Convergent asymmetric synthesis of indolizidines from (S)-5-(tosylmethyl)-2-pyrrolidinone: Synthesis of (-)-δ-coniceine

Article abstract of DOI:10.1016/S0957-4166(01)00377-9

The enantiomerically pure (S)-5-(tosylmethyl)-2-pyrrolidinone 2, prepared from commercially available (S)-pyroglutaminol, is dialkylated at the nitrogen atom and the α-sulfonyl position using several dielectrophiles using sodium hydride as the base to diastereoselectively afford indolizidine derivatives 5 and the less common hexahydropyrrolo[1,2-a]azepin-3-one 6 in moderate to good yield. This domino process has been applied to the synthesis of (-)-δ-coniceine.

Full text of DOI:10.1016/S0957-4166(01)00377-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2205–2211
Convergent asymmetric synthesis of indolizidines from
(S)-5-(tosylmethyl)-2-pyrrolidinone: synthesis of (−)-d-coniceine
Ana Costa, Carmen Na´jera* and Jose´ M. Sansano
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 8 August 2001; accepted 23 August 2001
Abstract—The enantiomerically pure (S)-5-(tosylmethyl)-2-pyrrolidinone 2, prepared from commercially available (S)-pyroglut-
aminol, is dialkylated at the nitrogen atom and the a-sulfonyl position using several dielectrophiles using sodium hydride as the
base to diastereoselectively afford indolizidine derivatives 5 and the less common hexahydropyrrolo[1,2-a]azepin-3-one 6 in
moderate to good yield. This domino process has been applied to the synthesis of (−)-d-coniceine. © 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
ganglia membranes.2 Hydroxylated derivatives V–VIII
are inhibitors of glycosidases with potential antibacte-
rial, antitumoral, antiviral, antiinflammatory or antidia-
betic activity and act as anti-HIV agents3 (Fig. 1).
These alkaloids are very important targets in organic
synthesis due to their scarcity in natural sources and
their important physiological effects. The majority of
strategies for constructing indolizidines are based on
divergent methods for particular structures. However,
convergent methods are especially appropriate for the
preparation of a variety of structurally similar alkaloids
from a common precursor. This objective can be easily
achieved starting from either proline4a–f or pyroglu-
tamic acid4g–h and using a three-carbon fragment for
the construction of the six-membered ring.4 In this
context, we have recently described that (E)-5-tosyl-4-
pentenamide 1 can be cyclised to 2-(tosylmethyl)-g-lac-
tam 2 by means of treatment with sodium hydride and,
after reaction with 1,3-dielectrophiles, transformed
stereoselectively into indolizidine derivatives 3 (Scheme
1).5
The family of indolizidine alkaloids1 is present in the
skins of central and South American frogs, fungi and
plants. Depending on their structure, they possess a
variety of important biological activities. Alkylated
indolizidines I–IV are non-competitive blockers of nico-
tinic acetyl choline receptor channels in muscle and
H
H
N
N
Bu
(+)-Coniceine I
(+)-Monomorine II
H
OH
H
N
N
C4H9
R
R=Me, (-)-Indolizidine 167B III
R=Bu, (-)-Indolizidine 209D IV
Pumilliotoxin 251D V
NaH
Ts
O
Ts
O
N
H
NH2
OH
OH
OAc
OH
OH
H
N
1
H
H
2
HO
OH
Ts
N
N
H2N
NaH
E+ E+
NaH
E+ E+
HO
Castanospermine VIII
R3
R2
Slaframine VI
Swainsonine VII
N
Figure 1. Selected examples of naturally occurring indolizidi-
nes.
R1
3
O
Scheme 1.
