Synthesis of the bicyclic core of pumiliotoxins

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3304::AID-EJOC3304>3.0.CO;2-A

The bicyclic core of the pumiliotoxins was synthesized in nine to eleven steps starting from L-(-)-proline. This chiral pool starting material was initially converted into an optically active 2-vinylpyrrolidine by standard operations. The first key step allowed the generation of a nine-membered ring lactam by means of a zwitterionic aza-Claisen rearrangement. The 1,4 chirality transfer was found to be low, but the double bond of the azoninone was generated with an exclusive trans configuration in a planar-S arrangement. The mixture of diastereomers thus obtained was immediately epoxidized; the planar chiral information could be completely used to build up new stereogenic centers. Subsequent ring closure under hydrogenolytic conditions resulted in the formation of the bicyclic core with a bridgehead of defined configuration. The hydroxyl group of that material could be protected as a TBS ether, or alternatively a sequence of a Swern oxidation and subsequent methyl Grignard addition gave the complete bicyclic framework with low C8 diastereoselectivity. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:19<3304::AID-EJOC3304>3.0.CO;2-A

FULL PAPER
Synthesis of the Bicyclic Core of Pumiliotoxins[‡]
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: Medium rings / Ring contractions / Ring expansion / Sigmatropic rearrangements / Zwitterions
The bicyclic core of the pumiliotoxins was synthesized in
nine to eleven steps starting from -(−)-proline. This chiral
pool starting material was initially converted into an optically
ized; the planar chiral information could be completely used
to build up new stereogenic centers. Subsequent ring closure
under hydrogenolytic conditions resulted in the formation of
the bicyclic core with a bridgehead of defined configuration.
L
active 2-vinylpyrrolidine by standard operations. The first
key step allowed the generation of a nine-membered ring The hydroxyl group of that material could be protected as a
lactam by means of a zwitterionic aza-Claisen rearrange- TBS ether, or alternatively a sequence of a Swern oxidation
ment. The 1,4 chirality transfer was found to be low, but the
double bond of the azoninone was generated with an exclus-
and subsequent methyl Grignard addition gave the complete
bicyclic framework with low C8 diastereoselectivity.
ive trans configuration in a planar-S arrangement. The mix- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
ture of diastereomers thus obtained was immediately epoxid-
2002)
Introduction
termediate in several allopumiliotoxin syntheses (R ϭ nBu:
allopumiliotoxin 267 A, Figure 1).[2]
A number of total syntheses of pumiliotoxins have been
developed since the isolation, the structure determination,
and first investigations of some interesting biologically
properties by Daly opened the goal to this class of alkal-
oids.[1] Since the natural source of these alkaloids is limited,
synthetic approaches have to provide sufficient material for
extensive tests. Convergent syntheses seem to be the method
of choice, because slight modifications of a sequence can
potentially allow a variety of important target molecules to
be produced.
Analysis of the structure of the pumiliotoxins shows most
compounds characterized by the bicyclic indolizidine sys-
tem, with some stereogenic centers and an exocyclic trisub-
stituted double bond of defined configuration. A retrosyn-
thetic cut through the double bond splits the skeleton into
a side chain (aldehyde) and a bicyclic 5- and 7-indolizidi-
none core. The 7-indolizidinone unit has served as key in-
Figure 1. Retrosynthetic analyses of the pumiliotoxins
For the synthesis of pumiliotoxin 251 D (R ϭ nBu),
several preparations of optically pure 5-indolizidinone pre-
cursors have been described in the literature (Figure 2). The
shortest sequences have been published by Barrett[3] and by
Ding,[4] by addition of C3 building blocks to the pyrrrolidi-
nyl ketone derived in four to six steps from -proline. While
Barrett introduced a titanium homoenolate, Ding suc-
ceeded in adding 3-metalated esters of propiolic acid. The
synthesis of the bicyclic core was always completed by two
further steps (seven to nine steps overall). However, both
sequences solely allow the synthesis of the natural series.
Martin started from -pyroglutamate.[5] The key step in
building up the target was described as a vinylogous Man-
nich reaction between the furan unit and the 2-methoxypyr-
rolidine in the presence of a Lewis acid. Finally, the stereo-
directing hydroxymethyl group of the five-membered ring
was removed by Raney Ni-mediated reduction. The bicyclic
[‡]
Total Synthesis of (ϩ)-Pumiliotoxin 251 D, 1.
[a]
Institut für Chemie Ϫ Organische Chemie, Freie Universität
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.
3304
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3304 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3304Ϫ3314

Synthesis of the Bicyclic Core of Pumiliotoxins
FULL PAPER
Figure 2. Retrosynthetic analyses of the pumiliotoxin bicyclic core
core (natural series) was generated in nine steps overall.
Gallagher[6] described a reasonably flexible route to syn-
thesize the 5-indolizidinone. The pyrrolidine ring was
formed by
a
Pd-mediated intramolecular amino
metallation, followed by CO insertion and methanolysis.
The enantiomers were separated with the aid of a chiral
phenylethylamine substituent. After generation of the allyl
alcohol, the missing C2 unit was introduced by means of a
Johnson orthoester rearrangement and, after lactam forma-
tion, the C8 OH group was added by a stereoselective oxy-
mercuration. Overall, nine steps were used to generate the
bicyclic core, and both enantiomers could be obtained
(quasi-resolution during the first cyclization).
With the intention to develop a new flexible synthesis of
the pumiliotoxin core, our retrosynthesis involved removal
of the methyl group, resulting in an indolizidinone I. Such
bicycles can be generated from nine-membered ring lactams
II by a stereoselective transannular ring closure,[7] while the
planar chiral properties of the azoninones II should allow
the generation, from the same optically active material,
both of the natural series I and of the unnatural series ent-
I. Unsaturated nine-membered ring lactams II have been
easily generated from vinylpyrrolidines III and carboxylic
acid fluorides by means of a zwitterionic aza-Claisen re-
arrangement.[8] The synthesis of the allylamines III ap-
peared achievable by a short ex-chiral pool synthesis start-
ing from commercially available -(Ϫ)-proline (Figure 2).
Scheme 1
the synthesis of the chiral vinylpyrrolidine 2.[13] No chroma-
tographic purification to obtain pure material was required
for any of these steps, and the overall yield was about
40Ϫ50%.[14]
The zwitterionic aza-Claisen rearrangement of the vinyl-
pyrrolidine 2 was regarded as the first crucial step of the
synthesis (Scheme 1). Chloroacetyl fluoride was chosen as
the reagent, in order to provide the best yields. Further-
more, it was anticipated that the resulting 3-chloroazoni-
nones 3 should allow reliable information concerning the
stereochemical outcome of the reaction to be obtained. The
vinylpyrrolidine 2 was thus treated with freshly prepared
chloroacetyl fluoride[15] and Me3Al in the presence of
K2CO3 in CH2Cl2 at 0 °C to give a mixture of two diastere-
omer azoninones Ϫ pS-3a and pS-3b Ϫ in 77% yield and a
ratio of 1.4:1. These could be separated by column chroma-
tography and preparative HPLC. These compounds were
handled carefully, any warming to 30Ϫ40 °C being avoided
in order to maintain the planar chiral properties (pS) of the
diastereomers resulting from the ring expansion.[16] To test
the conformational stability of both compounds, the separ-
ated diastereomers pS-3a and pS-3b were heated to about
60 °C.[17] From pS-3a, a second diastereomer Ϫ pR-3a Ϫ
appeared after 3 to 10 h, indicating flipping of the double
Results and Discussion
With the intention of testing several strategies to generate bond with respect to the ring. All spectroscopic data for the
the bicyclic core we carried out the synthesis of the vinyl- new diastereomer pR-3a were identical to those determined
pyrrolidine 2 on a 50 to 70 g scale (Scheme 1). -(Ϫ)-Proline for lactam pS-3b, except for the specific rotation, corrobor-
was treated with MeOH/HCl, and the resulting ester[9] was ating the formation of the enantiomer.[18] Lactam pS-3b un-
then subjected to N-benzylation with benzyl chloride and derwent the analogous process, generating pR-3b
an excess of Et3N.[10] The ester group was reduced with (enantiomer of pS-3a), but conversion was found to be in-
LiBH4 to give alcohol 1.[11] After a Swern oxidation of 1,[12] complete. The relative arrangement of the double bond and
a final methylene Wittig olefination allowed completion of the stereogenic center of the diastereomers was established
Eur. J. Org. Chem. 2002, 3304Ϫ3314
3305

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
by NOE analyses.[19] While the lactam pS-3b was character- anism involved an intermediate acyl aziridinium salt 5.[25]
ized by a single set of peaks (almost rigid conformation), Initially, the Agϩ removed the 8-iodide to form AgI and
the spectroscopic data for lactam pS-3a indicated the coex- the secondary cation, which might have been stabilized as
1
istence of two conformers (double set of peaks in H and a hypothetical (quasi-symmetric) N-acylaziridinium salt 5
13C spectra) potentially originating from some mobility of by transannular interactions with the lone pair of the lac-
the lactam function.[20]
tam nitrogen. Then, the weakly nucleophilic nitrate at-
The synthesis of the pumiliotoxin core 8 now required a tacked the former 8a-position of the highly reactive cation
transannular ring contraction to generate the indolizidinone to generate the rearranged indolizindinone 6 as a single re-
framework. First tests were conducted by treatment of the gioisomer. The high selectivity of the reaction might have
azoninone pS-3 with I2 in MeCN.[7] Smooth formation of been the consequence of efficient shielding of the original
the iodoindolizidinones 4a and 4b in satisfactory yield (53% C-8 by the eliminated iodide, dissociation of the interme-
from 2, ratio ഠ 1.4:1) was observed. An analytical sample diate ions being slow with respect to the trapping rate of
was separated by HPLC to provide the pure diastereomers the cation by the nucleophilic nitrate. The process seemed
4a and 4b. The relative configurations of all stereogenic cen- to be regio- and stereospecific. Further investigations con-
ters were determined by NOE analyses (Scheme 1).[19]
Substitution of the iodide by a hydroxyl group failed: the
cerning its scope and limitations are in progress.
Recent investigations had shown that planar chiral azoni-
direct SN2 process gave the corresponding elimination prod- nones underwent smooth cycloadditions to the double
ucts as the major compounds. Furthermore, clear differenti- bond, the planar chiral information of the E olefin being
ation between α chloride and γ iodide was tricky, depending completely transferred into the new stereogenic centers of
on the reactant diastereomer 4 (α- or β-Cl). Obviously, the the cycloadduct.[7] The pure diastereomers pS-3a and pS-3b
open book shape of the bicycles 4 bearing the exo iodides lactams were therefore treated with mCPBA/buffer at 5
dictated a disfavored endo attack of any nucleophile, pre- °C.[26] Similarly, the pS-3a/b mixture was used immediately
venting smooth introduction of the oxygen. Thus, an altern- after completion of the workup of the aza-Claisen re-
ative route involving an SNi reaction mechanism was arrangement, to avoid any flipping of the double bond. The
tested.[21] Treatment of iodoindolizidinones 4a/b with silver corresponding epoxides 9a and 9b were isolated in about
nitrate in acetone resulted in smooth substitution of the exo 90Ϫ100% yield. The separation of the diastereomers was
halide by the corresponding exo nitrate to build up 6a/b in
high yield (92%, ratio ഠ 1.4:1).[22] Again, separation of the
diastereomers by HPLC successfully provided pure diaster-
eomers. The deprotection of the OH function of 6a was
achieved by a final hydrogenolytic cleavage to give bicycle
7.[23] Preliminary spectroscopic analyses of 6a and 6b, in-
cluding NOE experiments,[19] gave no safe assignment con-
cerning the generation of the skeletons 7 or 8, respectively,
except for the IR carbonyl peak at about 1710 cmϪ1 (Ǟ
7). Finally, an X-ray analysis of nitrate 6a established the
formation of the indolizidinone bearing a γ-butyrolactam
unit (Figure 3).[24] Clearly, the ring junction had migrated
during the course of the SN1-type substitution of the iodide.
