Pyrrolizidine alkaloids by intramolecular palladium-catalysed allylic alkylation: Synthesis of (±)-isoretronecanol

Article abstract of DOI:10.1002/ejoc.200400135

An efficient and stereoconvergent approach to 3-substituted hexahydroindol-2-one derivatives by palladium-catalysed intramolecular allylic alkylation has been developed. Subsequently, the straightforward conversion of the hexahydroindol-2-one 7d into the alkaloid (±)-isoretronecanol has been performed. The synthesis entails 11 steps starting from 1,3-cyclohexadiene, affording the final target in a 29% overall yield. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400135

FULL PAPER
Pyrrolizidine Alkaloids by Intramolecular Palladium-Catalysed Allylic
Alkylation: Synthesis of (؎)-Isoretronecanol
[a]
[b]
[a]
[a]
´
Sebastien Lemaire, Giuliano Giambastiani, Guillaume Prestat, and Giovanni Poli*
Keywords: Alkaloids / Allylic alkylation / Palladium / Synthetic methods
An efficient and stereoconvergent approach to 3-substituted
hexahydroindol-2-one derivatives by palladium-catalysed
intramolecular allylic alkylation has been developed. Subse-
performed. The synthesis entails 11 steps starting from 1,3-
cyclohexadiene, affording the final target in a 29% overall
yield.
quently, the straightforward conversion of the hexahydroin- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
dol-2-one 7d into the alkaloid ( )-isoretronecanol has been
Germany, 2004)
Introduction
The last few years have witnessed a growing interest in
the development of new synthetic methodologies toward
pyrrolizidine alkaloids[1] such as isoretronecanol (1),[2] lab-
urnine (2),[3] and amphorogynine A (3)[4,5] (Figure 1).
Scheme 1
As a logical extension of this study, and in order to ob-
tain synthetically more interesting structures, we decided to
direct our investigations toward the cyclisation of alkyl-
bridged allylamides 6, so as to obtain, after cyclisation, bi-
cyclic 3,4,5-trisubstituted pyrrolidone systems 7.[7] Further-
more, we anticipated that double-bond cleavage of these
new bicyclic structures might lead to interesting synthetic
applications in the alkaloid field such as, for example, the
synthesis of isoretronecanol (1) (Scheme 2).
Figure 1. Pyrrolizidine alkaloids: (ϩ)-isoretronecanol (1); (ϩ)-lab-
urnine (2); amphorogynine A (3)
We have previously reported an efficient method for the
preparation of trans-3,4-disubstituted pyrrolidin-2-ones 5
by palladium-catalysed intramolecular allylic alkylation of
the N-allylamides 4 (Scheme 1).[6]
[a]
Laboratoire de Chimie Organique, UMR 7611 CNRS,
´
Universite Pierre et Marie Curie,
Scheme 2. General strategy toward bicyclic 3,4,5-trisubstituted pyr-
ˆ
4, Place Jussieu Boıte 183, 75252, Paris, France
rolidones and isoretronecanol [(Ϯ)-1]
Fax: (internat.) ϩ 33-1-44277567
E-mail: poli@ccr.jussieu.fr
[b]
CNR, Institute of Chemistry of Organometallic Compounds
ICCOM, Florence Research Area,
Such a variant involves new stereochemical implications
Via Madonna del Piano, 50019 Sesto Fiorentino, Firenze, Italy that were absent in the previous study. Indeed, in this case,
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DOI: 10.1002/ejoc.200400135
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Pyrrolizidine Alkaloids by Intramolecular Palladium-Catalysed Allylic Alkylation
FULL PAPER
the allylic amine necessary to build up the cyclisation pre- gave the desired allylic amine trans-9. Finally, standard
cursor is chiral. As a consequence, the stereogenic units al- acylation of the resulting amine with methyl 3-chloro-3-
ready present on the precursor may govern the diastereosel- oxopropionate or (phenylsulfonyl)acetic acid (DCC, cat.
ectivity of the cyclisation. Moreover, the use of enantiopure DMAP) gave the desired amides trans-6a and trans-6b,
precursors is conceivable. Accordingly, investigations to ob- respectively (Scheme 4).
tain bicyclic 3,4,5-trisubstituted pyrrolidone systems 7 were
first addressed.
Results and Discussion
Preparation of cis- and trans-Cyclohexenylamides
In order to study the key cyclisation step, both the cis
and trans precursors 6 were required. 1,3-Cyclohexadiene
was converted into cis-4-chloro-2-cyclohexen-1-yl acetate
(cis-8) and then into the corresponding cis-4-amino-2-cyclo-
Scheme 4. Synthesis of the allylamide precursors trans-6a,b; re-
agents and conditions: (i) ref.[8]; (ii) a: NEt3, MeOH/H2O, room
temp., 10 h, 73%; b: Ac2O, DMAP, Py, CH2Cl2, room temp., 17 h,
53%; (iii) NCS, PPh3, THF, 16 h, 97%; (iv) cat. Pd2dba3·CHCl3,
PPh3, BnNH2, THF, room temp., 10 h, 87%; (v) trans-6a:
hexen-1-yl acetates cis-9a,d by reaction with benzylamine
or 4-methoxybenzylamine (PMB-NH2), according to
Bäckvall’s procedure.[8,9] Standard treatment of the re-
sulting secondary amines with methyl 3-chloro-3-oxopro-
pionate, (phenylsulfonyl)acetic acid (with DCC and
DMAP), or cyanoacetic acid (with DCC and DMAP), gave
the 1,4-disubstituted amides cis-6aϪd (Scheme 3).
MeO2CCH2COCl, Et3N, CH2Cl2,
0 °C, 2 h, 94%; trans-6b:
PhSO2CH2CO2H, DCC, THF, room temp., 10 h, 92%
Palladium-Catalysed Cyclisation
With these precursors in hand, attention was turned to
the crucial cyclisation step. Gratifyingly, when the cis pre-
cursors cis-6a,b,d were treated with NaH (1.0 equiv.) and
added to
a DMF solution of the catalytic system
[Pd(OAc)2/1,2-bis(diphenylphosphanyl)ethane (dppe)], the
expected bicyclic amides 7a,b,d were isolated, all in 90%
yield (Scheme 5, Method A). Further experiments with cis-
6a showed that a catalytic amount of NaH (0.1 equiv.) was
sufficient to effect the cyclisation, with an unchanged 90%
yield. In contrast, the absence of NaH totally prevented the
cyclisation. In these three cases a single diastereoisomer was
formed. The coupling constant values in the 1H NMR spec-
trum of the bicyclic products suggest the presence of a cis
junction between the two rings, and a trans disposition be-
Scheme 3. Synthesis of the allylamide precursors cis-6aϪd; reagents
and conditions: (i) ref.[8], 90%; (ii) cis-9a: cat. Pd2dba3·CHCl3,
PPh3, BnNH2, THF, room temp., 12 h, 95%; cis-9d: PMB-NH2,
cat. Pd(OAc)2, PPh3, PhCH3, room temp., 10 h, 73%; (iii) cis-6a:
MeO2CCH2COCl, NEt3, CH2Cl2,
0 °C, 2 h, 94%; cis-6b:
PhSO2CH2CO2H, DCC, DMAP, THF, room temp., 12 h, 93%; cis-
6c: NCCH2CO2H, DCC, DMAP, THF, room temp., 12 h, 90%; cis-
6d: MeO2CCH2COCl, Et3N, CH2Cl2, 0 °C, 2 h, 88%
Accessing the corresponding trans analogues trans-6
proved to be more challenging. Indeed, nucleophilic substi-
tution (in the absence of palladium catalyst) of cis-4-chloro-
2-cyclohexen-1-yl acetate (cis-8) by benzylamine led to an
inseparable mixture of the corresponding allylamines cis-
9a and trans-9a in a 30:70 ratio. An alternative route was
therefore devised.