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00377-9

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A. Costa et al. / Tetrahedron: Asymmetry 12 (2001) 2205–2211
Herein, we report the preparation of optically active
indolizidines starting from a chiral sulfone (S)-5-(tosyl-
methyl)-2-pyrrolidinone (S)-2 from inexpensive (S)-
pyroglutamic acid6 and its application to the
asymmetric synthesis of different indolizidines such as
the simplest indolizidine alkaloid (−)-d-coniceine I.7,8
yields (Scheme 3 and Table 1). Despite the fact that
lithium hexamethyldisilazide is the most suitable base
for deprotonating similar sulfones,13 sodium hydride
(used as a 60% dispersion in mineral oil) gave the best
results. Other bases, such as n-BuLi, phosphazene bases
and tert-BuOK, using a wide range of temperatures
(from −78 to 50°C) did not improve on the results
obtained using sodium hydride. Using 1,3-dielec-
trophiles such as 1,3-dihalogenides and a,b-unsaturated
esters, indolizidine derivatives 5 were diastereoselec-
tively obtained through a stepwise dialkylation. The
first substitution reaction corresponded to that of
sodium amide, rather than the a-sulfonyl carbanion,14
as shown by the large amounts of dehydroiodinated
compound 85 (c.a. 40% yield) which were isolated in the
reaction of 2 with 1,3-diiodopropane (Table 1, entry 1
and Scheme 3). The side product 8 was obtained in
almost quantitative yield when 95% sodium hydride
was employed instead of a 60% dispersion in mineral
oil. Use of 2-(chloromethyl)-3-chloropropene as the
dielectrophile, in the presence of sodium iodide (2
equiv.), afforded enantiomerically pure exo-methylene
indolizidine 5b in 85% yield (Table 1, entry 2).
2. Results and discussion
For the synthesis of (S)-2-(tosylmethyl)-g-lactam 2, (S)-
pyroglutaminol9 was used as the starting material,
which was treated with p-toluenesulfonyl chloride, tri-
ethylamine and a catalytic amount of 4-(N,N%-dimethyl-
amino)pyridine (DMAP) in dichloromethane, at room
temperature, affording tosylate 4 in 60% yield.10 Com-
pound 4 underwent nucleophilic displacement by p-
methylthiophenol under basic media followed by
oxidation with oxone® giving enantiomerically pure
sulfone (S)-2 in 90% overall yield (Scheme 2).11
This synthesis was preferred to that employing the
nucleophilic substitution reaction of sodium p-toluene-
sulfinate onto homochiral (S)-5-(bromomethyl)-2-
pyrrolidinone12 because higher purity of the crude
sulfone (S)-2 was obtained. Subsequent reaction of
compound 2, generated with 1,3- and 1,4-dielec-
trophiles in the presence of 2 equiv. of sodium hydride
(60% dispersion in mineral oil) in DMF, gave the
indolizidine derivatives 5 and hexahydropyrrolo[1,2-
a]azepin-3-one 6, respectively, in moderate to good
Using a,b-unsaturated esters as the dielectrophile
afforded highly functionalised indolizidine derivatives
by employing substoichiometric amounts of base for
the Michael addition step. Thus, n-butyl methacrylate
generated a 10:1 cis/trans mixture of diastereomers in
low yield (Scheme 3, Table 1, entry 3). In the case of
methyl crotonate the reaction took place more rapidly,
1) p-TolSH, NaOH
TsCl, DMAP
OH
MeCN, reflux
OTs
Ts
R
O
O
O
Et3N, CH2Cl2
O
N
H
N
H
2) Oxone , H2
N
H
(S)-2
rt
MeOH, rt
(S)-Pyroglutaminol
4
[α]D25 +58.6 (c 1, CH2Cl2)
Scheme 2.
Ts
H
R R
2)
2)
X
X
H
Ts
O
N
N
R
R
O
5a,b
R1
8
OR3
R2
Ts
H
O
1) NaH, DMF
0ºC to rt
O
Ts
O
N
N
R1
H
R2
O
(S)-2
5c,d
Ts
H
2)
Cl
Cl
N
O
6
Scheme 3. R=H, ꢀCH2; R1, R2=H, Me; R3=n-Bu, Me.