The hypothetical WagnerϪMeerwein-type reaction mech-
Figure 4. ORTEP plots of the epoxides 9a and 9b (the Ph substitu-
ents of the N-Bn groups have been omitted for clarity); for com-
plete structures see supplementary material
Figure 3. ORTEP plot of nitrate 6a
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Eur. J. Org. Chem. 2002, 3304Ϫ3314

Synthesis of the Bicyclic Core of Pumiliotoxins
FULL PAPER
successfully achieved by preparative HPLC, and NOE ana- lyst (Pearlman’s catalyst) in MeOH at 5 °C to room temp.,
lyses validated the relative arrangement of the stereogenic the 3-chloride being removed simultaneously.[29] The re-
centers. Spectra of epoxy-azonanone 9a were characterized sulting complex mixture of hydroxy lactam 14 and some
by a doubled set of peaks originating from some flexibility amino ester 13 was treated with K2CO3 and heated to com-
of the lactam unit: the lactam of the major species could be plete the cyclization. After non-aqueous workup, the hy-
determined as a quasi-Z system (see Figure 4) with respect droxy lactam 14 was isolated in 77% yield (54%, in 3Ϫ4
to the arrangement of amide oxygen and benzyl group at steps, starting from 2, without any extensive chromato-
the partial CϭN double bond, whereas the minor con- graphic purification of intermediates on a 10 g scale), and
former displayed the corresponding E geometry.[19] In con- was immediately converted into the corresponding TBS
trast, the epoxy-azonanone 9b was found to adopt a single ether 15.[30] Indolizidinone 15 was less polar than the react-
conformation.[19] Finally, X-ray analyses of both epoxides ant hydroxyindolizidinone 14, and easily soluble in organic
9a and 9b confirmed the correct assignment of the absolute solvents. Alternatively, the bicyclic core of the pumiliotox-
and the relative configuration of all stereogenic centers ins could be obtained after a three-step sequence consisting
(Scheme 2, Figure 4).[24]
of a Swern oxidation, a methyl Grignard addition, and a
final OH protection as a TMS ether, in about 77% yield.
While a smooth oxidation was achieved, generating the in-
termediate ketone 16, the subsequent methylation was
found to be unselective. Treatment of the ketone 16 with
MeMgBr or MeMgI at Ϫ78 °C or 0 °C resulted predomin-
antly in β-methyl addition (up to 1:2, 17/18), giving the lac-
tam 20 after the final protection of the alcohol function.[31]
In contrast, MeLi addition at Ϫ78 °C gave a 1.8:1 (17/18)
mixture in favor of the desired lactam 19 after the final
silylation step.[32] However, the diastereomers had to be sep-
arated by preparative HPLC.[33] At present, no further ef-
forts to optimize the diastereoselectivity of the process are
being undertaken, because a suitable solution for this prob-
lem has been already published by Gallagher.[6] Replace-
ment of the ketone by an exo-methylene function and se-
quential oxymercuration and reductive workup afforded the
desired β-hydroxy lactam 17 with a 10:1 selectivity and in
60% yield.
Mechanistic Conclusions
Scheme 2
The zwitterionic aza-Claisen rearrangement served as a
The epoxy-azonanones were found to be unstable. Stor- first key step to generate the optically active azoninones.
age in solution at room temp. or treatment with acids or The stereochemical outcome of the reaction could be inter-
bases resulted in rapid conversion into the corresponding preted as follows (Figure 5).[8] Initially, the activated carb-
pyrrolidino lactones 11.[14] Generally, such lactones 11 can oxylic acid fluoride attacked the 2-vinylpyrrolidine 2 anti
be used as intermediates to generate the desired indolizidi- and syn with respect to the adjacent vinyl substituent to
nones 8/10 Ϫ after hydrogenolytic removal of the N-benzyl give two hypothetical diastereomeric zwitterions (ste-
function, a subsequent lactone lactam conversion should reogenic ammonium center, low 1,2-induction) with Z-enol-
provide the desired bicyclic products 8/10 and 14, respect- ate geometry, as known for amide and acylammonium enol-
ively Ϫ but such a strategy requires at least two steps and ates, respectively. The rearrangement of the syn adduct then
suffers from difficulties in reaction monitoring. Conversions proceeded via a boat-like transition state (ts-boat) to give
of 9a/b in the presence of LiCl or LiI and TMSCl afforded the 3β-lactam pS-3a. In contrast, the anti adduct re-
some type 8/10/12 indolizidinones, but the isolated yields arranged through a chair-like transition state (ts-chair), re-
were low.[27] Obviously, the removal of the benzyl group by sulting in the 3α-lactam pS-3b. Since both adducts passed
von Braun-type degradation of an intermediate acyl ammo- through transition state conformations with minimized re-
nium salt was the crucial step.[28] The competing lactoniz- pulsive interactions, the 2S configuration of the reactant
ation (Ǟ 11) was the major reaction path, especially when vinylpyrrolidine 2 initially effected the formation of the me-
handling more than 1 mmol quantities of the epoxides dium-sized ring, with a pS arrangement of the E double
9a/b. Hence, hydrogenolytic cleavage of the N-benzyl group bond (complete chirality transfer Ϫ central-S into planar-
prior to the ring closure promised to be the strategy of S). This planar diastereomer was stable when the material
choice. The best results were obtained by conducting the was kept at room temp. or below. Heating (40Ϫ60 °C) of
hydrogenolysis with H2 in the presence of a Pd(OH)2 cata- pS-3a resulted in a rapid flipping of the double bond with
Eur. J. Org. Chem. 2002, 3304Ϫ3314
3307

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
ring lactams were characterized by defined arrangements of
the olefin unit with respect to the ring, indicating almost
complete chirality transfer from the initially present ste-
reogenic center (in 2) to the planar chiral information of
the medium-sized ring (in 3). In contrast, the 1,4-chirality
transfer on formation of the C3 position in the azoninones
3 was low. The planar chiral information of 3 could be used
to generate new stereogenic centers. A transannular ring
contraction in the presence of iodine, producing the iodoin-
dolizidinone 4a/b, and the epoxidation of the double bond
to 9a/b proceeded with complete chirality transfer from the
stereogenic plane to the new stereogenic centers. Generally,
these specific conversions allowed one to choose either a
total synthesis of the natural series (starting from pS-3) or
of the enantiomers (starting from pR-3). The epoxides pS-
9a/b (structure determination by X-ray analyses) were
found to be the precursors of choice for synthesis of the
desired target 17/19. After hydrogenolytic cleavage of the
benzyl group and the 3-chloride the indolizidinone 14 was
obtained. Both C3 diastereomers were converted into a
single product. The OH function of the hydroxyindolizidi-
none 14 was protected as a TBS ether 15. Alternatively, the
missing C8 methyl group could be introduced with low dia-
stereoselectivity by a Swern oxidation/Grignard addition se-
Figure 5. Formation and reactions of the planar chiral azoni-
nones 3
respect to the ring, generating pR-3a as the enantiomer of quence. After protection of the tertiary alcohol, the dia-
pS-3b. A high activation barrier had to be overcome to stereomers 19 and 20 were separated by column chromato-
achieve the change of the planar chiral information. This graphy or HPLC. In view of the fact that this final separa-
allowed planar chiral information to be used to generate tion is the first necessary chromatography, the sequence is
new stereogenic centers, depending on the conformation of quite workable in spite of the use of about ten steps starting
the medium-sized ring. An electrophile would always be from -(Ϫ)-proline. The 5-indolizidinones 15, 19, and 20
forced to attack the unshielded face of the double bond. were used as key building blocks in enantiopure pumilio-
Complete chirality transfer was observed in the transannu- toxin syntheses.
lar ring contraction generating the iodoindolizidinones 4a
and 4b, respectively. Furthermore, the conversion was found
to be highly regioselective. The epoxidation of the double
bond yielded the epoxy-azonanones 9a and 9b, again with
complete chirality transfer. This step determined the abso-
Experimental Section
1
General Remarks: H NMR and 13C NMR spectra and NOE ex-
lute configuration of the target 5-indolizidinone 15, 19, and periments were recorded on Bruker AM 270 or Bruker AC 550 (3a,
NOEDS analyses of 4a/b, 9a/b) spectrometers at room temp. unless
specified otherwise. Tetramethylsilane was used as internal stand-
ard. For peak assignment, azabicyclononane numbering has been
used. IR spectra were obtained with PerkinϪElmer 257 or 580B
20: starting from the pS-3a/b azoninones, the sequence gave
the bicyclic core indolizidinones as reported (via epoxides
4a/b). From the pR-3a/b series, the enantiomers ent-15, ent-
19, and entϪ20 would have been generated (via epoxide ent-
9b, see ref.[7]). In summary, the sequence can selectively pro-
vide either the natural bicyclic core skeleton or the enanti-
omer by selection of the suitable planar chiral intermediate,
always starting from the same enantiopure -(Ϫ)-proline.
spectrophotometers. Optical rotations were measured with
a
PerkinϪElmer P 241 polarimeter in a 1 dm cell. Mass spectra were
recorded on Varian MAT 711 or 112S spectrometers; high-resolu-
tion mass spectra (HRMS) were obtained on the Varian MAT 711.
PFK was used as reference, and the results were determined by
the peak matching method, resolution: Ͼ 10,000. The ion source
temperature was 250 °C, the electron energy was 0.8 mA. The melt-
ing points (not corrected) were measured with a Büchi SMP 20. For
HPLC, Knaur pumps and UV- and RI-detectors and Rheodyne
injection systems were used. Preparative amounts of the lactams
were separated with a 32 mm ϫ 120 mm column and 5 µm Nucleo-
sil 50Ϫ5 (Macherey & Nagel), with a flow of about 80 mL/min.
Column chromatography was carried out with Merck silica gel
0.04Ϫ0.063 mm, 230Ϫ400 mesh A. Reaction progress was mon-
itored by thin layer chromatography (TLC) performed on alumi-
nium sheets pre-coated with silica gel 60 (thickness 0.25 mm). All
Summary
A flexible sequence to generate the bicyclic core skeleton
indolizidinone 19 (8-epi: 20) has been developed, and
should serve as a key intermediate for enantiopure pumili-
otoxin total syntheses. Five standard steps starting from -
(Ϫ)-proline allowed the formation of the 2-vinylpyrrolidine
(2) on a 50 g scale, without any need for chromatographic
purification. A zwitterionic aza-Claisen rearrangement con-
verted the allylamine 2 into the ring-enlarged azoninones
solvents were dried by standard procedures before use. X-ray ana-
˚
pS-3a/b, bearing E double bonds. These nine-membered lyses were performed with Mo-Kα radiation (λ ϭ 0.71073 A). The
3308
Eur. J. Org. Chem. 2002, 3304Ϫ3314

Synthesis of the Bicyclic Core of Pumiliotoxins
FULL PAPER
structure was determined by direct methods by use of the SHELXS
program. The H atoms were taken from difference Fourier syn-
thesis and were refined with isotropic thermal parameters. The
nonH atoms were refined with anisotropic thermal parameters. The
structure was refined on F values using 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.
