Asymmetric synthesis of a tricyclic core structure of the securinega alkaloids virosecurinine and allosecurinine

Article abstract of DOI:10.1016/S0040-4020(03)00406-X

A concise asymmetric synthesis of tricyclic core structures of virosecurinine [(+)-1] and allosecurinine [(-)-2] is presented. An asymmetric electrophilic α-amidoalkylation reaction employing a chiral enamide gave access to enantiopure (S)-2-anisylpiperidine with the diastereoselectivity (d.s.) of 93/7. The latter was transformed into the target compounds, with the main steps involving a Birch-reduction followed by an ozonolysis of the resulting 1,4-cylohexadiene and a final spirocyclization reaction.

Full text of DOI:10.1016/S0040-4020(03)00406-X

Tetrahedron 59 (2003) 3359–3368
Asymmetric synthesis of a tricyclic core structure of the
securinega alkaloids virosecurinine and allosecurinine
Rainer Kammler,a Kurt Polbornb and Klaus Th. Wannerc
,
*
aVerla-Pharm Arzneimittel, Bernrieder-Str. 1, 82327 Tutzing, Germany
bDepartment of Chemistry, Ludwig-Maximilians-University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany
cDepartment of Pharmacy, Ludwig-Maximilians-University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany
Received 31 January 2003; revised 25 February 2003; accepted 10 March 2003
Abstract—A concise asymmetric synthesis of tricyclic core structures of virosecurinine [(þ)-1] and allosecurinine [(2)-2] is presented. An
asymmetric electrophilic a-amidoalkylation reaction employing a chiral enamide gave access to enantiopure (S)-2-anisylpiperidine with the
diastereoselectivity (d.s.) of 93/7. The latter was transformed into the target compounds, with the main steps involving a Birch-reduction
followedbyanozonolysisoftheresulting1,4-cylohexadieneandafinalspirocyclizationreaction.q2003 Elsevier ScienceLtd. All rightsreserved.
1. Introduction
The securinega alkaloids comprise a small group of about
20 tetracyclic compounds produced by plants of the genera
Securinega, Phyllantus, Margaritaria and Breynia, which
belong to the family Euphorbiaceae. They exhibit a unique
ring skeleton composed of a 6-azabicyclo[3.2.1]octane
moiety as a core structure [B/C in (2)-1], which in addition
to an a,b-unsaturated-g-lactone unit [see D in (2)-1]1 is
either fused with a piperidine (securinine-type alkaloids;
ring A in (2)-1) or with a pyrrolidine ring (for nor-
securinine-type alkaloids). Securinine [(2)-1], the most
abundant alkaloid of this group, was isolated first in 19562
and was structurally elucidated in the early 1960s.3 Later on
also the three stereoisomers of securinine [(2)-1]-viro-
securinine [(þ)-1] (enantiomer of securinine), allo-
securinine [(2)-2] and viroallosecurinine [(þ)-2]-were
found in plants of the family Euphorbiaceae (Fig. 1).
The Securinega alkaloids show a great scope referring to
their biological activity. In Russia, for example, securinine
[(2)-1] has been used since 1968 as a CNS stimulating
drug.4 However, the mode of action of (2)-1 as a drug was
not uncovered before 1985, when it was found that
securinine [(2)-1] acts as a competitive antagonist at the
GABA binding site of the GABAA-receptor complex.5
Besides, also antibacterial6 and antimalarial activity have
been reported for this compound (2)-1.7
Figure 1.
alkaloid, though a few total syntheses for the racemate of
(2)-1 are known.8,9 This is surprising, as the securinine
alkaloids (2)-1, (þ)-1, (2)-2 and (þ)-2 display distinct
differences with respect to their pharmacological activity,
with securinine [(2)-1] being the most potent isomer
especially as a ligand of the GABA binding site of the
GABAA receptor complex.
Despite the wide scope of biological activities of (2)-1 no
enantioselective synthesis has been described so far for this
2. Synthetic strategy
Keywords: virosecurinine; allosecurinine; a-amidoalkylation.
*
Corresponding author. Tel.: þ49-89-2180-77249/77248; fax: þ49-89-
2180-77247; e-mail: klaus.wanner@cup.uni-muenchen.de
The goal of this study was the development of an
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00406-X

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R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
allow the introduction of the C-2-substituent in a stereo-
controlled manner. Some time ago we reported on a cationic
type of asymmetric synthesis involving chiral N-acyl-
iminium ions provided with an N-acyl group as chiral
auxiliary which we have termed Asymmetric Electrophilic
a-Amidoalkylation (AEaA).10 Enamide 5 shown in
Scheme 2 represents an optimized reagent that we
developed for the asymmetric synthesis of chiral piperidines
by asymmetric electrophilic a-amidoalkylation reactions.11
Especially, organomagnesium, organozinc and organo-
aluminum derivatives proved to be useful as trapping
reagents for the N-acyliminium ions (e.g. 6) derived from 5
which are formed during the course of the amidoalkylation
reactions. The asymmetric induction is assumed to be the
result of a coordination complex that might form from 6 by
addition of the organometallic reagent to the lactone
function of the chiral auxiliary.11c
Scheme 1.
asymmetric synthesis giving access to compounds like 3 and
4 as substructures of the securinine alkaloids (2)-1, (þ)-1,
(2)-2 and (þ)-2 comprising rings A, B and D of the
aforementioned compounds. As a reasonable approach a
strategy was envisaged where at first the stereocenter at C-2
of the piperidine ring is established, whereas the adjacent
spirocyclic stereocenter is set up in an independent later
step. In accord with the above concept and as outlined in
Scheme 1 compounds like III appeared to be a suitable
starting point for the synthesis of the desired compounds,
e.g. 3 and 4. Thus, the preparation of an enantiomerically
pure piperidine derivative III appeared to be a key step in
the overall synthesis. To this end the methyl derivative (S)-
2-anisylpiperidine (III, R¼Me) was selected.
In continuation of our interest in the exploration of 5 as an
amidoalkylation reagent, we decided to employ enamide 5
also in this study, which seemed, of course, also well suited
for a rapid and efficient access to the required 2-substituted
piperidine derivative (S)-9b. Thus, for the synthesis of (S)-
9b amidoalkylation reactions of 5 with organomagnesium
and organozinc compounds derived from 4-bromoanisole
were performed. For comparison purposes, in addition, also
the synthesis of the basic phenyl derivative (S)-9a was
studied. To accomplish the amidoalkylation reaction
enamide 5 was first treated with HCl (in CH2Cl2 at
2788C). The reactive intermediate thus formed—most
likely the corresponding a-chloroamide—was then trapped
by addition of the appropriate organometallic reagent (see
Table 1, entries 1, 2, 4 and 5). In a second set of experiments
one equivalent of BCl312 was added to the reaction mixture
prior to the addition of the organometallic reagent, as it was
speculated that this might improve the yields of the trapping
reaction. The results obtained for these reactions are
summarized in Table 1.