The diacetate cis-10, in turn obtained from 1,3-cyclo-
hexadiene,[10] was converted into the corresponding
[11]
´
monoacetate cis-11 by Zemplen-type methanolysis
fol-
Scheme 5. Palladium-catalysed cyclisation of the allylamides cis-
6aϪd and trans-6a,b; reagents and conditions: (i) Method A: a:
NaH (1.0 equiv.), b: Pd(OAc)2 (1.0 mol %), dppe (2.0 mol %),
DMF, 50 °C, 0.5 h, 7a 90%, 7b 90%, 7c 87%, 7d 90%; (ii) Method
B: a: NaH (1.0 equiv.), b: Pd(OAc)2 (5.0 mol %), dppe (10 mol %),
lowed by monoacetylation under controlled conditions.
Treatment of cis-11 with NCS/PPh3 gave trans-4-chloro-2-
cyclohexen-1-yl acetate (trans-8). Subsequent palladium-
catalysed allylic amination in the presence of benzylamine DMF, 100 °C, 0.5 h, 7a 60%, 7b 73%
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S. Lemaire, G. Giambastiani, G. Prestat, G. Poli
FULL PAPER
tween the electron-withdrawing group (EWG) and the car-
bon atom of the six-membered ring directly bound to the
vicinal position.[12] When the nitrile precursor cis-6c was
submitted to the same conditions as above (Scheme 5,
Method A), the expected cis-fused bicyclic product 7c was
obtained in 87% yield. However, in this case, a 60:40 insep-
arable mixture of diastereoisomers was obtained
(Scheme 5).
Cyclisation of the precursors trans-6a and trans-6b was
then addressed. Surprisingly, these transformations re-
quired harsher reaction conditions, and afforded the cis-
fused bicycles 7a and 7b as single diastereoisomers. Thus,
cyclisation of the trans-fused isomers gave the same product
as previously obtained from the corresponding cis-fused
ones, though in somewhat lower yields (Scheme 5, Method
B; 7a 60%, 7b 73%).
Scheme 7. Stereoconvergence of allylamides cis-6a and trans-6a
On the other hand, cyclisation of the precursor trans-6a
follows a less canonical path. We believe that the ionisation
step takes place with the usual inversion mechanism, so as
to form the expected η3-allyl system B (Scheme 7). How-
ever, in this case, intramolecular addition of the carbanion
anti to the palladium atom may be a forbidden process, as
the pseudo-equatorial CϪN bond disposition of the re-
acting complex is likely to prevent a correct orbital overlap.
As a result, the η3-allyl complex B may have enough time
to isomerize to complex A, the same as obtained from the
corresponding cis-fused isomer cis-6a. Although isomeri-
sation of (η3-allyl)palladium complexes is normally expected
to proceed by a π-σ-π mechanism,[14] such a pathway is ob-
viously not available to cyclic systems such as those under
consideration. As a consequence, B-to-A isomerisation ap-
pears to take place by a Pd0-promoted SN2-type substi-
tution, as first reported by Bäckvall et al.[15] and recently
confirmed by Amatore, Jutand, Moreno-Man˜as et al.[16]
Interestingly, an analogous behaviour of contrasting reac-
tivity between cis and trans vicinally substituted six-mem-
bered precursors has been reported by Oppolzer[17] and by
Bäckvall[18] in alkene- and allene-based carbopalladations,
respectively.
Plausible Reaction Mechanisms
The different behaviour between cis-6a,b,d, and cis-6c
may be accounted for by considering that a base-promoted
equilibration of the final products, by the acetate anion lib-
erated in the medium, is likely to take place. As a conse-
quence, while the methoxycarbonyl and phenylsulfonyl de-
rivatives strongly prefer to place these rather bulky groups
in the less-congested convex portion of space, location of
the small and linear nitrile function is likely to be immate-
rial in terms of energy differentiation in 7c (Scheme 6).
In order to stress the effectiveness of our methodology,
the synthesis of 12a, a compound already reported by Ogas-
awara et al. in enantiopure form,[2p] was undertaken. As
expected, simple decarboxylation of 7a under classical
Krapcho conditions[19] led to 12a in high yield (Scheme 8).
Interestingly, our synthetic route to 12a, though racemic,
compares favourably with the already reported one in terms
of straightforwardness and efficiency.[20]
Scheme 6. Isomerisation between epimeric hexahydroindol-2-one
derivatives 7
A mechanistic hypothesis that rationalises the stereocon-
vergence of cis-6 and trans-6 is depicted in Scheme 7. Ad-
dition of the Pd0 complex to the cis-fused allylic acetate is
expected to proceed with an inversion mechanism, as orig-
inally demonstrated by Hayashi,[13] so as to afford the (η3-
allyl)palladium intermediate A. In this complex, the nitro-
gen substituent occupies a pseudo-axial position and cycli-
sation can smoothly ensue, again with an inversion mecha-
nism, affording the cis-fused adduct 7a.
Scheme 8. Decarboxylation of hexahydroindol-2-one 7a; reagents
and conditions: (i) NaCl, wet DMSO, 10 h, 155 °C, 90%
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Pyrrolizidine Alkaloids by Intramolecular Palladium-Catalysed Allylic Alkylation
FULL PAPER
All the above experiments were carried out on racemic tions, thereby generating (Ϯ)-isoretronecanol (1) in 80%
substrates. Nonetheless, as the ensemble of transformations yield. This material proved identical in all respects, except
9 Ǟ 7 are expected to respect the configurational integrity optical rotation, with the natural product.[25]
of the stereogenic carbon atom linked to the nitrogen atom
(C-1 in 9), it can be reasonably anticipated that repetition
of the sequence on the enantiopure allylic amine cis-9 or
trans-9 should afford the bicyclic compounds 7 with undi-
Conclusion
minished enantiopurity. Interestingly, Bäckvall et al. have
reported that enzymatic desymmetrisation of the meso-di-
acetate 10 allowed preparation of the amine cis-9 in highly
enantioenriched form.[21] As a consequence, we have devel-
oped an easy and stereoconvergent access to bicyclic 3,4,5-
trisubstituted pyrrolidone systems 7, which is, in principle,
directly transposable to enantioenriched substrates.