A. Costa et al. / Tetrahedron: Asymmetry 12 (2001) 2205–2211
2207
Table 1. Diastereoselective synthesis of indolizidine derivatives 5 and hexahydropyrrolo[1,2-a]azepin-3-one 6
leading to higher conversions of the all-cis-diastereoiso-
mer 5d (Scheme 3, Table 1, entry 4). The moderate
yields obtained when using acrylic esters were pre-
sumably caused by a retro-Michael reaction before
cyclisation. This drawback, which was especially impor-
tant in the case of ethyl acrylate, was overcome by
employing an alternative two-step procedure based on
the use of caesium fluoride and tetramethoxysilane.15a,b
This methodology became particularly useful in organic
synthesis for the conjugate addition of amides to
Michael acceptors.15c,d Thus, Michael adduct 7 was
generated in quantitative yield and further anionic
cyclisation with sodium hydride (1 equiv.) in DMF,
gave the indolizidine derivative 5e in 72% overall yield
(Scheme 4 and Table 1, entry 5). Again, only one
diastereomer was detected in the crude product by
NMR analysis. In contrast, use of butyl methacrylate,
methyl fumarate and methyl maleate gave very disap-
pointing results, probably the related retro-Michael
addition was much faster in those examples under basic
reaction conditions.
When (Z)-1,4-dichloro-2-butene was allowed to react
with sulfone (S)-2, in the presence of NaH, function-
alised hexahydropyrrolo[1,2-a]azepin-3-one 6 was iso-
lated in 54% yield (Scheme 3, Table 1, entry 6). The
rare hexahydropyrrolo[1,2-a]azepin-3-one or 1-azabicy-
clo[5.3.0.]decane system is not a common skeleton but

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A. Costa et al. / Tetrahedron: Asymmetry 12 (2001) 2205–2211
H
Ts
CsF, Si(OMe)4
CO2Et
NaH, DMF
Ts
O
Ts
O
O
N
O
N
N
H
0ºC to rt
CO2Et
(S)-2
5e
7
Scheme 4.
it is present in some natural products and compounds
with biological interest such as thyroliberin,16 stemona
alkaloids17 and a novel alkaloid 275A.18 Because a few
procedures are described focussed on the synthesis of
this heterocyclic array,6,19 this process proved to be a
valuable alternative route to prepare them in a stereo-
controlled manner. However, when 1,4-diiodobutane
was employed the corresponding dehydroiodinated
product was obtained.
4. Experimental
4.1. General
Melting points were determined with a Reichert Ther-
movar hot plate apparatus and are uncorrected. IR
spectra were recorded on a Nicolet 510 P-FT and only
the structurally important peaks are listed. NMR spec-
tra were performed on a Bruker AC-300 and DRX-500.
CDCl3 as solvent and TMS as internal standard were
employed unless otherwise stated. Optical rotations
were measured on a Jasco DIP-1000 polarimeter. Low-
resolution electron impact (EI) mass spectra were
obtained at 70 eV on a Shimadzu QP-5000 and HRMS
(EI) were recorded on a Finnigan MAT 95S. Micro-
analyses were performed by the Microanalyses Service
of the University of Alicante. Analytical TLC was
performed on Schleicher & Schuell F1400/LS silica gel
plates and the spots visualized with UV light at 254 nm.
Flash chromatography employed Merck silica gel 60
(0.040–0.063 mm). Commercially available anhydrous
DMF (Aldrich) was used without any other treatment.
The stereochemistry of pure 6 and pure compounds 5
was deduced by NOESY experiments and by analysing,
in the case of compounds 5, the coupling constant
values between the a-sulfonyl proton and the ring
junction methyne proton (Jtrans=10.4 Hz).5 Irrespective
of the chosen method (one-pot or sequentially via 7) the
diastereomeric excess, determined by 1H NMR (500
MHz) from the crude reaction mixtures of the products
5 and 6, was higher than 98%. Molecular mechanical
and semi-empirical PM3 calculations20 predicted that
the trans arrangement for compound 5a is thermody-
namically more stable (about 2 kcal/mol) than the
undetected diastereoisomer cis-5a.