3J(H4u,H5o) ϭ 11.5, 3J(H4u,H3o) ϭ 9 Hz, 1 H, 4u-H], 3.12Ϫ3.02
[dd, 2J(H9u,H9o) ϭ 14.5, 3J(H9u,H8o) ϭ 5 Hz, 1 H, 9u-H],
2
3
3.45Ϫ3.33 [dd, J(H9o,H9u) ϭ 14.5, J(H9o,H8u) ϭ 10 Hz, 1 H, 9o-
H], 3.95Ϫ3.88 [d, 2J(HBnϪ2,HBn1) ϭ 14.5 Hz, 1 H, H-Bn-2],
3
3
4.62Ϫ4.55 [dd, J(H3o,H4u) ϭ 11.5, J(H3o,H4o) ϭ 2 Hz, 1 H, 3o-
H], 5.45Ϫ5.35 [d, 2J(HBnϪ1,HBn2)ϭ 14.5 Hz,
1 H, H-Bn-1],
5.55Ϫ5.45 (m, 1 H, 6u-H), 5.65Ϫ5.50 (m, 1 H, 5o-H), 7.40Ϫ7.20
(m, 5 H) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 26.0 (t), 31.6
(t), 39.3 (t), 44.7 (t), 47.6 (t, C-9), 56.3 (d, C-3), 127.4 (d), 128.2
(d), 128.5 (d), 134.8 (d), 136.7(s), 169.5 (s) ppm. IR (KBr, mixture
of pS-3a and pS-3b): ν˜ ϭ 3054 (m), 3031 (w), 2986 (m), 2940 (m),
2866 (m), 1643 (s), 1495 (w), 1453 (m), 1436 (m), 1421 (s), 1265 (s),
1185 (m), 994 (w), 896 (m) cmϪ1. MS (80 eV, EI, 70 °C, mixture of
pS-3a and pS-3b): m/z (%) ϭ 263 (8) [Mϩ·], 228 (4) [Mϩ Ϫ Cl], 172
(14) [Mϩ Ϫ C7H7], 136 (3), 91 (100) [C7H7ϩ·], 65 (5), 55 (3). HRMS
(80 eV, 120 °C, mixture of pS-3a and pS-3b): calcd. 263.107692 (for
C15H18ClNO), found 263.10934.
(pS)E-(3R)-1-Benzyl-3-chloro-1,3,4,7,8,9-hexahydro-2H-azonin-2-
one (3a) and (pS)E-(3S)-1-Benzyl-3-chloro-1,3,4,7,8,9-hexahydro-
2H-azonin-2-one (3b): Under argon, a solution of vinylpyrrolidine
(2) (5.1 g, 27.2 mmol) and K2CO3 (1.88 g, 0.5 eq, 13.6 mmol) in
dry CH2Cl2 (100 mL) was cooled to Ϫ10 °C. Chloroacetyl fluoride
(10.51 g, 4 equiv., 7.62 mL, 0.108 mol, d ϭ 1.3788) was added drop-
wise. Me3Al (27.3 mL, 54.5 mmol, 2 equiv, 2  in heptane) was then
added slowly, the internal temperature being maintained below 0
°C. After stirring overnight at 4 °C the orange-brown suspension
was slowly poured into Et2O (300 mL) to precipitate the aluminum
salts. The mixture was filtered through a short silica gel column.
The clear orange solution was then washed thoroughly with satur-
(3R,5R,6S)-3-Chloro-5-iodo-1-azabicyclo[4.3.0]nonan-2-one
(4a)
and (3S,5R,6S)-3-Chloro-5-iodo-1-azabicyclo[4.3.0]nonan-2-one
ated aqueous NaHCO3 and brine, and dried (Na2SO4). The solvent (4b): Two-step sequence starting from vinylpyrrolidine 2 without
was removed at 20 °C to suppress any epimerization of the planar
chiral information of the E olefin (pS Ǟ pR). The crude orange oil
was purified by flash chromatography on silica gel (EtOAc/n-hex-
ane 1:1), all distillation processes being performed below 20 °C!
intermediate purification of the azoninones pS-3 (efficient sup-
pressing of any epimerization pS Ǟ pR). Rearrangement: Reaction
of vinylpyrrolidine 2 (5.0 g, 26.7 mmol), K2CO3 (3.7 g, 1 equiv.,
26.7 mmol), chloroacetyl fluoride (10.3 g, 4 equiv., 7.4 mL, 0.106
Separation of the diastereomers by preparative HPLC (15% EtOAc mol), and Me3Al (26.6 mL, 53.4 mmol, 2 equiv., 2  in heptane)
in n-hexane, flow 64 mL/min; 32 ϫ 110 Nucleosil 50Ϫ5, UV
254 nm) gave two major fractions: pS-3a (retention time 5 min,
in CH2Cl2 (100 mL) by following the procedure as described for
pS-3a/b. Yield: 7.71 g of the crude mixture of pS-3a/b. Transannular
3.22 g, 12.2 mmol, 44.8%) and pS-3b (retention time 6 min, 2.34 g, reaction: The crude azoninones pS-3a/b were dissolved in dry
8.84 mmol, 32.5%). For a 130 mmol scale preparation, see supple-
mentary material.
CH2Cl2 (300 mL) at 20 °C, with stirring. A solution of I2 (3.39 g,
26.7 mmol, 1 equiv.) in dry CH2Cl2 (50 mL) was then added drop-
wise by syringe until the color of unchanged I2 remained (quasi-
titration). The reaction was found to be complete immediately after
the end of the addition (TLC monitoring). The mixture was stirred
for a further 15 min at room temperature. The solvent was then
evaporated, and the crude material was purified by column
chromatography on silica gel (hexane/EtOAc 1:1, Rf ϭ 0.14). Yield:
4.23 g (14.15 mmol, 53%, 2 steps) of a mixture of diastereomers 4a/
b. An analytical sample was separated by HPLC (32 ϫ 250, Nucleo-
sil 50-5, 122 mL/min flow, UV ϭ 254 nm, 30% EtOAc/n-hexane)
to yield pure 4b (retention time 20 min) and 4a (retention time
23 min).
Azoninone pS-3a was characterized by the coexistence of two con-
formers that could not be separated by HPLC. [α]2D0 ϭ Ϫ44.3 (c ϭ
1.7, CHCl3).1H NMR (major conformer pS-3a, 500 MHz, CDCl3):
δ ϭ 1.80Ϫ1.70 (m, 2 H, 8o-,8u-H), 2.18Ϫ2.00 (m, 1 H, 7o-H),
2.45Ϫ2.35 (m, 1 H, 7u-H), 2.75Ϫ2.58 [ddd, 2J(H4o,H4u) ϭ 13,
3J(H4o,H5o) ϭ 4, 3J(H4o,H3u) ϭ 4 Hz, 1 H, 4o-H], 2.82Ϫ2.72 [ddd,
3
3
2J(H4u,H4o) ϭ 13, J(H4u,H5o) ϭ 13, J(H4u,H3u) ϭ 2.5 Hz, 1 H,
4u-H], 3.10Ϫ3.00 (m,
1
H, 9u-H), 3.95Ϫ3.88 [d,
2J(HNϪBn2,HNϪBn1) ϭ 15 Hz, 1 H, HϪN-Bn2], 4.38Ϫ4.25 (m, 1 H,
9o-H), 5.04Ϫ5.00 [dd, 3J(H3u,H4o) ϭ 4, 3J(H3u,H4u) ϭ 2.5 Hz, 1
H, 3u-H], 5.28Ϫ5.18 [d, 2J(HNϪBn1,HNϪBn2) ϭ 15.5 Hz, 1 H,
HϪN-Bn1], 5.62Ϫ5.50 [ddd, 3J(H6u,H5o) ϭ 15, 3J(H6u,H7o) ϭ 9, Data for Indolizidinone 4a: M.p. 103Ϫ105 °C. [α]2D0 ϭ Ϫ11.9 (c ϭ
3J(H6u,H7u) ϭ 4 Hz, 1 H, 6u-H], 5.98Ϫ5.85 [ddd, 3J(H5o,H6u) ϭ
1.56, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 1.65Ϫ1.50 (m, 1
1
3
3
15, J(H5o,H4u) ϭ 10, J(H5o,H4o) ϭ 5 Hz, 1 H, 5o-H], 7.40Ϫ7.20 H, 7o-H), 1.85Ϫ1.70 (m, 1 H, 8u-H), 2.05Ϫ1.92 (m, 1 H, 8o-H),
(m, 5 H) ppm. 1H NMR (minor conformer pS-3a, 500 MHz,
CDCl3): δ ϭ 1.60Ϫ1.50 (m, 1 H, 8Ј-H) 2.00Ϫ1.90 (m, 2 H, 7o-,8-
2.45Ϫ2.35 (m, 1 H, 7u-H), 2.75Ϫ2.03 [ddd, 2J(H4u,H4o) ϭ 14.5,
3J(H4u,H5o) ϭ 14.5, 3J(H4u,H3u) ϭ 4 Hz, 1 H, 4u-H], 2.86Ϫ2.77
H), 2.40Ϫ2.28 (m, 1 H, 7u-H), 2.55Ϫ2.50 (m, 1 H, 4o-H), [ddd, J(H4o,H4u) ϭ 14.5, J(H4o,H5o) ϭ 3, J(H4o,H3u) ϭ 1.5 Hz,
2
3
3
2.90Ϫ2.80 (m, 1 H, 4u-H), 3.10Ϫ3.00 (m, 1 H, 9o-H), 3.75Ϫ3.60 1 H, 4o-H], 3.72Ϫ3.58 (m, 3 H, 6u-,9o-,9u-H), 4.18Ϫ4.08 [ddd,
2
(m, 1 H, 9u-H), 4.05Ϫ4.00 [d, J(HNϪBn2,HNϪBn1) ϭ 15 Hz, 1 H, 3J(H5o,H4u) ϭ 10, 3J(H5o,H6u) ϭ 10, 3J(H5o,H4o) ϭ 3.5 Hz, 1 H,
HϪN-Bn2], 4.86Ϫ4.80 [dd, 3J(H3u,H 4o) ϭ 10, 3J(H3u,H4u) ϭ 8 Hz, 5o-H], 4.28Ϫ4.25 [dd, 3J(H3u,H4u) ϭ 4, 3J(H3u,H4o) ϭ 1.5 Hz, 1
1 H, 3u-H], 5.28Ϫ5.18 [d, 2J(HNϪBn1,HNϪBn2) ϭ 15.5 Hz, 1 H,
H, 3u-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 17.6 (d, C-5),
HϪN-Bn1], 5.50Ϫ5.38 (m, 1 H, 5o-H), 5.70Ϫ5.55 (m, 1 H, 6u-H), 20.6 (t, C-8), 34.1 (t, C-7), 44.2 (t, C-4), 46.9 (t, C-9), 54.6 (d, C-
7.40Ϫ7.20 (m, 5 H) ppm. 13C NMR (both conformers, peaks are
partly overlapping. 62.9 MHz, CDCl3): δ ϭ 21.9, 27.8, 32.3, 35.7,
6), 66.7 (d, C-3) ppm. IR (KBr): ν˜ ϭ 3426 (s), 2945 (s), 2868 (s),
1673 (m), 1645 (s), 1448 (m), 1370 (w), 1321 (w), 1290 (m), 1250
36.6, 44.2, 45.9, 47.1, 49.1, 55.4, 64.8, 127.1, 127.3, 127.5, 128.4, (m), 1221 (w), 1192 (w), 1152 (w), 1110 (w), 657 (m) cmϪ1. MS
128.5, 129.8, 132.8, 135.2, 136.9, 169.2 (s). For NOE analysis see
Supplementary Material.
