Total synthesis of pumiliotoxins A and 225F [2]

Full text of DOI:10.1021/ja991918x

J. Am. Chem. Soc. 1999, 121, 9873-9874
9873
Scheme 1a
Total Synthesis of Pumiliotoxins A and 225F
Shintaro Hirashima, Sakae Aoyagi, and Chihiro Kibayashi*
School of Pharmacy
Tokyo UniVersity of Pharmacy & Life Science
Horinouchi, Hachioji, Tokyo 192-0392, Japan
ReceiVed June 9, 1999
A number of the amphibian alkaloids1 structurally related to
pumiliotoxin (PTX) A (1) and B (2), now totaling almost 30, are
grouped into a subclass called pumiliotoxins1a which are all
characterized structurally by a (Z)-alkylideneindolizidine ring
system differing in only the alkylidene side chain.2 For the
synthesis of these alkaloids, one significant challenge is the
stereoselective incorporation of the (Z)-alkylidene side chain at
C-6 of the indolizidine nucleus. In the search for control of the
exocyclic alkene geometry as well as the piperidine ring construc-
tion, comprehensive efforts by the Overman group3 have led to
the development of the general methods for the syntheses of the
pumiliotoxin alkaloids via two fundamental approaches based on
iminium ion cyclization. After these brilliant and extensive studies
and subsequent synthesis of pumiliotoxin 251D (3) by Gallagher
and co-workers,4 culminating in the total syntheses of pumil-
iotoxins A (1), B (2), and 251D (3), no further synthetic approach
has appeared. In this paper, we wish to disclose a general approach
for preparing the pumiliotoxin alkaloids, which led to asymmetric
total synthesis of pumiliotoxins A (1)5 and 225F (4); the latter
synthesis is the first reported.
a Reagents and conditions: (a) BuLi, (CH2O)n, THF, -78 f 0 °C;
(b) MsCl, Et3N, CH2Cl2, -30 °C; (c) (Me2PhSi)2Cu(CN)Li2, THF, -85
°C, 3 min; (d) HfCl4, CH2Cl2, -78 f 0 °C; (e) (Boc)2O, K2CO3.
The dibromoolefin 76 was converted to the homopropargyl
mesylate 8 by treatment with BuLi and paraformaldehyde
followed by mesylation (Scheme 1). Conversion of 8 to the
allenylsilane 9 was successfully achieved in 84% yield by using
the bis(dimethylphenylsilyl)cuprate reagent according to Flem-
ing’s method.7 Lewis acid-mediated nucleophilic addition8 of the
allenylsilane 9 to the trifluoroacetate salt of (S)-2-acetylpyrrolidine
(10)9 proceeded cleanly by using hafnium(IV) chloride to afford
the desired homopropargylic alcohol 12, which was isolated as
the N-Boc derivative 13, with complete stereocontrol in excellent
overall yield (92%). The stereochemical outcome of this HfCl4-
promoted propargylation can be interpreted in terms of a Cram
chelate transition-state model 11.10
Since the common structural motif shared by all the pumil-
iotoxin alkaloids is the presence of the (Z)-alkylideneindolizidine
fraction, the strategic disconnection of the pumiliotoxin alkaloids
at the C-12-C-13 bond of the alkylidene side chain (indicated
by the wavy line in eq 1) should be most appropriate for the
Radical-initiated hydrostannylation of 13 using triethylborane
and triphenyltin hydride proceeded with complete trans selectivity
to give the (Z)-3′-stannylalkene 14 (60%) along with the (Z)-4′-
stannyl regioisomer (28%) (Scheme 2). The assignment of the Z
stereochemistry of 14 was made on the basis of the large coupling
constant (89.3 Hz) between Sn and the vinyl proton.11 Upon
treatment with N-iodosuccinimide, 14 underwent iododestan-
nylation with retention of the Z configuration to afford the vinyl
iodide 15. Palladium-catalyzed carbonylation12 of 15 smoothly
occurred when treated with carbon monooxide and tributylamine
in the presence of a catalytic amount of Pd(OAc)2 (2 mol %) and
PPh3 (8 mol %) in HMPA at 100 °C,13 furnishing the lactone 16
in 97% yield. Deprotection of 16 followed by DIBAL reduction
gave the diol 17, which underwent smooth intramolecular
cyclodehydration14 with carbon tetrabromide and PPh3 to form
(1)
efficient and flexible synthesis of pumiliotoxin alkaloids. This
bond would be formed by cross-coupling reaction between a metal
derivative 5 of the (Z)-alkylideneindolizidine fraction and the vinyl
or alkyl halides 6. Our first efforts were thus directed toward the
development of stereoselective construction of the (Z)-alkyli-
deneindolizidine component as a pivotal common precursor.
