A general and efficient route to enantioselective synthesis of pumiliotoxin A alkaloids via a common key intermediate

Article abstract of DOI:10.1016/j.tetlet.2003.08.113

A general and efficient formal synthesis of pumiliotoxins and allopumiliotoxins has been achieved via a common key intermediate 3a. Our route featured a novel one-pot substitution-ring-opening sequence and an efficient Claisen-type condensation. This meth

Full text of DOI:10.1016/j.tetlet.2003.08.113

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7981–7984
A general and efficient route to enantioselective synthesis of
pumiliotoxin A alkaloids via a common key intermediate
Bing Wang, Kai Fang and Guo-Qiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
Received 12 May 2003; revised 27 June 2003; accepted 29 August 2003
Abstract—A general and efficient formal synthesis of pumiliotoxins and allopumiliotoxins has been achieved via a common key
intermediate 3a. Our route featured a novel one-pot substitution–ring-opening sequence and an efficient Claisen-type condensa-
tion. This method is also applicable to quinolizidine derivative 2b.
© 2003 Elsevier Ltd. All rights reserved.
The skin secretion of neotropical frogs of the family
Dendrobatidae have afforded a wide spectrum of alka-
loids, among which pumiliotoxin A1 class was believed
to serve in ‘chemical defence’ against predators.
Because of their structurally unique features and bio-
logical significances, pumiliotoxin A alkaloids have
aroused numerous synthetic efforts2 since the synthesis
of a relatively simple member, pumiliotoxin 251D, was
fulfilled by Overman’s group in 1981.2a In most previ-
We envisioned that Overman’s intermediate 16 and
lactam 2a could arise from a common key precursor 3a
via proper functional group transformations (Scheme
1). 3a in turn was derived from acetamide 4a via a
Claisen-type condensation. The pyrrolidine moiety of
4a could be constructed by intramolecular aminolysis of
epoxide. This strategy turned out to be successful.
Herein we report a novel, general and efficient synthesis
pumiliotoxin A alkaloids.
ous syntheses,
L-proline was the preferred starting
material, which provided five-membered ring and the
stereogenic center at the ring junction. However, this
chiral pool approach undoubtedly has its disadvantage
in terms of flexibility and generality. Especially, it limits
the synthetic diversity required in modern drug discov-
ery. Only a few attempts have been made to avoid the
use of proline in the documents.3 On the other hand,
the general method applicable for both pumiliotoxins
and its 7-hydroxy congener allopumiliotoxins has not
fully investigated so far.4 Thus, as our continuing inter-
est in the enantioselective syntheses of polyhydroxyl
alkaloids via transformation of epoxides,5 we focused
our attention on the following issues at the very begin-
ning of our research: 1) to construct the chiral azabi-
cyclic core in avoidance of using proline or its
homologue and 2) to develop general route and com-
mon key intermediate for the whole family of pumil-
iotoxin A alkaloids.
As shown in Scheme 2, we started from known com-
pound 5a, which was readily prepared from 1,4-butane-
diol.7 At
a
first glance, Sharpless asymmetric
aminohydroxylation8 seemed to be an apparent option
to establish the 2,3-syn-aminoalcohol structure in 4a.
However, this method was unsatisfactory for trisubsti-
tuted olefins in terms of enantioselectivity.8b We envis-
aged that this issue could be well addressed by a
dihydroxylation–double inversion (at C-3) sequence.
Sharpless asymmetric dihydroxylation (AD-mix-a)9 of
Keywords: pumiliotoxin A alkaloids; pumiliotoxins; allopumiliotoxin;
general route.
* Corresponding author. Tel.: +86-021-64163300/83223; fax: +86-021-
64166263; e-mail: lingq@mail.sioc.ac.cn
Scheme 1. Retrosynthetic analysis for a general solution.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.113

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B. Wang et al. / Tetrahedron Letters 44 (2003) 7981–7984
t
Scheme 2. Reagents and conditions: (a) AD-mix-a, BuOH,
H2O, MsNH2, 0°C, 98% for 6a and 96% for 6b; (b) MsCl,
pyridine, CH2Cl2, 0°C; (c) K2CO3, EtOH, rt, 95% for 7a and
89% for 7b (two steps); (d) H2, 10% Pd/C, EtOH; MsCl,
Et3N, CH2Cl2, 95% for 8a and 92% for 8b; (e) NaN3, DMF,
95% for 9a,b; (f) H2, Pd/C, EtOH, 70% for 10a.