(80 eV, EI, 80 °C, mixture of 4a and 4b): m/z (%) ϭ 299 (12) [Mϩ·],
264 (5) [Mϩ Ϫ Cl], 172 (100) [Mϩ Ϫ I], 145 (15), 136 (14), 108
(10), 82 (13), 80 (13), 70 (25), 67 (10), 55 (14), 53 (10). HRMS
(80 eV, 80 °C, mixture of 4a and 4b): calcd. 298.957394 (for
C8H1135Cl127INO2), found 298.95721.
Azoninone pS-3b: [α]2D0 ϭ Ϫ121.9 (c ϭ 1.9, CHCl3). 1H NMR
(270 MHz, CDCl3): δ ϭ 1.75Ϫ1.65 (m, 1 H, 8o-H), 2.00Ϫ1.88 (m,
1 H, 8u-H), 2.15Ϫ2.00 (m, 1 H, 7u-H), 2.46Ϫ2.36 (m, 1 H, 7o-H),
2.67Ϫ2.57 [ddd, 2J(H4o,H4o) ϭ 12, 3J(H4o,H5o) ϭ 5, 3J(H4o,H3o) ϭ Data for Indolizidinone 4b: M.p. 144Ϫ146 °C. [α]2D0 ϭ Ϫ45.6 (c ϭ
1
3 Hz,
1
H, 4o-H], 2.84Ϫ2.70 [ddd, 2J(H4u,H4o
)
ϭ
11.5, 1.44, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 1.60Ϫ1.45 (m, 1
Eur. J. Org. Chem. 2002, 3304Ϫ3314
3309

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
H, 7o-H), 1.90Ϫ1.70 (m, 1 H, 8u-H), 2.05Ϫ1.95 (m, 1 H, 8o-H),
(d, C-5), 168.9 (s) ppm. IR (KBr): ν˜ ϭ 2963 (w), 2935 (w), 2864
2.48Ϫ2.38 (m, 1 H, 7u-H), 2.70Ϫ2.55 [ddd, 2J(H4u,H4o) ϭ 14, (m), 1702 (s, CO), 1621 (s, NO), 1447 (m), 1431 (m), 1318 (m),
3
3J(H4u,H3o) ϭ 12.5, J(H4u,H5o) ϭ 11 Hz, 1 H, 4u-H], 3.13Ϫ3.04 1304 (m), 1277 (s), 1260 (s), 1189 (w), 1153 (m), 1118 (w), 1018
2
3
3
[ddd, J(H4o,H4u) ϭ 13, J(H4o,H3o) ϭ 6.5, J(H4o,H5o) ϭ 3 Hz, 1 (m), 975 (m), 894 (s), 885 (s), 865 (s), 806 (m), 762 (m), 737 (m),
H, 4o-H], 3.90Ϫ3.78 [ddd, 3J(H5o,H4u) ϭ 10, 3J(H5o,H6u) ϭ 10, 657 (m) cmϪ1. MS (80 eV, EI, 90 °C): m/z (%) ϭ 236 (0.05) [Mϩ·],
3J(H5o,H4o) ϭ 4 Hz, 1 H, 5o-H], 4.40Ϫ4.30 [dd, J(H3o,H4u) ϭ 10, 234 (0.1) [Mϩ·], 190 (8), 188 (24) [Mϩ Ϫ NO2], 172 (6) [Mϩ
Ϫ
3
3J(H3o,H4o) ϭ 7 Hz, 1 H, 3o-H] ppm. 13C NMR (67.9 MHz, NO3], 160 (9), 132 (6), 124 (8), 97 (16), 71 (100), 43 (51), 41 (38).
CDCl3): δ ϭ 19.5 (d, C-5), 21.3 (t, C-8), 34.8 (t, C-7), 45.2 (t, C-
4), 47.5 (t, C-9), 53.4 (d, C-6), 66.3 (d, C-3) ppm. IR (KBr): ν˜ ϭ
3425 (s), 2939 (s), 2873 (s), 1736 (w), 1709 (w), 1636 (s), 1459 (m),
1441 (m), 1381 (w), 1332 (w), 1274 (m), 1192 (w), 1153 (w), 660
HRMS (80 eV,120 °C): calcd. 234.04735 (for C8H11N2O4 35Cl1
[Mϩ]), found 234.04522.
(3R,5R,6S)-8-Chloro-5-hydroxy-1-azabicyclo[4.3.0]nonan-9-one (7):
The nitrate indolizidinone 6a (100 mg, 0.43 mmol) was dissolved in
MeOH (10 mL) and HOAc (2 mL). At 0 °C, zinc (powder, 100 mg,
1.72 mmol, 4 equiv.) was slowly added. The cooling bath was then
removed and the mixture was stirred overnight at room temper-
ature. Workup started with quenching with aqueous NaHCO3 and
extraction with CH2Cl2 (3 ϫ). The organic layers were then dried
(Na2SO4) and the solvent was evaporated to give hydroxyindolizidi-
none 7 (32.3 mg, 0.17 mmol, 40%) as a colorless oil. [α]2D0 ϭ Ϫ49.3
(m) cmϪ1
.
(3R,5R,6S)-8-Chloro-5-nitro-1-azabicyclo[4.3.0]nonan-9-one
(6a)
and (3S,5R,6S)-8-Chloro-5-nitro-1-azabicyclo[4.3.0]nonan-9-one
(6b): The iodoindolizidinones 4a/b (1.00 g, 3.34 mmol) in acetone
(50 mL) were treated with carefully powdered AgNO3 (1.13 g, 2
equi., 6.68 mmol) and stirred at 20 °C for 3 days. The precipitated
silver iodide was then filtered off and another equivalent of AgNO3
(0.57 g, 1 equiv., 3.34 mmol) was added. After the mixture had been
stirred overnight the precipitates were filtered off and the solvent
was removed. The crude product was purified by column chroma-
tography on silica gel (EtOAc/n-hexane 1:1, Rf ϭ 0.27 and Rf ϭ
0.13). Yield: 0.72 g (92%, 3.07 mmol) of a mixture of the nitrate
indolizidinones 6a and 6b. An analytical sample was separated by
preparative HPLC (20% EtOAc/n-hexane, 32 ϫ 110 mm, Nucleosil
50-5, flow 122 mL/min, UV ϭ220 nm) to provide 6a (retention time
9.9 min) and 6b (retention time 16.7 min) as pure compounds.
1
(c ϭ 1.61, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 1.50Ϫ1.30
(m, 2 H, 3Ј-,4o-H), 1.85Ϫ1.70 (m, 1 H, 3-H), 2.15Ϫ2.00 (m, 1 H,
4u-H), 2.40Ϫ2.30 [ddd, 2J(H7u,H7o) ϭ 13.5, 3J(H7u,H8u) ϭ 7,
3J(H7u,H6o) ϭ 6 Hz, 1 H, 7u-H], 2.60Ϫ2.50 [ddd, 2J(H7o,H7u) ϭ
3
3
14.5, J(H7o,H6o) ϭ 6, J(H7o,H8u) ϭ 2 Hz, 1 H, 7o-H], 2.70Ϫ2.60
(m, 1 H, 9o-H), 3.25Ϫ3.15 [ddd, 3J(H5u,H6o) ϭ 9.5, 3J(H5u,H4o) ϭ
9.5, 3J(H5u,H4u
) ϭ 3.5 Hz, 1 H, 5u-H], 3.43Ϫ3.32 [ddd,
3J(H6o,H5u) ϭ 9, 3J(H6o,H7u) ϭ 6.5, 3J(H6o,H7o) ϭ 6.5 Hz, 1 H,
6o-H], 4.05Ϫ3.95 [dd, 2J(H2u,H2o) ϭ 13, 3J(H2u,H8) ϭ 3.5 Hz, 1
H, 2u-H], 4.40Ϫ4.35 [dd, J(H8u,H7u) ϭ 7, J(H8u,H7o) ϭ 2 Hz, 1
H, 8u-H], 4.60Ϫ4.40 (s, 1 H, OH) ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 22.9 (t, C-3), 32.9 (t, C-7), 34.8 (t, C-4), 39.9 (t, C-2),
54.5 (d, C-8), 60.4 (d, C-6), 72.9 (d, C-5), 69.3 (s) ppm. IR (CHCl3):
ν˜ ϭ 3395 (m, br), 2929 (m), 2861 (m), 1697 (s, CϭO), 1441 (m),
1372 (m), 1272 (m), 1075 (m), 916 (s), 898 (s), 750 (s), 718 (s), 650
(s) cmϪ1. MS (80 eV, EI, 90 °C): m/z (%) ϭ 189 (27) [Mϩ·], 172 (6)
[Mϩ Ϫ OH], 154 (100) [Mϩ Ϫ Cl], 126 (32), 98 (11), 84 (25), 71
(35). HRMS (80 eV,120 °C): calcd. 189.055656 (for C8H12N1O2
35Cl1 [Mϩ]), found 189.05392.
3
3
Data for Nitrate Indolizidinone 6a: Colorless crystals, m.p. 75 °C.
[α]2D0 ϭ Ϫ54.9 (c ϭ 1.56, CHCl3). 1H NMR (270 MHz, CDCl3):
δ ϭ 1.68Ϫ1.50 (m, 2 H, 3Ј-,4o-H), 1.98Ϫ1.85 (m, 1 H, 3-H),
2.40Ϫ2.30 (m, 1 H, 4u-H), 2.42Ϫ2.30 [ddd, 2J(H7u,H7o) ϭ 14,
3J(H7u,H6o) ϭ 6.5, 3J(H7u,H8u) ϭ 6.5 Hz, 1 H, 7u-H], 2.61Ϫ2.50
2
3
3
[ddd, J(H7o,H7u) ϭ 14.5, J(H7o,H6o) ϭ 6.5, J(H7o,H8u) ϭ 2 Hz,
1
H, 7o-H], 2.77Ϫ2.63 (m, 1 H, 2o-H), 3.68Ϫ3.56 [ddd,
3J(H6o,H5u) ϭ 10.5, 3J(H6o,H7o) ϭ 6.5, 3J(H6o,H7u) ϭ 6.5 Hz, 1
H, 6o-H], 4.17Ϫ4.07 [ddd, 2J(H2u,H2o) ϭ 13, 3J(H2u,H8) ϭ 2.5,
3J(H2u,H8Ј) ϭ 1 Hz, 1 H, 2u-H], 4.42Ϫ4.37 [dd, J(H8u,H7u) ϭ 7,
3
3J(H8u,H7o) ϭ 2 Hz, 1 H, 8u-H], 4.65Ϫ4.54 [ddd, 3J(H5u,H6o) ϭ
(3R,5R,6R)-1-Benzyl-3-chloro-5,6-epoxyazonan-2-one (9a): The
azoninone pS-3a (3.05 g, 11.56 mmol, 1 mol equiv.) was dissolved
in a 1:1 mixture of CH2Cl2 and phosphate buffer (pH ϭ 7). m-
Chloroperbenzoic acid (2.64 g, 13.87 mmol, 1.2 equiv., mono hy-
drate) was then added and the mixture was stirred at 4 °C for 3Ϫ5 h
(TLC monitoring). The mixture was then poured into saturated
aqueous NaHCO3/NaHSO3. The organic layer was washed (satur-
ated aqueous NaHCO3 and brine) and dried (Na2SO4). After evap-
oration of the solvent, the product was purified by recrystallization
from CH2Cl2/n-hexane. The remaining mother liquor was purified
by HPLC (15% EtOAc/n-hexane, 32 ϫ 250 mm Nucleosil 50-5,
flow 64 mL/min).[34] Yield: 2.92 g (10.4 mmol, 90%) of epoxide 9a
as colorless crystals The epoxide was found to be heat-sensitive,
suffering from rearrangement to the more stable lactone 11a. In
contrast, no decomposition was observed while storing at Ϫ20 °C
10, J(H5u,H4o) ϭ 10, J(H5u,H4u) ϭ 3.5 Hz, 1 H, 5u-H] ppm. 13C
NMR (67.9 MHz, CDCl3): δ ϭ 22.6 (t, C-3), 28.5 (t, C-4), 34.8 (t,
C-7), 39.7 (t, C-2), 53.4 (d, C-8), 55.9 (d, C-6), 82.5 (d, C-5), 168.9
(s) ppm. IR (KBr): ν˜ ϭ 2965 (w), 2917 (w), 1701 (s, CO), 1697 (s),
1639 (s, NO), 1426 (m), 1318 (m), 1271 (s), 1196 (w), 1160 (w),
1109 (w), 1054 (w), 1018 (m), 978 (m), 897 (s), 884 (s), 959 (s), 755
(m), 692 (m), 650 (m) cmϪ1. MS (80 eV, EI, 100 °C): m/z (%) ϭ
236 (0.2) [Mϩ·], 234 (0.8) [Mϩ·], 190 (15), 188 (45) [Mϩ Ϫ NO2],
172 (17) [Mϩ Ϫ NO3], 160 (13), 132 (10), 124 (13), 97 (12), 71
(100), 43 (20). HRMS (80 eV, 120 °C): calcd. 234.040735 (for
C8H1135Cl1N2O4 [Mϩ]), found 234.04344.
