A convergent total synthesis of pumiliotoxins A and B via palladium-catalyzed cross-coupling reaction of homoallylic organozinc compounds with vinyl iodides

Article abstract of DOI:10.1016/S0022-328X(02)01160-9

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing a Pd(0)-catalyzed cross-coupling reaction between homoallylic organozincs and vinyl iodides, which led to the asymmetric total synthesis of (+)-pumilioto

Full text of DOI:10.1016/S0022-328X(02)01160-9

Journal of Organometallic Chemistry 653 (2002) 229–233
www.elsevier.com/locate/jorganchem
A convergent total synthesis of pumiliotoxins A and B via
palladium-catalyzed cross-coupling reaction of homoallylic
organozinc compounds with vinyl iodides
Chihiro Kibayashi *, Sakae Aoyagi
School of Pharmacy, Tokyo Uni6ersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 5 September 2001; received in revised form 26 November 2001; accepted 28 November 2001
Abstract
A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing a Pd(0)-catalyzed
cross-coupling reaction between homoallylic organozincs and vinyl iodides, which led to the asymmetric total synthesis of
(+)-pumiliotoxins A (1) and B (2). The (Z)-alkylideneindolizidine, which is a common organic part of the organozinc reagents
in this approach, was synthesized with a high degree of stereocontrol upon using HfCl4-mediated addition of the allenylsilane to
(S)-2-acetylpyrrolidine. The (Z)-iodoalkylideneindolizidine (31) thus obtained as an advanced common intermediate was con-
verted into the homoallylzinc chloride derivative 32, which underwent homoallyl-vinyl cross-coupling with the (E)-vinyl iodide
(13) using Pd(PPh3)4 catalyst to afford the 1,5-diene product 33. Subsequent deprotection provided (+)-pumiliotoxin A. On the
other hand, 31 was transformed into the homoallyl-tert-butyl zinc intermediate 39, which was cross-coupled with the (E)-vinyl
iodide (36) in the presence of the Pd(0) catalyst. The resulting 1,5-diene product 40 underwent subsequent deprotection to afford
(+)-pumiliotoxin B. © 2002 Published by Elsevier Science B.V.
Keywords: Palladium-catalyzed cross-coupling reaction; Homoallylzincs; Vinyl iodides; Alkylideneindolizidines; (+)-Pumiliotoxins A and B
The selective generation of E- and Z-exo-cyclic
olefins has traditionally been attained via p-bond con-
struction employing the Wittig reaction or aldol con-
densation, however, these methods have been less than
satisfactory. In this regard, stereodefined generation of
the (Z)-alkylidene side chain at C-6 of the indolizidine
nucleus is one significant challenge in the synthesis of
the pumiliotoxin class of alkaloids. In the search for
control of the exo-cyclic alkene geometry as well as the
piperidine ring construction, comprehensive efforts
were made by the Overman group [4] and have led to
the development of the total synthesis of pumiliotoxins
A, B, and 251D. After these pioneering studies and
subsequent synthesis of pumiliotoxin 251D by Gal-
lagher and co-workers [5], however, no further syn-
thetic approach to the total synthesis of the
pumiliotoxin alkaloids has appeared. Our own ap-
proach to the structural problem presented by this class
of molecules has thus been to focus on the development
of efficient construction of the (Z)-alkylidenein-
dolizidine as a common intermediate and subsequent
elaboration of a variety of the side chains based on a
1. Introduction
Neotropical poison-dart frogs of the family Dendro-
batidae have been a rich source of various structurally
unique and biologically significant alkaloids [1]. Among
these natural products, pumiliotoxins A (1) and B (2),
isolated as the major toxic alkaloids from skin extracts
of the Panamanian poison frog Dendrobates pumilio in
1967 [2], were the first representatives of the pumil-
iotoxin class of dendrobatid alkaloids. This class of
alkaloids closely related to pumiliotoxins A and B, now
totaling over 20 [1d], is all characterized structurally by
a (Z)-6-alkylidene-8-hydroxy-8-mehtylindolizidine ring
system differing in only the alkylidene side chain [1].
These alkaloids have shown to have modulatory effects
on voltage-dependent sodium channels, therefore, dis-
playing in some cases potent cardiotonic and myotonic
activity [3].
* Corresponding author. Tel.: +81-426-76-3275; fax: +81-426-76-
4475.
E-mail address: kibayasi@ps.toyaku.ac.jp (C. Kibayashi).
0022-328X/02/$ - see front matter © 2002 Published by Elsevier Science B.V.
PII: S0022-328X(02)01160-9

