Synthetic study toward pancracine

Article abstract of DOI:10.3987/COM-05-10470

A synthetic study toward pancracine (2) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).

Full text of DOI:10.3987/COM-05-10470

HETEROCYCLES, Vol. 65, No. 8, 2005
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HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1999 - 2004
Received, 2nd June, 2005, Accepted, 5th July, 2005, Published online, 8th July, 2005
SYNTHETIC STUDY TOWARD PANCRACINE
Meng-Yang Chang,*,a Hua-Ping Chen,a Chun-Yu Lin,a and Chun-Li Paib
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung
b
811, Taiwan Department of Chemistry, National Sun Yat-Sen University,
Kaohsiung 804, Taiwan
Abstract—A synthetic study toward pancracine (2) has been established starting
from trans-(2S,4R)-4-hydroxyproline (1).
1. INTRODUCTION
In view of structural framework of trans-(2S,4R)-4-hydroxyproline (1), it possesses three functional
groups that can be easily modified, including 1-amino, 2-carboxylate and 4-hydroxy groups.1 The
skeleton represents out the significant feature for producing a series of different carbon framework, such
as monocycles (pyrrole,2a pyrrolidine,2b-2c,2l piperidine2d and azanucleoside2e), fused or bridged bicycles
(pyrrolizidine2f or azabicycles2g-2h,2m) and polycycles2i-2k etc., using an efficient modification. Here we
report that a synthetic study toward pancracine (2) has been established by synthesizing Banwell’s
intermediate (3) from compound (1) (Figure 1). Pancracine, brunsvigine, montanine, coccinine and
manthine with pentacyclic ring system are the members of the subclass of Amaryllidaceae alkaloids and
differ only in the configurations of two stereocenters at C-2 and C-3.3a Because of the interesting carbon
framework and pharmacological potential, pancracine (2) has induced many attempts to synthesize.3b-3f
Figure 1.
O
O
OH
2
HO
O
O
OH
3
CO2H
N
H
N
N
Ts
trans-4-hydroxyproline (1)
Banwell's intermediate (3)
(-)-pancracine (2)
2. RESULTS AND DISCUSSION
Synthesis of prolinol (4) contains the following four-step reactions from trans-4-hydroxyproline (1): (i)
o
esterification with thionyl chloride and methanol in -78 C, (ii) N-tosylation with p-toluenesulfonyl

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HETEROCYCLES, Vol. 65, No. 8, 2005
chloride and triethylamine, (iii) O-silylation with t-butyldimethylsilyl chloride and imidazole, and (iv)
reduction of the ester with sodium borohydride in the presence of lithium chloride4 (Equation 1). Thus,
prolinol (4) was obtained in 90% overall yield with only once purification.2m
TBSO
HO
1) SOCl2, MeOH
2) TsCl, Et3N, CH2Cl2
[Eq. 1]
CO2H
N
N
H
3) TBSCl, Im., DMF
4) NaBH4, LiCl, MeOH
(four steps 90%)
Ts
OH
1
4
We first studied the approach to pancracine (2) from alcohol (4) as shown in Scheme 1. Alcohol (4) was
transformed into olefin (5) by Swern oxidation5 and Wittig olefination under standard conditions.
Hydrogenation of unsaturated compound (5) with a catalytic amount of 10% palladium on activated
carbon was achieved to saturated compound. The corresponding compound was transformed to ketone (6)
by desilyation with tetra-n-butylammonium fluoride in tetrahydrofuran followed by oxidation of the
resulting alcohol with pyridinium chlorochromate in dichloromethane using one-pot synthesis.
Scheme 1.
O
O
TBSO
TBSO
1) H2, 10% Pd/C (90%)
1) Swern ox.
OH
2) TBAF then PCC
(one-pot 81%)
2) Ph3P=CHCH2CH(OCH2)2
(two steps 75%)
N
Ts
N
Ts
H
4
5
O
O
O
O
O
O
O
O
p-TsOH
MgBr
1)
(78%)
N
2) BF3-OEt2, Et3SiH
(two steps 36%)
N
Ts
N
Ts
Ts
7
3
6
Intramolecular aldol condensation of ketone (6) with a catalytic amount of p-toluenesulfonic acid under
acid-mediated Dean-Stark distillation6 gave compound (7), which was then further converted to
Banwell’s intermediate (3)3c as the major product using Grignard addition and acidic dehydroxylation.2j,2l
1
The H-NMR spectral data of compound (3) were in accordance with those reported in the literature.3c
Sha and coworkers reported a facile anionic cyclization approach toward the hexahydro-1H-indol-3-one
skeleton, and also utilized the building block (7) to the synthesis of brunsvigine,3b steine3d and
lentiginosine.7