3
3
Data for Nitrate Indolizidinone 6b: Colorless crystals, m.p. 153 °C.
1
[α]2D0 ϭ Ϫ117.8 (c ϭ 1.25, CHCl3). H NMR (270 MHz, CDCl3):
δ ϭ 1.72Ϫ1.48 (m, 2 H, 3-,4o-H), 1.95Ϫ1.80 (m, 1 H, 3-H),
2.20Ϫ2.10 [ddd, 2J(H7u,H7o
)
ϭ
14, 3J(H7u,H6o
)
ϭ
5.5, for several months. M.p. 139Ϫ140 °C. [α]2D0 ϭ Ϫ148.6 (c ϭ 1.4,
3J(H7u,H8) ϭ 5.5 Hz, 1 H, 7u-H], 2.40Ϫ2.31 (m, 1 H, 4u-H),
CHCl3). The NMR spectra were characterized by the coexistence
2.73Ϫ2.60 (m, 1 H, 2o-H), 2.03Ϫ2.10 [ddd, 2J(H7o,H7u) ϭ 13.5, of two conformers:[35] 1H NMR (270 MHz, CDCl3, major con-
3J(H7o,H6o) ϭ 8, J(H7o,H8) ϭ 6 Hz, 1 H, 7o-H], 3.48Ϫ3.40 [ddd, former, 60%): δ ϭ 0.90Ϫ0.70 (m, 1 H, 7o-H), 1.90Ϫ1.80 (m, 1 H,
3
3J(H6o,H5u) ϭ 9.5, J(H6o,H7o) ϭ 7, J(H6o,H7u) ϭ 5 Hz, 1 H, 6o-
4u-H), 2.20Ϫ2.10 (m,
2
H, 8-,7u-H), 2.50Ϫ2.40 [ddd,
3
3
H], 4.15Ϫ4.05 (m, 1 H, 2u-H), 4.45Ϫ4.35 [ddd, 3J(H8o,H) ϭ 7, 3J(H5o,H6u) ϭ 8.5, 3J(H5o,H4u) ϭ 5, 3J(H5o,H4o) ϭ 2.5 Hz, 1 H,
3J(H8o,H) ϭ 6, J(H8o,H) ϭ 0.5 Hz, 1 H, 8o-H], 4.85Ϫ4.75 [ddd,
5o-H], 2.80Ϫ2.60 (m, 2 H, 6-,4o-H), 3.30Ϫ3.15 (m, 1 H, 9o-H),
5
3J(H5u,H6o) ϭ 9.5, J(H5u,H4o) ϭ 9.5, J(H5u,H4u) ϭ 3.5 Hz, 1 H, 4.00Ϫ3.80 [ddd, 2J(H9u,H9o) ϭ 15, 3J(H9u,H8) ϭ 12, 3J(H9u,H8) ϭ
3
3
5u-H] ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ 22.8 (t, C-3), 28.8 3.5 Hz, 1 H, 9u-H], 4.14Ϫ4.06 [d, J(HNϪBn2,HNϪBn1) ϭ 14.5 Hz,
2
(t, C-4), 33.4 (t, C-7), 39.9 (t, C-2), 53.1 (d, C-8), 56.3 (d, C-6), 82.2 1 H, HϪN-Bn2], 5.15Ϫ5.10 [dd, J(H3u,H4o) ϭ 7, J(H3u,H4u) ϭ
3
3
3310
Eur. J. Org. Chem. 2002, 3304Ϫ3314

Synthesis of the Bicyclic Core of Pumiliotoxins
FULL PAPER
3 Hz, 1 H, 3u-H], 5.18Ϫ5.13 [d, 2J(HNϪBn1,HNϪBn2) ϭ 15 Hz, 1 H,
HϪN-Bn1], 7.40Ϫ7.20 (m, 5 H, Ph-H) ppm. H NMR (270 MHz,
The methanol was removed and the black residue was dissolved in
CH2Cl2 (300 mL). A black solid was removed by filtration and
1
CDCl3, minor conformer, 40%): δ ϭ 1.20Ϫ1.10 (m, 1 H, 7o-H), washed with CH2Cl2 (2 ϫ 200 mL). The solvent of the combined
1.90Ϫ1.50 (m, 2 H, 8-,4u-H), 2.15Ϫ2.05 (m, 1 H, 7u-H), 2.30Ϫ2.20 clear extracts was evaporated to give 9.7 g of crude hydroxyindolizi-
(m, 1 H, 8-H), 2.80Ϫ2.60 (m, 2 H, 4o-,6u-H), 3.30Ϫ3.10 (m, 2 H, dinone 14. The crude solid was finely powdered and washed with
5o-,9u-H), 4.13Ϫ4.05 [d, 2J(HBn2,HBnϪ1) ϭ 15 Hz, 1 H, H-Bn2], cold Et2O (200 mL). Yield: 7.29 g (47.2 mmol, 59%, crude reactant
2
3
4.65Ϫ4.53 [dd, J(H9o,H9u) ϭ 15, J(H9o,H8) ϭ 9 Hz, 1 H, 9o-H],
9) and 9.64 g (62.4 mmol, 78%, pure reactant 9) of hydroxyindolizi-
dinone 14 as nearly colorless crystals. Optional: Purification by col-
3
3
5.08Ϫ5.03 [dd, J(H3u,H4o) ϭ 4.5, J(H3u,H4u) ϭ 2.5 Hz, 1 H, 3u-
H], 5.30Ϫ5.20 [d, J(HNϪBn1,HNϪBn2) ϭ 15 Hz, 1 H, HϪN-Bn1], umn chromatography on silica gel (EtOAc/MeOH 6:1). M.p.
2
7.40Ϫ7.20 (m, 5 H, Ph-H) ppm. 13C NMR (125.7 MHz, CDCl3):[36] 99Ϫ101 °C). [α]2D0 ϭ Ϫ37.7 (c ϭ 1.27, EtOH). 1H NMR (270 MHz,
δ ϭ 21.4 (t, C-8), 22.2 (t, C-8Ј), 26.0 (t, C-7), 29.8 (t, C-7Ј), 35.4
CDCl3): δ ϭ 1.60Ϫ1.45 (m, 1 H, 7o-H), 1.85Ϫ1.70 (m, 2 H, 4u-
(t, C-4Ј), 37.4 (t, C-4), 44.2 (t, C-9), 45.1 (t, C-9Ј), 47.6 (t, N-Bn), ,8u-H), 2.00Ϫ1.91 (m, 1 H, 8o-H), 2.13Ϫ2.00 (m, 1 H, 4o-H),
49.2 (t, N-BnЈ), 50.6 (d, C-3), 54.2 (d, C-6), 56.2 (d, C-6Ј), 56.5 (d, 2.47Ϫ2.28 (m, 2 H, 3o-,7u-H), 2.60Ϫ2.48 [ddd, 2J(H3u,H) ϭ 18,
C-5Ј), 57.1 (d, C-5), 59.2 (d, C-3Ј), 127.4 (d), 127.8 (d), 128.4 (d), 3J(H3u,H) ϭ 7, 3J(H3u,H) ϭ 2 Hz, 1 H, 3u-H], 3.32Ϫ3.21 [ddd,
128.7 (d), 136.4 (s), 168.2 (s, C-2Ј), 169.1 (s, C-2) ppm. IR (KBr):
ν˜ ϭ 3039 (w), 3015 (m), 2976 (m), 2940 (m), 2885 (m), 1638 (s, Cϭ
3J(H6u,H) ϭ 14, 3J(H6u,H) ϭ 8.5, 3J(H6u,H) ϭ 3.5 Hz, 1 H, 6u-
H], 3.60Ϫ3.43 (m, 3 H, 5o-,9o-,9u-H) ppm. 13C NMR (67.9 MHz,
O), 1495 (m), 1475 (m), 1461 (m), 1449 (m), 1429 (m), 1366 (m), CDCl3): δ ϭ 22.1 (t, C-8), 29.9 (t, C-4 and C-7), 31.6 (t, C-3), 45.5
1298 (w), 1259 (m), 1238 (w), 1210 (m), 1202 (s), 1157 (w), 1127 (t, C-9), 63.9 (d, C-6), 70.7 (d, C-5), 168.7 (s) ppm. IR (KBr): ν˜ ϭ
(w), 1107 (m), 1081 (m), 1064 (w), 971 (m), 922 (m), 908 (m), 825 3267 (s, OH), 2969 (m), 2952 (m), 2885 (m), 1601 (s, CϭO), 1479
(m), 796 (m), 765 (m), 792 (w), 708 (m), 634 (w), 610 (w) cmϪ1
(m), 1454 (m), 1442 (m), 1412 (m), 1339 (m), 1320 (w), 1287 (m),
.
MS (80 eV, EI, 120 °C): m/z (%) ϭ 281 (12) [Mϩ·], 279 (35) [Mϩ·], 1265 (s), 1224 (w), 1209 (w), 1167 (w), 1142 (w), 1132 (w), 1093
244 (49) [Mϩ Ϫ Cl], 204 (10), 188 (8) [Mϩ Ϫ C7H7], 160 (23), 120
(65), 91 (100), 70 (13). HRMS (80 eV, 120 °C): calcd. 279.1020607
(for C15H1835ClNO2), found 279.10409.
(m), 1063 (m), 990 (w), 960 (m), 843 (w), 770 (w), 667 (m) cmϪ1
MS (80 eV, EI, 130 °C): m/z (%) ϭ 155 (36) [Mϩ·], 138 (3) [Mϩ
OH], 127 (6), 111 (21), 99 (11), 83 (100), 70 (81), 55 (26), 41 (24).
HRMS (80 eV, 130 °C): calcd. 155.094629 (for C8H13N1O2 [Mϩ]),
found 155.09567.
.
Ϫ
(3S,5R,6R)-1-Benzyl-3-chloro-5,6-epoxyazonan-2-one (9b): This
compound was produced from pS-3b (2.55 g, 9.6 mmol) and m-
CPBA following the procedure described for epoxy azonanone 9a.