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palladium-catalyzed cross-coupling reaction which is
relevant to a convergent entry to the total synthesis of
pumiliotoxins A (1) and B (2) [6].
the pumiliotoxin alkaloids at the C-12ꢀC-13 bond of
the alkylidene side chain should be most appropriate
for the efficient and flexible synthesis of the pumil-
iotoxin class of alkaloids (Scheme 1). Our synthetic
plan thus called for connecting these two fragments, the
(Z)-alkylideneindolizidine (3) and the alkenyl halides
(4). This approach allows for utilization of 3 as a
common fragment, and which also allows for a conver-
gent entry into the pumiliotoxin alkaloids. The central
feature of this approach involving the construction of
the homoallyl–alkenyl bond relies on the palladium(0)-
based cross-coupling strategy. One potential problem
associated with the transition metal-catalyzed homoal-
lyl–alkenyl coupling would be the tendency of the
homoallylic compounds to undergo b-elimination. This
problem was overcome by Negishi [7], who subjected
homoallylic organozincs to the palladium-catalyzed
conjugate substitution reaction with alkenyl halides to
effect the construction of 1,5-dienes. We envisioned
that this coupling chemistry associated with the
organozincs effects the combination of 3 and 4, which
would proceed via a catalytic cycle involving oxidative
addition–transmetalation–reductive elimination se-
quence as depicted in Fig. 1, [8]. The critical homoal-
lyl–alkenyl coupling process between the alkenyl iodide
5 and the homoallylzinc 7 would proceed with complete
retention of configuration for the alkenyl iodide yield-
ing the 1,5-diene unit 9, which was expected to be
adopted for assembling of the alkylidene side chains of
pumiliotoxins A and B.
2. Synthetic strategy
Since the presence of the (Z)-alkylideneindolizidine
fraction is the common structural motif shared by not
only pumiliotoxins A (1) and B (2) but also all other
pumiliotoxin alkaloids, the strategic disconnection of
Scheme 1.
3. Total synthesis of (+)-pumiliotoxin A
3.1. Preliminary experiments on the cross-coupling
reaction
According to the above discussion, the synthesis
started with the preparation of the vinyl iodide cou-
pling partner 13 in homochiral form needed for the
synthesis of (+)-pumiliotoxin A (1). Thus, (R)-glycidol
(10) was converted to the ketone (12) in seven steps,
and subsequent iodo-olefination was carried out using
the Takai protocol [9] of treatment with CrCl2 and
iodoform to produce a chromatographically separable
mixture (71% yield) of the (E)-vinyl iodide 13 and the
(Z)-isomer in an 89:11 ratio favoring the desired (E)-
isomer (Scheme 2).
Fig. 1. Catalytic cycle for alkenyl–homoallyl cross-coupling.
Preliminary experiments were performed in order to
determine the feasibility of 13 as the coupling partner in
the Pd(0)-catalyzed cross-coupling reaction with the
organozinc compound. Hence, the iodide 15, prepared
from the alcohol 14 with standard procedures, under-
went halogen–metal exchange with two equivalents of
t-BuLi at −78 °C, followed by transmetalation with
one equivalent of ZnCl2. Subsequent one-pot treatment
Scheme 2.

C. Kibayashi, S. Aoyagi / Journal of Organometallic Chemistry 653 (2002) 229–233
231
excellent overall yield (92%). The stereochemical out-
come of the preferential formation of 24 in this HfCl4-
promoted propargylation can be accounted for by the
transition-state model 23 involving the chelation of the
NH and carbonyl groups with Hf (Scheme 5).
Radical-initiated hydrostannylation of 25 proceeded
with complete trans selectivity to give the pure (Z)-3%-
stannyl alkene 26 (60%) after chromatographic separa-
tion from the (Z)-4%-stannyl regioisomer (28%) (Scheme
6). Upon treatment with N-iodosuccinimide (26) under-
went iodolysis with retention of the Z configuration to
afford the vinyl iodide (27). Palladium-catalyzed car-
bonylation [13] of 27 smoothly occurred when treated
with carbon monooxide and tributylamine in the pres-
ence of a catalytic Pd(OAc)2 (2 mol%) and PPh3 (8
mol%) in HMPA, furnishing the lactone (28). Depro-
tection of the Boc group followed by DIBAL reduction
gave the diol (29), which underwent smooth intramolec-
ular cyclodehydration (CBr4, PPh3) to form the (Z)-
alkylideneindolizidine (30). Compound 30 was
converted into the iodide (31) as a key synthetic inter-
mediate in three steps involving silyl protection of the
tertiary alcohol, selective deprotection of the primary
TBDPS ether with difluorotrimethylsilicate (TAS-F)
[14], and iodination (I2, PPh3).
Scheme 3.
Scheme 4.
3.3. Synthesis of (+)-pumiliotoxin A 6ia
cross-coupling
of the resulting alkylzinc reagent 16 with 13 in the
presence of catalytic Pd(PPh3)4 led to the cross-coupled
product 17 in 55% yield with complete retention of the
(E)-geometry (Scheme 3).
We thus completed the stereoselective construction of
the (Z)-alkylideneindolizidine (31) possessing a com-
mon fundamental structural unit of the pumiliotoxin
alkaloids, and the stage was then set for the critical
cross-coupling reaction with the chiral (E)-vinyl iodide
(13) under conditions similar to those described above
for the cross-coupling between 15 and 13. The alkyli-
deneindolizidine (31) was subjected to halogen–metal
3.2. Preparation of the (Z)-iodoalkylideneindolizidine
(31)
On the basis of these results, we next envisioned
extending the cross-coupling strategy to the preparation
of pumiliotoxin A (1) utilizing combination of the
homoallylic zinc species of the (Z)-alkylidenein-
dolizidine (32 in Scheme 7) and the vinyl iodide 13.
With this approach in mind, we investigated the synthe-
sis of the (Z)-iodoalkylideneindolizidine (31) needed for
the preparation of the corresponding zinc reagent (32).
The synthesis began with the above-described chiral
alcohol (14), which was converted to the dibromoolefin
(18) as shown in Scheme 4, Treatment of 18 with BuLi
and paraformaldehyde followed by mesylation gave the
homopropargyl mesylate (19), which was then con-
verted to the allenylsilane (20) by using the bis(-
dimethylphenylsilyl)cuprate reagent according to
Fleming’s method [10]. Lewis acid-induced nucleophilic
addition [11] of 20 to the trifluoroacetate salt (22) of
(S)-2-acetylpyrrolidine [12] proceeded cleanly by using
hafnium(IV) chloride to afford the desired homo-
propargylic alcohol (24), which was isolated as the
N-Boc derivative 25, with complete stereocontrol in
Scheme 5.