4.2. Synthesis of (5S)-5-[(p-toluenesulfonyl)oxymethyl]-
We then applied the methodology developed to the
synthesis of (−)-d-coniceine I starting from indolizidine
derivative 5a. The reduction of the arylsulfonyl group
2-pyrrolidinone 422
To a stirred solution of (S)-(+)-5-hydroxymethyl-2-
pyrrolidinone (2.2 g, 20 mmol), triethylamine (3.3 mL,
24 mmol) and DMAP (0.12 g, 1.2 mmol) in
dichloromethane (90 mL) at 0°C, p-toluenesulfonyl
chloride (3.7 g, 0.02 mol) was slowly added. The mix-
ture was stirred at room temperature for 24 h. The
organic phase was sequentially washed with aqueous
HCl (2 M 3×10 mL), water (2×10 mL), NaHCO3 (3×10
mL) and brine (2×10 mL). The solvent was dried
(Na2SO4) and evaporated in vacuo affording 4. Colour-
less prisms, mp 117–118°C (n-hexane/ethyl acetate).
[h]D +16.5 (c 2.5, EtOH), {lit.10b [h]D +16.8 (c 2.6,
EtOH)}. Calculated for C12H15NO4S: C, 53.5; H, 5.6;
N, 5.2; S, 11.9. Found: C, 53.2; H, 5.9; N, 5.7; S,
11.7%. IR (CH2Cl2) wmax: 3265, 3179, 1665, 1298 and
5
with 6% sodium amalgam/Na2HPO4 gave intermediate
lactam 9 in 51% yield and final amide reduction was
accomplished with lithium aluminium hydride7b afford-
ing (−)-d-coniceine I in 85% yield21 (Scheme 5).
3. Conclusions
The dialkylation of optically pure sulfone (S)-2 with
1,3-dielectrophiles represents a concise, accessible and
straightforward convergent methodology for preparing
diastereoselectively sulfonylated optically active
indolizidine derivatives, which are precursors of natu-
rally occurring indolizidine alkaloids. The most simple
indolizidine alkaloid (−)-d-coniceine is prepared in only
three steps following this short synthetic route. The
1146 cm−1. H NMR (300 MHz) lH: 1.71–1.82 [m, 1H,
1
1×CH2CHN], 2.21–2.35 (2m, 3H, 1×CH2CHN,
CH2CO), 2.46 (s, 3H, CH3Ar), 3.86–3.89 (m, 2H,
CH2S), 4.03–4.06 (m, 1H, CHN), 6.68 (s, 1H, NH), 7.37
and 7.79 (2d, J=8.2 Hz, 4H, ArH). 13C NMR (75
functionalised
hexahydropyrrolo[1,2-a]azepin-3-one
skeleton can be easily obtained by reaction of (S)-2
with (Z)-1,4-dichloro-2-butene.
H
H
H
Ts
LiAlH4
Et2O
Na/Hg, MeOH
O
N
O
N
N
Na2HPO4
5a
9
(-)-Coniceine I
Scheme 5.

A. Costa et al. / Tetrahedron: Asymmetry 12 (2001) 2205–2211
2209
MHz) lC: 21.6 (CH3Ar), 22.7, 29.1 [(CH2)2], 52.6
(CHN), 71.9 (CH2S), 127.9, 130.1, 132.4, 145.4 (ArC)
and 177.6 (CO). MS m/z: 269 (M+, 2), 239 (17), 97 (10),
91 (32), 85 (17), 84 (100), 73 (64), 65 (15) and 41 (27).
J=10.4 and 7.3 Hz, 1H, CHN), 4.10 (dd, J=13.4 and
4.3 Hz, 1H, HCHN), 7.40 and 7.76 (2d, J=7.9, 4H,
ArH); lc 21.6 (CH3Ar), 23.3, 25.2, 25.3, 29.9
[(CH2)2CO, (CH2)2CHS], 39.1 (CH2N), 56.0 (CHS),
66.8 (CHN), 128.8, 129.9, 134.2, 145.3 (ArC), and 173.6
(CO). MS m/z: 293 (M+, 0.1%), 138 (17), 137 (100) and
136 (21). HRMS found: 293.1089. C15H19NO3S requires
293.1086.