In summary, we have developed an efficient and stereo-
convergent route to 3-substituted hexahydroindol-2-one de-
rivatives featuring a palladium-catalysed intramolecular al-
lylic alkylation as the key step. Further manipulation of the
hexahydroindol-2-one 7d allowed the straightforward con-
version of this intermediate into isoretronecanol [(Ϯ)-1].
The synthesis entails 11 steps starting from 1,3-cyclohexadi-
ene affording the final target in a 29% overall yield. We
believe that the above devised methodology extends the syn-
thetic potential of the palladium-catalysed allylation reac-
tion and may be adaptable to the preparation of other re-
lated pyrrolizidine derivatives.
Synthesis of (؎)-Isoretronecanol
The ready availability of the bicyclic amides 7aϪd
prompted us to exploit the above-described palladium-cata-
lysed cyclisation strategy in a synthetic application. Our
choice focused on isoretronecanol (1),[2] an alkaloid isolated
from Planchonella sp.[22] and Phalaenopsis equestris.[23]
In this instance, decarboxylation of the PMB-substituted
bicyclic amide 7d under Krapcho’s conditions[19] led to the
quantitative formation of 12d (Scheme 9). Subsequent cis-
dihydroxylation with cat. OsO4 and Me3NO in THF/H2O
gave the corresponding diol, which was directly submitted
to periodate cleavage. NaBH4 reduction of the thus formed
dialdehyde in situ provided diol 13 in a 95% overall yield for
the sequence. Judging a selective alcohol functionalisation a
difficult and unnecessary (vide infra) task,[2p] diol 13 was
then converted into the ditosylate derivative 14 in 82%
Experimental Section
General Remarks: All reactions were conducted under dried nitro-
gen or argon using oven-dried glassware. For air- and/or water-
sensitive reactions, glassware was flame-dried and then allowed to
cool under argon or dried nitrogen before use. All solvents were
purified and distilled according to standard methods. Chromato-
graphic purifications were conducted using 40Ϫ63 µm or 15Ϫ40
µm silica gel. All NMR spectra were recorded in CDCl3. Elemental
analyses were carried out with accepted tolerance of Ϯ0.3 units on
C, H and N. All compounds were isolated as oils unless otherwise
yield. Oxidative removal of the PMB protecting group with stated, and their purities were determined to be Ͼ 95% by NMR
CAN[24] afforded the corresponding secondary amide 15.
analysis. IR spectra were recorded with a PerkinϪElmer 1420. Ab-
sorption bands are reported in cmϪ1. NMR spectra were recorded
with either a Varian-Gemini 200/50 MHz or a Bruker ARX 400/
100 MHz. Chemical shifts (δ) are reported in parts per million
(ppm) down-field and high-field from the residual-solvent peak.
Treatment of the latter amide with NaH triggered a clean 5-
exo-tet cyclisation, leading to the pyrrolizidinone 16. After
quantitative tosylate-to-acetate replacement, treatment of
the thus formed bicyclic acetoxy amide 17 with LiAlH4 ef-
GC-MS spectra were recorded with a Shimadzu GC-17A and Shi-
fected concomitant reduction of the ester and amide func-
madzu Mass-spectrometer QP-5000.
General Procedure for Acylation with Methyl Chlorocarbonylacet-
ate: NEt3 (0.681 mL, 4.9 mmol) and methyl chlorocarbonylacetate
(0.394 mL, 3.675 mmol) were added dropwise in sequence to a
solution of the allylic amine (2.45 mmol) in CH2Cl2 (30 mL) cooled
to 0 °C. After 4 h of stirring at room temp., the mixture was diluted
with diethyl ether (50 mL) and water (3 ϫ 20 mL). The collected
organic layers were dried with MgSO4 and the solvents evaporated
under reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/ethyl acetate, 5:5) to afford the
desired product as a yellow oil.
(؎)-Methyl 3-{[(1S,4R)-4-(Acetyloxy)cyclohex-2-en-1-yl](benzyl)-
amino}-3-oxopropanoate (cis-6a): From cis-9a[21] (94%). 1H NMR
(CDCl3, 200 MHz): δ ϭ 7.39Ϫ7.18 (m, 5 H), 5.98Ϫ5.86 (m, 1 H),
3
5.78 (d, J ϭ 10.3 Hz, 1 H), 5.32Ϫ5.21 (m, 1 H, 70%), 5.11 (m, 1
Scheme 9. Conversion of hexahydroindol-2-one 7d into isoretrone-
H), 4.54 (AB system, 2 H, 30%), 4.49 (AB system, 2 H, 70%), 2.02
(s, 3 H, 30%), 1.98 (s, 3 H, 70%), 1.54Ϫ1.86 (m, 4 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ ϭ 169.4, 167.4, 167.2, 166.7, 165.6,
137.9, 137.0, 133.4, 133.1, 128.2, 128.1, 127.8, 127.6, 126.7, 126.3,
126.0, 125.0, 64.4, 63.8, 55.2, 51.7, 51.6, 51.0, 47.3, 46.0, 40.8, 40.7,
26.2, 26.2, 23.1, 21.8, 20.5 ppm. IR (CCl4): ν˜ ϭ 2958, 2248, 1721,
canol [(Ϯ)-1]; reagents and conditions: (i) NaCl, wet DMSO, 10 h,
155 °C, 99%; (ii) a: cat. OsO4, Me3NO·2H2O, THF/H2O (10:1),
room temp.; 12 h. b: NaIO4, MeOH, room temp.; 1 h; c: NaBH4,
MeOH; 2 h, 95% over 3 steps; (iii) TsCl, NEt3, DMAP, CH2Cl2,
room temp.; 5 h, 82%; (iv) CAN, CH3CN/H2O, 0 °C, 5 h, 89%; (v):
NaH, 0 °C Ǟ room temp., 12 h, quant.; (vi) Bu4NOAc, cat. NaI,
THF, 55 °C, 8 h, quant.; (vii) LiAlH4, THF, 66 °C, 2 h, 80%
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S. Lemaire, G. Giambastiani, G. Prestat, G. Poli
1639 cmϪ1. MS (EI): m/z (%) ϭ 345 [Mϩ] (2), 286 (14), 206 (9), 91 125.4, 68.7, 68.5, 60.5, 60.0, 56.3, 52.0, 47.4, 46.6, 27.9, 27.7, 27.5,
FULL PAPER
(100). C19H23NO5 (345.40): calcd. C 66.07, H 6.71, N 4.06; found
C 66.21, H 6.77, N 4.09.
25.8, 21.1 ppm. IR (CH2Cl2): ν˜ ϭ 3058, 2990, 1727, 1644, 1419,
1247 cmϪ1. MS (EI): m/z (%) ϭ 368 (26.3) [Mϩ Ϫ 59], 141 (12),
77 (81.2). C23H25NO5S (427.52): calcd. C 64.62, H 5.89, N 3.28;
found C 64.64, H 5.87, N 3.21.