3. Results and discussion
3.1. Preparation of the (S)-2-anisylpiperidine [(S)-9b]
Among the methods currently available for the asymmetric
synthesis of C-2 substituted piperidines the most intriguing
with regard to simplicity and flexibility, are those which
The reactions with the organomagnesium compounds
proceeded with reasonable diastereoselectivities and
Scheme 2. Reagents and conditions: (i) (1) HCl/CH2Cl2, (2) BCl3/n-heptane/2788C; (ii) MRn.

R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
Table 1. Preparation of 7a/b and 8a/b by amidoalkylation reactions with 5
3361
Entry
Product 7þ8
Reagent
Equiv.
Additive
d.s.a 7/8
Yield (%) 7þ8
1
2
3
4
5
6
a
a
a
b
b
b
PhMgBrb (Et2O)
1.1
1.1
3.0
3.0
3.0
2.5
–
–
88/12
94/6
91/9
85/15
93/7
93/7
47
47
91
74
56
99
ZnCl2c/PhMgBrb (1.0/1.7 equiv.; Et2O)
ZnCl2d/PhMgBre (1.0/1.7 equiv.; Et2O/THF)
4-MeOC6H4MgBre (THF)
ZnCl2c/4-MeOC6H4MgBre (1.0/2.0 equiv.; Et2O/THF)
ZnCl2d/4-MeOC6H4MgBre (1.0/1.6 equiv.; Et2O/THF)
1.1 equiv. BCl3
–
–
1.1 equiv. BCl3
a
Determined by HPLC from the crude reaction product.
b
c
d
e
3.0 M in Et2O.
1.0 M in Et2O.
0.7 M in Et2O.
1.0 M in THF.
mediocre to good yields (see Table 1, entries 1 and 4). With
the organozinc species the diastereoselectivity could be
significantly improved, whereas the yield remained
unchanged or dropped (see Table 1 entry 2 and 5). The
best results were finally seen for those reactions where in
addition to the organozinc compound one equivalent of
BCl3 had been applied. Though in case of the phenylation
reaction the diastereoselectivity slightly dropped (from 94/6
to 91/9), the yield rose to 91% (see Table 1, entry 3). The
result obtained for the introduction of the 4-methoxyphenyl
substituent was even more pleasing. In this case, the
diastereoselectivity remained unchanged (7b/8b¼93/7),
whereas the yield became almost quantitative (99%, see
Table 1 entry 6). We assume that with BCl3 as an additive
the a-chloroamide present in the reaction mixture is
completely transformed to the corresponding N-acyl-
iminium ion, thus giving rise to a highly efficient trapping
reaction. In the absence of an extra Lewis acid the
N-acyliminium ions most likely are formed by the
organometallic reagent, which, however, seems to be less
effective.
The stereochemistry of compound (S)-9a was established by
comparison of the optical rotation of the hydrochloride of
(S)-9a with the literature value reported for an authentic
sample. For the hydrochloride of (S)-9a an optical rotation
of [a]2D3¼þ9.58 was found, indicating that this compound
and consequently also the free amine (S)-9a must be of (S)-
1
configuration {lit. value13 for (R): [a]D¼29.68}. The H
NMR spectra of the major diastereomer 7a and the minor
diastereomer 8a of the phenyl adduct where found to be
quite similar to those of the major diastereomer 7b and
minor diastereomer 8b with a 4-methoxyphenyl substituent.
Thus, the relative stereochemistry of 7a and 7b and 8a and
8b, respectively, should be the same. Accordingly and by
taking into account that 7a is the precursor of 9a [with (S)-
configuration] and 7b the precursor of 9b, the piperidine
derivative 9b must be of (S)-configuration as well.
3.2. Birch-reduction and ozonisation of (S)-9b
The next steps of our synthesis were directed towards the
preparation of aldehyde (S)-12 utilizing the anisylpiperidine
(S)-9b as starting material, which had become available in
enantiomerically pure form by the amidoalkylation reaction
described above. The strategy we used was analogous to the
one Corey et al. had applied as key steps in the synthesis of a
juvenile hormone.14 Thus, in the first step (S)-9b was
subjected to a Birch-reduction whereupon the piperidine
derivate (S)-10 provided with a cyclohexadiene moiety was
obtained (yield 89%). Protection of the amino function of
(S)-10 with a Boc-group lead to the carbamate (S)-11, which
The mixture of diastereomers 7a/8a and 7b/8b resulting
from the amidoalkylation reactions were finally separated
by either preparative HPLC (7a/8a) or by flash chromato-
graphy (7b/8b) to give the single diastereomers in pure
form. From these for the subsequent reactions only the
major diastereomers 7a and 7b were used.
The next step involved the removal of the chiral auxiliary,
which was accomplished by a reductive cleavage procedure.
When Na[AlH2(OMe)2] was employed, which turned out to
be best suited for this purpose {2.0 equiv. Na[AlH2(OMe)2],
THF, 2258C}, the amines (S)-9a and (S)-9b were obtained
in good to excellent yields of 65 and 92%, respectively
(Scheme 3). In contrast, reagents like Red-Alw, Na[AlH4],
Na[AlH2Et2] and Li[AlH2(OMe)2] gave far lower yields.
Scheme 4. Reagents and conditions: (i) Li, NH3, Et2O, 2408C; (ii) EtOH;
(iii) MeCN, NEtiPr2, (Boc)2O, 258C, 3 days; (iv) O3, MeOH, 2788C, 2 h;
(v) Me2S.
Scheme 3. Reagents and conditions: (i) Na[AlH2(OMe)2], THF, 2258C,
24 h.

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R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
finally upon ozonisation provided the desired aldehyde (S)-
12 in a reasonable yield (50%) (see Scheme 4).
3.4. Cyclization to the target-lactones 3 and 4
To establish the furan ring, the synthetic task still left to
complete the synthesis of our target compounds, we
followed a procedure put forth by Cory et al.18 According
to this procedure the bicyclic lactam (S)-15 was first
subjected to an epoxidation reaction with MCPBA in
CH2Cl2 which resulted in the formation of the two
diastereomeric epoxy derivatives 16 and 17. Though the
total yield was quite pleasing (91%) the diastereoselectivity
amounted only to 2/1. Separation by flash chromatography
provided the pure diastereomers for the final lactonization
reaction. This cyclization was accomplished by first treating
the diastereomers with TFA in CH2Cl2 (for 6 h at room
temperature) and subsequently after removal of the solvent
with TFAA and NEt3. According to 1H NMR spectroscopy
with TFA only hydroxy lactones were formed, which then
had to be treated with TFAA/NEt3 to provide the
unsaturated compounds. Presumably, the acid catalyzed
ring opening of the oxirane moiety is facilitated by a
neighboring-group effect arising from the ester function.