4.3. Synthesis of (5S)-5-[(p-toluenesulfonyl)methyl]-2-
pyrrolidinone 2
Tosylate 4 (3.6 g, 13.4 mmol) and p-toluenethiol (2.9 g,
23 mmol) were dissolved in acetonitrile (75 mL) and
sodium hydroxide (1.1 g, 27.5 mmol) was added. The
resulting suspension was stirred under reflux for 24 h.
Acetonitrile was removed and ethyl acetate (30 mL)
was poured into the flask. The organic layer was
washed with water (3×10 mL) and evaporated in vacuo
giving crude sulfide. Without any other purification,
this thioether (3 g, 13 mmol) was dissolved in a 1:1
mixture of methanol and water (150 mL) and oxone®
(4.9 g, 8 mmol) was slowly added at 0°C and the
reaction was stirred for 12 h at room temperature.
Methanol was evaporated in vacuo and the aqueous
solution was extracted with ethyl acetate (3×20 mL).
The organic phase was dried (Na2SO4) and evaporated
under reduced pressure giving (S)-2 as a colourless
solid. Prisms, mp 139–140°C (n-hexane/diethyl ether).
Calculated for C12H15NO3S: C, 56.9; H, 6.0; N, 5.5; S,
12.6. Found: C, 56.5; H, 5.9; N, 5.2; S, 12.3%. IR
(CH2Cl2) wmax: 3278, 3177, 1660, 1301 and 1147 cm−1.
1H NMR (300 MHz) lH: 1.79, 2.34 [2m, 4H, (CH2)2],
2.48 (s, 3H, CH3Ar), 3.23 (m, 2H, CH2S), 4.10 (m, 1H,
CHN), 6.53 (s, 1H, NH); 7.41 and 7.80 (2d, J=8.2 Hz,
4H, ArH). 13C NMR (75 MHz) lC: 21.6 (CH3Ar), 27.1,
29.1 [(CH2)2], 48.5 (CHN), 61.7 (CH2S), 127.9, 130.2,
135.6, 145.5 (ArC) and 176.9 (CO). MS m/z: 253 (M+,
0.4%), 98 (50), 97 (96), 92 (14), 91 (32), 84 (100), 69
(30), 65 (21), 55 (23) and 41 (12).
4.4.2.
(8R,8aS)-6-Methylene-8-(p-toluenesulfonyl)per-
hydro-3-indolizidinone 5b. Pale yellow oil. IR (film) wmax
:
3062, 1599, 1687, 1290 and 1144 cm−1. H NMR (300
MHz) lH: 1.91–2.10, 2.36–2.61 [2×m with s at 2.49, 9H,
CH3Ar, (CH2)CHS, (CH2)2CO], 2.95 (ddd, J=12.2,
10.4, 4.3 Hz, 1H, CHS), 3.20 (d, J=14.0 Hz, 1H,
HCHN), 3.81 (dt, J=10.4 and 7.3 Hz, 1H, CHN), 4.49
(d, J=14.0 Hz, 1H, HCHN), 4.85, 4.99 (2×s, 2H,
CH2ꢀC), 7.42 and 7.77 (2×d, J=7.9 Hz, 4H, ArH). 13C
NMR (75 MHz) lc: 21.6 (CH3Ar), 24.8, 30.1, 33.3
[(CH2)2CO, CH2CHS], 45.2 (CH2N), 55.7 (CHS), 66.7
(CHN), 113.7, 134.1 (CꢀCH2), 128.8, 130.1, 136.7,
145.5 (ArC) and 173.1 (CO). MS m/z: 304 (M+−1, 1%),
150 (22), 149 (100), 148 (84), 134 (13), 91 (13) and 65
(10). HRMS found: 305.1080. C16H19NO3S requires
305.1086.
1
4.4.3.
