Total synthesis of (+)-pumiliotoxin 251D

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3315::AID-EJOC3315>3.0.CO;2-2

The convergent total synthesis of pumiliotoxins by attachment of the side chain to a suitably functionalized core indolizidinone derivative has been achieved. The use of an aldoltype addition condensation strategy, intended to provide for the stereoselective generation of the exocyclic double bond, gave no satisfactory results. The method of choice was a Homer olefination. Initially, the reactant core indolizidinone was converted into an α phosphono amide by amide enolate formation, enol phosphate generation, and a final phosphatephosphonate migration. The amido phosponates smoothly underwent Horner-type olefinations to allow successful introduction of the side chain with high Z selectivity in the exocyclic double bond. Similarly, the introduction of the phosphonate and the subsequent olefination could be run as a one-pot process. The final reductive removal of the lactam function provided (-)-8-epi-pumiliotoxin 209 F and (+)-pumiliotoxin 251 D. The structure of the pumiliotoxin 251 D was confirmed by X-ray analysis. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:19<3315::AID-EJOC3315>3.0.CO;2-2

FULL PAPER
Total Synthesis of (؉)-Pumiliotoxin 251D[‡]
Alexander Sudau,[a] Winfried Münch,[a] Jan-W. Bats,[b] and Udo Nubbemeyer*[a]
Dedicated to Prof. Dr. E. Winterfeldt on the occasion of his 70th birthday
Keywords: Aldol reactions / Alkaloids / Lactams / Olefinations / Total synthesis
The convergent total synthesis of pumiliotoxins by attach-
ment of the side chain to a suitably functionalized core indol-
izidinone derivative has been achieved. The use of an aldol-
underwent Horner-type olefinations to allow successful intro-
duction of the side chain with high Z selectivity in the ex-
ocyclic double bond. Similarly, the introduction of the phos-
type addition condensation strategy, intended to provide for phonate and the subsequent olefination could be run as a
the stereoselective generation of the exocyclic double bond,
gave no satisfactory results. The method of choice was a
Horner olefination. Initially, the reactant core indolizidinone
was converted into an α phosphono amide by amide enolate
formation, enol phosphate generation, and a final phosphate-
phosphonate migration. The amido phosponates smoothly
one-pot process. The final reductive removal of the lactam
function provided (−)-8-epi-pumiliotoxin 209 F and (+)-pumi-
liotoxin 251 D. The structure of the pumiliotoxin 251 D was
confirmed by X-ray analysis.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
figuration. In terms of the total syntheses of these alkaloids,
the most convergent approach seemed to be retrosynthetic
cleavage across the exocyclic double bond, dividing the mo-
lecule into a bicyclic core and a side chain A. The planning
of such a convergent step requires an efficient coupling re-
action, allowing introduction of the double bond in a ster-
eoselective manner. In the case of the synthesis of allopumi-
liotoxin 267 A and related compounds, an aldol condensa-
tion of the 7-indolizidinone and (R)-2-methylhexanal was
found to be the method of choice, always generating the
thermodynamically more stable E olefin.[6] In contrast, the
synthesis of pumiliotoxin 251 D implies the aldehyde A and
the 5-indolizidinone, and an aldol condensation would now
have to generate the less easily accessible Z olefin. Such a
sequence was originally described by Gallagher.[7] The bi-
cyclic core lactam and the aldehyde were coupled by means
of an aldol-type reaction. The final dehydration introduced
the exocyclic double bond, causing some problems con-
cerning the stereoselective olefin formation. The E/Z ratio
depended on the relative configuration of the aldol adduct
and the reaction mechanism of the final H2O elimination
(syn or anti elimination).
Since Daly’s isolation and structural determination of pu-
miliotoxins, and the initial investigations of some of their
interesting biological properties, a number of total syn-
theses have been developed.[1] These alkaloids have been
isolated from the skin secretions of some South and Central
American arrow poison frogs.[2] Pumiliotoxin 251 D was
reported as one major compound in an analysis of the al-
kaloid mixture secreted by Dendrobates tricolor (Ecu-
ador).[3] All these compounds are thought to serve as chem-
ical defense systems,[4] cardiotonic and myotonic properties
having been reported for several species. Interaction with
the charge-dependent ion channels of certain nerve cells in-
fluences signal transduction by induction of the opening of
Naϩ ion channels.[5]
Examination of the structures of the pumiliotoxins (Fig-
ure 1) shows that all compounds are characterized by the
bicyclic indolizidine system, with some stereogenic centers
and an exocyclic trisubstituted double bond of defined con-
[‡]
Introduction of the Side Chain, 2. Part 1: Ref.[11]
[a]
Institut für Chemie Ϫ Organische Chemie, Freie Universität
With the goal of avoiding such problems, alternative
strategies have been developed. Overman employed a vinyl-
silane iminium salt cyclization to generate the six-mem-
bered ring.[8] A more straightforward variant of the reaction
is the simultaneous anti addition of an iminium salt and an
iodide at an alkyne, stereoselectively generating the desired
double bond.[9] Kibayashi described a NozakiϪKishi coup-
Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: (internat.) ϩ 49-(0)30/838 55363
E-mail: udonubb@chemie.fu-berlin.de
[b]
Institut für Organische Chemie, J. W. Goethe Universität
Frankfurt,
Marie-Curie-Str. 11, 60439 Frankfurt/Main, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2002, 3315Ϫ3325  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3315 $ 20.00ϩ.50/0
3315

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
(R)-2-methylhexanal (1b) was synthesized according to
literature procedures by Evans’ methodology (not optim-
ized, Scheme 1).[13] The 3-propionoyloxazolidinone 2 de-
rived from (S)-alaninol was treated subsequently with
NaHMDS and crotyl bromide, the corresponding 2-methyl-
hexenoates 3 being isolated in 71.5% (2R) and 7.4% (2S)
yields.[14] The diastereomers could easily be separated by
preparative HPLC. The double bond was then removed by
hydrogenation and the (R)-2-methylhexanol (4) was ob-
tained after LiAlH4 reduction in 77% overall yield.[15]
A
final Swern oxidation generated the (R)-2-methylhexanal
(1b) in 97% yield (crude product). To avoid any racemiz-
ation, the aldehyde was always freshly prepared immedi-
ately before its employment in further transformations.[16]
Scheme 1
Initial studies concerning the introduction of the side
chain involved Gallagher’s aldol condensation route (I to
III, Scheme 2).[7] In contrast to the literature procedure,
which required two equivalents of LDA to achieve complete
deprotonation of the hydroxyindolizidinone I, only one
equivalent of the base was enough to form the enolate start-
ing from the protected indolizidinone 5. The less harsh ba-
sic conditions held out the prospect of avoiding any racem-
ization of the sensitive α-chiral hexanal 1b. The TBS-indoli-
zidinone 5 was deprotonated with one equivalent of LDA
at Ϫ78 °C, and the thus formed enolate was treated with
isobutyraldehyde 1a (R ϭ Me) and (R)-2-methylhexanal 1b
(R ϭ nBu) to yield mixtures of unchanged starting material
5 (40Ϫ60%) and about 27Ϫ43% aldol adducts 6/7, respect-
ively (64Ϫ72% if normalized to account for degree of con-
version). Mixtures of the two major diastereomers 6a/b and
7a/b were always obtained, and these were separated by
HPLC.[17] The relative configurations of the new ste-
reogenic centers were determined by NOE analyses. A
stable intramolecular hydrogen bond (OϪHϪOϭC) fixed
the conformation in such a way that the protons of C3 and
C3Ј of the side chain adopted defined positions, allowing
correlation to the stereogenic centers of the indolizidinone
ring.[18] Both major diastereomers of 6a/b and 7a/b showed
syn configurations of the C3 proton and the C3Ј OH group,
which would require anti elimination to generate the Z ol-
Figure 1. Retrosynthetic analyses of the pumiliotoxins
ling to generate allopumiliotoxins bearing the additional 7-
OH function.[10] These attempts, however, required earlier
introduction of the side chain, making the syntheses less
convergent.
In the planning of a convergent total synthesis of (ϩ)-
pumiliotoxin 251 D starting from a 5-indolizidinone-type
material,[11] the major challenge is the stereoselective gen-
eration of the exocyclic double bond (Figure 1). Two strat-
egies seemed to be favorable. On one hand, optimized aldol-
type condensations in the presence of a protected 8-OH
function, requiring less harsh basic conditions in the coup-
ling step, merited evaluation.[7] On the other hand, a
Horner reaction might serve as a suitable key step. Indeed,
the formation of E and Z olefins can be addressed select-
ively through variation of the ester substituents R1 on the
phosphonate [RЈ ϭ (R1O)2P(O)].[12] Two side chain alde-
hydes A were chosen for preliminary investigations: the use
of isobutyraldehyde (1a) being intended for the synthesis of
pumiliotoxin 209 F, and that of (R)-2-methylhexanal (1b)
to provide a new total synthesis of (ϩ)-pumiliotoxin 251 D.
Results and Discussion
Some suitable indolizidinone core compounds had been efin (in analogy to syn-II Ǟ III). The low degree of conver-
synthesized in nine to eleven steps, starting from -(Ϫ)-pro- sion of the reactant indolizidinone 5 and the predominantly
line.[11] In principle, that sequence should allow one to gen- syn arrangements of H and OH in 6a/b and 7a/b, requiring
erate the 5-indolizidinones and their corresponding enanti- the difficult anti elimination with potential low diastereose-
omers. Here, the natural series was used to generate the nat- lectivity, forced us to choose an alternative strategy to gen-
urally configured pumiliotoxins.
erate the exocyclic double bond with Z geometry.
3316
Eur. J. Org. Chem. 2002, 3315Ϫ3325

Total Synthesis of (ϩ)-Pumiliotoxin 251D
FULL PAPER
1
lyses.[23] In analysis of the H NMR spectra of both com-
pounds, the vinyl proton of the Z olefin was detected in a
high-field position (δ ϭ 5.6 ppm) while the side chain allyl
proton was found downfield (δ ϭ 3.9 ppm), because of the
deshielding effect of the syn carbonyl oxygen. For the cor-
responding E-olefin (E)-14a, the reverse was found. The vi-
nyl proton was found in downfield (δ ϭ 6.6 ppm), the side
chain allyl proton in a high-field position (δ ϭ 2.6 ppm).
