A novel approach to the enantioselective formal synthesis of pumiliotoxin 251D

Article abstract of DOI:10.1039/b004450o

An efficient enantioselective synthesis of the indolizidine framework 9 of pumiliotoxin 251D in good yield by using a Lewis acid (cat.)-promoted diastereoselective addition of ethyl lithiopropiolate to ketone 7 derived from L-proline as a key step is reported. Hydrogenation of the addition product 8a gave the desired lactam 9. At the same time the 8-epimer of 9 was synthesized for the first time.

Full text of DOI:10.1039/b004450o

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A novel approach to the enantioselective formal synthesis of
pumiliotoxin 251D
Yike Ni, Gang Zhao* and Yu Ding*
1
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai, 200032, People’s Republic of China. Fax: 86 21 64166128;
E-mail: dingyu@pub.sioc.ac.cn
Received (in Cambridge, UK) 1st June 2000, Accepted 3rd August 2000
First published as an Advance Article on the web 13th September 2000
An efficient enantioselective synthesis of the indolizidine framework 9 of pumiliotoxin 251D in good yield by using a
Lewis acid (cat.)-promoted diastereoselective addition of ethyl lithiopropiolate to ketone 7 derived from L-proline
as a key step is reported. Hydrogenation of the addition product 8a gave the desired lactam 9. At the same time the
8-epimer of 9 was synthesized for the first time.
Introduction
The neotropical frogs of the family Dendrobatidae are a rich
source of biologically significant alkaloids1 with varied struc-
ture prototypes. These alkaloids are usually released onto the
skin surface from cutaneous granular glands and many of them
play a chemical defense role. Among them, pumiliotoxins A (2),
B (3), and 251D (1) have shown ability to activate voltage-
dependent sodium channels, therefore displaying in some cases
cardiotonic and myotonic activity.2 Pumiliotoxins A and B were
first isolated from the Panamanian poisonous frog Dendrobates
pumilio in 1967 by Daly and co-workers.3 The structure of
pumiliotoxin A among dendrobatid alkaloids was not defined
until the structure and absolute configuration of pumiliotoxin
251D, a major component of the basic skin extracts of the
Ecuadorean poisonous frog Dendrobates tricolor, were estab-
lished by means of X-ray crystallographic analysis.4 Since the
natural source of these alkaloids is limited, it has stimulated the
development of comprehensive synthetic programmes from
the laboratories of Overman,5 Trost,6 and Gallagher.7 In 1996,
Cossy and co-workers presented an approach to the optically
active pumiliotoxin 251D skeleton by using a 6-exo-dig radical
cyclisation.8 Recently, Barrett reported a formal synthesis of
Scheme 1 Reagents, conditions (and yields): (a) (i) SOCl2, MeOH,
pumiliotoxin 251D via a highly diastereoselective addition of a
titanium homoenolate to an -proline derivative9 and Martin
described a formal synthesis of pumiliotoxin 251D by using a
vinylogous Mannich reaction to construct the ring skeleton.10
reflux; (ii) ZCl, K2CO3, CH3CN (84%, 2 steps). (b) MeMgI, Et2O (91%).
(c) SOCl2, Et3N, THF, Ϫ45 ЊC (60%). (d) O3, MeOH, Me2S (90%).
(e) Ethyl propiolate, LDA, THF, Ϫ78 ЊC. (f) H2, Pd/C, MeOH (80%).