This may finally lead to a stereocontrolled formation of the
g-lactone ring via inversion at the stereocenter being
affected.19 In support of this assumption from 16 only the
diastereomer 3 and from 17 only diastereomer 4 was
obtained, both in high yields (3 79%; 4 77%; see Scheme 6).
3.3. Formation of lactam (S)-15
At next, according to our synthetic plan, (S)-12 had to be
transformed to the bicyclic lactam (S)-15. To this end (S)-12
was subjected to an oxidation reaction with NaClO2 (in
tBuOH/phosphate-buffer) in the presence of 2-methyl-2-
butene as chlorine-scavenger,15 which provided the car-
boxylic acid (S)-13 in 90% yield. Deprotection with
16
BF3·Et2O in CH2Cl2 led to the g-amino acid (S)-14 as a
BF3 adduct. For convenience this was used for the
subsequent cyclization reaction without further purification.
Activation of the carboxylic acid function of (S)-14 with
Mukaiyama’s reagent (2-chloro-1-methylpyridinium
iodide)17 finally initiated a clean cyclization reaction
affording (S)-15 in 77% yield (Scheme 5).
The relative stereochemistry of the major cyclization
product 3 was established by an X-ray analysis (Fig. 2).
According to the result of this analysis and by taking into
account that (S)-9b as a precursor to 3 was found to be of
(S0)-co0nfiguration the spirocyclic compound 3 must possess
(1 R,8 aS)-stereochemistry. Hence compound 4 as a stereo-
isomer of 3 differing from the latter 0in the chirality of the
spirocyclic carbon must be of (1 S,80aS)-configuration.
Thus, with the synthesis of 3 and 4 tricyclic substructures
of the securinine-type alkaloids have been established with
their stereochemistry corresponding to virosecurinine [(þ)-
1] and allosecurinine [(2)-2], respectively. From the above
Scheme 5. Reagents and conditions: (i) NaClO2, 2-methyl-2-butene,
PO342-buffer (pH 7), tBuOH, 3 h; (ii) BF3·Et2O, CH2Cl2, 30 min;
(iii) 2-chloro-1-methylpyridinium iodide, NEtiPr2, CH2Cl2, 16 h.
Scheme 6. Reagents and conditions: (i) MCPBA, CH2Cl2, 24 h; (ii) TFA, CH2Cl2, 6 h; (iii) TFAA, 5 h; (iv) NEt3, 1 h.

R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
3363
HRMS: Jeol GCmateII GC-MS-System with direct inlet.
IR-Spectra: Spectral photometer 1600 (Perkin–Elmer) and
Paragon 1000 (Perkin–Elmer), liquids were run as films,
solids as KBr pellets. Optical rotation: Polarimeter 241 MC
(Perkin–Elmer). Combustion analysis: CHN Rapid
(Heraeus). Solvents were dried and kept under nitrogen
and were freshly distilled before use. Unless otherwise
indicated, all reactions were carried out under a nitrogen
atmosphere. Column chromatography (CC): Flash chroma-
tography on silicagel (Merck 60 F-254, 0.040–0.063 mm).
Analytical HPLC: L-6200 pump (Merck–Hitachi), L-4000
UV–Vis detector, 254 nm (Merck–Hitachi), D-2500 and
D-7500 Chromato Integrator (Merck–Hitachi), column
LiChroCARTw with LiChrospherw Si 60 cartridge (5 mm,
250£4 mm with precolumn 4£4 mm) (Merck). Preparative
HPLC: L-6000 pump, L-4000 UV–Vis dedector, 254 nm
(Merck–Hitachi), D-2000 Chromato Integrator (Merck–
Hitachi), column Hibar RT LiChrosorbw Si 60 (7 mm,
250£25 mm) (Merck).
Figure 2. X-Ray structure of 3.
5.2. Electrophilic a-amidoalkylation—general
procedure (GP1)
assignment also the stereochemistry of the epoxy deriva-
tives 16 and 17 may be deduced. As both cyclization
reactions gave single but different stereoisomers it is
reasonable to assume, that the cyclization—as a result of a
neighboring-group effect arising from the ester moiety—
proceeded with inversion at the spirocyclic stereocenter.
Consequently the epoxides 16 and 17 should display the
stereochemistry shown.
At 2788C by means of a gas-tight syringe first 3–10 equiv.
of HCl gas were passed into CH2Cl2 (4 ml per 1 mmol
enamide 5) before a solution of the enamide 5 in CH2Cl2
(4 ml per 1 mmol 5) was added dropwise under vigorous
stirring. Excess HCl was stripped off in vacuo at 260 to
2788C (60 min) and then a solution of the organometallic
reagent (1.1–3.0 equiv. referring to enamide 5) was added
dropwise. The reaction mixture was stirred for 90 min at
2788C and finally quenched with saturated NaHCO3-
solution. The aqueous layer was extracted several times
with CH2Cl2 and the combined organic layers were dried
(MgSO4) and concentrated. The d.s. of the reaction was
determined by HPLC from the resulting residue. The crude
products were purified by CC to yield a mixture of the
diastereomeres 7a,b/8a,b. Pure diastereomeres were
obtained by prep. HPLC.
4. Conclusion
In summary, we have developed an enantioselective
synthesis of the tricyclic compounds 3 and 4 representing
substructures of virosecurinine [(þ)-1] and allosecurinine
[(2)-2]. Starting from the enamide 5 the synthesis of the
substructures 3 and 4 has been accomplished in ten overall
chemical steps with a total yield of 12 and 6%, respectively.
5.2.1. (1S,5R)-1-[(S)-2-Phenylpiperidin-1-ylcarbonyl]-
5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one ((S)-7a)
and (1S,5R)-1-[(R)-2-Phenylpiperidin-1-ylcarbonyl]-
5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one ((R)-8a).
(A) According to GP1 from 100 mg (0.361 mmol) of 5
and 132 ml (0.396 mmol, 1.1 equiv.) of PhMgBr (3.0 M in
Et2O). CC (petrolether/EtOAc¼6/4) afforded 77 mg (60%)
of a mixture of 7a and 8a. The d.s. was determined by
analytical HPLC (n-heptane/iso-propanole¼98/2, 1.0 ml/
min): (S)-7a (26.2 min)/(R)-8a (20.6 min)¼88/12.). Separ-
ation of the diastereomers by prep. HPLC (n-heptane/
EtOAc¼85/15, 15 ml/min) yielded 60 mg (47%) of 7a and
7 mg (5%) of 8a.
The synthesis commenced with asymmetric electrophilic
a-amidoalkylation reactions employing the chiral enamide
5 providing (S)-7b as a key compound with the diastereo-
selectivity (d.s.) of 93/7. From the latter enantiopure (S)-2-
anisylpiperidine [(S)-9b] was obtained. Birch-reduction of
(S)-9b followed by an ozonolysis of the resulting 1,4-
cylohexadiene (S)-10 and a spirocyclization reaction, as
main transformations, led finally to 3 and 4. Work directed
towards the synthesis of securinine-type alkaloids based on
a related strategy is in progress.
