, 26.4, 26.2, 22.7; GC-MS m/z (%) 158.1
(Mþ, 1), 140.1 (1), 127.0 (7), 115.0 (24), 102.0 (16), 99.0 (100), 97.0 (73),
81.0 (64). The data was in agreement with those reported in Ref.[5]
3-Cyclohex-1-enyl-propan-1-ol (5). To a solution of compound 4
(1.58 g, 10 mmol) in CH2Cl2 (20 mL) and pyridine (3 mL) was added Ac2O
(1.3 mL, 13 mmol) and the resulting mixture was stirred at room temperature
for 1.5 hr. After addition of 3 M HCl (20 mL), the mixture was extracted with
Et2O (25 mL ꢀ 3). The solvent was removed under vacuum and a crude oil
(2 g) was obtained and used for the next step without further purification.
The crude oil (2 g) in pyridine (10 mL) was treated with SOCl2 (1 mL)
at 2158C under nitrogen for 15 min. After addition of 4 M HCl (35 mL),
the mixture was extracted with CH2Cl2 (20 mL ꢀ 3). The combined organic
phases were washed with water, NaHCO3, brine, and dried over Na2SO4.
After removal of the solvents, 0.91 g of crude oil was obtained and used for
the next step without further purification.
The oil (1.85 g) was dissolved in a solution of methanol in water
(v/v ¼ 1/1, 15 mL) and KOH (1.12 g, 20 mmol) was added to the resulting
mixture. The mixture was stirred for 1hr before extraction with Et2O
(15 mL ꢀ 3) and the combined organic phases were concentrated. The residue
was chromatographed on silica gel (petroleum ether–EtOAc ¼ 10/1) to give
compound 5 (1.34 g, 95%) as colorless oil. IR (nmax, cm21): 3318, 1667, 1438,
1059; 1H NMR (300 MHz, CDCl3): d 1.31–1.93 (m, 13H), 3.55 (t, J ¼ 6.5 Hz,
2H), 5.36 (br s, 1H); 13C NMR (75 MHz, CDCl3): d 137.5, 121.4, 62.9, 34.3,
30.6, 28.3, 25.3, 23.1, 22.6; GC-MS m/z (%) 140.1 (Mþ, 24), 122.1 (5), 109.1
(8), 107.0 (31), 97.1 (9), 96.0 (39), 94.0 (45), 81.0 (100), 79.0 (99); HRMS
(ESI) calcd for C9H17O [M þ H]þ: 141.1279, found: 141.1324.
3-Cyclohex-1-enyl-propinaldehyde (6). To a mixture of PCC (2.15 g,
10 mmol) in CH2Cl2 (20 mL) was added a solution of compound 5 (0.7 g,
5 mmol) in CH2Cl2 (20 mL). The resulting mixture was stirred at room temperature
for 1 hr. After dilution with Et2O (30 mL), the mixture was filtered through a
pre-loaded silica gel column (5 cm) and eluted with Et2O to give aldehyde 6
(0.7 g), which was used immediately in the next step without further purification.
1H NMR (300 MHz, CDCl3): d 1.20–1.54 (m, 4H), 1.83–1.96 (m, 4H), 2.19
(t, J ¼ 7.3 Hz, 2H), 2.43 (t, J ¼ 7.2 Hz, 2H), 5.34 (br s, 1H), 9.67 (s, 1H);

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Shao et al.
13C NMR (75 MHz, CDCl3): d 209.8, 137.5, 121.4, 41.0, 30.6, 28.3, 25.3,
23.1, 22.6.
1-Cyclohex-1-enyl-hexan-3-ol (7). The aldehyde (0.7 g) was dissolved
in THF (10 mL). To this solution, propylmagnesium chloride (4 M, in Et2O,
1.25 mL) was added dropwise at 08C. The reaction mixture was stirred for
30 min, then quenched by the sequential addition of water and 1 M HCl.