N-(Benzyloxycarbonyl)--proline methyl ester 4, formed from
-proline in two steps, was converted to propenyl derivative 6 by
the reaction with an excess of MeMgI in diethyl ether followed
by regioselective dehydration of the resulting tertiary alcohol 5
with thionyl dichloride and Et3N at low temperature. Ozon-
olysis of 6 with O3 in MeOH gave the ketone 7. Addition of
ethyl lithiopropiolate to ketone 7 to elongate the side-chain
by three carbon atoms with the terminal carboxylate group
necessary for the next cyclisation should provide a most concise
strategy. Garner and Park11 reported highly diastereoselective
addition of ethyl lithiopropiolate in hexamethylphosphonic
triamide–tetrahydrofuran (HMPA–THF) to N-Boc-N,O-iso-
propylidene--serinal, and Chen and Fang12 accomplished the
diastereoselective addition of ethyl lithiopropiolate to a chiral
α-keto ester in the presence of 1 equivalent of MgCl2. There-
fore, we investigated the effect of different Lewis, acids, includ-
ing YCl3, TiCp2Cl2, Ti(OPri)4, BF3ؒEt2O, ZnCl2, Ti(OPri)3Cl,
TiCl4–Ti(OPri)4, and SnCl4, on the addition of ethyl lithio-
Results and discussion
We report here a short novel synthesis of the lactam 9 with
the basic pumiliotoxin 251D skeleton and correct stereo-
chemistry, employing a diastereoselective addition of ethyl
lithiopropiolate to ketone 7 as a key step, as shown in Scheme 1.
3264
J. Chem. Soc., Perkin Trans. 1, 2000, 3264–3266
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004450o

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Table 1 The effect of different Lewis acids on the addition to ketone
Experimental
General
7a
Ratio to
ketone 7
Yield
(%)b
All reactions were conducted under nitrogen unless stated
otherwise and followed by TLC on precoated silica gel
HSGF254 plates (Yantai Chemical Co. Ltd). Column chromato-
graphy was performed on silica gel 300–400 µ (Yantai Chemical
Co. Ltd) and columns were eluted with petroleum spirit (60–
90 ЊC) (PS) and ethyl acetate (EA) mixtures. All solvents were
refluxed and distilled under nitrogen from sodium benzo-
phenone ketyl (THF, Et2O) or CaH2 (CH2Cl2, Pri2NH).
Entry
Lewis acid
8a:8bc
1
2
3
4
5
6
7
8f
9
YCl3
0.1 mol eq.
2 mol eq.
0.1 mol eq.
2 mol eq.
0.1 mol eq.
2 mol eq.
0.1 mol eq.
2 mol eq.e
0.1 mol eq.
2 mol eq.e
0.1 mol eq.
2 mol eq.
0.1 mol eq.
2 mol eq.e
0.1 mol eq.
2 mol eq.e
58
16
80
12
55
36
68.5
1:4.4d
1:3.5
1:7.5d
1:1.1
4.6:1
1:2.2
1:3.6
TiCp2Cl2
Ti(OPri)4
BF3ؒEt2O
ZnCl2
1
All H NMR spectra were recorded on a Bruker AMX-300
spectrometer and are reported in δ-units (ppm) and J-values
(Hz) with Me4Si as standard. Mass spectra (EI) were recorded
on an HP-5985-A mass spectrometer. Infrared (IR) spectra
were recorded on a Shimadzu IR-440 or a Digital FTIR and are
reported in wavenumbers (cmϪ1). Optical rotations were meas-
ured on a Perkin-Elmer 241 Autopol Polarimeter. [α]D-Values
are reported in units of 10Ϫ1 deg cm2 gϪ1. Element analyses were
performed on a Carlo Erba 1106.
77
1:1.7
Ti(OPri)3Cl
29.4
12
81
1.9:1
4.3:1
1.3:1
TiCl4–Ti(OPri)4
(1:1)
SnCl4
29
86
7.7:1
1:2.7
None
a The ratio of ethyl lithiopropiolate to ketone 7 = 2:1. b Isolated yield.
c The absolute configurations are determined according to those of their
cyclo-products. d The ratio is decided by isolation yield (others by
HPLC). e No analytical data due to complicated products. f The
solvent is toluene (THF in cases with no indication otherwise).
Methyl benzyloxycarbonyl-L-prolinate 4
A solution of -proline methyl ester (6.45 g, 50 mmol), contain-
ing K2CO3 (10.35 g, 75 mmol), in CH3CN (60 ml) was stirred at
25 ЊC for 10 min. After the mixture was cooled to 0 ЊC in an ice-
bath, benzyloxycarbonyl chloride (8.55 ml, 60 mmol) was
added dropwise slowly within 20 min. The reaction mixture was
stirred at 0 ЊC for 3 h and poured into ice-cooled, saturated aq.