(؎)-Methyl 3-{[(1S,4S)-4-(Acetyloxy)cyclohex-2-en-1-yl](benzyl)-
amino}-3-oxopropanoate (trans-6a): From trans-9[21] (94%). 1H
NMR (CDCl3, 200 MHz): δ ϭ 7.16Ϫ7.35 (m, 5 H), 5.78 (m, 1 H),
5.62 (m, 1 H), 5.20Ϫ5.42 (m, 2 H), 4.51 (AB system, 2 H, 30%),
4.45 (AB system, 2 H, 70%), 3.77 (s, 3 H, 30%), 3.69 (s, 3 H, 70%),
3.61 (s, 2 H, 30%), 1.40Ϫ2.21 (m, 4 H), 3.30 (s, 2 H, 70%), 2.03 (s,
3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 170.2, 167.7, 167.1,
165.9, 138.0, 137.1, 131.5, 130.8, 128.6, 128.0, 127.2, 126.6, 126.5,
125.3, 68.6, 68.4, 55.5, 52.1, 51.4, 47.4, 46.0, 41.3, 27.7, 27.6, 27.2,
25.6, 20.9 ppm. IR (CHCl3): ν˜ ϭ 3045, 2957, 1730, 1643 cmϪ1. MS
(EI): m/z (%) ϭ 346 [Mϩ] (1.2), 286 (11), 106 (53), 91 (78).
C19H23NO5 (345.40): calcd. C 66.07, H 6.71, N 4.06; found C
66.18, H 6.83, N 4.12.
(؎)-(1S,4R)-4-[Benzyl(cyanoacetyl)amino]cyclohex-2-en-1-yl Acet-
1
ate (cis-6c): From cis-9a (90%): H NMR (CDCl3, 400 MHz): δ ϭ
7.42Ϫ7.20 (m, 5 H), 5.35Ϫ5.28 (m, 1 H, 50%), 5.20Ϫ5.16 (m, 1 H),
2
2
4.72 (AB system, J ϭ 15.4 Hz, 1 H, 25%), 4.54 (AB system, J ϭ
18.2 Hz, 1 H, 75%), 4.49 (AB system, 2J ϭ 18.2 Hz, 1 H, 75%),
4.43 (AB system, 2J ϭ 15.4 Hz, 1 H, 25%), 4.30Ϫ4.20 (m, 1 H,
2
20%), 3.90 (AB system, J ϭ 13 Hz, 1 H, 30%), 3.86 (AB system,
2J ϭ 13 Hz, 1 H, 30%), 3.89 (AB system, 2J ϭ 18.5 Hz, 1 H, 20%),
2
2
3.64 (AB system, J ϭ 18.5 Hz, 1 H, 20%), 3.33 (AB system, J ϭ
2
19 Hz, 1 H, 50%), 3.29 (AB system, J ϭ 19 Hz, 1 H, 50%), 3.32
(m, 1 H, 30%), 2.08 (s, 3 H, 20%), 2.06 (s, 3 H, 30%), 2.05 (s, 3 H,
50%), 1.58Ϫ1.93 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
1710.6, 170.7, 163.5, 162.1, 137.0, 135.8, 133.1, 129.8, 128.8, 128.4,
127.3, 126.1, 125.9, 114.2, 67.6, 65.3, 64.9, 52.8, 52.7, 51.4, 48.3,
(؎)-Methyl 3-{[(1S,4R)-4-(Acetyloxy)cyclohex-2-en-1-yl](4-meth-
oxybenzyl)amino}-3-oxopropanoate (cis-6d): From cis-9d[9] (88%).
1H NMR (CDCl3, 400 MHz): δ ϭ 7.21 (d, 2J ϭ 8.7 Hz, 2 H, 34%),
27.1, 26.4, 26.2, 25.7, 23.0, 21.57 ppm. IR (neat): ν˜ ϭ 2980 cmϪ1
,
2
2
7.13 (d, J ϭ 8.7 Hz, 2 H, 66%), 6.90 (d, J ϭ 8.7 Hz, 2 H, 34%),
2280, 1740, 1670, 1450. C18H20N2O3 (312.37): calcd. C 69.21, H
6.45, N 8.97; found C 69.35, H 6.55, N 9.12.
6.83 (d, 2J ϭ 8.7 Hz, 2 H, 34%), 5.93 (m, 1 H), 5.80 (m, 1 H), 5.23
(m, 1 H, 66%), 5.14 (m, 1 H), 4.67 (AB system, J ϭ 15 Hz, 1 H,
2
34%), 4.49 (AB system, 2J ϭ 17.8 Hz, 1 H, 34%), 4.41 (AB system,
2J ϭ 17.8 Hz, 1 H, 66%), 4.35 (AB system, 2J ϭ 15 Hz, 34%, 1 H),
4.25 (m, 1 H, 34%), 3.80 (s, 3 H, 66%), 3.78 (s, 3 H, 34%), 3.77 (s,
3 H, 34%), 3.70 (s, 3 H, 66%), 3.60 (s, 2 H, 34%), 3.32 (s, 2 H,
66%), 2.05 (s, 3 H, 34%), 2.01 (s, 3 H, 66%), 1.6Ϫ1.8 (m, 4 H) ppm.
13C NMR (CDCl3, 100 MHz): δ ϭ 170.8, 168.4, 167.9, 159.4, 134.3,
129.8, 129.2, 129.0, 128.9, 127.6, 114.8, 114.2, 64.9, 56.6, 56.3, 55.7,
52.8, 52.2, 47.9, 41.9, 27.4, 27.3, 24.1, 22.9, 21.7 ppm. IR (neat):
ν˜ ϭ 1730 cmϪ1, 1640, 1430. C20H25NO6 (375.42): calcd. C 63.99,
H 6.71, N 3.73; found C 64.02, H 6.79, N 3.82.
General Procedure for the [Pd(OAc)2/PPh3]-Catalysed Intramolecu-
lar Allylic Alkylation. Method A: NaH (60% dispersion in mineral
oil; 1.36 mmol) was added to a solution of the cyclisation precursor
(1.36 mmol) in dry DMF (5 mL) under argon, cooled in a water/
ice bath, and the solution was stirred at room temp. for 10 min. In
a separate flask, Pd(OAc)2 (0.0136 mmol) and dppe (0.0272 mmol)
were dissolved in dry DMF (2 mL). The resulting enolate was then
transferred with a cannula under argon pressure to the preformed
palladium(0) complex, and the resulting mixture was stirred at 50
°C for 30 min. After cooling at room temp. and dilution with a
saturated aqueous solution of NH4Cl (10 mL), the product was
extracted with diethyl ether (3 ϫ 10 mL). The collected organic
layers were dried with MgSO4 and the solvents evaporated under
reduced pressure. The crude material was purified by flash chroma-
tography (petroleum ether/ethyl acetate, 6:4) to afford the expected
product of cyclisation as a yellow oil. Method B: The cyclisation
was performed as reported for Method A, but in the presence of
0.05 equiv. of Pd(OAc)2 and 0.1 equiv. of dppe and heating the
reaction mixture at 100 °C for 30 min.