(6S,8S,8aS)-6-Methyl-8-(p-toluenesulfonyl)per-
hydro-3,7-indolizidinedione cis-5c. Colourless oil. IR
(film) wmax: 1719, 1682, 1311 and 1149 cm−1. H NMR
1
(300 MHz) lH: 1.01 (d, J=6.1 Hz, 3H, CH3CH),
2.46–2.73 (m with s at 2.46, 9H, CH3Ar, CH2CH2CO,
CH3CH, HCHN), 3.92 (d, J=10.1 Hz, 1H, CHS), 4.25
(m, 1H, CHN), 4.41 (dd, J=12.4 and 6.0 Hz, 1H,
HCHN), 7.38 and 7.94 (2d, J=7.9 Hz, 4H, ArH). 13C
NMR (75 MHz) lc: 11.0 (CH3CN), 21.7 (CH3Ar), 25.7,
29.6, [(CH2)2], 44.6 (CH2N), 44.8 (CH3CH), 58.3
(CHS), 75.8 (CHN), 129.6, 129.7, 135.8, 145.5 (ArC),
173.4 (NCO) and 198.2 (COCHS). MS m/z: 321 (M+,
4%), 166 (100), 165 (36), 164 (74), 150 (10), 137 (17),
124 (16), 91 (20), 84 (16), 65 (11), 55 (12) and 41 (12).
HRMS found: 321.1039. C16H19NO4S requires
321.1035.
4.4. Synthesis of indolizidine derivatives 5a–5d and hexa-
hydropyrrolo[1,2-a]azepin-3-one 6. General procedure
To a stirred suspension of sodium hydride (60% disper-
sion in mineral oil, see Table 1) in anhydrous DMF,
under a nitrogen atmosphere, was added a solution of
sulfone (S)-2 (247 mg, 1 mmol) in anhydrous DMF (3
mL) at 0°C. The mixture was stirred at the same
temperature for 0.5 h. The dielectrophile (1.1 mmol)
was then added stirring the resulting mixture for times
depicted in Table 1 (see text). Saturated aqueous
ammonium chloride (20 mL) and ethyl acetate (15 mL)
were added. The organic phase was washed with water
(2×20 mL), dried (Na2SO4) and evaporated in vacuo.
The residue was purified by flash chromatography elut-
ing with mixtures of n-hexane/ethyl acetate affording
compounds 5a–5d and 6.
4.4.4.
(5S,8R,8aS)-5-Methyl-8-(p-toluenesulfonyl)per-
hydro-3,7-indolizidinedione 5d. Colourless oil. IR (film)
wmax: 1729, 1678, 1302 and 1148 cm−1. H NMR (300
1
MHz) lH: 1.28 (d, J=6.4 Hz, 3H, CH3CHN), 2.20,
2.65 [3×m with s at 2.45, 9H, CH3Ar, (CH2)2,
CH2CHNCH3], 3.75 (d, J=9.8 Hz, 1H, CHS), 4.38 (m,
1H, CHNCH3), 4.75 (ddd, J=9.8, 7.9 and 3.9 Hz, 1H,
CHSCHN), 7.38 and 7.76 (2×d, J=8.4 Hz, 4H, ArH).
13C NMR (75 Mz) lc: 19.6 (CH3CHN), 21.7 (CH3Ar),
25.5, 29.4 [(CH2)2], 45.2 (CHS), 45.2 (CH2CHNCH3),
52.8 (CHNCH3), 76.2 (CHN), 129.2, 129.9, 134.6, 145.9
(ArC), 173.5 (NCO) and 198.4 (COCHS). MS m/z: 321
(M+, 3%), 167 (11), 166 (100), 165 (93), 164 (14), 150
(65), 137 (13), 124 (23), 122 (12), 110 (11), 91 (31), 84
(16), 69 (11), 65 (13), 55 (14) and 41 (14). HRMS
found: 321.1046. C16H19NO4S requires 321.1040.
4.4.1. (8R,8aS)-8-(p-Toluenesulfonyl)perhydro-3-indolizi-
dinone 5a. Colourless needles, mp 172–173°C (n-hex-
ane/ethyl acetate). Calculated for C15H19NO3S: C, 61.4;
H, 6.5; N, 4.7; S, 10.9. Found: C, 61.1; H, 6.4; N, 4.8;
1
S, 10.7%. IR (film) wmax: 1673, 1287 and 1143 cm−1. H
4.4.5. (9R,9aS)-9-(p-Toluenesulfonyl)-2,3,5,8,9,9a-hexa-
hydro-1H-pyrrolo[1,2-a]azepin-3-one 6. Pale yellow oil.