NH4Cl, then extracted with Et2O. The organic layer was washed
with brine and dried over Na2SO4. After concentration, and
purification of the residue by chromatography (PS–EA 5:1),
the Z-protected methyl prolinate 4 (12.2 g, 92.8%) was given as
a colorless liquid, [α]D21 Ϫ55.6 (c 1.4 in CH3OH) {lit.,13 [α]D25 Ϫ57.5
(c 5.03 in CH3OH)}; νmax(neat) 3034, 2980, 2955, 2883, 1749,
1706, 1499, 1448, 1416; m/z (EI) 264 (Mϩ ϩ 1, 1%), 218 (4),
204 (Mϩ Ϫ CO2Me, 11), 160 (15), 91 (100) (Found: C, 63.55; H,
6.53; N, 5.27. Calc. for C14H17NO4: C, 63.85; H, 6.50; N,
5.32%).
propiolate to ketone 7 in detail. As the results show in Table 1
we found that the addition in the presence of only a catalytic
amount of TiCp2Cl2 (10% mol) provided an 80% yield of the
alcohols 8a and 8b in the ratio 1:7.5, while in the presence of
Ti(OPri)4 (10% mol) a 55% yield of the alcohols 8a and 8b in the
ratio 4.6:1 was obtained, which is the best complementary
promoters’ combination among the tested Lewis acids for the
preparation of the respective addition products 8b and 8a.
The diastereoselectivity of this addition in the presence of
Ti(OPri)nCl4 Ϫ n is opposite to that in the case of TiCp2Cl2.
It is interesting that 2 equivalents of Lewis acid reduced
yields and diastereoselectivity dramatically. We think that the
chelation of a catalytic amount of Lewis acid (10% mol) with
the carbonyl group promoted the nucleophilic addition of
ethoxycarbonylethynyl anion to the carbonyl group of ketone 7
and improved the diastereoselectivity, but the possible organo-
titanium or other organometallic compounds formed in the
stoicheiometric reaction of an excess of Lewis acid with ethyl
lithiopropiolate are less active in the addition to ketone 7 than is
the ethoxycarbonylethynyl anion, resulting in poor yields and
diastereoselectivity.
(2S)-N-Benzyloxycarbonyl-2-(1Ј-hydroxy-1Ј-methylethyl)pyrrol-
idine 5
To a solution of MeMgI prepared in advance from Mg (360
mg, 15 mmol), MeI (1 ml, 16 mmol) and dry diethyl ether (12
ml) was added a solution of 4 (1.32 g, 5 mmol) in diethyl ether
(5 ml) rapidly with vigorous stirring at room temperature. After
being stirred for another 10 min the reaction mixture was
refluxed for 3 h, cooled to room temperature, and stirred over-
night, then quenched by addition of saturated aq. NH4Cl and
extracted with EtOAc. The organic layer was washed with brine
and dried (Na2SO4). Concentration in vacuo and purification of
the residue by chromatography (PS–EA 4:1) gave the pyrrol-
idine 5 (1.2 g, 91%) as a colorless liquid, [α]D22 Ϫ58.4 (c 4.5 in
CHCl3) {lit.,14 [α]D20 Ϫ69.3 (c 3.0 in CHCl3)}; νmax(neat) 3389,
3034, 2976, 2887, 1674, 1498, 1455, 1415; m/z (EI) 264 (Mϩ ϩ 1,
27%), 246 (Mϩ Ϫ OH, 65), 204 (11), 202 (22), 160 (33), 91 (100)
(Found: C, 67.95; H, 8.30; N, 5.25. Calc. for C15H21NO3: C,
68.40; H, 8.04; N 5.32%).
Hydrogenation of 8a in MeOH at room temperature under 1
atm H2 provided the desired lactam 9 in 80% yield. Thus we
have constructed the pumiliotoxin 251D skeleton lactam 9 from
-proline in six steps with high diastereoselectivity and 18.2%
overall yield. Furthermore, hydrogenation of 8b under the same
conditions gave an 80% yield of lactam 10, which is the 8-epimer
of lactam 9.