General Procedure for Acylation by DCC: The acid derivative
(0.32 mmol), DCC (79 mg, 0.38 mmol) and a catalytic amount of
DMAP (4 mg, 0.032 mmol) were added in sequence to a solution
of the allylic amine (0.32 mmol) in dry THF (5 mL). After 15 h of
stirring at room temp., a large amount of hexane (7 mL) was added
and the resulting suspension was filtered through a Celite pad.
The organic layer was concentrated under reduced pressure and
the resulting crude material was purified by flash chromatography
(petroleum ether/ethyl acetate, 50:50) to afford the expected prod-
uct.
(؎)-Methyl (3R,3aR,7aR)-Benzyl-2-oxo-2,3,3a,6,7,7a-hexahydro-
1H-indole-3-carboxylate (7a): From cis-6a (Method A, 90%) or
from trans-6a (Method B, 60%). 1H NMR (CDCl3, 400 MHz): δ ϭ
7.36Ϫ7.24 (m, 5 H), 5.86Ϫ5.78 (m, 1 H), 5.61Ϫ5.54 (m, 1 H), 5.00
(AB system, 2J ϭ 15 Hz, 1 H), 4.03 (AB system, 2J ϭ 15 Hz, 1 H),
3.80 (s, 3 H), 3.70Ϫ3.61 (m, 1 H), 3.28 (d, 3J ϭ 7.8 Hz, 1 H),
3.19Ϫ3.13 (m, 1 H), 1.98Ϫ1.79 (m, 3 H), 1.54Ϫ1.39 (m, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ ϭ 169.0, 168.3, 135.0, 131.8, 127.6,
126.8, 126.6, 124.67, 53.3, 53.0, 51.6, 43.4, 35.5, 22.9, 20.3 ppm. IR
(CCl4): ν˜ ϭ 3033, 2937, 2846, 1733, 1680 cmϪ1. MS (EI): m/z (%) ϭ
285 [Mϩ] (100), 226 (85), 146 (91). C17H19NO3 (285.34): calcd. C
71.56, H 6.71, N 4.91; found C 71.48, H 6.63, N 4.79.
(؎)-(1S,4R)-4-{Benzyl[(phenylsulfonyl)acetyl]amino}cyclohex-2-en-
1-yl Acetate (cis-6b): From cis-9a (93%): 1H NMR (CDCl3,
200 MHz): δ ϭ 7.88 (m, 2 H), 7.53 (m, 3 H), 7.16 (m, 5 H),
5.97Ϫ5.86 (m, 1 H), 5.74Ϫ5.59 (m, 1 H), 5.27Ϫ5.16 (m, 1 H), 4.60
(s, 2 H), 4.38 (d, J ϭ 4.92 Hz, 1 H, 75%), 4.31 (d, J ϭ 4.92 Hz,
1 H, 25%), 4.02 (s, 2 H), 2.04 (s, 3 H, 25%), 2.03 (s, 3 H, 75%),
2.00Ϫ1.64 (m, 4 H) ppm. 13C NMR (CDCl3, 200 MHz): δ ϭ 170.5,
137.3, 134.3, 133.0, 129.6, 129.3, 129.2, 128.6, 128.4, 127.8, 127.3,
125.6, 65.0, 60.6, 52.1, 47.7, 26.7, 22.5, 21.3 ppm. IR (CH2Cl2):
ν˜ ϭ 3049, 2940, 1727, 1645 cmϪ1. C23H25NO5S (427.52): calcd. C
64.62, H 5.89, N 3.28; found C 64.72, H 5.93, N 3.34.
3
3
(؎)-(1S,4S)-4-{Benzyl[(phenylsulfonyl)acetyl]amino}cyclohex-2-en- (؎)-(3R,3aS,7aR)-1-Benzyl-3-(phenylsulfonyl)-1,3,3a,6,7,7a-hexa-
1-yl Acetate (trans-6b): From trans-9 (92%). M.p. 32Ϫ35 °C. 1H
hydro-2H-indol-2-one (7b): From cis-6b (Method A, 90%) or from
NMR (CDCl3, 200 MHz): δ ϭ 7.86 (m, 2 H), 7.52 (m, 3 H), 7.11 trans-6b (Method B, 73%). M.p. 151Ϫ153 °C. 1H NMR (CDCl3,
(m, 5 H), 5.78 (m, 1 H), 5.58 (m, 1 H), 5.28 (m, 1 H), 4.63 (s, 2
H), 4.34 (m, 1 H), 4.03 (s, 2 H), 2.04 (s, 3 H, 30%), 2.02 (s, 3 H,
200 MHz): δ ϭ 8.00 (m, 2 H), 7.75Ϫ7.55 (m, 3 H), 7.40Ϫ7.20 (m,
5 H), 5.90 (m, 1 H), 5.65 (m, 1 H), 5.01 (AB system, 2J ϭ 15.2 Hz,
2
3
70%), 1.48Ϫ2.05 (m, 4 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 1 H), 3.95 (AB system, J ϭ 15.2 Hz, 1 H), 3.78 (d, J ϭ 5.4 Hz,
170.5 162.6, 161.6, 138.8, 138.5, 137.6, 136.9, 134.8, 132.8, 132.3,
132.1, 130.7, 130.2, 129.0, 129.0, 128.3, 128.2, 127.6, 126.9, 126.8,
1 H), 3.86Ϫ3.75 (m, 1 H), 3.55Ϫ3.51 (m, 1 H), 2.00Ϫ1.50 (m, 4 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 165.0, 135.4, 134.2, 129.7,
2844
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 2840Ϫ2847

Pyrrolizidine Alkaloids by Intramolecular Palladium-Catalysed Allylic Alkylation
FULL PAPER
129.5, 129.0, 128.8, 127.8, 127.7, 125.4, 71.2, 53.6, 44.5, 33.9, 23.9,
20.3 ppm. IR (CHCl3): ν˜ ϭ 3008, 2933, 2848, 1691, 1308, 1145
cmϪ1. MS (NH3): m/z (%) ϭ 368 (3) [Mϩ ϩ 1], 226 (80), 91 (100),
77 (27). C21H21NO3S (367.46): calcd. C 68.64, H 5.76, N 3.81;
found C 68.70, H 5.93, N 3.62.
1610, 1510, 1430 cmϪ1. MS (EI): m/z (%) ϭ 257 (23) [Mϩ], 136 (6),
121 (100). C16H19NO2 (257.33): calcd. C 74.68, H 7.44, N 5.44;
found C 74.71, H 7.50, N 5.62.