Scheme 2
WittigϪHorner olefinations are powerful reactions for
stereoselective generation of either E or Z olefins, de-
pending on the substituents attached at the phosphorus.[12]
With the intention to test such a method as a convergent
key step in the pumiliotoxin synthesis, the smooth genera-
tion of a suitable β-amido phosphonate was a prerequisite
(Scheme 3).[19] According
a procedure published by
Wiemer, ketones and carboxylic acid derivatives can be con-
verted into the corresponding phosphonates by initial enol
phosphate generation and a final phosphate to phosphon-
ate rearrangement.[20] Such a strategy has been used by Sa-
vignac in cyclic systems to synthesize β-phosphonates of γ-
lactams.[21] The TBS-indolizidinone 5 was deprotonated
with one equivalent of LDA at Ϫ78 °C. The thus formed
amide enolate was trapped with chloro diethyl phosphate to
Scheme 3
The unsaturated lactam (Z)-14a seemed to be a suitable
generate the corresponding enol phosphate 8.[22] A second precursor for the total synthesis of pumiliotoxin 209 F
equivalent of LDA was then added in order to form the (Scheme 3). With the intention to avoid potential low dia-
vinyl anion 9, which underwent an immediate migration of stereoselectivity during the introduction of the missing C8
the phosphorus. The enol phosphate β-amidophosphonate methyl group into a keto lactam,[11] the lactam carbonyl
rearrangement occurred, producing the more stabilized en- group was removed in a first step. The unsaturated lactam
olate anion 10. On one hand, aqueous workup provided (Z)-14a was treated with a preformed mixture of LiAlH4
the corresponding phosphono amide 11 in high yield (100% and AlCl3 in Et2O at 0 °C.[24] The lactam CO function and
crude material) as a mixture of two C3 diastereomers, which the silyl ether protective group were removed in a single
were not separated. On the other hand, the β-amidophos- step to generate the corresponding amino alcohol 15 in 79%
phonate anion was treated with the isobutyraldehyde 1a yield. It should be pointed out that careful preparation of
(R ϭ Me) to induce the Horner reaction, the whole se- the AlH3 reagent was crucial to achieve a smooth reaction.
quence performed as a one-pot procedure. Since all steps On analysis of the crude product 15, only traces of potential
were carried out at Ϫ78 °C, the resulting α,β-unsaturated side products characterized by a reduced or an isomerized
lactam (Z)-14a was isolated with high selectivity (E/Z 1:13) olefin sub-unit were detected. The chemoselective oxidation
for the desired Z double bond. However, the one-pot pro- of the carbinol 15 to the corresponding ketone 16 failed
cedure was characterized by a moderate yield (49%). In completely. Swern-type oxidations suffered either from in-
contrast, the two-step reaction through a worked-up β-ami- ternal quenching of the sulfur reagent or from the migra-
dophosphonate intermediate 11 and a subsequent depro- tion of the double bond to yield an α,β-unsaturated ketone.
tonation/Horner olefination with isobutyraldehyde 1a suc- CrVI oxidations caused re-oxidation, generating the lactam
ceeded in 65% yield and with high Z selectivity (E/Z 1:13) 14a. Additionally, some migrated double bond was found.
in the newly formed double bond in (Z)-14a. The diastereo- TEMPO, DessϪMartin, and TPAP oxidations either gave
mers (Z)-14 and (E)-14a were separated by column chroma- no conversion or the material was destroyed during the
tography. The structures were established by NOE ana- course of the reaction. Since intermediate protection of the
Eur. J. Org. Chem. 2002, 3315Ϫ3325
3317

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
electron-rich amino function by protonation failed under contrast, deprotection with TBAF in THF gave no desired
various conditions, this path for a attempted total synthesis hydroxy amide 24, and the phosphate 25 was found as the
of the pumiliotoxins was abandoned (Scheme 3).[25]
major compound. This indicated a migration of the phos-
For the purpose of pumiliotoxin syntheses, the phos- phonate to the tertiary hydroxyl function under the basic
phonate introduction and Horner olefination sequence was reaction conditions.[16]
tested with the methyl indolizidinones 17 and 21 as suitable
reactants. In investigation of the 8-epi series starting from
bicycle 17, a smooth reaction was found (Scheme 4). The
one-pot procedure Ϫ consisting of initial deprotonation of
indolizidinone 17, trapping of the enolate with chloro phos-
phate, the vinyl anion formation, phosphate-phosphonate
rearrangement to 18, and the final olefination after addition
of the isobutyraldehyde 1a Ϫ gave the corresponding α,β-
unsaturated lactam (Z)-19a in 43% overall yield, the E/Z
ratio being about 1:15. An unoptimized two-step sequence
allowed isolation of the intermediate β-phosphono amide
18 in 74% yield, and this could be subjected to the ol-
efination conditions to yield the lactam (Z)-19a. The cor-
rect structure was determined by NMR and NOE ana-
lyses.[23] Finally, the total synthesis of the 8-epi-pumili-
otoxin 209 F (20) was achieved by reduction of the amide
with AlCl3/LiAlH4. The TMS protecting group was re-
moved under the reaction conditions, and the indolizidine
20 (8-epi-pumiliotoxin 209 F) was isolated in 79.6% yield.
Again, the suppression of the formation of any side prod-
ucts strongly depended on a high quality of the preformed
AlH3 reagent (Scheme 4).
Scheme 5
The potential migration of the phosphorus made the
Horner olefination of the hydroxy indolizidinone 24 ex-
tremely tricky, because of the use of a base as the initial
step for formation of the β-phosphono amide anion. With
use of a single equivalent of LDA in THF at Ϫ78 °C, the
phosphorus migration occurred as the predominant reac-
tion (Ǟ 25), only traces of the olefins 26 being found after
Scheme 4
the addition of the aldehyde 1. In contrast, the use of 2.3
In contrast, the natural series starting from methyl indoli- to 2.5 equivalents of LDA in THF at Ϫ78 °C produced
zidinone 21 behaved completely differently (Scheme 5). The only small amounts of phosphate 25. Obviously, the genera-
introduction of the phosphonate to 22 succeeded as de- tion of the bis-anion was much faster than the rearrange-
scribed above. Enol phosphate formation/deprotonation/ ment. Subsequent Horner olefination was then achieved by
phosphate-phosphonate migration gave the corresponding treatment of the intermediate with the isobutyraldehyde 1a
β-phosphono amide 22 in 97.5% yield as a mixture of two (R ϭ Me). The α,β-unsaturated lactam (Z)-26a was isolated
C3 diastereomers (not separated). All attempts to use this in 41% yield and with an E/Z ratio of about 1:10. The ol-
material in Horner olefinations to give (Z)-23 at low tem- efination with the chiral α-methylhexanal 1b (R ϭ nBu)
peratures (Ͻ Ϫ30 °C, to avoid the formation of the E again turned out to be crucial, because of the potential ra-
double bond) failed. Obviously, the bulky TMS protective cemization under the harshly basic reaction conditions.
group in 22 was preventing any attack of the aldehyde as After a short reaction time of about 30 min at Ϫ78 °C, the
the first step of the condensation. Neither the one-pot pro- desired α,β-unsaturated lactam (Z)-26b (R ϭ nBu) was isol-
cedure nor the two-step sequence gave any of the desired ated as the single diastereomer, but in a poor yield of only
product (Z)-23. Consequently, the TMS group was removed 20%. Prolongation of the reaction time increased the yield
prior to the Horner olefination. The desilylation succeeded to about 54%, but a mixture of the diastereomers (Z)-26b,
under acidic conditions by treatment of the phosphono (Z)-27b, (E)-26b, and (E)-27b was now isolated in a ratio of
amide 22 with HCl/MeOH. The carbinol 24 could be isol- 7:4:1:1. On analysis of this material, the double bond was
ated in 100% yield as a mixture of the C3 diastereomers. In found to have been generated predominantly with the Z
3318
Eur. J. Org. Chem. 2002, 3315Ϫ3325

Total Synthesis of (ϩ)-Pumiliotoxin 251D
FULL PAPER
configuration (E/Z ഠ 1:6). Furthermore, the side chain ste- deprotonated phosphonate (Scheme 3). Minimized repuls-
reogenic center was not formed selectively, indicating par- ive interactions could be presumed, with adoption of a tra-
tial racemization of the reactant aldehyde 1b. Nevertheless, jectory such as ts-12. The bulky side chain should be posi-
the diastereomers were separated by column chromato- tioned next to the small CH2 group of the indolizidinone.
graphy and preparative HPLC. The relative configurations Alternatively, a lithium chelate complex ts-13 might have
of the stereogenic centers and the double bond in (E/Z)-26b been passed through, as theoretically postulated by ab initio
and (E/Z)-27b were unambiguously corroborated by NOE calculations for open chain systems.[27] The carbon side
analyses.[23] All spectroscopic data were found to be in good chain should in this case be favorably positioned in an anti
accordance with those published by Gallagher in 1991, but arrangement with respect to the bulky phosphonate sub-
the specific rotation of (Z)-26b differed (published: Ϫ28°, stituent. However, open transition states (ts-12 and ts-13)
CHCl3, found Ϫ67.6°, CHCl3).[7] Surprisingly, the specific as described in Scheme 3 would always give rise to the same
rotation of the 11Ј-epi-indolizidinone (Z)-27b was charac- product independent of an α or a β addition of the aldehyde
terized by a positive sign (ϩ55°, CHCl3) whereas that of with respect to the indolizidinone ring plane. In instances
the naturally configured diastereomer (Z)-26b was negative of a fast and of an irreversible reaction, respectively, the
(Ϫ67.6°, CHCl3). Keeping in mind that the separation of nascent double bond would have to be Z-configured. The
both diastereomers required optimized HPLC techniques, absence of additional nucleophiles should be ensured in or-
the lower value published in the literature might have been der to prevent subsequent isomerization by a reversible
the consequence of some racemization of the chiral α- Michael addition to the α,β-unsaturated indolizidinones.
methylhexanal 1b (R ϭ nBu, R/S ϭ 1.4:1) during the course
of the aldol condensation used to introduce the side chain
On subjection of the indolizidinones 11, 18, 22, and 24
(Scheme 2). This is in good accordance with our findings, to the Horner reaction conditions, the last two species were
because both strategies needed the same harsh basic condi- characterized by exceptional modified reactivity. The
tions (bis-anions of the reactant bicyclic indolizidinones I TMSO lactam 22 gave no reaction (sterically hindered lone
and 24, respectively).
pair in B?), and the hydroxylactam lactam 24 suffered from
In completion of the total synthesis, the CO group of the a migration of the phosphonate to give phosphate 25. The
major α,β-unsaturated lactam (Z)-26b was reduced with a phosphorus migration could be explained by intramolecular
preformed mixture of LiAlH4 and AlCl3 in Et2O at 0 °C. attack of the kinetically formed quasi-axial alkoxide at a
The (ϩ)-pumiliotoxin 251D (28) was obtained in 57% yield 1,3-syn-oriented phosphonate C. The result was the final
as a colorless oil. All data of the obtained material were elimination of a more stabilized anion of the amide enolate
identical with those published in the literature, and the cor- D (in THF). After hydrolytic workup the phosphate 25 was
rect structure was verified by NOE analyses. Finally, the isolated. In the presence of two equivalents of base, in con-
indolizidine 28 was converted into the corresponding hydro- trast, the generation of the bis-anion E was much faster
chloride 29 by treatment with methanolic HCl. The mat- than the rearrangement. Presumably, the thus formed am-
erial was crystallized from EtOAc/CH2Cl2, and an X-ray ido phosphonate anion in E was efficiently protected
analysis of 29 confirmed the correct structure (Fig- against any intramolecular nucleophilic attack of the alkox-
ure 2).[23,26]
ide. Thus, the Horner reaction was favored, but the ex-
tremely basic bis-anion E might have caused some racemi-
zation of the (2R)-2-methylhexanal reactant 1b (Figure 3).