(2S)-N-Benzyloxycarbonyl-2-(1Ј-methylethenyl)pyrrolidine 6
To a solution of 5 (132 mg, 0.5 mmol) in THF (5 ml) at Ϫ50 ЊC
was added dropwise cold SOCl2 (0.1 ml), followed by cold Et3N
(1.4 ml). The reaction temperature was kept between Ϫ45
and Ϫ50 ЊC. The reaction mixture was stirred at the same tem-
perature for another 30 min and was then allowed to warm to
room temperature, poured onto 5 g of ice and extracted with
diethyl ether; the extract was washed (brine) and dried
(Na2SO4). Purification on silica gel (PS–EA 10:1) gave 6 (73
mg, 60%) as a colorless liquid, [α]D24 Ϫ24 (c 0.89 in CHCl3) {lit.,5b
Scheme 2
Indolizidine skeleton 9 could be converted to pumiliotoxin
251D in three steps as already described,7 and pumiliotoxins A
and B could be synthesized by the same strategy. Therefore we
have found a shorter enantioselective approach (nine steps) to
pumiliotoxin 251D, and are the first to have synthesised the
8-epimer of 9.
J. Chem. Soc., Perkin Trans. 1, 2000, 3264–3266
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[α]D25 Ϫ27.9 (c 6.05 in CH3OH)}; νmax(neat) 3034, 2972, 2879,
1705, 1654, 1541, 1498, 1449; m/z (EI) 245 (Mϩ, 0.2%), 204 (2),
186 (1), 160 (9), 154 (3), 139 (7), 114 (18), 91 (100) (Found: C,
73.03; H, 8.07; N, 6.16. Calc. for C15H19NO2: C, 73.43; H, 7.80;
N, 5.71%).
The reaction mixture was stirred under H2 (1 atm) for 10 h, then
filtered through Celite and concentrated in vacuo to give a
slightly yellow crude product, which was recrystallised to pro-
vide 9 (19 mg, 80%) as colorless needles, mp 88.3–91.1 ЊC (from
n-hexane–diethyl ether) {lit.,9 89–91 ЊC; lit.,7 90–92 ЊC; lit.,10
94–95 ЊC}; [α]D26–50.7 (c 0.55 in CHCl3) {lit.,7 [α]D21 Ϫ47.0 (c 0.97
in CHCl3); lit.,9 [α]2D9 Ϫ53.0 (c 0.97 in CHCl3); lit.,10 [α]D22 Ϫ55.0
(c 0.79 in CHCl3)}; νmax(KBr) 3370, 2971, 2881, 1616, 1475,
1412; m/z (EI) 170 (Mϩ ϩ 1, 26%), 169 (Mϩ, 41), 154
(Mϩ Ϫ CH3, 4), 126 (16), 112 (15), 111 (18), 99 (13), 98 (12), 83
(81), 70 (100); δH (400 MHz; CDCl3) 3.45 (dd, J 4.4 and 9.5,
2H), 3.30 (dd, J 5.6 and 10, 1H), 3.15 (s, 1H, disappeared when
exchanged with D2O), 2.50 (ddd, J 7.2, 11.2 and 18.6, 1H), 2.35
(dd, J 7.2 and 18.2, 1H), 1.65–2.00 (m, 6H), 1.20 (s, 3H).
For 10, mp 128.3–129.7 ЊC (from n-hexane–diethyl ether); [α]D25
Ϫ57.8 (c 0.6 in CHCl3); νmax(KBr) 3279, 2952, 2885, 1610, 1483,
1450, 1413; m/z (EI) 170 (Mϩ ϩ 1, 11.5%), 169 (Mϩ, 32), 154
(Mϩ Ϫ CH3, 4), 136 (1), 112 (13), 111 (16), 99 (12), 98 (11), 83
(79), 70 (100); δH (300 MHz; CDCl3) 3.50 (m, 3H), 2.50 (ddd,
J 3.8, 6.0 and 17.5, 1H), 2.35 (dd, J 7.3 and 18.0, 1H), 2.30 (s,
1H), 1.60–2.15 (m, 6H), 1.20 (s, 3H).