(؎)-(4R,5R)-4-(Hydroxymethyl)-5-(3-hydroxypropyl)-1-(4-methoxy-
benzyl)pyrrolidin-2-one (13): Me3NO·2H2O (977 mg, 8.80 mmol)
was added portionwise to a solution of 12d (1.13 g, 4.40 mmol) in
THF (40 mL) and distilled water (4 mL). After dissolution of the
amine N-oxide, OsO4 (4.5% solution in iPrOH, 496 mg,
0.088 mmol) was added and the mixture was stirred at room temp.
overnight. A saturated aqueous solution of sodium sulfite (0.5 mL)
was added and stirring was continued for 30 min. The reaction mix-
ture was then treated with brine (10 mL) and the organic layer was
extracted with a large amount of EtOAc (3 ϫ 50 mL). The collected
organic layers were dried with MgSO4 and the solvents evaporated
under reduced pressure. The resulting crude solid material was used
in the next step without further purification. The crude diol (1.29 g)
in methanol (20 mL) was treated with NaIO4 (1.04 g, 4.84 mmol,
1.1 equiv.) in one portion and the resulting mixture was stirred at
room temp. for 1 h, until appearance of a white suspension. The
reaction was monitored by TLC (CH2Cl2/MeOH, 95:5). The sus-
pension was filtered through a Celite pad, the filtrate was cooled
to 0 °C and treated portionwise with solid NaBH4 (665 mg,
17.6 mmol, 4.0 equiv.). After 2 h of stirring at room temp., the mix-
ture was cooled again to 0 °C and treated with a saturated aqueous
NH4Cl solution (15 mL). A standard extractive workup with
EtOAc (3 ϫ 100 mL) gave, after removal of solvents, a crude mate-
rial which was purified by flash chromatography (CH2Cl2/MeOH,
95:5) to afford 13 as a colourless oil (1.22 g, 95%). 1H NMR
(؎)-(3R/S,3aR,7aR)-1-Benzyl-2-oxo-2,3,3a,6,7,7a-hexahydro-1H-
1
indole-3-carbonitrile (7c): From cis-6c (Method A, 87%). H NMR
(CDCl3, 200 MHz): δ ϭ 7.40Ϫ7.10 (m, 5 H), 6.05 (m, 1 H, 40%),
5.92 (m, 1 H, 60%), 5.80Ϫ5.65 (m, 1 H), 4.99 (AB system, 2J ϭ
15.2 Hz, 1 H, 40%), 4.97 (AB system, 2J ϭ 15.2 Hz, 1 H, 60%),
2
4.04 (AB system, 2J ϭ 15.2 Hz, 1 H), 3.69 (d, J ϭ 8.9 Hz, 1 H,
2
40%), 3.66Ϫ3.40 (m, 1 H), 3.30 (d, J ϭ 9.8 Hz, 1 H, 60%), 3.05
(m, 1 H), 2.10Ϫ1.50 (m, 4 H) ppm. 13C NMR (CDCl3, 50 MHz):
δ ϭ 166.4, 165.7, 135.9, 135.8, 131.9, 130.9, 129.3, 129.2, 128.4,
123.9, 122.6, 116.9, 115.8, 54.9, 54.5, 45.4, 45.2, 39.9, 39.5, 38.3,
34.6, 34.3, 25.9, 25.3, 24.1, 23.8, 22.4, 21.1 ppm.
(؎)-Methyl (3R,3aR,7aR)-1-(4-Methoxybenzyl)-2-oxo-2,3,3a,6,7,7a-
hexahydro-1H-indole-3-carboxylate (7d): From cis-6d (Method A,
90%). 1H NMR (CDCl3, 200 MHz): δ ϭ 7.18 (d, 3J ϭ 8.7 Hz, 2
3
H), 6.84 (d, J ϭ 8.7 Hz, 2 H), 5.80 (m, 1 H, Hd), 5.55 (m, 1 H),
4.93 (AB system, 2J ϭ 15.0 Hz, 1 H), 3.96 (AB system, 2J ϭ
3
15.0 Hz, 1 H), 3.75 (s, 6 H), 3.62 (m, 1 H), 3.26 (d, J ϭ 7.4 Hz, 1
H,), 3.11 (m, 1 H), 2.1Ϫ1.7 (m, 3 H), 1.6Ϫ1.4 (m, 1 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ ϭ 170.2, 169.4, 159.2, 129.4, 128.8,
128.3, 125.8, 114.1, 53.4, 54.5, 21.5 Cg, 54.1, 52.8, 44.1, 39.7, 24.1
ppm. IR (neat): ν˜ ϭ 1740 cmϪ1, 1690, 1520, 1440, 1260 cmϪ1. MS
(EI): m/z (%) ϭ 315 (17) [Mϩ], 194 (4), 121 (100). C18H21NO4
(315.37): calcd. C 68.55, H 6.71, N 4.44; found C 68.66, H 6.82,
N 4.56.
3
3
(CDCl3, 400 MHz): δ ϭ 7.16 (d, J ϭ 8.4 Hz, 2 H), 6.86 (d, J ϭ
2
8.4 Hz, 2 H), 4.97 (AB system, J ϭ 14.9 Hz, 1 H), 3.89 (AB sys-
tem, 2J ϭ 14.9 Hz, 1 H), 3.81 (s, 3 H), 3.77 (ABX system, 2J ϭ
10.9, 3J ϭ 7.4 Hz, 1 H), 3.70 (ABX system, 2J ϭ 10.9, 3J ϭ 6.1 Hz,
1 H), 3.61 (m, 2 H), 3.56 (m, 1 H), 2.55 (m, 1 H), 1.58Ϫ1.54 (m, 2
H, Hg), 2.44 (ABX system, 2J ϭ 16.5, 3J ϭ 8.3 Hz, 1 H), 2.34
General Procedure for the Demethoxycarbonylation: Water
(0.176 mL, 9.28 mmol, 4 equiv.) and NaCl (177 mg, 3.02 mmol, 1.3
equiv.) were added in sequence to a solution of the methyl ester
derivative (2.32 mmol, 1equiv.) in DMSO (5 mL) and the resulting
mixture was warmed at the appropriate temperature. The reaction
mixture was then cooled to room temp., water (20 mL) was added
and the mixture was extracted with chloroform (3 ϫ 15 mL). The
collected organic layers were washed with a saturated NaCl aque-
ous solution (3 ϫ 10 mL), dried with MgSO4 and the solvents were
evaporated under reduced pressure. The crude oil was purified by
flash chromatography (petroleum ether/ethyl acetate, 55:45) to af-
ford the decarboxylated product as a brown oil.
2
3
(ABX system, J ϭ 16.5, J ϭ 9.0 Hz, 1 H), 1.90 (br. s, 2 H, OH),
1.70Ϫ1.66 (m, 2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 175.4,
160, 130.2, 129.5, 115.0, 63.2, 62.1, 59.0, 56.2, 44.9, 39.5, 35.0,
29.5,25.3 ppm. IR (neat): ν˜ ϭ 3375, 2930, 1658, 1245 cmϪ1
.
C16H23NO4 (293.36): calcd. C 65.51, H 7.90, N 4.77; found C
65.45, H 7.80, N 4.85.