Figure 2. ORTEP plot of (ϩ)-pumiliotoxin 251 D (·HCl) (29)
Mechanistic Conclusions
Horner olefination of the β-phosphonoamides 11, 17,
and 24 has been found to serve as reliable method to pro-
duce the exocyclic double bond with a high Z selectivity
(5Ϫ15:1, Z/E). A low reaction temperature was crucial to
obtain satisfactory results with the standard diethyl phos-
phonate. The high selectivity could be explained as a result
of a defined preorientation of the aldehyde attacking the
Figure 3. Reactions of phosphonates 22 and 24 with base and alde-
hydes 1
Eur. J. Org. Chem. 2002, 3315Ϫ3325
3319

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
Conclusion
electron energy was 0.8 mA. The melting points (not corrected)
were measured with a Büchi SMP 20. For HPLC, Knaur pumps
UV and RI detectors and Rheodyne injection systems were used.
A convergent total synthesis of enantiopure pumiliotox-
ins has been developed, the bicyclic core skeleton indolizidi-
nones 5, 17, and 21 and the side chain aldehyde 1 being
combined in the key step. An initial investigation to test the
aldol strategy first described by Gallagher was found to be
less efficient. The moderate level of conversion of the react-
ant lactam and the low diastereoselectivity of the addition
made the selective generation of the exocyclic olefin ex-
tremely difficult. Alternatively, a Horner olefination could
to be used as a reliable method to introduce the desired
trisubstituted double bond with Z selectivity. Such strategy
required an efficient route to the reactant β-amidophos-
phonates as a prerequisite. The phosphonate was intro-
duced by a sequence developed by Wiemer and Savignac.
The core indolizidinone was converted into the correspond-
ing enol phosphate after deprotonation and phosphoryl-
ation. A second equivalent of base then generated the vinyl
anion, which immediately underwent a phosphate-phos-
phonate migration. The thus formed β-amidophosphonate
anion was treated with the aldehyde 1 to induce the Horner
reaction. This one-pot procedure gave the α,β-unsaturated
indolizidinones with a high Z selectivity and a moderate
yield. However, the intermediate isolation of the β-amido-
phosphonates followed by a separate olefination gave
higher yields, favoring this two-step procedure. The indolizi-
dinones 5 and 17 smoothly gave the α,β-unsaturated indoli-
zidinones (Z)-14 and (Z)-19, while the analogous reaction
with the 5-indolizidinone 21 failed. The phosphonate intro-
duction to 22 caused no problems, but the subsequent ol-
efination required the initial deprotection of the tertiary al-
cohol function prior to the Horner reaction. The hydro-
xyindolizidinone 24 was found to be very sensitive under
the basic reaction conditions. However, the generation of
the side chain to yield (Z)-26a and (Z)-26b succeeded, al-
though the minor diastereomers had to be separated. In
completion of the total syntheses, the amide functions of
(Z)-19a and (Z)-26b were removed by AlH3 reduction. The
(Ϫ)-8-epi-pumiliotoxin 209 F (20) and the (ϩ)-pumiliotoxin
251 D (28) were therefore synthesized in 12 to 14 steps over-
all. The structure of the latter (as the hydrochloride 29) was
confirmed by X-ray analysis.
Preparative amounts of the lactams were separated with
a
MachereyϪNagel & Co 32 mm ϫ 120 mm column and 5 µm Nu-
cleosil 50-5, with a flow of about 80 mL/min. Column chromato-
graphy was carried out with Merck silica gel (0.04Ϫ0.063 mm,
230Ϫ400 mesh A). Progress of reactions was monitored by thin
layer chromatography (TLC) performed on aluminum sheets pre-
coated with 60 silica gel (thickness 0.25 mm). All solvents were
dried before use by standard procedures. X-ray analyses were per-
˚
formed with Mo-Kα radiation (λ ϭ 0.71073 A). The structure was
determined by direct methods with the SHELXS program. The H
atoms were taken from a difference Fourier synthesis and were re-
fined with isotropic thermal parameters. The non-H atoms were
refined with anisotropic thermal parameters. The structure was re-
fined on F values with the weighting scheme: ω(F) ϭ 4·F2/[σ2(F2)
ϩ (0.03·F2)2]. The final difference density was between Ϫ0.29 and
ϩ0.36 e/A3.
(5R,6S)-5-(tert-Butyldimethylsilyloxy)-3-(diethoxyphosphoryl)aza-
bicyclo[4.3.0]nonan-2-one (11), (3Z)-(5R,6S)-5-(tert-Butyldimethyl-
silyloxy)-3-isobutylideneazabicyclo[4.3.0]nonan-2-one [(Z)-14a], and
(3E)-(5R,6S)-5-(tert-Butyldimethylsilyloxy)-3-isobutylideneazabi-
cyclo[4.3.0]nonan-2-one (E-14a). Two-Step Procedure: Phosphonate
introduction: Under argon, LDA (1.53 mL, 3.07 mmol, 1.2 equiv.,
2  in THF) was diluted with dry THF (10 mL) and cooled to
Ϫ78 °C. Indolizidinone 5 (690 mg, 2.56 mmol) in dry THF (3 mL)
was added by syringe over a period of 5 min. After the mixture had
been stirred at Ϫ78 °C for 30 min, diethyl chlorophosphate (0.74
mL, 883 mg, 5.12 mmol, 2 equiv.) in dry THF (2 mL) was added
dropwise. The mixture was stirred for 2.5 h at Ϫ78 °C. A second
portion of LDA (2 mL, 4 mmol, 2  in THF) was then injected.
After the mixture had been stirred for another 3.5 h at Ϫ78 °C, the
cooling bath was removed and the excess of LDA was quenched
with saturated aqueous NH4Cl (30 mL). The aqueous layer was
extracted with Et2O (3 ϫ 20 mL), the combined organic layers were
dried (Na2SO4), and the solvent was removed to yield phosphonate
11 (1.13 g, 2.56 mmol, 100%) as a colorless oil pure enough for
further transformations. Analytically pure 11 (mixture of C3 dias-
tereomers) could be obtained by column chromatography on silica
gel (EtOAc/n-hexane, 1:1, Rf ϭ 0.1).
Horner Olefination: Under argon, phosphonate 11 (1.13 g,
2.56 mmol) in pre-cooled anhydrous THF 10 mL, Ϫ78 °C) was
treated with LDA (1.66 mL, 3.32 mmol, 1.3 equiv., 2  in THF,
injection over a period of 5 min). After the mixture had been stirred
for 1 h at Ϫ78 °C, isobutyraldehyde 1a (0.93 mL, 738 mg,
10.2 mmol, 4 equiv., R ϭ Me) was added and the mixture was
stirred at Ϫ78 °C overnight. The cooling bath was removed and
the excess of LDA was quenched with saturated aqueous NH4Cl
(30 mL). The aqueous layer was extracted with Et2O (3 ϫ 20 mL),
the combined organic layers were dried (Na2SO4), and the solvent
was removed. The crude oil was purified by column chromato-
graphy on silica gel (EtOAc/n-hexane 1:1, Rf ϭ 0.55). Yield 0.54 g
(1.67 mmol, 65.2%) isobutylideneindolizidinones 14a as a colorless
oil. The E/Z ratio was determined by 1H NMR spectroscopy (E/
Z ϭ 1:13.5).
Experimental Section
General Remarks: 1H NMR,13C NMR spectra, and NOE experi-
ments were recorded on Bruker AM 270 or Bruker AC 550 (11,
NOEDS analyses) spectrometers at room temp. unless specified
otherwise. Tetramethylsilane was used as internal standard. For
peak assignment, azabicyclononane numbering is used. IR spectra
were obtained with a PerkinϪElmer 257 or 580B spectrophoto-
meter. Optical rotations were measured with a PerkinϪElmer P 241
One-Pot Procedure: Phosphonate introduction was as described for
polarimeter in a 1 dm cell. Mass spectra were recorded on a Varian the two-step procedure without workup: LDA (0.65 mL,
MAT 711 or 112S, The high-resolution mass spectra (HRMS) were 1.29 mmol, 1.2 equiv., 2  in THF) in dry THF (50 mL), indolizidi-
obtained with a Varian MAT 711 spectrometer. PFK was used as
reference, the results were determined by peak matching methods,
resolution: Ͼ 10,000. The ion source temperature was 250 °C, the
none 5 (0.29 g, 1.08 mmol) in THF (1 mL), chloro phosphate (309
µL, 2.152 mmol, 2 equiv.), second portion of LDA (0.85 mL,
1.7 mmol, 1.2 equiv., 2  in THF). Careful TLC monitoring was
3320
Eur. J. Org. Chem. 2002, 3315Ϫ3325

Total Synthesis of (ϩ)-Pumiliotoxin 251D
FULL PAPER
essential in order to detect the complete formation of the interme-
Ϫ C4H9], 192 (8), 183 (5), 156 (9), 148 (7), 136 (5), 96 (7), 81 (16),
diate phosphonate 11. Isobutyraldehyde 1a (0.39 mL, 4.3 mmol, 4 75 (31), 73 (43), 70 (12). HRMS (80 eV, 90 °C): calcd. 323.228058
equiv.) was then added and the mixture was stirred at Ϫ78 °C over- (for C18H33N1O2Si [Mϩ]), found 323.22644.
night. The cooling bath was removed and the excess of LDA was
Data for E-Isobutylidene Indolizidinone (E)-14a: [α]2D0 ϭ Ϫ33.4 (c ϭ
quenched with saturated aqueous NH4Cl (40 mL). The aqueous
layer was extracted with Et2O (4 ϫ 30 mL), the combined organic
0.84, CHCl3). 1H NMR (270 MHz, CDCl3): δ ϭ 0.07 (s, 3 H,
SiϪCH3), 0.08 (s, 3 H, SiϪCH3), 0.88 [s, 9 H, SiϪC(CH3)3], 0.99 [d,
3J(H3cЈ,H3b) ϭ 5.5 Hz, 3 H, 3cЈ-H], 1.02 [d, 3J(H3c,H3b) ϭ 5.5 Hz, 3
H, 3c-H], 1.53Ϫ1.40 (m, 1 H, 7o-H), 1.80Ϫ1.65 (m, 1 H, 8u-H),
2.00Ϫ1.90 (m, 1 H, 8o-H), 2.31Ϫ2.18 (m, 2 H, 7u-,4u-H),
2.58Ϫ2.43 (m, 1 H, 3b-H), 2.83Ϫ2.73 [ddd, 2J(H4o,H4u) ϭ 15.5,
3J(H4o,H5o) ϭ 5, 4J(H4o,H3a) ϭ 1.5 Hz, 1 H, 4o-H], 3.40Ϫ3.28 (m,
layers were dried (Na2SO4), and the solvent was removed. The
crude oil was purified by column chromatography on silica gel
(EtOAc/n-hexane 1:1, Rf ϭ 0.55). Yield 0.17 g (0.53 mmol, 49%)
isobutylidene indolizidinones 14a as a colorless oil. The E/Z ratio
1
was determined by H NMR spectroscopy (E/Z ϭ 1:12.8).