(6) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(7) Fleming, I.; Terrett, N. K. J. Organomet. Chem. 1984, 264, 99.
(8) For the TiCl4-mediated addition of allenylsilanes to carbonyl com-
pounds, see: (a) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3925.
(b) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem. 1986,
51, 3870.
(9) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org. Chem.
1992, 57, 1179.
(10) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748.
(b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462.
(1) (a) Daly, J. W. Alkaloids 1998, 50, 141. (b) Daly, J. W.; Spande, T. F.
In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1986; Vol. 4, Chapter 1, pp 1-274. (c) Daly, J. W.;
Garraffo, H. M.; Spande, T. F. Alkaloids 1993, 43, 185.
(2) The pumiliotoxin subclass of alkaloids belongs to the pumiliotoxin A
class of “dendrobatid alkaloids” together with the closely related subclasses
of allopumiliotoxins and homopumiliotoxins.
(3) Franklin, A. S.; Overman, L. E. Chem. ReV. 1996, 96, 505.
(4) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.; Gallagher,
T. J. Am. Chem. Soc. 1991, 113, 2652.
(5) For total syntheses of pumiliotoxin A, see: (a) Overman, L. E.; Lin,
N.-H. J. Org. Chem. 1985, 50, 3669. (b) Overman, L. E.; Sharp, M. J.
Tetrahedron Lett. 1988, 29, 901. (c) Lin, N.-H.; Overman, L. E.; Rabinowitz,
M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996,
118, 9062.
(11) In our earlier study, smaller coupling constants (ca. 35 Hz) have been
observed for (E)-stannyl alkenes prepared by syn selective palladium-catalyzed
hydrostannylation. See: Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J. Am. Chem.
Soc. 1993, 115, 11393.
(12) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(13) Procedure according to Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem.
1978, 43, 1684.
10.1021/ja991918x CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999

9874 J. Am. Chem. Soc., Vol. 121, No. 42, 1999
Communications to the Editor
Scheme 2a
a Reagents and conditions: (a) Ph3SnH, Et3B, benzene, 5 days; (b) NIS, CH2Cl2, 0 °C; (c) CO, Pd(OAc)2 (2 mol %), PPh3 (8 mol %), Bu3N, HMPA,
100 °C; (d) (i) CF3CO2H, CH2Cl2, 0 °C; (ii) DIBALH, toluene, -30 °C; (e) CBr4, PPh3, CH2Cl2, 0 °C, 30 min; (f) Bu4NF, THF; (g) TBDMSOTf,
2,6-lutidine, DMAP, CH2Cl2, 0 °C; (h) (Me2N)3S(Me3SiF2) (1.5 equiv), DMF; (i) I2, PPh3, imidazole, CH2Cl2; (j) (i) t-BuLi, Et2O, -110 °C; (ii) ZnCl2,
THF, -78 f 0 °C; (k) Pd(PPh3)4 (13 mol %), benzene; (l) Bu4NF, DMF, 60 °C; (m) Li, NH3-THF, MeOH, -78 °C.
the (Z)-alkylideneindolizidine 18 in 85% yield. Subsequent
treatment of 18 with Bu4NF resulted in the first total synthesis
of (-)-pumiliotoxin 225F (4). The synthetic material displayed
spectral properties (13C NMR and MS) that matched those of the
natural product.15 However, the observed rotation of synthetic 4
([R]24D -25.3 (c 0.25, CHCl3)) was found to be significantly lower
than the reported value15 ([R]D -87.4 (c 0.23, CHCl3)). The reason
for this discrepancy in the optical rotations is unclear at present,
although it might be attributed to the contamination of a small
amount of a highly optically active impurity in the natural sample.