After workup the product 9b was recrystallized from CH2Cl2/n-
hexane. Yield 2.70 g (100%) of 9b, initially as a colorless oil, which
(5R,6S)-5-(tert-Butyldimethylsilyloxy)azabicyclo[4.3.0]nonan-2-one
(15): The hydroxyindolizidinone 14 (500 mg, 3.22 mmol) in CH2Cl2
(50 mL) was treated consecutively with imidazole (395 mg,
5.79 mmol, 1.8 equiv.) in CH2Cl2 (50 mL) and with TBSCl (534 mg,
slowly crystallized at Ϫ20 °C, mp: 92Ϫ95 °C. [α]2D0 ϭ ϩ5.5 (c ϭ
1
1.39, CHCl3). H NMR (270 MHz, CDCl3): δ ϭ 1.20Ϫ1.00 (m, 1 3.54 mmol, 1.1 equiv.). The mixture was stirred overnight at ambi-
H, 7o-H), 1.80Ϫ1.65 (m,
1
H, 8Ј-H), 1.95Ϫ1.80 [ddd, ent temperature. The excess TBSCl was quenched with MeOH (10
mL). After a further 30 min stirring, the solvent was evaporated at
2J(H4u,H4o) ϭ 12.5, 3J(H4u,H3o) ϭ 12.5, 3J(H4u,H5o) ϭ 10 Hz, 1
H, 4u-H], 2.15Ϫ1.95 (m, 1 H, 8-H), 2.30Ϫ2.18 (m, 1 H, 7u-H), temperatures below 30 °C. The residue was dissolved in Et2O (150
3
2.73Ϫ2.60 (m, 2 H, 4o-,6u-H), 2.80Ϫ2.73 [ddd, J(H5o,H4u) ϭ 10, mL), and the organic phase was extracted with saturated aqueous
3
3J(H5o,H6u) ϭ 4, J(H5o,H4o) ϭ 2 Hz, 1 H, 5o-H], 3.25Ϫ3.15 [dd, NH4Cl to remove the imidazole and dried (Na2SO4). The solvent
2J(H9u,H9o) ϭ 15, 3J(H9u,H8) ϭ 5.5 Hz, 1 H, 9u-H], 3.70Ϫ3.58 [dd, was removed and indolizidinone 15 was isolated as a colorless oil
3
2J(H9o,H9u) ϭ 15, J(H9o,H8) ϭ 11 Hz, 1 H, 9o-H], 4.07Ϫ4.02 [d, pure enough for further transformations. Optional: final extraction
2J(HNϪBn2,HNϪBn1) ϭ 14.5 Hz, 1 H, N-Bn2], 5.03Ϫ4.94 [dd,
with CH2Cl2 and purification by column chromatography on silica
3J(H3o,H4u) ϭ 12.5, J(H3o,H4o) ϭ 1.5 Hz, 1 H, 3o-H], 5.40Ϫ5.30 gel. Yield: 780 mg (2.90 mmol, 90%). [α]2D0 ϭ Ϫ36.2 (c ϭ 0.85,
3
2
[d, J(HNϪBn1,HNϪBn2) ϭ 14.5 Hz, 1 H, N-Bn1], 7.40Ϫ7.20 (m, 5
CHCl3). 1H NMR (270 MHz, CDCl3): δ ϭ 0.00 (s, 6 H, SiϪCH3),
H, Ph-H) ppm. 13C NMR (62.9 MHz, CDCl3): δ ϭ 21.6 (t, C-8), 0.81 [s, 9 H, SiϪC(CH3)3], 1.45Ϫ1.30 (m, 1 H, 7o-H), 1.75Ϫ1.60
29.4 (t, C-7), 38.9 (t, C-4), 44.6 (t, C-9), 47.9 (t, N-Bn), 52.0 (d, C- (m, 2 H, 4u-,8u-H), 1.95Ϫ1.85 (m, 2 H, 4o-,8o-H), 2.35Ϫ2.10 (m,
3), 55.2 (d, C-6), 57.0 (d, C-5), 127.6 (d), 128.1 (d), 128.6 (d), 136.1 2 H, 3o-,7u-H), 2.50Ϫ2.35 [ddd, J(H3u,H) ϭ 18, J(H3u,H) ϭ 7,
2
3
(s), 169.5 (s, C-2) ppm. MS (80 eV, EI, 120 °C): m/z (%) ϭ 281 (11) 3J(H3u,H) ϭ 2 Hz, 1 H, 3u-H], 3.23Ϫ3.13 [ddd, 3J(H6u,H) ϭ 14,
[Mϩ·], 279 (30) [Mϩ·], 244 (40) [Mϩ Ϫ Cl], 188 (5) [Mϩ Ϫ C7H7], 3J(H6u,H) ϭ 8.5, J(H6u,H) ϭ 3.5 Hz, 1 H, 6u-H], 3.50Ϫ3.30 (m,
3
160 (24), 158 (18), 156 (52), 141 (18), 139 (57), 120 (15), 111 (25),
3 H, 5o-,9o-,9u-H) ppm. 13C NMR (67.9 MHz, CDCl3): δ ϭ Ϫ4.9
91 (100), 75 (12). HRMS (80 eV,120 °C): calcd. 279.10206 (for (q, SiϪCH3), Ϫ4.5 (q, SiϪCH3), 17.6 [SiϪC(CH3)3], 21.9 (t, C-8),
C15H18NO235Cl), found 279.10434.
25.4 [SiϪC(CH3)3], 29.9 (t, C-7), 30.6 (t, C-4), 31.9 (t, C-3), 45.4
(t, C-9), 63.9 (d, C-6), 72.0 (d, C-5), 168.0 (s) ppm. IR (CHCl3):
ν˜ ϭ 3018 (s), 1956 (s), 1930 (s), 2885 (m), 2858 (m), 1624 (m), 1470
(m), 1463 (m), 1416 (m), 1387 (w), 1361 (m), 1273 (m), 1257 (m),
1221 (s), 1210 (s), 1128 (m), 1104 (m). 867 (m), 837 (m) cmϪ1. MS
(80 eV, EI, 50 °C): m/z (%) ϭ 269 (1) [Mϩ·], 254 (3) [Mϩ Ϫ CH3],
212 (100) [Mϩ Ϫ C4H9], 156 (4), 138 (18), 129 (19), 115 (9), 101
(7), 83 (18), 73 (12).
(5R,6S)-5-Hydroxyazabicyclo[4.3.0]nonan-2-one (14): A mixture of
the epoxy-azonanones 9a/b (22.3 g, 80 mmol)[37] and Pearlman’s
catalyst (10% Pd(OH)2/C, 2 g, 1.42 mmol) in MeOH (500 mL) was
cooled to 5 °C. The flask was then evacuated (70Ϫ80 mbar) and
refilled with nitrogen (2 ϫ) and hydrogen (3 ϫ). The mixture was
vigorously stirred for 5 h at 5 °C and for another 7 days at room
1
temperature until the H NMR spectrum of an analytical sample
showed no remaining peak originating from α-chlorolactam proton (6S)-Azabicyclo[4.3.0]nonan-2,5-dione (16), (5R,6S)-5-Methyl-5-
[dd at δ ϭ 4.63 ppm (3-H)]. Additionally, all peaks of the aromatic
section (8Ϫ7 ppm in H NMR) should have disappeared. The hy-
drogen was then replaced by nitrogen, solid K2CO3 (26 g, 0.19 mol)
(trimethylsilyloxy)azabicyclo[4.3.0]nonan-2-one (19), and (5R,6R)-5-
Methyl-5-(trimethylsilyloxy)azabicyclo[4.3.0]nonan-2-one (20):
Swern Oxidation: Freshly distilled oxalyl chloride (2.81 mL, 4.09 g,
1
was added, and the mixture was heated to about 45 °C for 6 h to 0.032 mol, 2 equiv.) in dry CH2Cl2 (100 mL) was cooled under
bring about the recyclization of potentially cleaved indolizidinones.
argon to Ϫ78 °C and treated dropwise with DMSO (2.34 mL,
Eur. J. Org. Chem. 2002, 3304Ϫ3314
3311

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
2.58 g, 0.033 mol, 2.05 equiv.) in dry CH2Cl2 (5 mL), the internal
temperature being kept below Ϫ70 °C. After stirring for 1 h at
(1.48 g, 22 mmol, 2 equiv.) and TMSCl (1.76 mL, 13 mmol, 1.2
equiv.) and stirred overnight at ambient temperature. The excess of
about Ϫ70 °C, the mixture was cooled again to Ϫ78 °C and hydro- TMSCl was quenched with MeOH (5 mL) and the solvent was
xyindolizidinone 14 (2.5 g, 0.016 mol) in dry CH2Cl2 (50 mL) was
added slowly. After the mixture had been further stirred at Ϫ55 to
Ϫ60 °C, Et3N (11.0 mL, 0.08 mol, 5 equiv.) was injected slowly at
about Ϫ65 °C. The cooling bath was removed and the mixture was
stirred for 1 h until the temperature reached 20 °C. The solvent was
then removed under reduced pressure and the residue was sus-
pended in EtOAc. The white precipitate of Et3N·HCl was filtered
off and remaining impurities of the salt fraction were removed by
removed at temperatures below 30 °C. The residue was dissolved
in Et2O (150 mL), extracted with saturated aqueous NH4Cl to re-
move the imidazole, and dried (Na2SO4). After evaporation of the
solvent, 2.14 g of the products 19/20 was obtained as a colorless
oil. The diastereomers were separated by preparative HPLC (10%
iPrOH/n-hexane, 32 ϫ 110 mm Nucleosil 50-5, UV ϭ 220 nm, flow
95 mL/min). Yield: 1.23 g (5.13 mmol, 46.6%; retention time
2.8 min) of indolizidinone 20 (colorless oil) and 0.54 g (2.26 mmol,
passing the EtOAc solution through a short silica gel column. After 20.5%; retention time 5.5 min) of indolizidinone 19 (colorless oil).
evaporation of the solvent at temperatures below 30 °C, the crude
ketone 16 was obtained as a colorless oil, which was used without
further purification. Yield: 2.5 g (0.016 mol, 100%) of ketone 16.