5. Experimental
5.1. General
Compound (S)-7a. Colorless crystals, mp 1628C.
[a]2D0¼228.6 (c¼0.50, CH2Cl2). TLC: Rf¼0.42 (petrol-
ether/EtOAc¼6/4). 1H NMR ([D2] 1,1,2,2-tetrachloro-
ethane, 1208C): d¼0.89 (s, 3H, CH3), 1.00 (s, 3H, CH3),
1.27 (s, 3H, CH3), 1.44–2.02 (m, 7H, CH2), 2.22–2.37 (m,
2H, CH2), 2.43–2.83 (m, 1H, CH2), 2.94–3.08 (m, 1H,
NCH2ax), 3.54–3.68 (m, 1H, NCH2eq), 3.89 (d, J¼10.6 Hz,
1H, CH2OCO), 4.13 (d, J¼10.6 Hz, 1H, CH2OCO), 5.82–
5.88 (m, 1H, NCH), 7.18–7.22 (m, 1H, C6H5), 7.23–7.35
Melting points (uncorrected): Dr Tottoli (Bu¨chi Nr. 510)
apparatus. 1H NMR-spectra and 13C NMR-spectra: Jeol
JNMR-GX 400, d-scale (ppm), TMS int. stand., in several
cases coalescence occurred and the signals were broadened
and unresolved (unr.) and as a consequence thereof no exact
integrals could be obtained. Mass spectra: Hewlett Packard
5989 A with 59980 B particle beam LC/MS interface

3364
R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
(m, 4H, C H ). IR: n¼1729 cm21, 1629. MS (CH4, CI); m/z
Compound (R)-8b. Colorless oil. TLC: Rf¼0.43 (petrol-
˜
6
5
(%): 356 (100) [MþHþ]. C22H29NO3 (355.5): calcd C
ether/EtOAc¼60/40). H NMR (C2D2Cl4, 1308C): d¼0.93
1
74.34, H 8.22, N 3.94; found C 74.46, H 7.97, N 4.06.
(s, 3H, CH3), 1.10 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.45–
1.73 (m, 4H, CH2), 1.76–1.87 (m, 1H, CH2), 1.88–2.08 (m,
2H, CH2), 2.33 (d, J¼13.6 Hz, 2H, CH2), 2.36–2.61 (m,
unr., 1H, CH2,) 2.99 (t, J¼12.9 Hz, 1H, NCH2ax), 3.73–3.83
(m, 1H, NCH2eq), 3.83 (s, 3H, OCH3), 3.92 (d, J¼10.8 Hz,
1H, CH2OCO), 4.16 (d, J¼10.8 Hz, 1H, CH2OCO), 5.52–
5.74 (m, 1H, NCHR), 6.93 (d, J¼8.2 Hz, 2H, C6H4), 7.28 (d,
J¼8.2 Hz, 2H, C6H4). MS (CH4, CI); m/z (%): 386 [MþHþ]
(11), 83 (100).
Compound (R)-8a. Colorless oil. TLC: Rf¼0.42 (petrol-
ether/EtOAc¼6/4). 1H NMR ([D2] 1,1,2,2-tetrachloro-
ethane, 1208C): d¼0.88 (s, 3H, CH3), 1.06 (s, 3H, CH3),
1.31 (s, 3H, CH3), 1.42–2.07 (m, 7H, CH2), 2.22–2.37 (m,
2H, CH2), 2.35–2.55 (m, unr., 1H, CH2), 2.90–3.04 (m, 1H,
NCH2ax), 3.73–3.90 (m, 1H, NCH2eq), 3.86 (d, J¼10.7 Hz,
1H, CH2OCO), 4.11 (d, J¼10.7 Hz, 1H, CH2OCO), 5.56–
5.69 (m, unr., 1H, NCRH), 7.17–7.21 (m, 1H, C6H5), 7.26–
7.38 (m, 4H, C6H5). MS (CH4, CI); m/z (%): 356 (100)
[MþHþ].
(B) According to GP1 from 96 mg (0.35 mmol) of 5 and
3.0 ml (0.99 mmol, 3.0 equiv.) of an organozinc reagent
generated by treating 2.0 ml (2.0 mmol) of 4-MeOC6H4-
MgBr (1 M in THF) with 1.0 ml (1.0 mmol) of ZnCl2 (1 M
in Et2O). CC (petrolether/EtOAc¼6/4) afforded 75 mg
(56%) of a mixture of 7b and 8b.
(B) According to GP1 from 52 mg (0.187 mmol) of 5 and
1.4 ml (0.21 mmol, 1.1 equiv.) of an organozinc reagent
generated by treating 0.5 ml (1.5 mmol) of PhMgBr (3 M in
Et2O) in 5.5 ml THF with 0.9 ml (0.9 mmol of ZnCl2 1 M in
Et2O). CC (petrolether/EtOAc¼6/4) afforded 31 mg (47%)
of a mixture of 7a and 8a.
Analytical HPLC: (S)-7b/(R)-8b¼93/7.
(C) According to GP1 from 3.850 g (13.88 mmol) of 5.
After removal of excess HCl 13.8 ml (13.8 mmol,
0.99 equiv.) of BCl3 (1 M in n-heptane) was added at
2788C followed by 105 ml (35.0 mmol, 2.5 equiv.) of an
organozinc reagent generated by treating 55.0 ml
(55.0 mmol) of 4-MeOC6H4MgBr (1 M in THF) with
50.0 ml (35.0 mmol) of ZnCl2 (0.7 M in Et2O). CC
(petrolether/EtOAc¼6/4) afforded 5.320 mg (99%) of a
mixture of 7b and 8b.
Analytical HPLC. (S)-7a/(R)-8a¼94/6.
(C) According to GP1 from 299 mg (1.078 mmol) of 5.
After removal of excess HCl 1.0 ml (1.0 mmol, 0.93 equiv.)
of BCl3 (1 M in n-heptane) was added at 2788C followed by
10.0 ml (3.21 mmol, 3.0 equiv.) of an organozinc reagent
generated by treating 10.0 ml (10.0 mmol) of PhMgBr (1 M
in THF) with 8.4 ml (5.9 mmol) of ZnCl2 (0.7 M in Et2O)
after 3 h. CC (petrolether/EtOAc¼6/4) afforded 347 mg
(91%) of a mixture of 7a and 8a.
Analytical HPLC: (S)-7b/(R)-8b¼93/7.
Analytical
HPLC
(n-heptane/iso-propanole¼98/2,
5.3. Reductive cleavage of the amide bond—general
procedure (GP2)
1.0 ml/min): (S)-7a (26.2 min)/(R)-8a (20.6 min)¼91/9.