(؎)-3-[(2R,3R)-1-(4-Methoxybenzyl)-3-({[(4-methylphenyl)sulfonyl]-
oxy}methyl)-5-oxopyrrolidin-2-yl]propyl 4-Methylbenzenesulfonate
(14): NEt3 (0.85 mL, 6.12 mmol, 4.0 equiv.) and a catalytic amount
of DMAP (2 mg, 0.015 mmol) were added in sequence to a solution
of 13 (450 mg, 1.53 mmol) in dry CH2Cl2 (15 mL). The resulting
mixture was cooled to 0 °C and TsCl (877 mg, 4.61 mmol, 3.0
equiv.) was added in one portion. After 15 min of stirring at 0 °C,
the mixture was left to warm to room temp. and then stirred for a
further 6 h. A saturated aqueous NaHCO3 solution (2 mL) was
then added and the mixture was extracted with diethyl ether (3 ϫ
10 mL). After drying with MgSO4 and concentration under re-
duced pressure, the crude oil was purified by flash chromatography
(petroleum ether/ethyl acetate, 3:7) to afford 14 as a colourless oil
(755 mg, 82%). 1H NMR (CDCl3, 400 MHz): δ ϭ 7.78 (d, 3J ϭ
(؎)-(3aS,7aR)-1-Benzyl-1,3,3a,6,7,7a-hexahydro-2H-indol-2-one
(12a): From 7a (90%). 1H NMR (CDCl3, 400 MHz): δ ϭ 7.37Ϫ7.23
(m, 5 H), 5.81Ϫ5.77 (m, 1 H), 5.61Ϫ5.55 (m, 1 H), 5.03 (AB sys-
tem, 2J ϭ 15 Hz, 1 H), 4.00 (AB system, 2J ϭ 15 Hz, 1 H),
2
3.98Ϫ3.55 (m, 1 H), 2.87Ϫ2.76 (m, 1 H), 2.65 (ABX system, J ϭ
3
2
3
16.6, J ϭ 9 Hz, 1 H), 2.27 (ABX system, J ϭ 16.6, J ϭ 7.4 Hz,
1 H), 2.00Ϫ1.60 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
174.4, 136.9, 128.7, 128.0, 127.6, 55.3, 44.0, 37.5, 32.2, 23.7, 21.2
ppm. MS (NH3): m/z (%) ϭ 228 (100) [Mϩ ϩ 1]. C15H17NO
(227.31): calcd. C 79.26, H 7.54, N 6.16; found C 79.46, H 7.79,
N 6.19.
(؎)-(3aS,7aR)-1-(4-Methoxybenzyl)-1,3,3a,6,7,7a-hexahydro-2H-
indol-2-one (12d): From 7d (99%). 1H NMR (CDCl3, 200 MHz): 7.6 Hz, 2 H), 7.76 (d, 3J ϭ 7.6 Hz, 2 H), 7.38 (d, 3J ϭ 7.6 Hz, 4
3
3
δ ϭ 7.10 (d, J ϭ 8.9 Hz, 2 H), 6.76 (d, J ϭ 8.9 Hz, 2 H), 5.70 (s,
H), 7.09 (d, 3J ϭ 8.4 Hz, 2 H), 6.83 (d, 3J ϭ 8.4 Hz, 2 H), 4.86
2
1 H), 5.45 (m, 1 H), 4.86 (AB system, 2J ϭ 14.8 Hz, 1 H), 3.84 (AB system, J ϭ 14.8 Hz, 1 H), 4.01 (m, 2 H), 3.88 (m, 2 H), 3.80
2
(AB system, 2J ϭ 14.8 Hz, 1 H), 3.69 (s, 3 H), 3.46 (m, 1 H),
(AB system, J ϭ 14.8 Hz, 1 H), 3.79 (s, 3 H), 2.46 (m, 1 H), 2.63
2
3
2
1.9Ϫ1.4 (m, 4 H), 2.12 (ABX system, J ϭ 16, J ϭ 6.9 Hz, 1 H), (m, 1 H), 2.46 (s, 6 H), 2.38 (ABX system, J ϭ 16.8, 3J ϭ 8.6 Hz,
2.52 (ABX system, J ϭ 16, 3J ϭ 8.8 Hz, 1 H), 2.67 (m, 1 H) ppm. 1 H), 2.13 (ABX system, 2J ϭ 16.8, 3J ϭ 9.2 Hz), 1 H, 1.6Ϫ1.4 (m,
2
13C NMR (CDCl3, 50 MHz): δ ϭ 174.3, 158.9, 129.3, 127.6, 114.0, 4 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 197.6, 173.6, 160.1,
55.2, 43.3, 37.5, 32.1, 23.6, 21.1 ppm. IR (neat): ν˜ ϭ 2900, 1680,
146.4, 146.0, 133.8, 133.2, 131.1, 130.9, 130.2, 129.0, 128.8, 115.1,
Eur. J. Org. Chem. 2004, 2840Ϫ2847
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2845

S. Lemaire, G. Giambastiani, G. Prestat, G. Poli
70.6, 69.2, 58.0, 56.2, 45.1, 36.6, 34.3, 25.9, 25.2, 22.6 ppm. IR at room temp. for 30 min and at 65 °C for 2 h. It was then allowed
FULL PAPER
(neat): ν˜ ϭ 2940, 1650, 1520, 1460 cmϪ1
.
to cool to room temp. and treated with wet diethyl ether (1 mL).
An aqueous NaOH solution (15% wt, 15 µL) and water (50 µL)
were added in sequence and stirring was maintained for a further
30 min. The reaction mixture was then filtered and washed with
warm EtOAc (3 ϫ 5 mL). Concentration of the organic layers un-
der reduced pressure gave the pure alkaloid 1 (5.5 mg, 80%). 1H
NMR (CDCl3, D2O, 400 MHz): δ ϭ 4.70 (HOD), 3.71 (m, 2 H),
3.54 (m, 1 H), 3.11 (m, 1 H), 2.99 (m, 1 H), 2.64 (m, 1 H), 2.52
(m, 1 H), 2.47 (m, 1 H), 1.90 (m, 1 H), 1.82 (m, 1 H), 1.72 (m, 2
H), 1.56 (m, 1 H), 1.43 (m, 1 H) ppm. 13C NMR (CDCl3,
400 MHz): δ ϭ 66.6, 64.8, 55.9, 26.3 C, 54.3, 44.5, 27.7, 26.9 ppm.
IR (neat): ν˜ ϭ 3346, 2924, 2854, 1457, 1049 cmϪ1. MS (EI): m/z
(%) ϭ 141 (11) [Mϩ], 124 (8), 110 (7), 83 (100).