HETEROCYCLES, Vol. 65, No. 8, 2005
2001
3. CONCLUSION
In summary, we have developed a straightforward approach to the hexahydro-1H-indol-3-one skeleton
ring system (7) based on intramolecular aldol condensation of ketone (6) under acidic condition and
applied this route to synthesize Banwell’s intermediate (3) in the synthetic study toward pancracine (2).
4. EXPERIMENTAL
General. Tetrahydrofuran was distilled prior to use from a deep-blue solution of sodium-benzophenone
ketyl. All other reagents were obtained from commercial sources and used without further purification.
Reaction was routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Extract
was dried with anhydrous magnesium sulfate before concentration in vacuo. Crude product was purified
using column chromatography on silica gel.
(2S,4R)-4-t-Butyldimethylsilyloxy-2-[3-(1,3-dioxolan-2-yl)prop-1-en-1-yl]-1-(4-methylphenylsulfonyl)-
pyrrolidine (5).
A solution of oxalyl chloride (400 mg, 3.15 mmol) in dichloromethane (20 mL) was mixed with dimethyl
sulfoxide (400 mg, 5.13 mmol) at –78 oC. The solution was warmed to –40 oC for 15 min and recooled to
o
–78 C, and then a solution of prolinol (4)2m (1.0 g, 2.60 mmol) in dichloromethane (10 mL) was added
followed by excess triethylamine (4 mL, 28.46 mmol) for 30 min. The reaction mixture was warmed to rt
and poured into 15% ammonium chloride solution (2 mL). The residue was diluted with water (15 mL)
and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with brine and water, dried,
filtered and concentrated to produce crude aldehyde (950 mg). To
a
solution of
[2-(1,3-dioxolan-2-yl)ethyl]triphenylphosphonium bromide (1.77 g, 4.0 mmol) in dry tetrahydrofuran (40
o
mL) was added n-butyllithium (2.0 mL, 1.6 M in hexane, 3.2 mmol) at –78 C. The orange red colored
mixture was stirred for 1 h. The crude aldehyde (950 mg) in dry tetrahydrofuran (5 mL) was added to the
o
reaction mixture at –78 C via a syringe and the mixture was further stirred for 8 h. The reaction was
quenched with 15% ammonium chloride solution (10 mL) and the mixture was extracted with ethyl
acetate (3 x 50 mL) and the combined organic layers were washed with brine, dried, filtered and
evaporated to yield crude compound. Purification on silica gel (hexane/ethyl acetate = 10/1) afforded
product (5) (910 mg, two steps 75% from 4) as a viscous oil. [α]26D -21.79o (c 0.48, CHCl3); IR (CHCl3)
2955, 1670 cm-1; FAB-MS: C23H38NO5SSi m/z (%) = 73 (100), 91 (29), 133 (21), 354 (6), 468 (M++1, 2);
1
HRMS (ESI, M++1) calcd for C23H38NO5SSi 468.2240, found 468.2240; H NMR (500 MHz, CDCl3) δ
7.71 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.70-5.51 (m, 2H), 4.94-4.88 (m, 1H), 4.33 (dd, J = 8.5,
15.5 Hz, 1H), 4.24 (br s, 1H), 4.01-3.95 (m, 2H), 3.90-3.84 (m, 2H), 3.64 (dd, J = 4.0, 11.0 Hz, 1H), 3.20
(d, J = 11.0 Hz, 1H), 2.56-2.43 (m, 2H), 2.41 (s, 3H), 1.90-1.71 (m, 2H), 0.71 (s, 9H), -0.08 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 144.16, 134.05, 129.48 (2x), 127.79 (2x), 125.95, 123.15, 103.51, 69.66,
65.00 (2x), 57.84, 55.90, 42.88, 32.50, 25.54 (3x), 21.47, 17.79, -4.94, -5.06.