5.2.2. (1S,5R)-1-[(S)-2-(4-Methoxyphenyl)piperidin-1-
ylcarbonyl]-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-
one ((S)-7b) and (1S,5R)-1-[(R)-2-(4-methoxyphenyl)-
piperidin-1-ylcarbonyl]-5,8,8-trimethyl-3-oxabicyclo-
[3.2.1]octan-2-one ((R)-8b). (A) According to GP1 from
92 mg (0.33 mmol) of 5 and 1.0 ml (1.0 mmol, 3.0 equiv.)
of 4-CH3OC6H4MgBr (1.0 M in THF). CC (petrolether/
EtOAc¼6/4) afforded 93 mg (74%) of a mixture of 7b and
8b. Prep. HPLC (n-heptane/1,4-dioxane¼88/12, 9 ml/min)
yielded 78 mg (61%) of 7b and 12 mg (8%) of 8b.
Analytical HPLC (n-heptane/1,4-dioxane¼88/12, 1.0 ml/
min): (S)-7b (28.4 min)/(R)-8b (24.8 min)¼85/15.
To a solution of 1.0 mmol of 7a,b in 5 ml of THF 2 equiv. of
Na[AlH2(OMe)]2 (0.925 M in THF) was added dropwise at
2258C. The reducing agent has been generated by treating
1 equiv. of NaAlH4 (1.0 M in THF) with 2 equiv. of MeOH.
After stirring for 24 h at 2258C the reaction mixture was
quenched by addition of MeOH, acidified with dilute HCl
and extracted several times with Et2O. Then 2 M NaOH was
added and the alkaline aqueous layer was extracted several
times with Et2O. The combined organic layers were dried
(MgSO4) and concentrated. The crude product was purified
by CC.
5.3.1. (S)-2-Phenylpiperidinium chloride ((S)-9a).
According to GP2 from 195 mg (0.549 mmol) of 7a. CC
(Et2O/NEtMe2¼98/2) afforded the pure amine which was
redissolved in 15 ml of Et2O. Addition of 12 M HCl at 08C
under vigorous stirring and subsequent removal of the
solvent in vacuo yielded 70 mg (65%) of (S)-9a.
Compound (S)-7b. Colorless crystals, mp 1218C.
[a]2D0¼239.4 (c¼0.96, CH2Cl2). TLC: Rf¼0.38 (petrol-
1
ether/EtOAc¼60/40). H NMR (C2D2Cl4, 1308C): d¼0.94
(s, 3H, CH3), 1.05 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.52–
1.78 (m, 5H, CH2), 1.78–1.89 (m, 1H, CH2), 1.91–2.02 (m,
2H, CH2), 2.33 (d, J¼14.0 Hz, 2H, CH2), 3.04 (t,
J¼12.6 Hz, 1H, NCH2ax), 3.60–3.68 (m, 1H, NCH2eq),
3.83 (s, 3H, OCH3), 3.94 (d, J¼11.1 Hz, 1H, CH2OCO),
4.18 (d, J¼11.1 Hz, 1H, CH2OCO), 5.83–5.90 (m, 1H,
NCHR), 6.92 (d, J¼8.2 Hz, 2H, C6H4), 7.24 (d, J¼8.2 Hz,
Colorless crystals, mp 193–1958C (lit.13: 194–1958C).
[a]2D3¼þ9.5 (c¼1.30, MeOH) {lit.13: (R)-9a: [a]D¼29.6
(MeOH)}.
2H, C H ). IR: n¼2933 cm21, 1733, 1617. MS (CH4, CI);
5.3.2.
(S)-2-(4-Methoxyphenyl)piperidine
((S)-9b).
˜
6
4
m/z (%): 386 [MþHþ] (2), 83 (100). C23H31NO3 (385.5):
calcd C 71.66, H 8.11, N 3.63; found C 71.63, H 8.22, N
3.55.
According to GP2 from 3.30 g (8.65 mmol) of 7b. The
crude product was purified by CC (Et2O/NEtMe2¼98.5/1.5)
to yield 1.501 g (92%) of (S)-9b.

R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
3365
Colorless oil. [a]2D2¼221.1 (c¼0.54, MeOH). TLC:
Rf¼0.31 (Et2O/NEtMe2¼98.5/1.5). 1H NMR (CDCl3):
d¼1.41–1.69 (m, 5H, 2£CH2, NH), 1.73–1.80 (m, 1H,
CH2), 1.84–1.91 (m, 1H, CH2), 2.79 (td, J¼11.4/2.6 Hz,
1H, NHCH2ax), 3.18 (d, J¼11.4 Hz, 1H, NHCH2eq), 3.53
(dd, J¼10.0/2.5 Hz, 1H, NHCR), 3.80 (s, 3H, OCH3), 6.86
(d, J¼8.6 Hz, 2H, Haromat.), 7.29 (dt, J¼8.6/2.1 Hz, 2H,
5.3.5. tert-Butyl (S)-(E)-2-(1-methoxycarbonyl-5-oxo-
pent-2-en-3-yl)piperidine-1-carboxylate ((S)-12). Into a
solution of 250 mg (0.852 mmol) of (S)-11 in 8.5 ml of
MeOH at 2788C 1 equiv. of ozone was passed. After
stirring at 2788C for 2 h 233 ml (3.17 mmol, 3.7 equiv.) of
Me2S was added dropwise. The reaction mixture was
allowed to warm to room temperature within 19 h. Then it
was concentrated and the crude product was purified by CC
(i-hexane/EtOAc¼6/4) to yield 140 mg (50%) of (S)-12.
Haromat.). IR: n¼3322 cm21, 2997, 2932, 2851, 2785, 1611,
˜
1584, 1513. MS (70 eV); m/z (%): 191 [Mþ] (1), 83 (100).
C12H17NO (191.3): calcd C 75.35, H 8.96, N 7.32; found C
75.46, H 8.92 N 7.26.
Colorless oil. [a]D25¼279.0 (c¼1.25, CH2Cl2). TLC:
Rf¼0.35 (i-hexane/EtOAc¼6/4). 1H NMR (CDCl3):
d¼1.44 (s, 9H, C(CH3)3), 1.53–1.73 (m, 5H, CH2), 2.01
5.3.3. (S)-2-(4-Methoxycyclohexa-1,4-dienyl)piperidine
((S)-10). To a solution of 1.400 g (7.319 mmol) of (S)-9b
in 39 ml of Et2O at 2788C ,155 ml of liquid NH3 was
added. The resulting mixture was warmed to 2408C before
1.072 g (154.4 mmol, 21.1 equiv.) of Lithium as small
pieces was added. The resulting blue colored solution was
kept at 2408C for 30 min before it was quenched by
addition of distilled EtOH and allowed to slowly warm to
room temperature (,16 h) in order to remove the solvent
(attention gaseous NH3). Then 100 ml of H2O was added
and the aqueous layer was extracted several times with
CH2Cl2. The combined organic layers were dried (MgSO4)
and concentrated in vacuo and the crude product was
purified by CC (Et2O/NEtMe2¼98.5/1.5) to yield 1.250 g
(89%) of (S)-10.