IR (film) wmax: 1672, 1615, 1289 and 1147. H NMR
NMR (300 MHz) lH: 1.26–2.11, 2.34–2.55 [2×m with s
at 2.48, 12H, CH3Ar, (CH2)2HCHN, (CH2)2CO], 2.84
(ddd, J=12.2, 10.4 and 3.7 Hz, 1H, CHS), 3.68 (dt,
1
(300 MHz) lH: 2.06–2.20 (m, 1H, 1×CH2CH2CO),

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A. Costa et al. / Tetrahedron: Asymmetry 12 (2001) 2205–2211
2.31–2.42 (m, 3H, 1×CH2CH2CO, CH2CO), 2.48 (s,
3H, CH3Ar), 3.02–3.18 (m, 1H, H2CCHSO2), 3.36–3.50
(m, 1H, H2CCHSO2), 3.61–3.73 (m, 1H, CHS), 4.01–
4.23 (m, 2H, CH2N), 4.62–4.78 (m, 1H, HCN), 5.40–
5.83 (2m, 2H, HCꢀCH), 7.43 and 7.87 (2d, J=8.2 Hz,
4H, ArH). 13C NMR (75 MHz) lc: 21.7 (CH3Ar), 24.7
(CH2CHN), 29.1 (CH2CO), 37.7 (CH2CHSO2), 52.9
(CHSO2), 58.8 (CH2N), 77.4 (CHN), 127.1, 127.9
(HCꢀCH), 130.1, 130.2, 145.4, 160.6 (ArC) and 174.5
(CꢀO). MS m/z: 305 (M+, 83), 266 (689), 255 (24), 254
(28), 231 (27), 219 (24), 169 (38), 155 (369), 148 (42),
139 (30), 137 (36), 136 (69), 122 (21), 111 (26), 110 (36),
108 (30), 105 (23), 98 (269, 95 (23), 91 (30), 90 (22), 84
(54), 79 (34), 69 (59), 67 (36), 66 (22), 65 (39), 63 (21),
55 (100), 53 (67), 43 (46), and 41 (46). HRMS found:
305.1087. C16H19NO3S requires 305.1086.
added a solution of sulfone 5a (73 mg, 0.25 mmol) in
anhydrous methanol at 0°C. The reaction mixture was
stirred at room temperature for 48 h. Water was added
(15 mL) and the suspension filtrated through a Celite
path. Ethyl acetate was added and the resulting organic
solution washed with water (2×20 mL), dried (Na2SO4)
and evaporated in vacuo. The obtained residue was
purified by flash chromatography eluting with mixtures
of n-hexane/ethyl acetate affording lactam 9. Oil, [h]D25
−33.5 (c 0.2, CHCl3) {lit7c [h]D25 +35.4 (c 0.2, CHCl3) for
1
(+)-enantiomer}. IR (film) wmax: 1650 cm−1. H NMR
(300 MHz) lH: 1.10 (m, 1H, 1×CH2CHN), 1.09–2.39
(m, 9H, CH2CH2CO, CH2CH2CN and 1×CH2N), 2.63
(m, 1H, 1×CH2N), 3.40 (m, 1H, 1×CH2N) and 4.08 (m,
1H, CHN). 13C NMR (75 MHz) lc: 24.4 (CH2CH2CO),
25.3 (CH2CH2N), 29.7 (CH2CO), 30.3 (CH2CHN),
46.2 (CH2N), 56.1 (CHN) and 173.0 (CO). MS m/z:
139 (M+, 64), 138 (80), 124 (14), 110 (13), 96 (20), 84
(26), 83 (66), 82 (23), 69 (17), 68 (29), 67 (11), 57 (13),
56 (62), 55 (95), 53 (19), 41 (100) and 40 (23). HRMS
found: 139.0980. C8H13NO requires 139.0984.