Scheme 3. Reagents and conditions: (a) BnNH2, MeCN, reflux
48 h, 97% for 11a,b; (b) BnBr, KH, reflux 30 min, 91% for
12a and 95% for 12b; (c) H2, 10% Pd/C, EtOH, rt; (d) Ac2O,
Et3N, CH2Cl2, 0°C, 83% for 4a and 80% for 4b (two steps).
Moreover, this reaction showed remarkably high
regioselectivity, no regioisomer (C-2 opening product)
was found. This observation was in agreement with
Baldwin’s rule as 5/6-exo-tet cyclization being favored
over 6/7-endo-tet process,12 since nucleophilic opening
of epoxide was not always regioselective and not solely
dependent on steric factors.13 Our strategy compared
favorably with other methods such as azidolysis of
epoxide14 in simplicity and efficiency. The tertiary
hydroxyl of 11 was protected with benzyl in high yield
under the reported conditions.15 Selective removal of
N-benzyl (10% Pd/C, EtOH) followed by acetylation
(Et3N, Ac2O, CH2Cl2) furnished acetamide 4 in good
yield.
the trisubstituted olefin 5a afforded chiral diol 6a in
98% yield and 95% ee. 6a was mono-mesylated under
mild conditions (MsCl, pyridine, CH2Cl2, 0°C) without
affecting the more sterically hindered tertiary hydroxyl
group. Upon subsequent treatment of the crude mesyl-
ate with K2CO3, epoxide 7a was obtained with inver-
sion of configuration at C-3 of 6a. Catalytic
hydrogenolysis followed by conversion to mesylate fur-
nished 8a smoothly. With 8a in hand, we first explored
the construction of the pyrrolidine ring. Azide 9a was
prepared in 95% yield, which was subject to catalytic
hydrogenation under atmospheric pressure. We were
pleased to find that proline derivative 10a was formed
in 70% yield resulting from the anticipated one-pot
azide reduction and intramolecular aminolysis of the
epoxide of 9a. The rate of the ring-opening process is
far greater than that of the reduction of azide as no
intermediate was detected. However, with 9b as sub-
strate, which was prepared along the same line as its
homologue 9a, the reaction was very complex.10 We
assumed that the failure to give the piperidine deriva-
tive 10b was due to the much lower reaction rate in
six-membered ring formation as compared to five-mem-
bered ring formation,11 hence side reactions such as
intermolecular condensation, which was negligible in
the case of 9a, predominated in the reaction of 9b.
Taking advantage of the structural feature that the
a,a-disubstituted ester was non-enolizable and non-
epimerizable, we adopted an acetamide16 version of the
Claisen condensation for the construction of the
indolizidine/quinolizidine core. In the screening of
bases for this purpose, we found that while the previ-
ously reported DBU and sodium ethoxide16 were inef-
fective, the use of LDA did afford the desired product,
however, in low conversion. With this in mind, KH was
then tried, which effected irreversible deprotonation of
4a, and it was found that the cyclization was complete
within 60 minutes. HPLC showed that the ee of 3a is
equal to that of 6a, confirming the stereo-integrity of
the above reaction sequences. A single recrystallization
afforded optically pure 3a in 87% recovery. We then set
out to reduce the ketonic carbonyl in 3a to methylene.
Reduction with sodium borohydride furnished 13a in
quantitative yield, the configuration of the 7-hydroxyl
To solve the problem associated with the intrinsic
kinetic difference, another approach was examined. We
reasoned that if the terminal primary amine produced
by the reduction of 9b could be properly protected,
lowering its nucleophilicity and increasing the steric
hindrance simultaneously, the undesired intermolecular
condensation could thus be suppressed. Benzyl group
was ideal for this purpose due to its easy and mild
removal at later stages in our synthesis. However, as no
intermediate could be isolated in the hydrogenation of
9a or 9b, this protection must be incorporated into the
substrate beforehand. Thus 8a,b were reacted with ben-
zylamine (MeCN, reflux 48 h), in the hope that a
stepwise substitution–ring-opening sequence would
afford the desired product 11a,b (Scheme 3). To our
delight, both pyrrolidine and piperidine derivatives
were obtained in one pot in excellent yields (>95%).