(dbroad
,
J¼14.0 Hz, 1H, NCHRCH2eq), 2.65 (td,
J¼13.3/2.8 Hz, 1H, NCH2ax), 3.07–3.14 (m, 4H, MeO2-
CCH2 and CHOCH2), 3.69 (s, 3H, OCH3), 3.92 (dbroad
,
J¼13.3 Hz, 1H, NCH2eq), 4.70–4.75 (m, 1H, NCHR), 5.80
(td, J¼7.2/2.1 Hz, vCH), 9.57 (t, J¼2.0 Hz, 1H, COH). IR:
n¼2939 cm21, 2867, 1740, 1723, 1690. MS (CH4, CI); m/z
˜
(%): 326 (5) [MþHþ], 208 (100). C17H27NO5 (325.4): calcd
C 62.75, H 8.36, N 4.30; found C 62.52, H 8.33, N 4.57.
5.3.6. (S)-(E)-3-(1-tert-Butyloxycarbonylpiperidin-2-yl)-
5-methoxycarbonyl-pent-3-enoic acid ((S)-13). To
165 mg (0.507 mmol) of S-(12) in 11.0 ml of tBuOH and
2.5 ml of 2-methyl-2-butene within 10 min 73.3 mg
(0.648 mmol, 1.28 equiv.) of NaClO2 (80%) in 1.8 ml of
phosphate buffer ((pH¼7, c¼1.0 M) and 2.2 ml H2O was
added at room temperature. After 3 h of stirring the reaction
mixture was concentrated and the resulting residue was
extracted several times with 10 ml of Et2O. The combined
organic layers were dried (Na2SO4) and concentrated. The
crude product was purified by CC (EtOAc/HOAc¼98/2) to
yield 156 mg (90%) of (S)-13.
Colorless crystals, mp 378C. [a]2D2¼219.9 (c¼1.07,
MeOH). TLC: Rf¼0.48 (Et2O/NEtMe2¼95/5). 1H NMR
(CDCl3): d¼1.25–1.49 (m, 3H, CH2), 1.49–1.63 (m, 2H,
NCH2CH2eq and NH), 1.67 (dbroad, J¼11.4 Hz, 1H,
NCHRCH2eq), 1.83 (dbroad, J¼8.7 Hz, 1H, NCH2CH2-
CH2eq), 2.67 (td, J¼12/2.6 Hz, 1H, NHCH2ax),
2.74 (sbroad
, 2H, vCHCH2), 2.76–2.94 (m, 2H,
vCHCH2), 2.97 (dbroad, J¼10.3 Hz, 1H, NHCRH), 3.12
(d, J¼12 Hz, 1H, NHCH2eq), 3.55 (s, 3H, OCH3), 4.63–
4.67 (m, 1H, CH3OCvCH), 5.59–5.64 (m, 1H,
Colorless oil. [a]D23¼2123.3 (c¼0.60, CH2Cl2). TLC:
Rf¼0.50 (EtOAc/HOAc¼98/2). 1H NMR (CDCl3):
d¼1.46 (s, 9H, C(CH3)3), 1.55–1.76 (m, 5H, CH2), 2.05
,
HNCHCRvCH). IR: n¼1695 cm21, 1663. MS (CH4,
(dbroad, J¼13.3 Hz, 1H, NCHRCH2eq), 2.70 (tbroad
˜
CI); m/z (%): 194 (100) [MþHþ]. C12H19NO (193.3):
calcd C 74.57, H 9.91, N 7.25; found C 74.44, H 10.20,
N 7.09.
J¼13.4 Hz, 1H, NCH2ax), 2.98 (d, J¼15.3 Hz, 1H,
HOOCCH2), 3.12 (d, J¼15.3 Hz, 1H, HOOCCH2), 3.18–
3.32 (m, 2H, MeOOCCH2), 3.70 (s, 3H, OCH3), 3.92 (dbroad
,
J¼13.4 Hz, 1H, NCH2eq), 4.71–4.76 (m, 1H, NCHR), 5.78
5.3.4. tert-Butyl (S)-2-(4-methoxycyclohexa-1,4-dienyl)-
piperidine-1-carboxylate ((S)-11). To a solution of 338 mg
(1.75 mmol) of (S)-10 and 499 mg (2.29 mmol, 1.3 equiv.)
of (Boc)2O in 17.5 ml of MeCN 326 ml of NEtiPr2 was
added dropwise at room temperature. After three days of
stirring the reaction mixture was concentrated and purified
by CC (petrolether/EtOAc¼6/4) to yield 510 mg (99%) of
(S)-11.
(t, J¼7.0 Hz, 1H, vCH). IR: n¼3170 cm21, 2940, 2958,
˜
2604, 1738, 1694, 1644. MS (CH4, CI); m/z (%): 342 (1)
[MþHþ], 242 (100). C17H27NO6 (341.4): calcd C 59.81, H
7.97, N 4.10; found C 59.39, H 8.24, N 3.94.
5.3.7. (S)-(E)-3-Piperidin-2-yl-5-methoxycarbonylpent-
3-enoic acid ((S)-14). (A) ((S)-14·CF3CO2H): To 73 mg
(0.21 mmol) of (S)-13 in 200 ml of CH2Cl2 1.0 ml of
CF3CO2H was added dropwise and the reaction mixture was
stirred for 5 h at room temperature. Removal of the solvent
in vacuo yielded 76 mg (,100%) of (S)-14·CF3CO2H.
Colorless crystals, mp 56–588C. [a]2D5¼283.6 (c¼1.00,
MeOH). TLC: Rf¼0.65 (petrolether/EtOAc¼6/4). 1H NMR
(CDCl3): d¼1.46 (s, 9H, C(CH3)3), 1.50–1.67 (m, 5H,
CH2), 2.00 (dbroad, J¼13.6 Hz, 1H, NCHRCH2eq), 2.55–
2.83 (m, 5H, 2xvCHCH2, NCH2ax), 3.56 (s, 3H, OCH3),
3.96 (dbroad, J¼14.0 Hz, 1H, NCH2eq), 4.64 (t, J¼3.5 Hz,
1H, NCRH), 4.62–4.69 (m, 1H, MeOCvCH), 5.45–5.50
Yellowish oil. [a]D23¼213.0 (c¼0.67, H2O). 1H NMR
(D2O): d¼1.33–1.55 (m, 3H, CH2), 1.66–1.84 (m, 3H,
CH2), 2.86 (td, J¼13/3.0 Hz, 1H, HNCH2ax), 3.07 (d,
J¼7.6 Hz, 2H, MeOOCCH2), 3.11–3.15 (m, 2H,
HOOCCH2), 3.26 (dbroad, J¼13 Hz, 1H, HNCH2eq), 3.50
(s, 3H, OCH3), 3.54 (dbroad, J¼11.0 Hz, 1H, HNCHR), 5.83
(m, 1H, HNCHCRvCH). IR: n¼2936 cm21, 1690. MS
˜
(CH4, CI); m/z (%): 294 (9) [MþHþ], 266 (3), 238 (100).