(remark: aqueous workup caused severe decreases in the yield be-
cause of the great solubility of 16 in H2O). [α]2D0 ϭ Ϫ245 (c ϭ 1.56,
CHCl3). 1H NMR (270 MHz, CDCl3, showed some minor impurit-
ies of the side product O-MTM ether): δ ϭ 2.00Ϫ1.70 (m, 3 H, 7Ј-,
8o-,8u-H), 2.20Ϫ2.10 (m, 1 H, 7-H), 2.70Ϫ2.40 (m, 4 H, 3o-,3u-,
Data for indolizidinone 19: [α]2D0 ϭ Ϫ35.1 (c ϭ 1.08, CHCl3). 1H
NMR (270 MHz, CDCl3): δ ϭ 0.05 [s, 9 H, HϪSi(CH3)3], 1.25
(s, 3 H, 5-HϪCH3), 1.90Ϫ1.60 (m, 6 H, 8o-,8u-,7o-,7u-,4o-,4u-H),
2.35Ϫ2.21 (m, 1 H, 3u-H), 2.48Ϫ2.35 (m, 1 H, 3o-H), 3.21Ϫ3.14
[dd, 3J(H6u,H7o) ϭ 10, 3J(H6u,H7u) ϭ 5.5 Hz, 1 H, 6u-H],
3.48Ϫ3.38 (m, 2 H, 9o-,9u-H) ppm. 13C NMR (67.9 MHz, CDCl3):
δ ϭ 2.2 [q, Si(CH3)3], 21.9 (t, C-8), 26.2 (t, C-4), 26.3 (q, 5-CH3),
28.3 (t, C-7), 35.2 (t, C-3), 45.7 (t, C-9), 67.4 (d, C-6), 70.4 (s, C-
5), 168.9 (s) ppm. IR (CHCl3): ν˜ ϭ 2975 (m), 2955 (m), 2880 (w),
1621 (s, CϭO), 1470 (m), 1413 (m), 1378 (m), 1316 (w), 1273 (m),
4o-,4u-H), 3.60Ϫ3.30 (m,
2 H, 9o-,9u-H), 3.98Ϫ3.90 [dd,
3J(H6,H7o) ϭ 8, 3J(H6,H7u) ϭ 8 Hz, 1 H, 6-H] ppm. 13C NMR
(67.9 MHz, CDCl3): δ ϭ 22.6 (t), 27.4 (t), 30.5 (t), 34.4 (t), 45.0
(t), 64.5 (d, C-6), 168.7 (s), 207.0 (s, CϭO) ppm. IR (CHCl3): ν˜ ϭ
2983 (m), 2970 (m), 2916 (m), 2891 (m), 1732 (s, CϭO), 1653 (s,
NϪCϭO), 1450 (s), 1381 (m), 1346 (m), 1330 (m), 1321 (m), 1290
(m), 1203 (m), 1177 (m), 1132 (m), 1103 (m) cmϪ1. MS (80 eV, EI,
30 °C): m/z (%) ϭ 153 (100) [Mϩ·], 141 (12), 125 (77), 110 (16), 97
(50), 91 (34), 84 (44), 78 (30), 75 (14), 70 (20). HRMS (80 eV, 30
°C): calcd. 153.078979 (for C8H11NO2 [Mϩ]), found 153.07655.
1265 (m), 1253 (m), 1224 (w), 1134 (m), 1068 (m), 1021 (m) cmϪ1
.
MS (80 eV, EI, 30 °C): m/z (%) ϭ 241 (100) [Mϩ·], 226 (30) [Mϩ
Ϫ CH3], 198 (28), 178 (7), 171 (13), 144 (43), 143 (42), 130 (16),
129 (25), 111 (65), 83 (76), 75 (29), 73 (47), 70 (50). HRMS (80 eV,
30 °C): calcd. 241.149808 (for C12H23N1O2Si [Mϩ]), found
241.14755.
Data for indolizidinone 20: [α]2D0 ϭ Ϫ38.2 (c ϭ 1.30, CHCl3). 1H
NMR (270 MHz, CDCl3): δ ϭ 0.07 [s, 9 H; HϪSi(CH3)3], 1.12 (s,
3 H, 5-HϪCH3), 1.60Ϫ1.50 (m, 1 H, 7o-H), 1.75Ϫ1.60 (m, 1 H,
8u-H), 1.90Ϫ1.80 (m, 3 H, 4o-,4u-,8o-H), 2.00Ϫ1.90 (m, 1 H, 7u-
H), 2.33Ϫ2.18 (m, 1 H, 3o-H), 2.52Ϫ2.40 (m, 1 H, 3u-H),
3.50Ϫ3.30 (m, 3 H, 9o-,9u-,6u-H) ppm. 13C NMR (67.9 MHz,
CDCl3): δ ϭ 2.54 [q, Si(CH3)3], 19.8 (q, CH3), 22.1 (t, C-8), 27.3
(t, C-4), 30.2 (t, C-7), 37.2 (t, C-3), 45.8 (t, C-9), 66.9 (d, C-6), 72.7
(s, C-5), 167.9 (s) ppm. IR (CHCl3): ν˜ ϭ 2976 (m), 2951 (m), 2884
(m), 1624 (s, CϭO), 1649 (m), 1417 (m), 1382 (m), 1299 (w), 1282
(w), 1252 (m), 1216 (m), 1159 (s), 1127 (m), 1072 (m), 1023 (m),
995(w) cmϪ1. MS (80 eV, EI, 30 °C): m/z (%) ϭ 241 (100) [Mϩ·],
226 (20) [Mϩ Ϫ CH3], 206 (8), 198 (28), 144 (43), 143 (44), 130
(18), 129 (28), 111 (64), 83 (75), 75 (48), 73 (59), 70 (48). HRMS
(80 eV, 30 °C): calcd. 241.149808 (for C12H23N1O2Si [Mϩ]), found
241.14787.
Grignard Addition with Methylmagnesium Iodide: MeI (10.6 mL,
0.161 mol) was added dropwise from a dropping funnel to magnes-
ium (5.1 g, 0.193 mol, turnings) in Et2O (10 mL) under argon. The
mixture began to boil under reflux, and subsequent addition of
further portions of Et2O allowed the temperature of the halide/
metal exchange to be controlled. Heating at reflux was continued
for another 30 min after the complete addition of the MeI to give a
gray solution (remaining traces of Mg). The crude ketone 16 (2.5 g,
16.3 mmol) in dry THF (250 mL) was cooled under argon to Ϫ78
°C. The freshly prepared methylmagnesium iodide solution was ad-
ded to this by double-ended needle, while the mixture was stirred
by a mechanical stirrer. The internal temperature was kept below
Ϫ60 °C, and a white precipitate of the magnesium salts appeared.
After stirring at Ϫ78 °C overnight, the mixture was allowed to
warm up to room temperature. The excess of methylmagnesium
iodide was quenched by addition of saturated aqueous NH4Cl (100
mL). All solvents (incl. H2O!) were then removed under reduced
pressure at temperatures below 40 °C. The remaining solid material
was extracted carefully with CH2Cl2 (5 ϫ 250 mL). The solvent was
removed and the crude product was purified by passing through a
short silica gel column (EtOAc/MeOH 3:1) and by preparative
HPLC to separate remaining reactant ketone 16 (25% iPrOH/hex-
ane, 32 ϫ 110 mm Nucleosil 50-5, UV ϭ 220 nm, flow 64 mL/
min). The pure carbinols 17 and 18 were obtained as an inseparable
mixture of diastereomers, yield 4.21 g (12.55 mmol, 77%) For spec-
troscopic data see supplementary material. (Retention time 16:
2 min, carbinols 17/18: 7Ϫ9 min). Some analogous reactions were
carried out with MeLi (Ϫ78 °C, 17/18: 1.8:1), MeMgBr (4 °C, 17/
18: 1:1.1), and MeMgI (0 °C, 17/18: 1:1.9) as methylation reagents.
All reactions were conducted as described for the MeMgI addition
described above.
X-ray Crystallographic Studies
Indolizidinone 6a (CCDC-172938): Colorless, transparent prism
from CH2Cl2/n-hexane at room temp. C8H11ClN2O4 (Mr
ϭ
234.64); crystal dimensions 0.64 ϫ 0.64 ϫ 0.14 mm; monoclinic;
˚
P21, a ϭ 8.8883(18), b ϭ 9.1550(14), c ϭ 12.5246(18) A, Z ϭ 4,
3
V ϭ1006.9(3) A , ρcalcd. ϭ 1.548 g/cm3, T ϭ 146 K, 2Θ max ϭ
˚
66.3°; of the 20,797 reflections measured 6262 were independent
reflections (Rint ϭ 0.0248, ωR ϭ 0.0632, and S ϭ 1.325);
SiemensϪSMART-diffractometer, Mo-Kα radiation (λ ϭ 0.71073
˚
A). The structure was determined by direct methods by the
SHELXS program. 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 by using the
weighting scheme: w(F) ϭ 4·F2/[σ2(F2) ϩ (0.03·F2)2]. The final dif-
ference density was between Ϫ0.175 and ϩ0.228 e/A3.
The mixture of C5 diastereomer carbinols 17/18 (1.85 g, 11 mmol)
The structure contains two crystallographically independent molec-
in dry CH2Cl2 (50 mL) was subsequently treated with imidazole ules. The dimensions of both molecules are very similar. A small
3312 Eur. J. Org. Chem. 2002, 3304Ϫ3314

Synthesis of the Bicyclic Core of Pumiliotoxins
FULL PAPER
difference of 6° is found for the torsion angle about the NϪO single
bond of the nitrate side chains. The conformation of the 1-azabicy-
clo[4.3.0]nonan-9-one group is similar to the conformation of this
group as found in other crystal structures (CSD ref-codes: GON-
JEY, HIHKAK, and PAWTAI): the six-membered ring has a chair
conformation, the five-membered ring has a 7-envelope conforma-
tion. The nitrate group is in an equatorial position with respect to
the six-membered ring. The Cl atoms is in a pseudo-axial position
with respect to the five-membered ring. The nitrogen atoms are
almost planar. The molecules show no significant intramolecular
interactions. The crystal packing shows three intermolecular
CϪH···Cl interactions with H···Cl distances of between 2.93 and
Data Center, 12, Union Road, Cambridge CB2 1EZ, UK; Fax:
(internat.) ϩ44Ϫ1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie, and the Schering Research Foundation for
support of this work.
[1]
[1a] Review on total syntheses 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.
˚
3.03 A and six intermolecular CϪH···O interactions with H···O
˚
distances of between 2.48 and 2.61 A.
[2] [2a]
L. E. Overman, S. W. Goldstein, J. Am. Chem. Soc. 1984,
[2b]
106, 5360Ϫ5361.
C.-H. Tan, T. Stork, N. Feeder, A. B.
Epoxy-azonanone 9a (CCDC-172936): Colorless, transparent prism
from CH2Cl2/n-hexane at Ϫ20 °C. C15H18ClNO2 (Mr ϭ 275.75);
crystal dimensions 0.50 ϫ 0.40 ϫ 0.19 mm; orthorhombic; P212121,
[2c]
Holmes, Tetrahedron Lett. 1999, 40, 1397Ϫ1400.
D. L.
Comins, S. Huang, C. L. McArdle, C. L. Ingalls, Org. Lett.
2001, 3, 469Ϫ472.
˚
[3]
[4]
[5]
a ϭ 9.5482 (16), b ϭ 9.56918 (8), c ϭ 15.0739 (17) A, Z ϭ 4, V ϭ
A. G. M. Barrett, F. Damiani, J. Org. Chem. 1999, 64,
3
1377.3(3) A , ρcalcd. ϭ 1.349 g/cm3, T ϭ 144 K, 2Θ max ϭ 60°; of
1410Ϫ1411.
˚
Y. Ni, G. Zhao, Y. Ding, J. Chem. Soc., Perkin Trans. 1 2000,
3264Ϫ3266.
the 25,245 reflections measured 4509 were independent reflections
(Rint ϭ 0.0377, ωR ϭ 0.0719, and S ϭ 1.203); Siemens-SMART
S. F. Martin, S. K. Bur, Tetrahedron 1999, 55, 8905Ϫ8914.
˚
diffractometer, Mo-Kα radiation(λ ϭ 0.71073 A). The structure was
[6] [6a]
D. N. A. Fox, D. Lathbury, M. F. Mahon, K. C. Molloy,
determined by direct methods by 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 by using the weighting scheme: w(F) ϭ 4·F2/
[σ2(F2) ϩ (0.03·F2)2]. The final difference density was between
Ϫ0.178 and ϩ0.270 e/A3.
T. Gallagher, J. Am. Chem. Soc. 1991, 113, 2652Ϫ2656. [6b] For
a related application in the allo-pumiliotoxin series see: allo-
px 267A, 339 B see: S. W. Goldstein, L. E. Overman, M. H.