Data for Phosphonate 11:[28] 1H NMR (500 MHz, CDCl3): δ ϭ 0.00 1 H, 6u-H), 3.60Ϫ3.40 (m, 3 H, 5-,9o-,9u-H), 6.68Ϫ6.60 [ddd,
(s, 3 H, SiϪCH3), 0.01 (s, 3 H, SiϪCH3), 0.04 (s, 3 H, SiϪCH3), 3J(H3a,H3b) ϭ 9, 4J(H3a,H4u) ϭ 2.5, 4J(H3a,H4o) ϭ 1.5 Hz, 1 H,
0.06 (s, 3 H, SiϪCH3), 0.81 [s, 9 H, Si(CH3)3], 0.82 [s, 9 H,
Si(CH3)3], 1.30Ϫ1.25 (m, 12 H, 2-H ϫ CH2ϪCH3), 1.45Ϫ1.35 (m, Ϫ4.2 (q, SiϪCH3), 17.9 [s, SiC(CH3)3], 21.8 (q, C-3cЈ), 22.0 (q, C-
3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ Ϫ4.7 (q, SiϪCH3),
1 H, 7-H), 1.50Ϫ1.40 (m, 1 H, 7Ј-H), 1.75Ϫ1.60 (m, 2 H, 8-,8Ј-
H), 1.95Ϫ1.85 (m, 3 H, 8-,8Ј-,4Ј-H), 2.07Ϫ1.95 (m, 2 H, 4-,4Ј-H),
3c), 22.5 (t, C-8), 25.7 [q, SiC(CH3)3], 27.5 (d, C-3b), 32.2 (t, C-4),
34.6 (t, C-7), 46.1 (t, C-9), 63.6 (d, C-6), 72.0 (d, C-5), 125.0 (s, C-
2.23Ϫ2.10 (m, 2 H, 7-,7Ј-H), 2.37Ϫ2.29 (m, 1 H, 4-H), 3.05Ϫ2.90 3), 145.5 (d, C-3a), 163.6 (s) ppm. IR (KBr): ν˜ ϭ 3409 (m), 2958
(m, 2 H, 3-,3Ј-H), 3.20Ϫ3.15 (m, 1 H, 6-H), 3.37Ϫ3.30 (m, 1 H, (s), 2929 (s), 2858 (s), 1664 (s), 1622 (s), 1443 (s), 1425 (s), 1384
6Ј-H), 3.55Ϫ3.38 (m, 5 H, 9o-,9u-,9oЈ-,9uЈ-,5Ј-H), 4.00Ϫ3.93 (m, 1
(m), 1361 (m), 1337 (m), 1306 (w), 1257 (s), 1208 (m), 1190 (m),
H, 5-H), 4.25Ϫ4.00 (m, 8 H, 2-H ϫ OϪCH2 and OϪCH2Ј) ppm. 1126 (s), 1102 (s), 1054 (m), 1030 (m), 1006 (m), 985 (m), 928 (m),
13C NMR (125.8 MHz, CDCl3): δ ϭ Ϫ4.9 (q, SiϪCH3), Ϫ4.9 (q, 900 (m), 881 (m), 864 (m), 837 (s), 777 (s), 733 (s), 681 (m), 670
SiϪCH3), Ϫ4.5 (q, SiϪCH3), Ϫ4.4 (q, SiϪCH3), 16.2 and 16.2 and
16.3 and 16.4 and 16.5 (multiple signals, no defined structure,
(s), 563 (m) cmϪ1. MS (80 eV, EI, 80 °C): m/z (%) ϭ 323 (14) [Mϩ·],
308 (5) [Mϩ Ϫ CH3], 266 (100) [Mϩ Ϫ C4H9], 237 (10), 222 (80),
OϪCH2ϪCH3 and OϪCH2ϪCH3Ј, 4 sets of doublets from qua- 194 (12), 180 (68), 155 (15), 124 (38), 99 (10), 75 (25), 73 (25).
druplets), 17.8 [s, Si-C(CH3)3], 22.0 (t, C-8Ј), 22.3 (t, C-8), 25.5 [q, HRMS (80 eV, 90 °C): calcd. 323.228058 (for C18H33N1O2Si [Mϩ]),
SiϪC(CH3)3], 25.6 [q, SiϪC(CH3)3], 31.8 (t, C-4Ј), 32.2 (t, C-7 and
C-7Ј and C-4), 40.4 [dd, 1J(31P,13C) ϭ 138.9 Hz, C-3Ј], 40.5 [dd,
1J(31P,13C) ϭ 135.8 Hz, C-3], 45.9 (t, C-9Ј), 46.5 (t, C-9), 61.8 [dt,
OϪCH2Ј, 2J(31P,13C) ϭ 7.5 Hz], 62.0 [dt, 2J(31P,13C) ϭ 7.5 Hz,
found 323.22838.
(3Z)-(5R,6S)-5-Hydroxy-3-(isobutylidene)azabicyclo[4.3.0]nonane
(15): Under argon, LiAlH4 (80 mg, 2.1 mmol, 3.75 equiv.) in dry
Et2O (10 mL) was cooled to 0 °C and treated with AlCl3 (93 mg,
0.7 mmol, 1.25 equiv.) in dry Et2O (2 mL). The color of the suspen-
sion turned from deep gray to light gray (grainy suspension).[29]
The cooling bath was removed and the resultant mixture was
stirred at room temp. for 1 h. The mixture was then cooled to 0
°C, and indolizidinone (Z)-14a (180 mg, 0.56 mmol) in dry Et2O (2
mL) was added by syringe. The mixture was stirred overnight at
ambient temperature. Workup started with the dropwise addition
of H2O (0.3 mL) to form a white precipitate of aluminum salts.
After the mixture had been stirred for a further 15 min, aqueous
KOH (0.3 mL, 2.5 ) was added and the precipitate coagulated.
The colorless organic solution was decanted and the solid residue
was extracted with Et2O (40 mL). The organic layers were dried
(Na2SO4) and the solvent was removed. The crude indolizidine 15
was purified by column chromatography on silica gel (MeOH/
EtOAc, 1:4, TLC: MeOH/EtOAc, 1:3 Rf ϭ 0.25Ϫ0.37). Yield:
86.5 mg (0.44 mmol, 79.1%) of indolizidine 15 as a clear, colorless
OϪCH2Ј], 63.1 [dt, 2J(31P,13C)
ϭ 6 Hz, OϪCH2], 63.2 [dt,
2J(31P,13C) ϭ 6 Hz, OϪCH2], 63.4 (d, C-6Ј), 64.4 (d, C-6), 69.1 (d,
C-5), 72.0 [dd, 3J(31P,13C) ϭ 13 Hz, C-5Ј], 163.2 (s), 163.3 (s) ppm.
31P NMR (202.5 MHz, CDCl3): δ ϭ 22.32, 22.72 ppm. IR
(CHCl3): ν˜ ϭ 3019 (m), 2982 (m), 2956 (m), 2931 (m), 1886 (m),
2858 (m), 1636 (s, CϭO), 1462 (m), 1443 (m), 1389 (m), 1362 (m),
1252 (s), 1216 (s), 1128 (m), 1103 (m), 1028 (s), 965 (m) cmϪ1. MS
(80 eV, EI, 90 °C): m/z (%) ϭ 405 (8) [Mϩ·], 390 (5) [Mϩ Ϫ CH3],
348 (84) [Mϩ Ϫ C4H9], 320 (26), 302 (4), 292 (10), 274 (15), 263
(10), 235 (7), 212 (96), 181 (35), 155 (18), 136 (100) [PO(OEt)2],
129 (20), 109 (15), 99 (59), 84 (35), 75 (31), 73 (40), 70 (36). HRMS
(80 eV, 80 °C): calcd. 405.21004 (for C18H36N1O5PSi [Mϩ]),
found 405.21331.
Data for (Z)-Isobutylideneindolizidinone (Z)-14a: [α]2D0 ϭ Ϫ61.4
1
(c ϭ 1.7, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 0.04 (s, 3 H,
SiϪCH3), 0.05 (s, 3 H, SiϪCH3), 0.86 [s, 9 H, SiC(CH3)3],
1.00Ϫ0.90 (m, 6 H, 3c-H), 1.52Ϫ1.38 (m, 1 H, 7o-H), 1.80Ϫ1.60 oil. [α]2D0 ϭ Ϫ23.0 (c ϭ 1.45, CHCl3). 1H NMR (270 MHz, CDCl3):
(m, 1 H, 8u-H), 2.00Ϫ1.85 (m, 1 H, 8o-H), 2.25Ϫ2.15 (m, 1 H, 7u-
δ ϭ 0.87 [d, 3J(H3cЈ,H3b) ϭ 6.5 Hz, 3 H, 3cЈ-H], 0.94 [d,
H), 2.53Ϫ2.45 (m, 2 H, 4o-,4u-H), 3.33Ϫ3.23 [ddd, J(H6u,H5o) ϭ 3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 2.05Ϫ1.45 (m, 5 H, 8o-,8u-,6u-,
3
3
3
2
2
10, J(H6u,H7o) ϭ 10, J(H6u,H7u) ϭ 5 Hz, 1 H, 6u-H], 3.60Ϫ3.40 7u-,7o-H), 2.24Ϫ2.13 [ddd, J(H9u,H9o) ϭ 8.5, J(H9u,H8o) ϭ 8.5,
(m, 3 H, 9o-,9u-,5o-H), 3.90Ϫ3.75 (m, 1 H, 3b-H), 5.60Ϫ5.55 [ddd,
2J(H9u,H8u) ϭ 8.5 Hz, 1 H, 9u-H], 2.35Ϫ2.30 [d, 2J(H2u,H2o) ϭ
12.5 Hz, 1 H, 2u-H], 2.60Ϫ2.40 (m, 2 H, 4o-,3b-H), 3.05Ϫ2.95
4
4
3J(H3a,H3b) ϭ 9.5, J(H3a,H4o) ϭ 1.5, J(H3a,H4u) ϭ 1.5 Hz, 1 H,
3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ Ϫ4.8 (q, SiϪCH3), [ddd, 2J(H9o,H9u) ϭ 8.5, 2J(H9o,H8) ϭ 8.5, 2J(H9o,H8) ϭ 2 Hz, 1
Ϫ4.3 (q, SiϪCH3), 17.8 [s, SiC(CH3)3], 22.5 (t, C-8), 22.8 (q, C-
3cЈ), 22.8 (q, C-3c), 25.6 [q, SiC(CH3)3], 27.2 (d, C-3b), 32.0 (t, C-
H, 9o-H], 3.20Ϫ3.00 (s, 1 H, OH), 3.35Ϫ3.25 [ddd, 3J(H5o,H) ϭ
3
3
13, J(H5o,H) ϭ 8.5, J(H5o,H) ϭ 4 Hz, 1 H, 5o-H], 3.75Ϫ3.67 [d,
4), 41.9 (t, C-7), 45.6 (t, C-9), 64.2 (d, C-6), 71.9 (d, C-5), 123.6 (s, 2J(H2o,H2u) ϭ 12.5 Hz, 1 H, 2o-H], 5.08Ϫ5.00 [d, 3J(H3a,H3b) ϭ
C-3), 150.4 (d, C-3a), 163.7 (s) ppm. IR (KBr): ν˜ ϭ 2955 (s), 2860
8.5 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 21.1
(s), 1658 (s), 1620 (s), 1464 (m), 1472 (m), 1445 (s), 1423 (s), 1389 (t, C-8), 23.1 (q, C-3cЈ), 23.5 (q, C-3c), 26.7 (d, C-3b), 27.9 (t, C-
(m), 1378 (m), 1349 (m), 1258 (s), 1146 (m), 1115 (s), 1057 (w), 7), 43.7 (t, C-4), 51.8 (t, C-9), 53.8 (t, C-2), 70.0 (d, C-6), 72.5 (d,
1023 (w), 1005 (m), 991 (m), 939 (m), 901 (m), 865 (s), 838 (s), 777 C-5), 129.8 (s, C-3), 133.9 (d, C-3a) ppm. IR (CHCl3): ν˜ ϭ 3618
(s), 735 (m), 680 (m), 573 (w), 483 (w) cmϪ1. MS (80 eV, EI, 90 (m), 2961 (s), 2935 (m), 2870 (m), 2804 (m), 1465 (m), 1447 (m),
°C): m/z (%) ϭ 323 (100) [Mϩ·], 308 (6) [Mϩ Ϫ CH3], 266 (34) [Mϩ
1378 (m9, 1215 (w), 1153 (w), 1127 (w), 1095 (w), 1059 (w), 1020
Eur. J. Org. Chem. 2002, 3315Ϫ3325
3321

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
(w) cmϪ1. MS (80 eV, EI, 80 °C): m/z (%) ϭ 195 (37) [Mϩ·], 180 ing the procedure as described for indolizidine 15. Purification by
(18) [Mϩ Ϫ CH3], 152 (96) [Mϩ Ϫ C3H7], 134 (12), 111 (12), 108
column chromatography on silica gel (MeOH/EtOAc, 1:9, TLC:
(17), 98 (16), 82 (17), 70 (100), 55 (31). HRMS (80 eV, 30 °C): MeOH/EtOAc, 1:3 Rf ϭ 0.25Ϫ0.37). Yield: 192.6 mg (0.92 mmol,
calcd. 195.162314 (for C12H21N1O1 [Mϩ]), found 195.16433.