C17H27NO3 (293.4): calcd C 69.59, H 9.28, N 4.77; found C
69.46, H 9.41, N 4.79.
(t, J¼7.6 Hz, 1H, vCH). IR: n¼3446 cm21, 2958, 2865,
˜
2526, 1731, 1672. MS (CH4; CI); m/z (%): 242 (13)

3366
R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
[MþHþ], 224 (100). C14H20F3NO6 (355.3): calcd C 47.32,
(CD2Cl2): d¼1.20–1.38 (m, 2H, NCHRCH2ax, NCH2-
CH2ax), 1.42 (qt, J¼13/3 Hz, 1H, NCH2CH2CH2ax), 1.60–
1.68 (m, 1H, NCH2CH2eq), 1.68–1.74 (m, 1H,
NCHRCH2eq), 1.84–1.94 (m, 1H, NCH2CH2CH2eq), 2.36
(dd, J¼18.2/1.7 Hz, 1H, NCOCH2), 2.45 (dd, J¼17.0/
6.1 Hz, 1H, MeOCOCH2), 2.59 (dd, J¼17.0/6.1 Hz, 1H,
MeOCOCH2), 2.63 (d, J¼18.2 Hz, 1H, NCOCH2), 2.62–
2.69 (m, 1H, NCH2ax), 3.36 (dd, J¼12.0/3.5 Hz, 1H,
NCHR), 3.41 (t, J¼6.1 Hz, 1H, COHR), 3.69 (s, 3H,
OCH3), 4.17 (ddt, J¼13/5/1.7 Hz, 1H, NCH2eq). 100 MHz
13C NMR (CD2Cl2): d¼23.48 (NCH2CH2CH2), 24.43
(NCH2CH2), 29.03 (NCHRCH2), 33.92 (NCOCH2), 35.37
(MeO2CCH2), 39.82 (NCH2), 51.97 (OCH3), 54.46
(CHOR), 61.64 (NCR2H), 63.37 (CR3OR), 168.60 (NCO),
H 5.67, N 3.94; found C 46.82, H 5.50, N 3.78.
(B) ((S)-14·BF3): To 173 mg (0.507 mmol) of (S)-14 in
7.0 ml CH2Cl2 at room temperature within 5 min 195 ml
(1.55 mmol, 3.06 equiv.) of BF3·OEt2 was added. Removal
of the solvent (in vacuo) after 30 min yielded 205 mg
(,98%) of (S)-14·2.5BF3. The formula was delineated from
the results of the combustion analysis, but no attempts were
made to determine the nature of the formed complex.
Colorless oil. 1H NMR (D2O): d¼1.37–1.60 (m, 3H, CH2),
1.72–1.90 (m, 3H, CH2), 2.92 (td, J¼12.7/3.0 Hz, 1H,
HNCH2ax), 3.12 (d, J¼7.4 Hz, 2H, MeOOCCH2), 3.17–
3.19 (m, 2H, HOOCCH2), 3.31 (dbroad, J¼12.7 Hz, 1H,
HNCH2eq), 3.56 (s, 3H, OCH3), 3.59 (dbroad, J¼12.1 Hz,
1H, HNCHR), 5.88 (t, J¼7.4 Hz, 1H, vCH). IR:
170.25 (OCO). IR: n¼3456 cm21, 2940, 2858, 1738, 1694.
˜
MS (CH4, CI); m/z (%): 240 (100) [MþHþ]. HRMS (2008C,
EI 70 eV): calcd for C12H17NO4: 239.11576. Found: 239.
1126.
n¼3208 cm21, 2953, 2859, 2500, 1732, 1715, 1652. MS
˜
(CH4, CI); m/z (%): 242 (1) [MþHþ], 224 (100).
C12H19NO4·2.5BF3 (410.8): calcd C 35.09, H 4.66, N
3.41; found C 35.19, H 5.21, N 3.50.
Compound 17. Colorless oil. [a]2D3¼216.7 (c¼0.30,
1
CH2Cl2). TLC: Rf¼0.19 (EtOAc/HOAc¼98/2). H NMR
(CD2Cl2): d¼1.20–1.42 (m, 3H, NCHRCH2ax, NCH2-
CH2ax, NCH2CH2CH2ax), 1.44–1.52 (m, 1H, NCHRCH2eq),
1.63–1.71 (m, 1H, NCH2CH2eq) 1.88–1.96 (m, 1H,
NCH2CH2CH2eq), 2.27 (d, J¼18.2 Hz, 1H, NCOCH2),
2.52 (dd, J¼16/6 Hz, 1H, MeOCOCH2), 2.57 (dd, J¼16/
6 Hz, 1H, MeOCOCH2), 2.56–2.65 (m, 1H, NCH2ax), 2.71
(dd, J¼18.2/1.7 Hz, 1H, NCOCH2), 3.28 (t, J¼6.0 Hz, 1H,
COHR), 3.60 (dd, J¼11.5/3.5 Hz, 1H, NCHR), 3.69 (s, 3H,
OCH3), 4.11–4.18 (m, 1H, NCH2eq). 100 MHz 13C NMR
(CD2Cl2): d¼23.10 (NCH2CH2CH2), 24.24 (NCH2CH2),
25.54 (NCHRCH2), 34.57 (NCOCH2), 35.34 (MeO2CCH2),
39.92 (NCH2), 52.01 (OCH3), 54.49 (CHOR), 58.93
(NCR2H), 62.15 (CR3OR), 168.99 (NCO), 170.38 (OCO).
5.3.8. Methyl (S)-(E)-3-(3-oxoindolizidin-1-ylidene) pro-
pionate ((S)-15). To 95 mg (0.23 mmol) of (S)-14·BF3
(method B) in 4.8 ml of CH2Cl2 66 mg (0.26 mmol,
1.1 equiv.) of 2-chloro-1-methylpyridinium iodide was
added at room temperature followed by the dropwise
addition of 162 ml (0.932 mmol, 3.61 equiv.) of NiPr2Et.
The reaction mixture was stirred for 16 h at room
temperature, concentrated and purified by CC (EtOAc/
HOAc¼98/2). The crude product was dissolved in 3.0 ml of
saturated NaHCO3-solution and extracted several times
with CH2Cl2. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to yield 40 mg (77%)
of (S)-15.