1
was assigned to be S on the basis of H NMR coupling
constants (JH7–6=10.7, 6.6 Hz). 13a was converted to
mesylate, which was subject to elimination under basic
conditions (DBU, toluene, reflux) to provide 14a in
90% yield. Saturation of the double bond and debenzyl-
ation were carried out in one pot to give 2a in 100%
yield. Since 2a has been employed as the key intermedi-
ate in several syntheses of pumiliotoxins,17a–f our route
constituted a formal synthesis of this subclass of alka-
loid in good overall yield. Moreover, all reactions in
Scheme 4 worked equally well with 4b, providing
quinolizidine derivative 2b as intermediate for homo-
pumiliotoxin synthesis.17g

B. Wang et al. / Tetrahedron Letters 44 (2003) 7981–7984
7983
Acknowledgements
We thank the National Natural Sciences Foundation
(No. 297912045) and the Major Basic Research Devel-
opment Program (G 2000 077506) for financial aid.
References
1. For reviews, see: (a) Daly, J. W.; Garraffo, H. M.;
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Spande, T. F. Alkaloids 1993, 43, 185; (c) Tokuyama, T.;
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Daly, J. W.; Garraffo, H. M.; Jain, P.; Spande, T. F.;
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2. For some selected reports on chemical synthesis, see: (a)
Overman, L. E.; Bell, K. L. J. Am. Chem. Soc. 1981, 103,
1851; (b) Franklin, A. S.; Overman, L. E.; Chem. Rev.
1996, 96, 505 and references cited therein; (c) Okamoto,
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2002, 67, 5517.
Scheme 4. Reagents and conditions: (a) KH, THF, rt, 87% for
3a and 90% for 3b; (b) NaBH4, MeOH, 0°C, 100% for 13a, b;
(c) MsCl, Et3N, CH2Cl2, 0°C; (d) DBU, toluene, reflux, 90%
for 14a and 97%for 14b (two steps); (e) H2, 10% Pd/C, EtOH,
100% for 2a and 90% for 2b.
For the synthesis of Overman’s intermediate,6 lactam
3a was reduced with LiAlH4 to afford tertiary amine 15
(Scheme 5). Then the benzyl protection was removed
cleanly (Li0/4,4-di-tert-butylbiphenyl, THF, −78°C)18 to
give crystalline 16, the spectroscopic data of which were
in agreement with those reported.3a This also confirmed
our assignment of the structure of 12a.19 Finally, 16
was oxidized to ketone 1 in 75% yield with Swern’s
protocol, while Dess–Martin oxidation resulted in ring
cleavage. Thus, an efficient formal synthesis of allo-
pumiliotoxin 267A (when R=n-Bu in Scheme 5) was
achieved in 12 steps starting from 5a with an estimated
overall yield of 12% according to the literature.6
3. (a) Comins, D. L.; Huang, S. L.; McArdle, C. L.; Ingalls,
C. Org. Lett. 2001, 3, 469; (b) Tan, C.-H.; Stork, T.;
Feeder, N.; Holmes, A. B. Tetrahedron Lett. 1999, 40,
1397.
4. It seems that only reported general method compatible
for the syntheses of both subclasses is the iminum ion–
alkyne cyclization developed by Overman’s group, see:
(a) Arnold, H.; Overman, L. E.; Sharp, M. J.; Witschel,
M. C. Org. Synth. 1991, 70, 111; (b) Caderas, C.; Lett,
R.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118,
9073.
5. (a) Shi, Z.-C.; Lin, G.-Q. Tetrahedron: Asymmetry 1995,
6, 2907; (b) Liu, D.-G.; Wang, B.; Lin, G.-Q. J. Org.
Chem. 2000, 65, 9114; (c) Wang, B.; Yu, X.-M.; Lin,
G.-Q. Synlett 2001, 904.
In summary, a general and efficient synthesis of all
three known subclasses of pumiliotoxin A alkaloids has
been developed. This route featured a one-pot substitu-
tion–ring-opening sequence and an efficient Claisen-
type condensation. With simple linear 1,v-diol
compounds as the starting material, the synthesis can
be carried out in multigram scale under mild condi-
tions. Our work provides a novel and practical access
to natural and unnatural products possessing
indolizidine and quinolizidine skeletons, thus compli-
ments earlier work in this field.2,17 Efforts toward the
total synthesis of homopumiliotoxins are underway and
will be reported in due course.
6. Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J.
Org. Chem. 1992, 57, 1179.
7. Parker, K. A.; Iqbal, T. J. Org. Chem. 1987, 52, 4369.
8. (a) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless,
K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2810; (b)
Sharpless, K. B.; Nicolaou, K. C.; Li, G.; Guy, R. WO
982751A2.
9. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
10. Side products of low polarity and higher molecular
weight were isolated which suggested formation of side
products resulting from intermolecular condensation of
the reduction product of 9b.
11. (a) Mandolini, L. J. Am. Chem. Soc. 1978, 100, 550; (b)
Galli, C.; Illuminati, G.; Mandolini, L.; Tamborra, P. J.
Am. Chem. Soc. 1977, 99, 2591.
12. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
13. Schneider, C. Synlett 2000, 1840.
Scheme 5. Reagents and conditions: (a) LiAlH4, THF, reflux,
75%; (b) Li-DBB, THF, −78°C, 85%; (c) (COCl)2, DMSO,
CH2Cl2, −78°C; Et3N, −78°C, then rt, 75%.

7984
B. Wang et al. / Tetrahedron Letters 44 (2003) 7981–7984
14. (a) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2000,
311; (b) Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M.
Tetrahedron 1995, 48, 13409.
1H), 2.10–1.40 (m, 6H), 1.51 (s, 3H); 13C NMR (CDCl3,
75 MHz) l: 203.80, 165.16, 137.68, 128.45, 127.73,
127.05, 80.38, 66.53, 64.36, 45.64, 44.04, 26.16, 24.66,
24.49, 16.62; IR (w, KBr): 3065, 3027, 2953, 2860, 2511,
1890, 1616, 1575, 1542, 1499, 1451, 1329, 1298, 1232,
1194 cm−1; EI-MS (m/z, %): 288 (0.4), 84 (100), 91 (32),
86 (23), 196 (22); HR-MS calcd for C16H19NO3:
287.1517. Found: 287.1512.
15. Lett, R. M.; Overman, L. E.; Zablocki, J. Tetrahedron
Lett. 1988, 29, 6541.
16. (a) Schneider, M. J.; Harris, T. M. J. Org. Chem. 1984,
49, 3681; (b) Akiba, K.; Nakatani, M.; Wada, M.;
Yamamoto, Y. J. Org. Chem. 1985, 50, 63; (c) Ver-
cauteren, J.; Bideau, A.; Massiot, G. Tetrahedron Lett.
1987, 28, 1267.
1
Compound 12a: [h]2D0=+5.8° (c 1.60, CHCl3).; H NMR
(CDCl3, 300 MHz) l: 7.40–7.20 (m, 10H), 4.65–4.30 (AB,
J
AB=11.4 Hz, 2H), 4.55–3.35 (AB, JAB=13.3 Hz, 2H),
17. (a) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy,
K. C.; Gallagher, T. J. Am. Chem. Soc. 1991, 113, 2652;
(b) Barrett, A. G. M.; Damiani, F. J. Org. Chem. 1999,
64, 1410; (c) Martin, S. F.; Bur, S. K. Tetrahedron 1999,
55, 8905; (d) Sudau, A.; Muech, W.; Bats, J.-W.; Nubbe-
meyer, U. Eur. J. Org. Chem. 2002, 3315; (e) Cossy, J.;
Cases, M.; Gomez-Pardo, D. Synlett 1996, 909; (f) Ni,
Y.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1
2000, 3264; (g) Santos, L. S.; Pilli, R. A. Tetrahedron
Lett. 2001, 42, 6999.
18. (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem.
1980, 45, 1924; (b) Ireland, R. E.; Smith, M. G. J. Am.
Chem. Soc. 1988, 110, 854.
19. All novel compounds were fully characterized by IR, MS,
1H and C NMR spectra and satisfactory elemental analy-
sis or high-resolution MS. Some selected examples are as
follows.
4.46 (q, J=7.1 Hz, 2H), 3.30–3.20 (m, 1H), 3.05–2.85 (m,
1H), 2.30–2.15 (m, 1H), 1.95–1.50 (m, 4H), 1.75 (s, 3H),
1.28 (t, J=7.1 Hz, 3H); IR (w, film): 3064, 3030, 1731,
1605, 1496, 1454, 1382, 1263, 1243, 1109 cm−1; EI-MS
(m/z, %): 367 (0.1), 294 (2.3), 160 (100), 91 (59), 161 (15).