79.6%) of 5-epi-pumiliotoxin 209 F (20) as colorless crystals, m.p.
1
73Ϫ77 °C. [α]2D0 ϭ Ϫ20.6 (c ϭ 1.38, CHCl3). H NMR (270 MHz,
(5R,6S)-5-tert-Butyldimethylsilyloxy-3-(diethoxyphosphonyl)aza-
bicyclo[4.3.0]nonan-2-one (18) and (3Z)-(5R,6S)-5-tert-Butyldime-
thylsilyloxy-3-(isobutylidene)azabicyclo[4.3.0]nonan-2-one (Z-19a).
β-Amidophosphonate 18: Reaction of indolizidinone 17 (630 mg,
2.6 mmol) by following the procedure as described for phosphonate
11. Enolate formation: 50 min, enol phosphateϪphosphonate mi-
gration: 40 min. Purification by column chromatography on silica
gel (MeOH/EtOAc 1:9, Rf ϭ 0.3). Yield: 0.73 g (1.92 mmol, 74%)
of β-amidophosphonate 18 as a colorless oil. [α]2D0 ϭ Ϫ15.2 (c ϭ
1.38, CHCl3). 1H NMR (270 MHz, CDCl3): δ ϭ 0.05 [s, 9 H,
Si(CH3)3], 1.05 (s, 3 H, 5-CH3), 1.30Ϫ1.20 (m, 6 H, H-PO-
CH2ϪCH3), 1.60Ϫ1.46 (m, 1 H, 7u-H), 1.90Ϫ1.60 (m, 2 H, 8o-,
8u-H), 2.00Ϫ1.90 (m, 1 H, 7o-H), 2.20Ϫ2.00 (m, 2 H, 4o-,4u-H),
2.95Ϫ2.76 [ddd, 2J(H3o,P) ϭ 26.5, 3J(H3o,H4u) ϭ 11, 3J(H3o,H4o) ϭ
8 Hz, 1 H, 3o-H], 3.50Ϫ3.30 (m, 3 H, 9o-,9u-,6u-H), 4.28Ϫ3.93
(m, 4 H, PO-CH2) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 2.43
(q, SiϪCH3), 16.1, 16.1, 16.2, 16.3, 16.35 and 16.4 (multiple signals,
no defined structure, OϪCH2ϪCH3, 2 sets of doublets from quad-
ruplets), 19.5 (q, C-5ϪCH3), 22.1 (t, C-8), 27.3 (t, C-7), 38.9 [dt,
2J(13C,31P) ϭ 3.5 Hz, C-4], 40.8 [dd, 1J(13C,31P) ϭ 139 Hz, C-3],
46.7 (t, C-9), 61.8 [dt, 2J(13C,31P) ϭ 7 Hz, PO-CH2], 63.3 [dt,
CDCl3): δ ϭ 0.87Ϫ0.85 [d, 3J(H3cЈ,H3b) ϭ 6.5 Hz, 3 H, 3cЈ-H],
0.92Ϫ0.90 [d, 3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 1.08 (s, 3 H, 5-
CH3), 1.85Ϫ1.50 (m, 5 H, 8o-,8u-,7o-,7u-,6u-H), 2.20Ϫ2.00 (m, 3
H, 9u-,4o-,4u-H), 2.37Ϫ2.30 [d, 2J(H2u,H2o) ϭ 12.5 Hz, 1 H, 2u-
H], 2.58Ϫ2.42 (m, 1 H, 3b-H), 3.06Ϫ2.97 [ddd, 2J(H9o,H9u) ϭ 8.5,
3
3J(H9o,H8u) ϭ 8.5, J(H9o,H8o) ϭ 2 Hz, 1 H, 9o-H], 3.70Ϫ3.65 [d,
2J(H2o,H2u) ϭ 12.5 Hz, 1 H, 2o-H], 5.02Ϫ4.95 [d, 2J(H3a,H3b) ϭ
9.5 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 20.4
(d, C-3b), 20.9 (t, C-8), 23.3 (q, C-3cЈ), 23.4 (q, C-3c), 23.8 (t, C-
7), 26.7 (q, 5-CH3), 50.4 (t, C-4), 52.8 (t, C-9), 54.7 (t, C-2), 71.3
(s, C-5), 72.8 (d, C-6), 130.2 (s, C-3), 134.0 (d, C-3a) ppm. IR
(CHCl3): ν˜ ϭ 3019 (m), 2961 (m), 2880 (w), 2795 (w), 1637 (w),
1519 (w), 1464 (m), 1429 (w), 1382 (w), 1216 (s, CϪO), 1149 (w),
1106 (m), 912 (s) cmϪ1. MS (80 eV, EI, 30 °C): m/z (%) ϭ 209 (42)
[Mϩ·], 194 (18) [Mϩ Ϫ CH3], 176 (10), 166 (99) [Mϩ Ϫ C3H7], 148
(11), 136 (6), 108 (10), 96 (11), 84 (35), 70 (100), 55 (12). HRMS
(80 eV, 30 °C): calcd. 209.177965 (for C13H23N1O1 [Mϩ]), found
209.17488.
(5S,6S)-3-(Diethoxyphosphonyl)-5-methyl-5-(trimethylsilyloxy)-
azabicyclo[4.3.0]nonan-2-one (22): Reaction of indolizidinone 21
(350 mg, 1.45 mmol) in THF (100 mL) by following the procedure
as described for phosphonate 11. Enolate formation: 50 min. Puri-
fication by column chromatography on silica gel (MeOH/EtOAc
1:9, Rf ϭ 0.25). Yield: 533.7 mg (1.41 mmol, 97.5%) of β-amido-
phosphonate 22 as a colorless oil. [α]2D0 ϭ Ϫ10.7 (c ϭ 1.58, CHCl3).
1H NMR (270 MHz, CDCl3): δ ϭ 0.02 [s, 9 H, Si(CH3)3],
1.30Ϫ1.15 (m, 9 H, 5-CH3, POCH2ϪCH3), 1.85Ϫ1.45 (m, 4 H,
4Ј-,7Ј-,8-,8Ј-H), 2.05Ϫ1.93 (m, 2 H, 7-,4-H), 3.02Ϫ2.85 [ddd,
2J(H3o,31P) ϭ 25.5, 3J(H3o,H4u) ϭ 10, 3J(H3o,H4o) ϭ 8 Hz, 1 H,
3o-H], 3.45Ϫ3.20 (m, 3 H, 9o-,9u-,6u-H), 4.23Ϫ3.98 (m, 4 H, PO-
CH2) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 2.00 [q, Si(CH3)3],
3
2J(13C,31P) ϭ 6 Hz, PO-CH2], 66.3 (d, C-6), 72.8 [d, J(13C,31P) ϭ
13 Hz, C-5], 163.1 [dd, 2J(13C,31P) ϭ 5 Hz, C-1] ppm. IR (CHCl3):
ν˜ ϭ 2996 (s), 2884 (m), 1634 (s), 1456 (m), 1441 (m), 1385 (m),
1296 (m), 1284 (m), 1252 (s), 1215 (s), 1161 (s), 1123 (m), 1028 (s),
974 (m), 909 (s), 876 (m), 843 (s) cmϪ1. MS (80 eV, EI, 85 °C):
m/z (%) ϭ 377 (2) [Mϩ·], 362 (4) [Mϩ Ϫ CH3], 332 (2), 288 (8), 280
(3), 251 (1), 240 (5), 237 (3), 219 (3), 198 (2), 170 (1), 150 (100),
110 (5), 73 (8). HRMS (80 eV, 80 °C): calcd. 377.17874 (for
C16H32N1O5PSi [Mϩ]), found 377.17645.
Indolizidinone (Z)-19a: Reaction of indolizidinone 17 (1.14 g,
4.72 mmol) by following the one-pot procedure as described for
indolizidinone 5. After addition of the isobutyraldehyde 1a: stirring
for 3 h at Ϫ65 °C and at Ϫ78 °C overnight. Purification by column
chromatography on silica gel (n-hexane/EtOAc 2:1, Rf ϭ 0.45).