IR: n¼3446 cm21, 2948, 2854, 1738, 1694. MS (CH4, CI);
˜
m/z (%): 240 (100) [MþHþ]. C12H17NO4 (239.3): calcd C
Colorless crystals, mp 508C. [a]2D3¼215.7 (c¼1.05,
60.24, H 7.16, N 5.85; found C 59.77, H 7.02, N 5.71.
1
CH2Cl2). TLC: Rf¼0.23 (EtOAc/HOAc¼98/2). H NMR
(CD2Cl2): d¼1.20 (tdd, J¼13/11/3.3 Hz, 1H, NCHRCH2ax),
1.30 (qdd, J¼13/5/3.5 Hz, 1H, NCH2CH2ax), 1.48 (qt,
J¼13/3.5 Hz, 1H, NCH2CH2CH2ax), 1.61–1.69 (m, 1H,
NCH2CH2eq), 1.85–1.92 (m, 1H, NCH2CH2CH2eq), 1.93–
2.00 (m, 1H, NCHRCH2eq), 2.61 (tdbroad, J¼13/3.5 Hz, 1H,
NCH2ax), 2.94–2.98 (m, 2H, NCOCH2), 3.02 (dq,
J¼7/1.5 Hz, 2H, MeOOCCH2), 3.65 (s, 3H, OCH3), 3.92
(dbroad, J¼11 Hz, 1H, NCHR), 4.12 (ddt, J¼13/5/1.5 Hz,
5.3.10. (10R,80aS) Spiro[furan-2,10-indolizidine]-30,5(2H)-
dione (3). 22 mg (0.092 mmol) of 16 in 200 ml of CH2Cl2
were treated with 1.0 ml of TFA for 6 h at room temperature
The solvent was removed in vacuo and to the resulting
residue 200 ml of CH2Cl2 and 1.0 ml of TFAA were added.
Then the reaction mixture was stirred for 5 h at room
temperature before it was concentrated in vacuo. The
residue was redissolved in 1.0 ml of CH2Cl2, 250 ml of NEt3
was added and the mixture was stirred for an additional 1 h
at room temperature. The crude product that was obtained
after removal of the solvent was purified by CC (EtOAc/
HOAc¼90/10) to yield 15 mg (79%) of 3.
1H, NCH2eq), 5.52–5.60 (m, 1H, vCH). IR: n¼3460 cm21
,
˜
2940, 2858, 1738, 1694, 1682. MS (70 eV); m/z (%): 223 (9)
[Mþ], 150 (100). C12H17NO3·0.25H2O (227.8): calcd C
63.28, H 7.74, N 6.15; found C 63.08, H 7.37, N 6.08.
5.3.9. Methyl (1R,30R,8aS)-3-oxo-spiro[indolizidin-1,20-
oxiran]-30-ylacetate ((16)) and methyl (1S,30S,8aS)-3-
oxo-spiro[indolizidin-1,20-oxiran]-30-ylacetate ((17)). To
40 mg (0.179 mmol) of (S)-15 in 1.5 ml of CH2Cl2 85 mg
(,0.27 mmol, ,1.5 equiv.) MCPBA was added and the
reaction mixture was stirred for 24 h at room temperature
The solvent was evaporated and the residue was purified by
CC (EtOAc/HOAc¼98/2) to yield 26 mg (61%) of 16 and
13 mg (30%) of 17.
Colorless crystals, mp 137–1388C. [a]2D3¼þ56.8 (c¼0.37,
1
CH2Cl2). TLC: Rf¼0.14 (EtOAc/HOAc¼90/10). H NMR
(CD2Cl2): d¼1.30–1.40 (m, 2H, NCHRCH2ax and NCH2-
CH2ax), 1.40–1.50 (m, 2H, NCH2CH2CH2ax and
NCHRCH2eq) 1.66–1.75 (m, 1H, NCH2CH2eq), 1.88–1.96
(m, 1H, NCH2CH2CH2eq), 2.52 (d, J¼17.6 Hz, 1H,
NCOCH2), 2.59–2.68 (m, 1H, NCH2ax), 2.77 (dd,
J¼17.6/1.8 Hz, 1H, NCOCH2), 3.52–3.57 (m, 1H,
NCHR), 4.05–4.12 (m, 1H, NCH2eq), 6.12 (d, J¼5.5 Hz,
1H, OCOCHv), 7.36 (d, J¼5.5 Hz, 1H, OCOCHvCH).
100 MHz 13C NMR (CD2Cl2): d¼23.36 (NCH2CH2CH2),
23.75 (NCH2CH2), 24.00 (NCRHCH2), 40.90 (NCH2 and
Compound 16. Colorless oil. [a]2D3¼219.7 (c¼1.13,
1
CH2Cl2). TLC: Rf¼0.25 (EtOAc/HOAc¼98/2). H NMR

R. Kammler et al. / Tetrahedron 59 (2003) 3359–3368
3367
NCOCH2), 62.09 (NCHR), 88.36 (CR3OR), 122.78
(O2CCv), 155.16 (O2CCHvCH), 169.53 (NCO), 171.43
the Cambridge Crystallographic Data Center. The data will
be sent on quoting the CCDC-200973 number (e-mail:
deposit@ccdc.cam.ac.uk).
(O C). IR: n¼3446 cm21, 3109, 2951, 2862, 1780, 1693.
˜
2
MS (CH4, CI); m/z (%): 208 (100) [MþHþ]. C11H13NO3
(207.2): calcd C 63.76, H 6.32, N 6.76; found C 63.43, H
6.31, N 6.59.
Acknowledgements
5.3.11. (10S,80aS)-Spiro[furan-2,10-indolizidine]-30,5(2H)-
dione (4). 6 mg (0.025 mmol) of 17 in 200 ml of CH2Cl2
were treated with 0.5 ml of TFA for 6 h at room
temperature. The solvent was removed in vacuo and to the
resulting residue 100 ml of CH2Cl2 and 0.5 ml of TFAA
were added. Then the reaction mixture was stirred for 5 h at
room temperature before it was concentrated in vacuo. The
residue was redissolved in 0.5 ml of CH2Cl2, 100 ml of NEt3
was added and the mixture was stirred for an additional h at
room temperature. The crude product, that was obtained
after removal of the solvent, was purified by CC (EtOAc/
HOAc¼90/10) to yield 4 mg (77%) of 4.
Financial support of this work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the
BMBF is gratefully acknowledged.
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Crystal data for 3. C11H13NO3, M¼207.22, monoclinic,
space group C2, a¼15.792 (3), b¼5.4734(8), c¼12.599
3
˚
˚
(3) A, b¼109.83 (2), volume¼1024.5 (3) A , Z¼4,
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0.9979, R1¼0.0346, wR2¼0.0849 for all 1522 reflections
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˚
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˚
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3368
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