Anal. calcd for C23H29NO3: C, 75.17; H, 7.95; N, 3.81.
Found: C, 74.98; H, 7.96; N, 3.59.
Compound 13a: mp 164.5–165.5°C; [h]2D0=−70.5° (c 0.99,
CHCl3); 1H NMR (CDCl3, 300 MHz) l: 7.40–7.20 (m,
5H), 4.95–4.70 (AB, JAB=12.2 Hz, 2H), 3.91 (dd, J=
10.3, 7.0 Hz, 1H), 3.65–3.40 (m, 3H), 3.40–3.20 (dd,
J=9.9, 5.4 Hz, 1H), 2.85–2.65 (dd, J=17.2, 6.7 Hz, 1H),
2.65–2.50 (dd, J=17.2, 10.7 Hz, 1H), 2.20–1.60 (m, 4H),
1.46 (s, 3H); 13C NMR (CDCl3, 75 MHz) l: 168.18,
139.71, 128.30, 127.10, 126.70, 74.30, 73.31, 66.75, 65.82,
45.59, 37.76, 26.04, 22.39, 16.98; IR (w, KBr): 3201, 2977,
2854, 1617, 1450 cm−1; EI-MS (m/z, %): 276 (8.2), 70
(100), 91 (39), 184 (15), 97 (13), 43 (11), 96 (10); HR-MS
calcd for C16H21NO3: 275.1531. Found: 275.1541.
Compound 3a: mp 109–110°C; [h]2D0=−11.3° (c 0.5,
CHCl3); 1H NMR (CDCl3, 400 MHz) l: 7.50–7.20 (m,
5H), 4.60–4.20 (AB, JAB=11.7 Hz, 2H), 3.75–3.55 (m,
3H), 3.40–3.25 (AB, JAB=10.4 Hz, 2H), 2.40–1.80 (m,
4H), 1.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) l:
204.10, 164.82, 137.39, 128.49, 127.77, 126.93, 78.29,
66.44, 63.66, 46.17, 44.31, 25.58, 22.69, 14.25; IR (w,
Compound 13b: mp 151–151.5°C; [h]2D0=+3.9° (c 1.06,
CHCl3); 1H NMR (CDCl3, 300 MHz) l: 7.40–7.20 (m,
5H), 4.80–4.70 (m, 1H), 4.76–4.61 (AB, JAB=11.7 Hz,
2H), 3.91 (m, 1H), 3.20–3.10 (m, 2H), 2.77 (part of AB-d,
KBr): 2925, 2864, 1731, 1645, 1605, 1558, 1457 cm−1
;
J
AB=17.4 Hz, J=7.5 Hz, 1H), 2.58 (part of AB-d, JAB=
17.1 Hz, J=4.8 Hz, 1H), 2.38 (t-like, 1H), 2.00–1.70 (m,
3H), 1.70–1.55 (m, 1H), 1.46 (s, 3H), 1.50–1.30 (m,
2H);13C NMR (CDCl3, 75 MHz) l: 167.06, 138.81,
128.33, 127.34, 126.87, 74.88, 71.12, 65.51, 65.25, 43.76,
36.71, 26.94, 25.04, 25.01, 19.10; IR (w, KBr): 3243, 2955,
2860, 1616, 1450 cm−1; EI-MS (m/z, %): 289 (2.5), 198
(9.8), 91 (36.4), 84 (100); HR-MS calcd for C17H23NO3:
289.1698. Found: 289.1718.
EI-MS (m/z, %): 274 (12), 70 (100), 91 (64), 182 (35.0), 42
(25), 41 (15), 96 (15), 65 (13); HR-MS calcd for
C9H12NO3 (M−Bn): 182.0862. Found: 182.0907.
Compound 3b: mp 138–139.5°C; [h]2D0=+15.9° (c 1.32,
CHCl3); 1H NMR (CDCl3, 300 MHz) l: 7.50–7.20 (m,
5H), 4.80–4.60 (d-like, 1H), 4.60–4.30 (AB, JAB=11.4
Hz, 2H), 3.80–3.20 (AB, JAB=18.5 Hz, 2H), 3.25–3.10
(dd, J=12.5, 2.4 Hz, 1H), 2.70–2.40 (td, J=12.4, 2.7 Hz,