Yield: 0.6 g (2.03 mmol, 43%) of indolizidinone (Z)-19a as a color-
less oil, E/Z ϭ 1:6 by NMR analysis. [α]2D0 ϭ Ϫ35.9 (c ϭ 1.56,
CHCl3). 1H NMR (270 MHz, CDCl3): δ ϭ 0.12 [s, 9 H, Si(CH3)3],
0.96Ϫ0.94 [d, 3J(H3cЈ,H3b) ϭ 3.5 Hz, 3 H, 3cЈ-H], 0.98Ϫ0.96 [d,
3J(H3c,H3b) ϭ 3.5 Hz, 3 H, 3c-H], 1.08 (s, 3 H, 5-CH3), 2.00Ϫ1.50
16.10 [qd, 3J(13C,31P)
ϭ 6 Hz, POCH2ϪCH3], 16.24 [qd,
3J(13C,31P) ϭ 6 Hz, POCH2ϪCH3], 22.0 (t, C-8), 25.5 (q, 5-CH3),
26.3 (t, C-7), 37.3 [dt, 2J(13C,31P) ϭ 3.5 Hz, C-4], 39.0 [dd,
1J(13C,31P) ϭ 139 Hz, C-3], 46.5 (t, C-9), 61.5 [dt, 2J(13C,31P) ϭ
6 Hz, PO-CH2], 63.1 [dt, 2J(13C,31P) ϭ 7 Hz, PO-CH2], 66.9 (d, C-
6), 70.5 [d, 3J(13C,31P) ϭ 9.5 Hz, C-5], 163.9 [d, 2J(13C,31P) ϭ
4.5 Hz, C-1] ppm. IR (CHCl3): ν˜ ϭ 2980 (s), 2953 (s), 2909 (m),
2881 (m), 1633 (s, CϭO), 1460 (s), 1393 (m), 1378 /m), 1364 (m),
1340 (w), 1319 (w), 1295 (m), 1253 (s, CϪO), 1217 (s, CϪO), 1151
(m), 1130 (m), 1050 (s), 1028 (s), 979 (s), 969 (s) cmϪ1. MS (80 eV,
EI, 50 °C): m/z (%) ϭ 377 (22) [Mϩ·], 362 (10) [Mϩ Ϫ CH3], 288
(38), 286 (22), 241 (15), 240 (9), 219 (6), 198 (7), 170 (8), 153 (20),
150 (33), 126 (79), 109 (22), 98 (88), 80 (100), 75 (20), 73 (32), 70
(34). HRMS (80 eV, 40 °C): calcd. 377.17874 (for C16H32N1O5PSi
[Mϩ]), found 377.17682.
2
(m, 4 H, 7o-,7u-,8o-,8u-H), 2.40Ϫ2.34 [d, J(H4o,H4u) ϭ 14.5 Hz,
1 H, 4o-H], 2.70Ϫ2.65 [dd, 2J(H4u,H4o) ϭ 14, 3J(H4u,H3a) ϭ 2 Hz,
1 H, 4u-H], 3.55Ϫ3.43 (m, 3 H, 9o-,9u-,6u-H), 3.95Ϫ3.83 (m, 1 H,
3b-H), 5.57Ϫ5.53 [dd, 3J(H3a,H3b) ϭ 9.5, 3J(H3a,H4o) ϭ 2 Hz, 1
H, 3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 2.6 [q,
Si(CH3)3], 20.3 (q, 5-Me), 22.3 (t, C-8), 22.8 (q, C-3cЈ), 22.9 (q, C-
3c), 27.1 (d, C-3b), 27.2 (t, C-7), 45.6 (t, C-4), 49.3 (t, C-9), 67.4
(d, C-6), 72.7 (s, C-5), 124.3 (s, C-3), 150.5 (d, C-3a), 163.6 (s) ppm.
IR (CHCl3): ν˜ ϭ 3019 (s), 2968 (w), 2863 (w), 1651 (w), 1602 (w),
1522 (w), 1429 (w), 1223 (s), 1210 (s), 1158 (w), 1125 (w), 1017 /
w), 929 (w), 844 (w) cmϪ1. MS (80 eV, EI, 50 °C): m/z (%) ϭ 295
(100) [Mϩ·], 280 (14) [Mϩ Ϫ CH3], 252 (40) [Mϩ Ϫ C3H7], 224
(15), 223 (14), 183 (20), 155 (9), 143 (7), 142 (6), 96 (9), 81 (13), 75
(17), 73 (54), 70 (27). HRMS (80 eV, 90 °C): calcd. 295.19676 (for
C16H29N1O2Si [Mϩ]), found 295.19488.
(5S,6S)-3-Diethoxyphosphonyl-5-hydroxy-5-methylazabicyclo[4.3.0]-
nonan-2-one (24) and (3Z)-(5S,6S)-5-Hydroxy-3-isobutylidene-5-
methylazabicyclo[4.3.0]nonan-2-one (Z)-26a: The amido phosphon-
ate 22 (433.0 mg, 1.15 mmol) in HCl/MeOH (10 mL, 1 ) was
stirred at room temp. for 1 h. The solvent was then removed under
reduced pressure. The residue was dissolved in CH2Cl2 and passed
through a short pad of silica gel, eluting with MeOH/EtOAc (1:3).
The solvent was removed to give hydroxy phosphonate 24 (351 mg,
1.15 mmol, 100%) as a clear oil. In small-scale experiments, the
crude hydroxy phosphonate 24 was dried by stirring in THF in the
(3Z)-(5R,6S)-3-Isobutylidene-5-methylazabicyclo[4.3.0]nonan-5-ol
(20) (5-epi-pumiliotoxin 209 F): Reaction of indolizidinone (Z)-19a
(342 mg, 1.15 mmol) and LiAlH4/AlCl3 (7.5:2.5 equiv.) by follow-
˚
presence of molecular sieves (4 A). The resulting material was used
3322
Eur. J. Org. Chem. 2002, 3315Ϫ3325

Total Synthesis of (ϩ)-Pumiliotoxin 251D
FULL PAPER
without any further purification. 1H NMR (270 MHz, CDCl3, mix-
26b, retention time 3.3 min, 14.2 mg (0.05 mmol, 4.7%) of (E)-26b,
ture of two C3 diastereomers, ratio: 1:3, marked with CЈ and C): retention time 4.5 min; 16.2 mg (0.6 mmol, 5.3%) of (E)-27b, reten-
δ ϭ 1.30Ϫ1.40 (m, 9 H, 5-CH3 and POCH2ϪCH3), 1.60Ϫ2.40 (m,
6 H, 4-,7-,8-H), 3.05 and 3.40 (m, 2 ϫ 3-H), 3.40Ϫ3.60 (m, 3 H,
9o-,9u-,6-H), 4.00Ϫ4.40 (m, 4 H, PO-CH2) ppm. 13C NMR
(67.9 MHz, CDCl3): δ ϭ 16.1, 16.2, 16.3, and 16.4 (q, 2 ϫ
POCH2ϪCH3 and 2 ϫ POCH2ЈϪCH3Ј), 21.8 (t, C-8Ј), 22.2 (t, C-
8), 25.6 (q, 5-CH3), 26.1 (t, C-7), 26.2 (q, 5-CH3Ј), 26.3 (t, C-7Ј),
tion time 5.8 min.
Data for (Z)-Alkylideneindolizidinone (Z)-26b: [α]2D0 ϭ Ϫ67.6 (c ϭ
1.64, CHCl3). M.p. 135Ϫ140 °C. 1H NMR (270 MHz, CDCl3): δ ϭ
0.89Ϫ0.80 [t, 3J(H3g,H3f) ϭ 6.5 Hz, 3 H, 3g-H], 0.98Ϫ0.93 [d,
3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 1.36Ϫ1.18 (m, 6 H, 3d-,3e-,3f-
H), 2.04Ϫ1.65 (m,
2J(H4o,H4u) ϭ 15 Hz, 1 H, 4o-H], 2.73Ϫ2.63 [dd, 2J(H4u,H4o) ϭ
14.5, 3J(H4u,H3a)
2 Hz, H, 4u-H], 3.47Ϫ3.40 [dd,
4 H, 7o-,7u-,8o-,8u-H), 2.47Ϫ2.38 [d,
2
2
36.3 [dt, J(13C,31P) ϭ 3.5 Hz, C-4Ј], 36.6 [dt, J(13C,31P) ϭ 3 Hz,
C-4], 38.3 [dd, 1J(13C,31P) ϭ 137.5 Hz, C-3], 39.3 [dd, 1J(13C,31P) ϭ
ϭ
1
2
135.5 Hz, C-3Ј], 46.5 (t, C-9Ј), 47.7 (t, C-9), 62.2 [dt, J(13C,31P) ϭ
3J(H6u,H7o) ϭ 9.5, 3J(H6u,H7u) ϭ 5.5 Hz, 1 H, 6u-H], 3.58Ϫ3.51
[dd, 2J(H9o,9u,H9) ϭ 8.5, 3J(H9o,9u,H8) ϭ 5 Hz, 2 H, 9o-,9u-H],
3.87Ϫ3.72 (m, 1 H, 3b-H), 5.64Ϫ5.60 [dd, 3J(H3a,H3b) ϭ 10,
4J(H3a,H4) ϭ 2 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 14.08 (q, C-3 g), 20.8 (q, C-3c), 22.1 (t, C-8), 22.9 (t,
C-3e), 25.2 (q, 5-CH3), 26.1 (t, C-7), 29.6 (t, C-3d), 32.5 (d, C-3b),
37.2 (t, C-3c), 45.5 (t, C-4), 47.0 (t, C-9), 66.5 (d, C-6), 67.7 (s, C-
5), 122.8 (s, C-3), 152.4 (d, C-3a), 163.7 (s, CϭO) ppm. IR (CHCl3):
ν˜ ϭ 3019 (s), 1650 (w), 1600 (w), 1522 (w), 1472 (w), 1425 (w),
1215 (s), 1031 (w), 929 (w) cmϪ1. MS (80 eV, EI, 50 °C): m/z (%) ϭ
265 (73) [Mϩ·], 250 (3) [Mϩ Ϫ CH3], 236 (10) [Mϩ Ϫ C2H5], 222
(100) [Mϩ Ϫ C3H7], 208 (6) [Mϩ -C4H9], 180 (8), 169 (27), 153
(19), 126 (72), 109 (15), 108 (15), 98 (66), 80 (61), 70 (24). HRMS
(80 eV, 50 °C): calcd. 265.204179 (for C16H27N1O2 [Mϩ]), found
265.20523.
7 Hz, POCH2Ј], 63.9 [dt, 2J(13C,31P) ϭ 7 Hz, POCH2], 63.7 [dt,
2J(13C,31P)
ϭ ϭ 6 Hz,
7 Hz, POCH2], 64.8 [dt, 2J(13C,31P)
POCH2Ј], 66.8 (d, C-6), 67.0 (d, C-6Ј), 67.3 [dd, 3J(13C,31P) ϭ
8.5 Hz, C5 and C-5Ј], 166.3 (s, CϭO). MS (80 eV, EI, 120 °C): m/z
(%) ϭ 305 (14) [Mϩ·], 288 (6) [Mϩ Ϫ OH], 265 (5), 260 (19), 234
(5), 222 (6), 208 (5), 195 (5), 168 (5), 155 (12), 151 (100), 136 (18),
127 (8), 111 (16), 99 (13), 96 (9), 83 (24), 70 (47). HRMS (80 eV, 120
°C): calcd. 305.139212 (for C13H24N1O5P [Mϩ]), found 305.13687.