The mixture was extracted with Et2O (20 mL ꢀ 3). After removal of the
solvents, the residue was chromatographed on silica gel [petroleum ether-
EtOAc ¼ 12/1 ! 10/1] to give compound 7 (0.77 g, 85%) as colorless
1
oil. IR(nmax, cm21): 3347, 1667, 1438, 1059; H NMR (300 MHz, CDCl3):
d 0.84 (t, J ¼ 7.0 Hz, 3H), 1.35–1.53 (m, 10H), 1.85–1.92 (m, 6H), 2.22
(br s, 1H), 3.50 (br s, 1H), 5.35 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d 136.8, 120.0, 70.5, 38.7, 34.3, 33.4, 27.4, 24.3, 22.0, 21.6, 17.9, 13.1;
GC-MS m/z (%) 182.1 (Mþ, 4), 164.1 (3), 139.0 (11), 135.0 (20), 122.0
(11), 121.0 (97), 107.0 (19), 92.9 (52), 86.0 (23), 81.0 (40), 78.9 (100);
HRMS (ESI) calcd for C12H23O [M þ H]þ: 183.1748, found 183.1703.
1-Cyclohex-1-enyl-hexan-3-one (8). The CrO3 (3 g, 30 mmol) was added
to a solution of pyridine (4.75 g, 60 mmol) in CH2Cl2 (70 mL). The resulting
mixture was stirred at room temperature for 15 min. To this mixture, a
solution of alcohol 7 (0.91 g, 5 mmol) in CH2Cl2 (5mL) was added and the
resulting mixture was stirred for 15 min at room temperature. The mixture was
diluted with Et2O (100 mL) and the organic layer was washed with 5% NaOH
(50 mL), 5% HCl (50 mL), 5% Na2CO3 (50 mL) and brine, and dried over
Na2SO4. After removal of the solvents, 0.9 g (100%) compound 8 was obtained.
IR (nmax, cm21): 1713, 1670, 1439, 1066; 1H NMR (300MHz, CDCl3): d 0.83
(t, J ¼ 7.3 Hz, 3H), 1.40–1.56 (m, 6H), 1.83–1.91 (m, 4H), 2.11 (t, J ¼ 7.2 Hz,
2H), 2.31 (t, J ¼ 7.2 Hz, 2H), 2.41 (t, J ¼ 7.2 Hz, 2H), 5.30 (br s, 1H); 13C NMR
(75 MHz, CDCl3): d 211.2, 136.7, 121.6, 45.0, 41.4, 32.2, 28.7, 25.5, 23.2, 22.7,
17.6, 14.0; GC-MS m/z (%) 180.2 (Mþ, 42), 165.2 (6), 137.1 (17), 119.1 (13),
109.1 (52), 94.1 (95), 71.1 (100), 67.1 (81), 55.1 (30), 43.1 (83); HRMS (ESI)
calcd for C12H21O [M þ 1]þ: 181.1592, found: 181.1588.
Benzyl-[1-(2-cyclohex-1-enyl-ethyl)-butyl]-amine (2). The crude oil
(0.9 g), p-toluenesulfonic acid (30 mg), and benzylamine (0.75 g, 7 mmol)
were dissolved in benzene. The resulting mixture was stirred at reflux for
8 hr. After removal of the solvent, the residue was dissolved in EtOH
(15 mL) and NaBH4 (194 mg, 5 mmol) was added in small portions at 08C
over a period of 10 min. The reaction mixture was stirred for 1 hr at room
temperature, then quenched by addition of water. The mixture was extracted
with EtOAc (20 mL ꢀ 3). After removal of the solvent, the residue was chro-
matographed on silica gel (petroleum ether–EtOAc ¼ 4/1) to give compound
2 (1.08 g, 80%) as colorless oil. IR (nmax, cm21): 3025, 1627, 1454, 1138;
1H NMR (300 MHz, CDCl3): d 0.82 (t, J ¼ 7.0 Hz, 3H), 1.27–1.31 (m, 5H),

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1.42–1.51 (m, 6H), 1.83–1.90 (m, 6H), 2.46 (m, 1H), 3.65 (s, 2H), 5.30 (br s,
1H), 7.12–7.22 (m, 5H); 13C NMR (75 MHz, CDCl3): d 141.5, 138.3, 128.7,
128.6, 127.2, 121.2, 56.8, 51.6, 36.8, 34.6, 32.3, 28.9, 25.7, 23.5, 23.0, 19.4,
14.8; GC-MS m/z (%) 271.0 (Mþ, 16), 228.0 (98), 215.0 (18), 187.9 (10),
174.9 (21), 161.9 (99), 147.0 (22), 131.9 (11), 120.8 (15), 105.9 (16), 90.8
(100); HRMS (ESI) calcd for C19H30N [M þ H]þ: 272.2378, found 272.2384.