(؎)-3-[(2R,3R)-3-({[(4-Methylphenyl)sulfonyl]oxy}methyl)-5-oxo-
pyrrolidin-2-yl]propyl 4-Methylbenzenesulfonate (15):
(NH4)2Ce(NO)6 (2.55 g, 4.66 mmol) was added in one portion to a
solution of 14 (700 mg, 1.16 mmol) in a CH3CN/H2O (3:1) mixture
(12 mL) cooled to 0 °C. After 2 h of stirring, EtOAc (10 mL) and
brine (5 mL) were added. The mixture was extracted with a large
amount of EtOAc (3 ϫ 50 mL). The collected organic layers were
dried with MgSO4 and the solvents evaporated under reduced
pressure. The crude material was purified by flash chromatography
(ethyl acetate/acetone, 9:1) to afford the expected N-deprotected
1
pyrrolidone 15 (493 mg, 89%). H NMR (CDCl3, 400 MHz): δ ϭ
7.79 (m, 4 H), 7.39 (m, 4 H), 7.33 (s, 1 H, NH), 4.03 (m, 4 H), 3.62
(m, 1 H), 2.82 (m, 1 H), 2.47 (s, 6 H), 2.31 (ABX system, 2J ϭ
16.8, 3J ϭ 8.6 Hz, 1 H), 2.05 (ABX system, 2J ϭ 16.8, 3J ϭ 9.3 Hz,
1 H), 1.71 (m, 1 H), 1.61 (m, 1 H), 1.46 (m, 1 H), 1.29 (m, 1 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 197.6, 146.3, 145.9, 133.6,
133.2, 131.1, 131.0, 128.7, 128.8, 70.9, 69.3, 56.1, 38.1, 27.4, 26.7,
Acknowledgments
This work was supported by the Ministe`re de l’Education Nation-
´
ale, de la Recherche et de la Technologie (MENRT), the Comite
22.6 ppm. IR (neat): ν˜ ϭ 2918, 2850, 1779, 1678, 1358, 1035 cmϪ1
.
National de la Recherche Scientifique (CNRS). The support and
sponsorship concerted by COST Action D24 ‘‘Sustainable Chemi-
cal Processes: Stereoselective Transition Metal-Catalyzed Reac-
tions’’ are kindly acknowledged. The authors thank Dr. Simona
Pampana for her contribution in preliminary experiments.
(؎)-[(1R,7aR)-3-Oxohexahydro-1H-pyrrolizin-1-yl]methyl 4-Meth-
ylbenzenesulfonate (16): NaH (33 mg, 0.82 mmol, 60% dispersion
in mineral oil) was added in one portion to a cooled solution (0
°C) of the secondary amide precursor 15 (395 mg, 0.82 mmol) in
dry THF (16 mL) under argon. The mixture was stirred at room
temp. for 12 h, then it was cooled again to 0 °C, and a saturated
aqueous NH4Cl solution (2 mL) was added dropwise. The mixture
was extracted with a large amount of EtOAc (3 ϫ 50 mL). The
collected organic layers were dried with MgSO4 and the solvents
evaporated under reduced pressure. The crude oil was purified by
flash chromatography (ethyl acetate/acetone, 8:2) to afford the ex-
pected pyrrolizidine derivative 16 (353 mg, quant.). 1H NMR
[1] [1a]
[1b]
J. R. Liddell, Nat. Prod. Rep. 2002, 19, 773Ϫ781.
J. T.
´
Wrobel, in The Alkaloids: Chemistry and Pharmacology (Ed.:
A. Brossi), Academic Press, San Diego, 1985; vol 26, chapter
7, p. 327.
[2]
For previous syntheses of isoretronecanol, see: [2a] D. J. Robins,
S. Sakdarat, J. Chem. Soc., Chem. Commun. 1979, 1181Ϫ1182.
[2b]
D. J. Robins, S. Sakdarat, J. Chem. Soc., Perkin Trans. 1
1981, 909Ϫ913. [2c] H. Rüeger, M. Benn, Heterocycles 1982, 19,
1677Ϫ1680.
3
3
(CDCl3, 400 MHz): δ ϭ 7.79 (d, J ϭ 8.2 Hz, 2 H), 7.38 (d, J ϭ
8.2 Hz, 2 H), 4.04 (m, 1 H), 3.94 (m, 2 H), 3.46 (m, 1 H), 3.08 (m,
1 H), 2.83 (2H), 2.47 (s, 3 H), 2.1Ϫ1.9 (m, 3 H), 1.82 (m, 1 H),
1.38 (m, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 173.6, 146.2,
133.4, 131.0, 128.9, 70.1, 63.9, 41.9, 37.9, 34.3, 26.6, 22.6 ppm. IR
(neat): ν˜ ϭ 2919, 1675, 1011 cmϪ1. MS (EI): m/z (%) ϭ 309 (6)
[Mϩ], 185 (2), 124 (18), 91 (32), 70 (100).
[2d]
T. Iwashita, T. Kusumi, H. Kakisawa, J. Org.
[2e]
Chem. 1982, 47, 230Ϫ233.
K. Tatsuta, H. Takahashi, Y.
Amemiya, M. Kinoshita, J. Am. Chem. Soc. 1983, 105,
4096Ϫ4097. [2f] T. Moriwake, S. Hamano, S. Saito, Heterocycles
1988, 27, 1135Ϫ1139. [2g] Y. Nagao, W.-M. Dai, M. Ochiai, M.
Shiro, Tetrahedron 1990, 46, 6361Ϫ6380. [2h] J. G. Knight, S. V.
[2i]
Ley, Tetrahedron Lett. 1991, 32, 7119Ϫ7122.
D. W. Knight,
A. C. Share, P. T. Gallagher, J. Chem. Soc., Perkin Trans. 1
[2j]
(؎)-[(1R,7aR)-3-Oxohexahydro-1H-pyrrolizin-1-yl]methyl Acetate
(17): nBu4NOAc (44 mg, 0.15 mmol) and a catalytic amount of NaI
were added in sequence to a solution of the tosylate 16 (15 mg,
0.05 mmol) in dry THF (0.5 mL) under argon. The mixture was
stirred at room temp. for 12 h, then the solvent was evaporated
under reduced pressure and the crude product was purified by flash
chromatography (EtOAc/acetone, 8:2) to afford 17 as a colourless
oil (9 mg, quant.). 1H NMR (CDCl3, 400 MHz): δ ϭ 4.15 (ABX
system, 2J ϭ 11.2, 3J ϭ 7.6 Hz, 1 H), 4.03 (m, 1 H), 4.01 (ABX
system, 2J ϭ 11.2, 3J ϭ 6.6 Hz, 1 H), 3.52 (ABX system, 2J ϭ 11.7,
3J ϭ 8.4 Hz, 1 H), 3.11 (ABX system, 2J ϭ 11.7, 3J ϭ 3.0 Hz, 1
H), 2.91 (m, 1 H), 2.82 (m, 1 H), 2.26 (m, 1 H), 2.15 (m, 1 H), 2.06
(s, 3 H), 2.02 (m, 1 H), 1.83 (m, 1 H), 1.51 (m, 1 H) ppm. 13C
NMR (CDCl3, 400 MHz): δ ϭ 173.9, 171.1, 64.3, 63.7, 41.6, 38.0,
33.6, 25.9, 21.2, 27.0 ppm. IR (neat): ν˜ ϭ 3000, 1770, 1720, 1450,
1280 cmϪ1. MS (EI): m/z (%) ϭ 197 (19) [Mϩ], 155 (4), 124 (14),
70 (100), 43 (86). C10H15NO3 (197.23): calcd. C 60.90, H 7.67, N
7.10; found C 60.93, H 7.79, N 7.21.
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2846
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2840Ϫ2847

Pyrrolizidine Alkaloids by Intramolecular Palladium-Catalysed Allylic Alkylation
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Support for such an assignment comes from analysis of the
Received February 26, 2004
Eur. J. Org. Chem. 2004, 2840Ϫ2847
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2847