Indolizidinone (Z)-26a: Under argon, LDA (136 µL, 0.27 mmol, 2.5
equiv., 2  in THF) was diluted with dry THF (2 mL) and cooled
to Ϫ78 °C. Hydroxy phosphonate 24 (32.5 mg, 0.11 mmol) in dry
THF (2 mL) was added over a period of 5 min. The mixture was
stirred at Ϫ78 °C for 30 min, isobutyraldehyde 1a (40 µL,
0.4 mmol, 4 equiv.) was then added, and stirring was continued for
another 2.5 h. The cooling bath was removed and the excess of
LDA was quenched with saturated aqueous NH4Cl (10 mL). The
aqueous layer was extracted with Et2O (3 ϫ 10 mL), the combined
organic layers were dried (Na2SO4), and the solvent was removed
to yield crude indolizidinone (Z)-26a (10 mg, 0.045 mmol, 41%) as
Data for (Z)-Alkylideneindolizidinone (Z)-27b: [α]2D0 ϭ ϩ 55.0 (c ϭ
1.79, CHCl3). M.p. 85 °C. 1H NMR (270 MHz, CDCl3): δ ϭ
0.85Ϫ0.79 [t, 3J(H3g,H3f) ϭ 6.5 Hz, 3 H, 3g-H], 0.95Ϫ0.90 [d,
3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 1.30Ϫ1.15 (m, 6 H, 3d-,3e-,3f-
H), 2.04Ϫ1.65 (m,
4 H, 7o-,7u-,8o-,8u-H), 2.43Ϫ2.38 [d,
1
a colorless oil. The E/Z ratio was about 1:10 by H NMR analysis.
2J(H4o,H4u) ϭ 15 Hz, 1 H, 4o-H], 2.65Ϫ2.60 [d, 2J(H4u,H4o) ϭ
[α]2D0 ϭ Ϫ68.7 (c ϭ 0.91, CHCl3). 1H NMR (270 MHz, CDCl3):
δ ϭ 1.00Ϫ0.95 (m, 6 H, 3c-,3cЈ-H), 1.24 (s, 3 H, 5-CH3), 2.0Ϫ1.70
14.5 Hz,
1 ) ϭ 9.5,
H, 4u-H], 3.43Ϫ3.35 [dd, 3J(H6u,H7o
3J(H6u,H7u) ϭ 5.5 Hz, 1 H, 6u-H], 3.53Ϫ3.45 (m, 2 H, 9o-,9u-H),
2
(m, 4 H, 8o-,8u-,7o-,7u-H), 2.42Ϫ2.37 [d, J(H4o,H4u) ϭ 14.5 Hz,
3.80Ϫ3.65 (m, 1 H, 3b-H), 5.60Ϫ5.54 [d, J(H3a,H3b) ϭ 10 Hz, 1
3
1 H, 4o-H], 2.65Ϫ2.60 [dd, 2J(H4u,H4o) ϭ 14.5, 4J(H4u,H3a) ϭ
H, 3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 13.9 (q, C-3 g),
20.4 (q, C-3c), 22.0 (t, C-8), 22.8 (t, C-3e), 25.1 (q, 5-CH3), 26.0 (t,
C-7), 29.6 (t, C-3d), 32.5 (d, C-3b), 37.2 (t, C-3c), 45.4 (t, C-4),
47.0 (t, C-9), 66.5 (d, C-6), 67.5 (s, C-5), 123.0 (s, C-3), 151.9 (d,
C-3a), 163.7 (s, CϭO) ppm. IR (CHCl3): ν˜ ϭ 3019 (s), 2977 (m),
2929 (m), 1653 (m), 1604 (m), 1523 (w), 1450 (m), 1437 (m), 1426
(m), 1294 (m), 1265 (s), 1215 (s), 1046 (m), 929 (w) cmϪ1. MS
(80 eV, EI, 50 °C): m/z (%) ϭ 265 (59) [Mϩ·], 250 (3) [Mϩ Ϫ CH3],
2.5 Hz,
1 ) ϭ 9.5,
H, 4u-H], 3.43Ϫ3.37 [dd, 3J(H6u,H7o
3J(H6u,H7u) ϭ 5.5 Hz, 1 H, 6u-H], 3.55Ϫ3.45 (m, 2 H, 9o-,9u-H),
3.92Ϫ3.80 (m, 1 H, 3b-H), 5.65Ϫ5.60 [dd, 3J(H3a,H3b) ϭ 9.5,
4J(H3a,H4u) ϭ 2 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 22.1 (t, C-8), 22.7 (q, C-3cЈ), 22.9 (q, C-3c), 25.2 (q,
5-CH3), 26.1 (t, C-7), 27.5 (d, C-3b), 45.5 (t, C-4), 46.9 (t, C-9),
66.5 (d, C-6), 67.7 (s, C-5), 122.3 (s, C-3), 152.8 (d, C-3a), 163.7 (s)
ppm. IR (CHCl3): ν˜ ϭ 2977 (m), 2932 (w), 2899 (w), 2866 (w),
1729 (w), 1653 (m), 1604 (m), 1468 (m), 1451 (m), 1437 (m), 1381
(m), 1295 (w), 1252 (w), 1099 (w), 919 (s), 899 (s), 751 (s), 718 (s),
236 (7) [Mϩ Ϫ C2H5], 222 (100) [Mϩ Ϫ C3H7], 208 (6) [Mϩ
Ϫ
C4H9], 180 (4), 169 (29), 81 (7), 70 (22). HRMS (80 eV, 50 °C):
calcd. 265.204179 (for C16H27N1O2 [Mϩ]), found 265.20733.
651 (s) cmϪ1
.
Data for (E)-Alkylideneindolizidinone (E)-26b: [α]2D0 ϭ Ϫ65.1 (c ϭ
1.40, CHCl3). M.p. 150Ϫ153 °C. 1H NMR (270 MHz, CDCl3): δ ϭ
0.88Ϫ0.80 [t, 3J(H3g,H3f) ϭ 6.5 Hz, 3 H, 3g-H], 0.98Ϫ0.92 [d,
(3Z)-(5S,6S)-5-Hydroxy-3-[(R)-2-methylhexylidene]-5-methylazabi-
cyclo[4.3.0]nonan-2-one (Z)-26b, (3Z)-(5S,6S)-5-Hydroxy-3-[(S)-2-
methylhexylidene]-5-methylazabicyclo[4.3.0]nonan-2-one
(Z)-27b, 3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 1.40Ϫ1.20 (m, 6 H, 3d-,3e-,3f-
(3E)-(5S,6S)-5-Hydroxy-3-[(R)-2-methylhexylidene]-5-methylazabi-
cyclo[4.3.0]nonan-2-one (E)-26b, and (3E)-(5S,6S)-5-Hydroxy-3-
[(S)-2-methylhexylidene]-5-methylazabicyclo[4.3.0]nonan-2-one (E)-
27b: Reaction of hydroxy phosphonate 24 (351 mg, 1.15 mmol) by
following the procedure as described for indolizidinone (Z)-26a,
H), 2.04Ϫ1.70 (m, 4 H, 7o-,7u-,8o-,8u-H), 2.48Ϫ2.30 (m, 1 H, 3b-
H), 2.43Ϫ2.38 [d, 2J(H4u,H4u) ϭ 16, 4J(H4u,H3a) ϭ 2.5 Hz, 1 H,
2
4u-H], 2.78Ϫ2.70 [d, J(H4o,H4o) ϭ 16 Hz, 1 H, 4o-H], 3.63Ϫ3.40
(m,
3 ) ϭ 10,
H, 9o-,9u-,6u-H), 6.81Ϫ6.73 [dd, 3J(H3a,H3b
4J(H3a,H4u) ϭ 2 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz,
with LDA (1.15 mL, 2.3 mmol, 2.1 equiv., 2  in THF) in dry THF CDCl3): δ ϭ 14.0 (q, C-3g), 19.7 (q, C-3c), 22.2 (t, C-8), 22.8 (t,
(15 mL) and (R)-2-methylhexanal 1b (648 µL, 4.5 mmol, 4 equiv.).
After addition of the aldehyde: stirring for 4 h at Ϫ78 °C. Purifica-
C-3e), 25.3 (q, 5-CH3), 26.4 (t, C-7), 29.6 (t, C-3d), 32.7 (d, C-3b),
36.5 (t, C-3c), 39.5 (t, C-4), 46.1 (t, C-9), 65.7 (d, C-6), 67.7 (s, C-
tion by column chromatography on silica gel (MeOH/EtOAc 1:9, 5), 124.3 (s, C-3), 147.3 (d, C-3a), 163.7 (s, CϭO) ppm. IR (CHCl3):
Rf ϭ 0.45). Separation of the diastereomers by preparative HPLC
(10% iPrOH in n-hexane, 32 ϫ 110 mm, Nucleosil 50Ϫ5, UV
ν˜ ϭ 3019 (s), 2976 (m), 2895 (w), 1601 (w), 1521 (w), 1476 (w),
1420 (w), 1215 (s), 1046 (m), 929 (w) cmϪ1. MS (80 eV, EI, 80 °C):
254 nm, flow 64 mL/min. Yields: 56.3 mg (0.21 mmol, 18.4%) of m/z (%) ϭ 265 (53) [Mϩ·], 236 (7) [Mϩ Ϫ C2H5], 222 (100) [Mϩ
Ϫ
(Z)-27b, retention time 2.7 min, 97.9 mg (0.37 mmol, 32.1%) of (Z)-
C3H7], 208 (6) [Mϩ Ϫ C4H9], 194 (5), 180 (20), 169 (17), 138 (15),
Eur. J. Org. Chem. 2002, 3315Ϫ3325
3323

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
126 (8), 92 (13), 86 (23), 70 (88). HRMS (80 eV, 80 °C): calcd.
1.05Ϫ1.01 [d, 3J(H3c,H3b) ϭ 5.5 Hz, 3 H, 3c-H], 1.28 (s, 3 H, 5-
CH3), 1.40Ϫ1.20 (m, 6 H, 3d-,3e-,3f-H), 2.20Ϫ1.95 (m, 6 H, 6u-
,9u-,7o-,7u-,8o-,8u-H), 2.50Ϫ2.30 (m, 2 H, 4o-,4u-H), 3.20Ϫ3.05
(m, 1 H, 3b-H), 3.34 (s, 1 H, NH), 3.45Ϫ3.39 [d, 2J(H2u,H2o) ϭ
11 Hz, 1 H, 2u-H], 3.64Ϫ3.52 (m, 1 H, 9o-H), 4.42Ϫ4.33 [d,
2J(H2o,H2u) ϭ 13 Hz, 1 H, 2o-H], 5.35Ϫ5.28 [d, 3J(H3a,H3b) ϭ
9.5 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz, CD3OD): δ ϭ 14.7
(q, C-3 g), 20.8 (t, C-3f), 21.7 (q, C-3c), 23.0 (t, C-3e), 24.1 (t, C-
3d), 26.3 (q, 5-CH3), 31.0 (t, C-8), 33.7 (d, C-3b), 38.6 (t, C-7), 47.7
(t, C-4), 52.6 (t, C-9), 54.3 (t, C-2), 68.9 (s, C-5), 74.1 (d, C-6),
125.7 (s, C-3), 140.9 (d, 3a). For further data see ref. 3, 7 and 8.