4.5. Synthesis of (8S,8aS)-8-(p-toluensulfonyl)perhydro-
3,7-indolizidinedione 5e
A suspension of pyrrolidone (S)-2 (144 mg, 0.75 mmol),
CsF (106 mg, 0.7 mmol) in tetramethylorthosilicate15c,d
(1 mL) was stirred at room temperature for 24 h. The
reaction was quenched with saturated aqueous ammo-
nium chloride (15 mL). Ethyl acetate (20 mL) was
added and the resulting organic solution washed with
water (4×20 mL) and dried (Na2SO4) then evaporated
in vacuo furnishing the intermediate Michael adduct,
which was treated without any additional purification
with sodium hydride (60% dispersion in mineral oil, 27
mg, 0.63 mmol) in anhydrous DMF and stirred under
an inert atmosphere for 24 h. The reaction was
quenched with saturated aqueous ammonium chloride
(10 mL). Ethyl acetate (10 mL) was added and the
resulting organic solution washed with water (2×20
mL), dried (Na2SO4) and evaporated in vacuo affording
a residue, which was purified by flash chromatography
eluting with n-hexane/ethyl acetate. Compound 5e was
obtained as pale yellow oil. IR (film) wmax: 1725, 1667,
4.7. d-(−)-Coniceine I7
To a suspension of lithium aluminium hydride (42 mg,
0.88 mmol) in anhydrous ether (10 mL), under a nitro-
gen atmosphere at 0°C, a solution of lactam 9 (30 mg,
0.22 mmol) in anhydrous ether (7 mL) was added
slowly. The resulting mixture was stirred at room tem-
perature for 24 h. After hydrolysis with saturated
aqueous ammonium chloride (10 mL), ethyl acetate (15
mL) was added and the mixture was stirred under
reflux for 0.5 h. The organic phase was separated, dried
(Na2SO4) and evaporated in vacuo furnishing pure
1
d-(−)-coniceine. H NMR (300 MHz) lH: 1.09–1.40 (m,
8H, 4×CH2), 1.57–1.78 (m, 6H, 2×CH2N and CH2CH)
and 2.21–2.35 (m, 1H, CHN). [h]2D5 −10.1 (c 1.8, EtOH)
{lit.7l [h]2D5 −10.2 (c 1.77, EtOH)}.
1
1297 and 1143 cm−1. H NMR (300 MHz) lH: 2.23–
2.31 (m, 1H, CCH2CH2CO), 2.47–2.51 (m with s at
2.48, 8H, CH3Ar, 1×CCH2CH2CO, 2×CH2CO), 3.23–
3.33 (m, 1H, 1×CH2N), 3.81 (d, J=9.8 Hz, 1H, CHS),
4.10–4.21 (m, 1H, 1×CH2N), 4.54–4.62 (m, 1H, CHN),
7.39 and 7.81 (2d, J=8.2, 4H, ArH). 13C NMR (75
MHz) lc: 21.7 (CH3Ar), 26.3 (CH2CHN), 29.5
(CH2CO), 37.6 (CH2CH2N), 38.8 (CH2N), 55.8 (CHN),
77.2 (CHS), 129.4, 129.8, 139.9, 144.1 (ArC), 167.2
(NCO) and 210.3 (CO). MS m/z: 307 (M+, 53), 306
(72), 305 (96), 280 (45), 267 (24), 266 (33), 255 (69), 243
(45), 236 (28), 230 (41), 219 (23), 217 (31), 205 (21), 193
(50), 181 (69), 155 (23), 150 (89), 148 (40), 136 (87), 130
(71), 122 (22), 119 (61), 111 (41), 108 (29), 107 (26), 106
(33), 105 (42), 97 (24), 92 (27), 91 (100), 84 (52), 83 (26),
82 (30), 80 (35), 79 (23), 70 (46), 69 (31), 67 (46), 55
(49), 43 (72) and 41 (84). HRMS found: 307.0887.
C15H17NO4S requires 307.0878.
Acknowledgements
We thank the Spanish Ministerio de Educacio´n y Cul-
tura (M.E.C.) (PB97-0123) and Generalitat Valenciana
(GVDOC00-14-02) for financial support.
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