(2S)-2-Acetyl-N-(benzyloxycarbonyl)pyrrolidine 7
To a solution of 6 (389 mg, 1.58 mmol) in absolute MeOH (100
ml) at Ϫ78 ЊC was introduced O3 until the reaction became blue
(ca. 10 min), followed by introduction of O2 to make the solu-
tion colorless again and then the reaction mixture was allowed
to warm to room temperature. To the solution was added Me2S
(0.5 ml) and the mixture was stirred for 30 min. Concentration
and purification by chromatography (PS–EA 3:1) gave 7 (351
mg, 90%) as a colorless oil, [α]D20 Ϫ43.9 (c 2.1 in CHCl3) {lit.,9 [α]D27
Ϫ42.2 (c 1.0 in CHCl3)}; νmax(neat) 3034, 2958, 2884, 1704,
1499, 1448, 1416; m/z (EI) 248 (Mϩ ϩ 1, 0.15%), 204 (13), 160
(18), 91 (100) (Found: C, 67.60; H, 7.12; N, 5.60. Calc. for
C14H17NO3: C, 68.00; H, 6.93; N, 5.66%).
Ethyl 4-[(2ЈS)-N-(benzyloxycarbonyl)pyrrolidin-2Ј-yl]-4-hydroxy-
pent-2-ynoate 8
Acknowledgements
To a solution of Pri2NH (0.16 ml, 1.09 mmol) in THF (6 ml)
was added dropwise 1.6 M n-BuLi (0.68 ml, 1.09 mmol) at 0 ЊC.
The solution was then warmed to room temperature and stirred
for 20 min. After it had been cooled to Ϫ78 ЊC and ethyl propi-
olate (0.12 ml, 1.09 mmol) had been added dropwise, the reac-
tion mixture was stirred for 70 min. Then TiCp2Cl2 (14 mg,
0.055 mmol) was added and the mixture was stirred for another
20 min. A solution of 7 (135 mg, 0.546 mmol) in THF (1 ml)
was added dropwise. Stirring at Ϫ78 ЊC was continued until the
starting material had disappeared on TLC. The reaction mix-
ture was treated dropwise with saturated aq. NH4Cl, extracted
with diethyl ether, and the extract was washed (brine) and dried
(Na2SO4). Concentration, and purification by chromatography
(PS–EA 4:1) gave 8a and 8b (150 mg, 80%) in the ratio 7.5:1 as
a yellow liquid: 8a [α]D24 ϩ217.4 (c 1.3 in CHCl3); νmax(neat) 3331,
3035, 2985, 2899, 2243, 1712, 1670, 1499, 1455, 1413; m/z (EI)
346 (Mϩ ϩ 1, 0.4%), 328 (0.8), 302 (1), 204 (13), 160 (39), 91
(100); δH (300 MHz; CDCl3) 7.40 (m, 5H), 6.00 (br s, 1H), 5.15
(s, 2H), 4.30 (m, 1H), 4.23 (q, J 7.1, 2H), 3.71–3.79 (m, 1H),
3.36–3.44 (m, 1H), 1.67–2.26 (m, 4H), 1.41 (s, 3H), 1.30 (t, J 7.1,
3H) (Found: C, 66.22; H, 6.64; N, 4.13. Calc. for C19H23NO5: C,
66.06; H, 6.71; N, 4.06%).
We thank the Analytical Department of the Shanghai Institute
of Organic Chemistry, Academia Sinica for help with elemental
analysis and HPLC assay.
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2241, 1712, 1668, 1499, 1454, 1419; m/z (EI) 346 (Mϩ ϩ 1,
0.3%), 328 (0.5), 302 (0.4), 204 (13), 160 (39), 91 (100); δH (300
MHz; CDCl3;) 7.30 (m, 5H), 5.14 (s, 2H), 4.17 (q, J 7.1, 2H),
3.94 (t, J 7.5, 1H), 3.75 (dt, J 3.1 and 7.6, 1H), 3.35 (m, 1H),
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3266
J. Chem. Soc., Perkin Trans. 1, 2000, 3264–3266