1-Benzyl-2-propyl-1, 2, 3, 4, 6, 7, 8, 8a-octahydroquinoline (1). The
secondary amine 2 (271 mg, 1 mmol) in CH2Cl2 (20 mL) was stirred at
2788C under nitrogen for 5 min. Dry bromine (1.2 mmol, pre-washed with
concentrated sulfuric acid) was added dropwise over a period of 5 min. The
mixture was then stirred at room temperature for 10 min. The CH2Cl2 was
removed under vacuum and DMF (15 mL) was then added together with
K2CO3 (1 g). The resulting mixture was heated to 608C for 10 hr. After
removal of the solvent, the residue was diluted with water (10 mL) and
extracted with Et2O (15 mL ꢀ 3). The organic phases were combined and
washed with brine and dried over Na2SO4. After removal of the solvents,
the residue was chromatographed on silica gel (petroleum ether–
EtOAc ¼ 20/1 ! 15/1) to afford the key intermediate 1 (151 mg, 63%) as
major product and the minor isomer (16.8 mg, 7%).
The major product (syn-isomer): IR (nmax, cm21): 1672, 1454, 1138; 1H
NMR (300 MHz, CDCl3): d 0.71 (t, J ¼ 6.8 Hz, 3H), 1.06–1.40 (m, 7H),
1.40–1.95 (m, 5H), 1.96–2.10 (m, 1H), 2.12–2.28 (m, 1H), 2.54 (m, 1H),
3.12 (m, 1H), 3.62 (s, 2H), 5.46 (br s, 1H), 7.10 (d, J ¼ 7.1 Hz, 1H), 7.18
(dd, J ¼ 7.1, 7.2 Hz, 2H), 7.32 (d, J ¼ 7.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d 142.5, 135.3, 126.9, 126.4, 124.8, 121.7, 61.9, 61.1, 51.6, 36.4,
32.3, 28.8, 28.6, 24.5, 20.6, 18.7, 13.3; GC-MS m/z (%): 269.2 (Mþ, 3),
241.1 (16), 226.1 (58), 198.1 (24), 90.9 (100); HRMS (ESI) calcd for
C19H28N [M þ 1]þ: 270.2221, found: 270.2254.
1
The minor isomer (anti-isomer): H NMR (300 MHz, CDCl3): d 0.78
(t, J ¼ 6.9 Hz, 3H), 1.07–1.97 (m, 12H), 1.98–2.02 (m, 1H), 2.18–2.31
(m, 1H), 2.64 (m, 1H), 3.26 (m, 1H), 3.59 (d, J ¼ 14.3 Hz, 1H), 3.76
(d, J ¼ 14.3 Hz, 1H), 5.40 (br s, 1H), 7.10 (d, J ¼ 7.1 Hz, 1H), 7.21
(dd, J ¼ 7.0, 7.0 Hz, 2H), 7.29 (d, J ¼ 7.2 Hz, 2H); GC-MS m/z (%): 269.2
(Mþ, 2), 241.1 (15), 227.2 (9), 226.1 (52), 198.1 (26), 90.9 (100).
ACKNOWLEDGMENTS
This work was partially supported by a Grant (20272049) from National
Natural Science Foundation of China and a Grant (2002GH04) from the Inter-
national Cooperation Division of Yunnan provincial Science & Technology
Department.

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Received in Japan September 30, 2003

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