265.204179 (for C16H27N1O2 [Mϩ]), found 265.20654.
Data for (E)-Alkylideneindolizidinone (E)-27b: [α]2D0 ϭ ϩ38.1 (c ϭ
1.63, CHCl3). M.p. 105Ϫ110 °C. 1H NMR (270 MHz, CDCl3): δ ϭ
0.88Ϫ0.80 [t, 3J(H3g,H3f) ϭ 6.5 Hz, 3 H, 3g-H], 1.01Ϫ0.97 [d,
3J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-H], 1.40Ϫ1.10 (m, 6 H, 3d-,3e-,3f-
H), 2.05Ϫ1.75 (m, 4 H, 7o-,7u-,8o-,8u-H), 2.43Ϫ2.28 (m, 1 H, 3b-
2
4
H), 2.39Ϫ2.30 [d, J(H4u,H4u) ϭ 16, J(H4u,H3a) ϭ 2 Hz, 1 H, 4u-
2
H], 2.79Ϫ2.70 [d, J(H4o,H4o) ϭ 16 Hz, 1 H, 4o-H], 3.62Ϫ3.42 (m,
3
H, 9o-,9u-,6u-H), 6.80Ϫ6.70 [ddd, 3J(H3a,H3b
)
ϭ
10,
4J(H3a,H4u) ϭ 3, 4J(H3a,H4) ϭ 1.5 Hz, 1 H, 3a-H] ppm. 13C NMR
(67.9 MHz, CDCl3): δ ϭ 14.0 (q, C-3g), 20.3 (q, C-3c), 22.2 (t, C-
8), 22.7 (t, C-3e), 25.3 (q, 5-CH3), 26.4 (t, C-7), 29.7 (t, C-3d), 32.8
(d, C-3b), 36.5 (t, C-3c), 39.7 (t, C-4), 46.2 (t, C-9), 65.7 (d, C-6),
67.7 (s, C-5), 124.3 (s, C-3), 147.3 (d, C-3a), 163.8 (s, CϭO) ppm.
IR (CHCl3): ν˜ ϭ 3390 (w), 3019 (s), 2976 (m), 2930 (m), 1658 (m),
1600 (m), 1522 (w), 1450 (m), 1439 (m), 1386 (w), 1296 (w), 1215
(s), 1046 (m), 929 (w) cmϪ1. MS (80 eV, EI, 115 °C): m/z (%) ϭ
265 (35) [Mϩ·], 222 (100) [Mϩ Ϫ C3H7], 208 (4) [Mϩ Ϫ C4H9], 180
(20), 152 (3), 70 (30). HRMS (80 eV, 100 °C): calcd. 265.204179
(for C16H27N1O2 [Mϩ]), found 265.20822.
Crystal Data of Pumiliotoxin 251 D Hydrochloride (29): Crystal
data for pumiliotoxin 251 D hydrochloride (29:) colorless, transpar-
ent needles from ethyl acetate/n-hexane at room temperature.
C16H30ClNO (Mr ϭ 287.86); crystal dimensions 1.50 ϫ 0.06 ϫ
0.05 mm; monoclinic; P21, a ϭ 10.2863(16), b ϭ 6.9189(13), c ϭ
3
11.959(2) A, Z ϭ 2, V ϭ 842.9(3) A , ρcalcd. ϭ 1.134 g/cmϪ3, T ϭ
146 K, 2Θ max ϭ 62°; of the 11,029 reflections measured, were
4707 independent reflections (Rint ϭ 0.0880, ωR ϭ 0.1092, and S ϭ
0.973); SiemensϪSMART diffractometer, Mo-Kα radiation (λ ϭ
˚
˚
˚
0.71073 A). The structure was determined by direct methods with
the program SHELXS. The H atoms were taken from a difference
Fourier synthesis and were refined with isotropic thermal para-
meters. The non-H atoms were refined with anisotropic thermal
parameters. The structure was refined on F values with the
weighting scheme: w(F) ϭ 4·F2/[σ2(F2) ϩ (0.03·F2)2]. The final dif-
ference density was between Ϫ0.278 and ϩ0.386 e/A3.
CCDC-172939 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
(3Z)-(5S,6S)-3-[(R)-2-Methylhexylidene]-5-hydroxy-5-methylazabi-
cyclo[4.3.0]nonane (28) ؊ Pumiliotoxin 251 D ؊ and (3Z)-(5S,6S)-
5-Hydroxy-3-[(R)-2-methylhexylidene]-5-methylazabicyclo[4.3.0]-
nonane Hydrochloride (29). Pumiliotoxin 251 D ·HCl: Reaction of
indolizidinone (Z)-26b (36.6 mg, 0.14 mmol) and LiAlH4/AlCl3
(7.5:2.5 equiv.) by following the procedure as described for indolizi-
dine 15. Purification by column chromatography on silica gel
(MeOH/EtOAc 1:9, TLC: MeOH/EtOAc, 1:3 Rf ϭ 0.05Ϫ0.15).
Purification by preparative HPLC with 10% iPrOH in hexane (4 ϫ
250 mm, Nucleosil 50Ϫ5, UV ϭ 210 nm, flow 2 mL/min).[30] Yield:
19.7 mg (0.08 mmol, 56.8%) of 26.
CB2 1EZ, UK; Fax: (internat.)
deposit@ccdc.cam.ac.uk].
ϩ 44-1223/336-033; E-mail:
(؉)-Pumiliotoxin 251 D Hydrochloride (29): The pumiliotoxin 251
D 28 (19.7 mg, 0.08 mmol) was dissolved in HCl/MeOH (4 mL, 1
). The solvent was removed to give the pure hydrochloride 29
(21.8 mg, 0.076 mmol, 97%), which was recrystallized (CH2Cl2/
EtOAc) to provide crystals appropriate for X-ray analysis.
Acknowledgments
We thank the DFG, the FCI, and Schering AG for support of
this research.
Data for Pumiliotoxin 251 D (28): [α]2D0 ϭ Ϫ8.5 (c ϭ 1.03, CHCl3).
1H NMR (270 MHz, CDCl3): δ ϭ 0.87Ϫ0.80 [t, 3J(H3g,H3f) ϭ
[1]
[1a] Review on total synthesis of pumiliotoxins: L. E. Overman,
A. S. Franklin, Chem. Rev. 1996, 96, 505Ϫ522. [1b] Further ref.:
B. M. Trost, T. S. Scanlan, J. Am. Chem. Soc. 1989, 111,
4988Ϫ4990.
3
6.5 Hz, 3 H, 3g-H], 0.96Ϫ0.93 [d, J(H3c,H3b) ϭ 6.5 Hz, 3 H, 3c-
H], 1.11 (s, 3 H, 5-CH3), 1.30Ϫ1.10 (m, 6 H, 3d-,3e-,3f-H),
1.78Ϫ1.60 (m, 4 H, 7o-,7u-,8o-,8u-H), 1.99Ϫ1.92 (m, 1 H, 6u-H),
2.12Ϫ2.08 (s, 2 H, 4o-,4u-H), 2.25Ϫ2.15 (m, 1 H, 9u-H), 2.35Ϫ2.29
[d, 2J(H2u,H9o) ϭ 12 Hz, 1 H, 2u-H], 2.43Ϫ2.40 (m, 1 H, 3b-H),
2.65 (s, 1 H, OH), 3.07Ϫ3.00 (m, 1 H, 9o-H), 3.78Ϫ3.73 [d,
2J(H2o,H2u) ϭ 12 Hz, 1 H, 2o-H], 5.04Ϫ4.97 [d, 3J(H3a,H3b) ϭ
9.5 Hz, 1 H, 3a-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 14.1
(q, C-3 g), 21.0 (t, C-3f), 21.6 (q, C-3c), 22.8 (t, C-3e), 23.2 (t, C-
3d), 24.2 (q, 5-CH3), 29.9 (t, C-8), 32.0 (d, C-3b), 37.4 (t, C-7), 48.8
(t, C-4), 53.2 (t, C-9), 54.5 (t, C-2), 68.3 (s, C-5), 71.7 (d, C-6),
129.8 (s, C-3), 134.6 (d, C-3a) ppm. IR (CHCl3): ν˜ ϭ 2959 (m),
2929 (m), 2871 (w), 2857 (w), 2792 (w), 1794 (w), 1466 (m), 1382
(m), 1310 (w) cmϪ1. MS (80 eV, EI, 30 °C): m/z (%) ϭ 251 (26)
[Mϩ·], 236 (5) [Mϩ Ϫ CH3], 208 (17) [Mϩ Ϫ C3H7], 206 (12), 194
(20) [Mϩ Ϫ C4H9], 176 (5), 166 (100), 148 (7), 137 (9), 123 (9), 112
(12), 84 (18), 70 (76). HRMS (80 eV, 30 °C): calcd. 251.224915 (for
C16H29N1O1 [Mϩ]), found 251.22622.
[2]
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MeOH; ϩ28.0, c ϭ 0.62, MeOH, ref.[8b]). M.p. 203Ϫ205 °C
(205Ϫ206 °C ref.[8b]; 200Ϫ201 °C ref.[7a]). 1H NMR (270 MHz,
CD3OD): δ ϭ 0.91Ϫ0.84 [t, 3J(H3g,H3f) ϭ 6.5 Hz, 3 H, 3g-H],
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3324
Eur. J. Org. Chem. 2002, 3315Ϫ3325

Total Synthesis of (ϩ)-Pumiliotoxin 251D
FULL PAPER
paration procedures and spectroscopic data see supporting in-
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[12a]
An X-ray analysis was obtained for pumiliotoxin 251 D-HCl
29. For detailed data see Exp. Sect. and information deposited
with the Cambridge Data Centre. X-ray data for 29 (CCDC-
172939): colorless, transparent prism crystallized from EtOAc/
n-hexane at room temp.. C16H30ClNO (Mr ϭ 287.86); crystal
dimensions 1.50 ϫ 0.06 ϫ 0.05 mm3; monoclinic; P21 (Figure
2).
K. Ando, J. Org. Chem. 1999, 64, 6815Ϫ6821.
The peak assignment was difficult because of the coexistence
of two C-3 diastereomers (presumably fast equilibration). Peak
assignment based on 13C-1H-HMQC, 31P-1H-HMQC, and
H,H-COSY spectra.
The quality of the LiAlH4 was crucial for a successful reduc-
tion, because the exact molar ratio of LiAlH4: AlCl3 (3:1) must
be maintained. If, after the addition of AlCl3, no grainy sus-
pension but a sticky precipitate was formed (no stirring pos-
sible), the reduction failed.
The HPLC behavior of PTX 251 D 28 strongly depends on the
injected concentration, the product was purified considering
its tendency of a decreasing retention time when the column
was overloaded.
for stereoselective Z Horner olefinations see:
W. C. Still,
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.
[16] ]
For preparation procedures and spectroscopic data see sup-
porting information.
[17]
The reaction of the hexanal and the core indolizidinone yielded
a small amount of a third diastereomer, but the configuration
of the new stereogenic centers were not established. For pre-
Received March 27, 2002
[O02180]
Eur. J. Org. Chem. 2002, 3315Ϫ3325
3325