For the formation of the (Z)-alkylideneindolizidine metal
species 5 (led by the illustrated disconnection in eq 1) as the
coupling partner, 18 was protected as the TBDMS ether 19, and
the selective deprotection of the primary TBDPS ether was
performed using tris(dimethylamino)sulfonium difluorotrimeth-
ylsilicate (TAS-F)16 to provide the primary alcohol 20 (85%),
which was then converted to the iodide 21 (95%).
coupling reaction with the chiral (E)-vinyl iodide 23 for the
synthesis of pumiliotoxin A (1). One potential problem associated
with the transition metal-catalyzed homoallyl-alkenyl coupling
would be the tendency of the homoallylic compounds to undergo
â-elimination. This problem was overcome by Negishi,17 who
adapted homoallylic organozincs to the palladium-catalyzed
conjugate substitution reaction with alkenyl halides to effect the
construction of 1,5-dienes. In view of these results, we explored
the use of the organozinc for the cross-coupling reaction.18 Thus,
the homoallyl iodide 21 was subjected to halogen-metal exchange
with tert-butyllithium at -110 °C, followed by transmetalation
with ZnCl2. Subsequent one-pot treatment of the resulting
homoallylzinc reagent 22 with the chiral (E)-vinyl iodide 2319 in
the presence of catalytic Pd(PPh3)4 afforded the cross-coupled
product 24 in 60% yield from 21 with complete retention of
configuration of the stereocenter(s) and (Z)-geometry. Finally,
We thus completed the stereoselective construction of 21
possessing a common fundamental structural unit of the pumil-
iotoxin alkaloids, and the stage was then set for the critical cross-
removal of the TBDMS protecting group gave 25 ([R]22 -2.7
D
(c 0.59, CHCl3) [lit.5a [R]25D -2.1 (c 0.70, CHCl3]) (66% or 81%
based on 18% recovery of 24), which was subjected to benzyl
ether cleavage through the Overman protocol5a (Li, NH3, MeOH)
(14) For intramolecular cyclodehydration via alkoxyphosphonium salts,
see: Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876.
(15) Tokuyama, T.; Tsujita, T.; Garraffo, H. M.; Spande, T. F.; Daly, J.
W. Tetrahedron 1991, 47, 5415.
(16) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D.
S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(17) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298.
to provide (+)-pumiliotoxin A (1) ([R]25D +16.7 (c 0.84, CHCl3)
1
[lit.5a [R]23 +14.9 (c 0.65, CHCl3]) in 81% yield. The H and
D
13C NMR data of synthetic 1 were identical with those of natural
pumiliotoxin A (307A′).20
(18) For reviews of organozinc reagents, see: (a) Erdik, E. Tetrahedron
1992, 48, 9577. (b) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
(19) Prepared from (R)-glycidol in 33% overall yield (after chromatographic
separation of the desired E isomer) by the following sequence involving CrCl2-
mediated stereoselective construction of alkenyl halides with one-carbon
homologation (Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408) as a key step (unpublished results).
The new strategy developed herein has served to demonstrate
the potential of the homoallyl-alkenyl coupling protocol for a
general entry to the convergent asymmetric synthesis of the
pumiliotoxin alkaloids. It relies on a palladium(0)-based cross-
coupling reaction employing a novel, complex homoallylzinc
molecule with a nitrogen heterocycle, which is, to the best of
our knowledge, the first example of the application of such a
reaction in natural product synthesis.21,22 Studies to extend this
methodology to other pumiliotoxin alkaloids are in progress.
(20) Tokuyama, T.; Daly, J. W.; Highet, R. J. Tetrahedron 1984, 40, 1183.
(21) Only a limited number of applications of the homoallyl-alkenyl
coupling strategy using functionalized nonnitrogenous homoallylic zinc species
in natural product synthesis have been published. See ref 17 and also: William,
D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198.
(22) For examples of other applications of organozinc couplings in natural
products synthesis, see: (a) Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J.
H. J. Am. Chem. Soc. 1991, 113, 5775. (b) Wipf, P.; Lim, S. J. Am. Chem.
Soc. 1995, 117, 558. (c) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi,
K. J. Am. Chem. Soc. 1995, 117, 12011. (d) Amat, M.; Hadida, S.; Pshenichnyi,
G.; Bosch, J. J. Org. Chem. 1997, 62, 3158. (e) Smith, A. B., III; Friestad, G.
K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Spoors,
P. G.; Bertounesque, E.; Salvatore, B. A. J. Org. Chem. 1998, 63, 7596. (f)
Hu, T.; Panek, J. S. J. Org. Chem. 1999, 64, 3000.
Acknowledgment. This work was supported in part by a Grant-in-
Aid for Science Research from the Ministry of Education, Sports and
Culture of Japan (No. 10671999) to which we are grateful.
Supporting Information Available: Spectroscopic data for com-
pounds 1, 4, 9, 13-21, 24, and 25 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA991918X