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C. Kibayashi, S. Aoyagi / Journal of Organometallic Chemistry 653 (2002) 229–233
exchange (t-BuLi, THF, −110 °C) followed by
transmetalation with ZnCl2 to form the homoallylzinc
derivative 32, which underwent the cross-coupling reac-
tion with 13 in the presence of catalytic Pd(PPh3)4 to
give the cross-coupled product 33 in 60% yield from 31
(Scheme 6). Finally, removal of the TBDMS and benzyl
protecting groups provided (+)-pumiliotoxin A (1).
Scheme 8.
4. Total synthesis of (+)-pumiliotoxin B
Having achieved the total synthesis of (+)-pumil-
iotoxin A (1) based on the cross-coupling reaction of
the homoallylic organozinc (32), we next directed our
efforts toward the synthesis of (+)-pumiliotoxin B (2)
by applying the related convergent cross-coupling ap-
proach. In this case, the (E)-vinyl iodide (36) was
needed for coupling with the (Z)-alkylideneindolizidine
Scheme 6.
fragment 31. Thus, starting from dimethyl
D-tartrate,
the ketone (35) was prepared through the alcohol (34)
by the standard method as outlined in Scheme 8.
Compound 35 was transformed via iodo-olefination
using the Takai protocol (CrCl2, CHI3) [9] into the
(E)-vinyl iodide (36) along with the (Z)-isomer in a
5.1:1 ratio. To test the possibility of exploiting 36 for
the organozinc-based cross-coupling reaction, the
alkylzinc reagent (16) described above was allowed to
react with the vinyl iodide (36) in the presence of
catalytic Pd(PPh3)4 in a manner similar to that de-
scribed above for the coupling reaction of the vinyl
iodide (13) with the alkylzinc (16). However, this proce-
dure resulted in the formation of the desired cross-cou-
pled product 37 in low yield (28%) together with a
complex mixture, presumably due to accompanying
cleavage of the isopropylidene acetal group caused by
in situ generated Lewis acidic zinc halide.
Scheme 7.

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233
The recent report by Smith et al. [15] demonstrated in
the natural product synthesis the efficiency of a dialkylz-
inc derivative for the alkyl–vinyl coupling based on the
modified Negishi cross-coupling reaction. In view of this
protocol, we considered employing the dialkylzinc in-
stead of the alkylzinc chloride for the cross-coupling
reaction of the vinyl iodide (36). Hence, the dialkylzinc
(38) was prepared by addition of one equivalent of zinc
chloride to a solution of the iodide (15) at −90 °C
followed by addition of three equivalent of t-BuLi. The
vinyl iodide (35) was added to the resulting mixture along
with the palladium catalyst, affording the cross-coupled
product 37 in 50% yield (Scheme 7).
employing novel, complex homoallylzinc molecules
derived from the (Z)-iodoalkylideneindolizidine which
served as an advanced common synthetic intermediate,
leading to an efficient approach to the asymmetric
synthesis of (+)-pumiliotoxins A and B.
References
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Scheme 9.