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HETEROCYCLES, Vol. 65, No. 8, 2005
(2R)-2-[3-(1,3-Dioxolan-2-yl)prop-1-yl]-1-(4-methylphenylsulfonyl)pyrrolidin-3-one (6).
Compound (5) (1.0 g, 2.14 mmol) was dissolved in ethyl acetate (30 mL) and 10% palladium on activated
carbon as catalyst was added. Then hydrogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 10 h. Filtration through a short plug of Celite and washing with ethyl acetate (3 x 10
mL) resulted in crude saturated product (900 mg, 90%) as a viscous oil. Without further purification, a
solution of tetra-n-butylammonium fluoride (1.2 mL, 1.0 M in tetrahydrofuran, 1.2 mmol) in
tetrahydrofuran (1 mL) was added to a solution of the corresponding saturated compound (700 mg) in
tetrahydrofuran (5 mL) at rt for 1 h. A mixture of pyridinium chlorochromate (1.08 g, 5.01 mmol), Celite
(3.0 g) and dichloromethane (20 mL) was added to the stirring reaction. After being stirred at rt for 10 h,
the mixture was filtered through a short silica gel column. The filtrate was dried, filtered and evaporated
to yield crude compound. Purification on silica gel (hexane/ethyl acetate = 5/1) yielded product (6) (430
mg, 81%) as a viscous oil. [α]22D -2.55o (c 0.075, CHCl3); FAB-MS: C17H24NO5S m/z (%) = 91 (29), 155
1
(8), 354 (M++1, 15); HRMS (ESI, M++1) calcd for C17H24NO5S 354.1375, found 354.1377; H NMR
(500 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.83 (t, J = 4.5 Hz, 1H), 4.21 (ddd,
J = 2.5, 6.5, 15.5 Hz, 1H), 3.96-3.92 (m, 2H), 3.87-3.82 (m, 2H), 3.78 (d, J = 19.0 Hz, 1H), 3.64 (d, J =
19.0 Hz, 1H), 2.43 (s, 3H), 2.20 (dd, J = 9.0, 19.0 Hz, 1H), 2.11 (dd, J = 2.5, 19.0 Hz, 1H), 1.74-1.64 (m,
2H), 1.60-1.43 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 210.05, 144.21, 134.78, 130.09 (2x), 127.24 (2x),
104.09, 64.84, 64.82, 57.63, 52.90, 42.31, 35.47, 33.18, 21.51, 19.96; Anal. Calcd for C17H23NO5S: C,
57.77; H, 6.56; N, 3.96. Found: C, 58.00; H, 6.38; N, 4.13.
(7aR)-1-(4-Methylphenylsulfonyl)-1,2,5,6,7,7a-hexahydro-1H-indol-3-one (7).3b
Compound (6) (350 mg, 0.99 mmol) was dissolved in toluene (20 mL), and a catalytic amount of
p-toluenesulfonic acid (20 mg) was added. The mixture was reflux for 5 h under Dean-Stark condition.
Saturated sodium bicarbonate solution (5 mL) was added to the resulting mixture and the solution was
concentrated under reduced pressure. The residue was diluted with water (1 mL) and extracted with ethyl
acetate (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated
to yield crude compound. Purification on silica gel (hexane/ethyl acetate = 4/1) yielded product (7) (225
o
mg, 78%) as a colorless solid. mp = 167-168 C (dichloromethane/methanol); IR (CHCl3) 2980, 2887,
1733, 1660 cm-1; FAB-MS: C15H18NO3S m/z (%) = 77 (52), 91 (58), 107 (36), 136 (100), 154 (71), 292
1
(M++1, 14); HRMS (ESI, M++1) calcd for C15H18NO3S 292.1007, found 292.1005; H NMR (500 MHz,
CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.83 (dd, J = 3.0, 6.5 Hz, 1H), 3.87 (d, J =
17.0 Hz, 1H), 3.72-3.68 (m, 1H), 3.40 (d, J = 17.0 Hz, 1H), 2.81-2.78 (m, 1H), 2.46 (s, 3H), 2.37-2.20 (m,
2H), 2.00-1.90 (m, 1H), 1.58-1.49 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 195.31, 144.47, 137.45,

HETEROCYCLES, Vol. 65, No. 8, 2005
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135.47, 131.46, 129.97 (2x), 128.15 (2x), 58.26, 55.50, 29.35, 25.07, 21.58, 19.62; Anal. Calcd for
C15H17NO3S: C, 61.83; H, 5.88; N, 4.81. Found: C, 61.95; H, 5.80; N, 4.93.
(3S,7aR)-2,3,5,6,7,7a-Hexahydro-3-(3,4-methylenedioxyphenyl)-1-(4-methylphenylsulfonyl)-1H-
indole (3).3c
A solution of 3,4-methylenedioxyphenylmagnesium bromide (0.5 mL, 1.0 M in tetrahydrofuran, 0.5
o
mmol) was added to a solution of compound (7) (88 mg, 0.3 mmol) in tetrahydrofuran (10 mL) –78 C.
After stirring at the same temperature for 5 h, the mixture was concentrated in vacuo. Ethyl acetate (20
mL) was added to the residue, and the solution was washed with saturated sodium bicarbonate solution
(10 mL) and brine, dried, filtered, then concentrated in vacuo to yield crude product (82 mg). Without
further purification, a mixture of the resulting tertiary alcohol (82 mg), boron trifluoride etherate (0.01
mL), and triethylsilane (2 mL) was stirred at rt for 10 h, and then the mixture was concentrated in vacuo.
Ethyl acetate (20 mL) was added to the residue, and the solution was washed with saturated sodium
bicarbonate solution (10 mL) and brine, dried, filtered, then concentrated in vacuo to give crude product.
The crude product was purified by column chromatography (hexane/ethyl acetate = 3/1) to yield
compound (3) (43 mg, two steps 36% from 7) as a viscous oil. The 1H NMR spectral data of compound (3)
were in accordance with those reported in reference 3c.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC 93-2113-M-390-004 & NSC
94-2113-M-390-001) of the Republic of China for financial support.
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