[6c]
Rabinowitz, J. Org. Chem. 1992, 57, 1179Ϫ1190.
allo-px
323BЈ see: C.-H. Tan, A. B. Holmes, Chem. Eur. J. 2001, 7,
1845Ϫ1854.
[7]
A. Sudau, W. Münch, U. Nubbemeyer, J.-W. Bats, Chem. Eur.
J. 2001, 7, 611Ϫ621.
[8] [8a]
The conformation of the nine-membered ring is very similar to that
found in the corresponding compound with a TBSO group at-
tached to C7. Differences are only found for the torsion angles
about the C6ϪC7 and C7ϪC8 bonds (about 10°) and for the tor-
sion angles about the NϪC9 and C9ϪC10 bonds (about 5°). The
A. Sudau, W. Münch, U. Nubbemeyer, J.-W. Bats, J. Org.
[8b]
Chem. 2000, 65, 1710Ϫ1720.
for a racemic synthesis of the
unsaturated azoninone see: E. Edstrom, J. Am. Chem. Soc.
1991, 113, 6690Ϫ6691.
L. F. Tietze, T. Eicher, Reaktionen und Synthesen im Organisch-
Chemischen Praktikum, 2nd ed., Thieme, Stuttgart, 1991, p.
135.
[9]
˚
molecule shows a short repulsive intramolecular distance of 2.04 A
between H2 and H8B. The intramolecular O1···H9B distance of
[10]
T. Rosen, S. W. Fesik, D. Chu, T. W. Pernet, G. Andre, Syn-
thesis 1988, 40Ϫ44.
˚
2.28 A approaches the van der Waals contact distance. The crystal
[11] [11a]
packing only shows very weak, intermolecular electrostatic interac-
S. Itsuno, K. Ito, A. Hirao, S. Nakahama, J. Chem. Soc.,
[11b]
˚
˚
tions: H4···Cl: 2.88 A (1/2 ϩ x, 1/2 Ϫ y, 1 Ϫ z), H6b···Cl: 2.99 A
Perkin Trans. 1 1984, 2887Ϫ2893.
C. Deur, M. W. Miller,
˚
L. S. Hegedus, J. Org. Chem. 1996, 61, 2871Ϫ2876.
A. J. Mancuso, D. Swern, Synthesis 1981, 165Ϫ196.
(1/2 Ϫ x, Ϫy, z Ϫ 1/2), H14···Cl: 3.01 A (1/2 Ϫ x, 1 Ϫ y, z Ϫ 1/2),
H15···Cl: 3.07 A (1/2 Ϫ x, 1 Ϫ y, z Ϫ 1/2), H7B···O2: 2.62 A (1 Ϫ
x, 1/2 ϩ y, 1/2 Ϫ z), and H13···O1: 2.69 A (x Ϫ 1/2, 3/2 Ϫ y, 1 Ϫ z).
[12]
[13] [13a]
˚
˚
E. J. Corey, R. Greenwald, M. Chaykovsky, J. Org. Chem.
˚
[13b]
1963, 28, 1128Ϫ1129.
Carroll, J. Org. Chem. 1966, 31, 2933Ϫ2941.
shall, W. F. Huffmann, J. A. Ruth, J. Am. Chem. Soc. 1972, 94,
J. A. Marshall, M. T. Pike, R. D.
[13c]
J. A. Mar-
Epoxy-azonanone 9b (CCDC-172937): Colorless, transparent block
from product oil at Ϫ20 °C. C15H18NO2Cl (Mr ϭ 275.75); crystal
dimensions 1.00 ϫ 0.80 ϫ 0.43 mm; orthorhombic; P212121, a ϭ
[13d]
4691Ϫ4696.
2713Ϫ2716.
G. Magnusson, Tetrahedron Lett. 1977,
˚
8.9639(16), b ϭ 11.9771(13), c ϭ 13.5890(15) A, Z ϭ 4, V ϭ
[14]
For detailed information see supporting information.
3
1458.9(3) A , ρcalcd. ϭ 1.247 g/cm3, T ϭ 202 K, 2Θ max ϭ 62°; of
˚
[15] [15a]
G. A. Olah, M. Nojima, I. Kerekes, Synthesis 1973,
[15b]
the 30,222 reflections measured 4621 were independent reflections
487Ϫ488.
89, 862Ϫ864.
G. A. Olah, S. Kuhn, S. Beke, Chem. Ber. 1956,
(Rint ϭ 0.0268, ωR ϭ 0.1522, and S ϭ 1.049); Siemens-SMART-
[16] [16a]
˚
diffractometer, Mo-Kα radiation(λ ϭ 0.71073 A). The structure was
The Schlögl nomenclature is used to describe the planar
chiral properties: K. Schlögl, Top. Curr. Chem. 1984, 125,
27Ϫ62. [16b] Alternatively: use of P (pR) and M (pS): V. Prelog,
G. Helmchen, Angew. Chem. 1982, 94, 614Ϫ631; Angew. Chem.
Int. Ed. Engl. 1982, 21, 567Ϫ583.
determined by direct methods by 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 by using the weighting scheme: w(F) ϭ 4·F2/
[σ2(F2) ϩ (0.03·F2)2]. The final difference density was between
Ϫ0.349 and ϩ0.252 e/A3.
[17]
Preliminary kinetic investigations of the conversion of pS-3a
into pR-3a: half-life period at 43 °C: 347 min, half-life period
at 55 °C: 84 min, half-life period at 65 °C: 26.4 min, half-life
period at 75 °C: 10.5 min, activation energy (∆G*) of the epi-
merization: about 24 kcal·molϪ1 (ϩ/Ϫ3).
CCDC-172938 (6a), CCDC-172936 (9a), and CCDC-172937(9b)
contain 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
[α]2D0, CHCl3: pS-3a: Ϫ44.8; pR-3a: Ϫ147.5; pS-3b: ϩ121.9
(enantiomer of pR-3a).
[18]
[19]
For detailed information on NOE data see supporting informa-
tion
Eur. J. Org. Chem. 2002, 3304Ϫ3314
3313

A. Sudau, W. Münch, J.-W. Bats, U. Nubbemeyer
FULL PAPER
[20]
[30]
Azoninone pS-3a was characterized by the coexistence of two
E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,
6190Ϫ6191.
conformers that could not be separated by means of HPLC.
However, in the 1H NMR spectrum the signals could be as-
signed and the nature of the conformational change was deter-
mined by NOE measurements.
[31] [31a]
K. Paulvannan, J. R. Stille, Tetrahedron Lett. 1993, 34,
[31b]
6673Ϫ6676.
G. Ageno, L. Banfi, G. Cascio, G. Guanti, E.
Manghisi, R. Riva, R. Rocca, Tetrahedron 1995, 51,
8121Ϫ8134. [31c] C.-H. Tan, T. Stork, N. Feeder, A. B. Holmes,
Tetrahedron Lett. 1999, 40, 1397Ϫ1400.
[21]
The stereochemical outcome of the reaction can be described
as a sequence of two consecutive inversions.
R. C. Cambie, B. A. Hume, P. S. Rutledge, P. D. Woodgate,
[32]
[33]
D. M. Hodgson, C. R. Maxwell, I. R. Matthews, Synlett
1998, 1349Ϫ1350.
[22]
Aust. J. Chem. 1983, 36, 2569Ϫ2574.
R. H. Peters, D. F. Crowe, M. A. Avery, W. K. M. Chong, M.
For synthesis and spectroscopic data for the unprotected indol-
[23]
izidinones 17 and 18 see supplementary material, refs.[3Ϫ5,6a]
,
Tanabe, J. Med. Chem. 1989, 32, 2306Ϫ2310.
X-ray analyses were obtained from nitrate 6a and the epoxides
[33a]
and:
A. Azzouzi, M. Dufour, J.-C. Gramain, R. Remuson,
[24]
Heterocycles 1988, 27, 133Ϫ148. [33b] J. Cossy, M. Cases, D. G.
Pardo, Bull. Soc. Chim. Fr. 1997, 134, 141Ϫ144.
9a and 9b. For detailed data see supporting information and
information deposited with the Cambridge Data Centre. X-ray
data for nitrate 6a (CCDC-172938): colorless, transparent
prism crystallized from CH2Cl2/n-hexane at room temp..
C8H11ClN2O4 (Mr ϭ 234.64); crystal dimensions 0.64 ϫ 0.64
ϫ 0.14 mm; monoclinic; P21 (Figure 3). X-ray data for epoxide
9a (CCDC-172936): colorless, transparent prism crystallized
[34]
The reaction was carried out similarly with the crude mixture
of pS-3a/b. The separation of higher quantities of the diastere-
omer epoxides 9a and 9b was successfully accomplished by
HPLC: 63 ϫ 187 mm Nucleosil 50-5 column, flow 250 mL/
min, UV 254 nm, 20% EtOAc/n-hexane, injected as a solution
in CH2Cl2, retention times 12 and 15 min. The removal of the
solvent should be carried out under mild thermal conditions
(30Ϫ40 °C) because the epoxides tend to rearrange to the more
stable lactones 11.
from CH2Cl2/n-hexane at Ϫ20 °C. C15H18ClNO2 (Mr
ϭ
275.75); crystal dimensions 0.50 ϫ 0.40 ϫ 0.19 mm; ortho-
rhombic; P212121 (Figure 3). X-ray data for epoxide 9b
(CCDC-172937): colorless, transparent block crystallized from
product oil at Ϫ20 °C. C15H18ClNO2 (Mr ϭ 275.75); crystal
dimensions 1.00 ϫ 0.80 ϫ 0.43 mm; orthorhombic; P212121
(Figure 4).
[35]
The position of the protons of the two conformers 9a-major
1
and 9a-minor in the H NMR spectrum could be determined
from a magnetization transfer during the NOE experiment on
9a resulting from a fast chemical equilibration between 9a-ma-
jor and 9a-minor. The assignment of the three-dimensional
structure is from the structural correlation of the protons with
the change of the characteristic 4J coupling between the first
H-9/N-Bn pair and the second during the course of the iso-
merization.
[25] [25a] For intermediate acylaziridinium ions see: G. V. De Lucca,
[25b]
J. Org. Chem. 1998, 63, 4755Ϫ4766.
ment via aziridinium salts, see: A. El Nemr, Tetrahedron 2000,
56, 8579Ϫ8629.
For ring rearrange-
[26] [26a]
M. Imuta, H. Ziffer, J. Org. Chem. 1979, 44, 1351Ϫ1352.
N. N. Schwartz, H. Blumbergs, J. Org. Chem. 1964, 29,
Peak assignment based on 13C-1H-HMQC spectrum
(500 MHz) in combination with DEPT and 1H-1H-COSY
spectra (Peaks of the minor conformer are marked as C-3Ј)
The pure mixture of 9a/b could also be used instead of the
crude epoxy-azonanones 9a/b immediately after the workup of
the epoxidation step. The yield was somewhat higher in this
case.
[36]
[37]
[26b]
1976Ϫ1979.
[27] [27a]
S. E. Denmark, P. A. Barsanti, K.-T. Wong, R. A.
[27b]
Stavenger, J. Org. Chem. 1998, 63, 2428Ϫ2429.
C. E. Gar-
rett, C. G. Fu, J. Org. Chem. 1997, 62, 4534Ϫ4535.
J. H. Cooley, E. J. Evain, Synthesis 1989, 1Ϫ7.
For a synthesis of 14 (no data published) see: M. G. M. DЈOca,
R. A. Pilli, I. Vencato, Tetrahedron Lett. 2000, 41, 9709Ϫ9712.
[28]
[29]
Received March 27, 2002
[O02179]
3314
Eur. J. Org. Chem. 2002, 3304Ϫ3314