Selenium-promoted synthesis of enantiopure octahydroindolizines, hexahydro-1H-pyrrolizines and hexahydro-3H-pyrrolizin-3-ones

Article abstract of DOI:10.1016/j.tetasy.2008.10.006

Enantiomerically pure disubstituted pyrrolidines, recently synthesized from commercially available enantiomerically pure β-aminoalcohol, were used as starting materials to synthesize enantiomerically pure hexahydro-1H-pyrrolizines and octahydroindolizine through a cyclization reaction promoted by N-(phenylseleno)phthalimide. Similarly, starting from enantiopure 5-(hydroxymethyl)pyrrolidin-2-ones, enantiopure hexahydro-3H-pyrrolizin-3-ones were obtained.

Full text of DOI:10.1016/j.tetasy.2008.10.006

Tetrahedron: Asymmetry 19 (2008) 2411–2416
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Tetrahedron: Asymmetry
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Selenium-promoted synthesis of enantiopure octahydroindolizines,
hexahydro-1H-pyrrolizines and hexahydro-3H-pyrrolizin-3-ones
*
*
Marcello Tiecco , Lorenzo Testaferri, Luana Bagnoli , Catalina Scarponi
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, 06123 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure disubstituted pyrrolidines, recently synthesized from commercially available
enantiomerically pure b-aminoalcohol, were used as starting materials to synthesize enantiomerically
pure hexahydro-1H-pyrrolizines and octahydroindolizine through a cyclization reaction promoted by
N-(phenylseleno)phthalimide. Similarly, starting from enantiopure 5-(hydroxymethyl)pyrrolidin-2-ones,
enantiopure hexahydro-3H-pyrrolizin-3-ones were obtained.
Received 22 September 2008
Accepted 10 October 2008
Available online 5 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tive procedure could involve an asymmetric cyclization reaction
promoted by selenium reagents.7
Pyrrolidine, piperidine heterocycles, and their fused analogs are
ubiquitous in nature, and display a wide range of biological activ-
ities.1 In particular, hexahydro-1H-pyrrolizines and octahydroind-
olizines are structural units present in compounds, which have
several applications in biological and therapeutic fields.2 Several
polyhydroxylated octahydroindolizines and hexahydro-1H-pyrr-
olizines have shown inhibitory action toward various glycosidate
enzymes.3 Moreover, the hexahydro-1H-pyrrolizines together with
octahydroindolizines represent a new class of non-opiate antinoci-
ceptive agents.4 Due to their importance, some synthetic
approaches for the preparation of these bicyclic nitrogen heterocy-
cles have been reported in the literature.3,5,6 On the basis of our
previous experiences, we thought that a very convenient alterna-
Whereas considerable attention has been devoted to cyclization
reactions leading to the pyrrolidine ring,8,9 only sporadic examples
have been described for bicyclic nitrogen heterocycles.10 We have
recently described the synthesis of enantiomerically pure substi-
tuted pyrrolidines starting from commercially available aminoal-
cohols11 and using simple organoselenium reagent promoted
conversions.12 As indicated in Scheme 1, the (R)-2-phenylglycinol
1, after double protection, was converted into the b-amino selenide
3 by displacing the tosyl group with phenyl selenolate anion. The
phenylseleno group was then substituted by an allyl group. The
reaction of this allylic derivative with an electrophilic phenylsele-
nium reagent afforded the two diastereoisomeric 2-phenyl-5-
[(phenylseleno)methyl] pyrrolidines 5 and 6, as the result of a
OH
OTs
SePh
b
a
Ph
NH2
Ph
NHBoc
Ph
+
NHBoc
Ph
NHBoc
2
4
1
3
c
Ph
Ph
N
H
N
H
SePh
SePh
5
-6
(2S,5S)
(2S,5R)-
Scheme 1. Reagents and conditions: (a) (PhSe)2, NaBH4, DMF, 40 °C; (b)
, AIBN, C H , 80 °C; (c) N-PSP, BF ꢀEt O, CH Cl , rt.
SnBu3
6
6
3
2
2
2
* Corresponding authors. Tel.: +39 075 5855100; fax: +39 075 5855116 (M.T.).
E-mail address: tiecco@unipg.it (M. Tiecco).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.006

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M. Tiecco et al. / Tetrahedron: Asymmetry 19 (2008) 2411–2416
5-exo-trig cyclization. These two products were easily separated by
column chromatography. The presence of the organoselenium
function in the cyclization products 5 and 6 allowed the introduc-
tion of several other groups to be easily effected.11,13
Herein, we report that the radical substitution of the phenylse-
leno moiety by an allyl group gives rise to allyl derivatives, which
can be used to effect cyclization reactions to afford enantiopure
hexahydro-1H-pyrrolizines and octahydroindolizines.
Structural attributions were made on the basis of the chemical
shift values of protons at the 7a and 8a positions14 and on the basis
of the results of NOESY experiments. The chemical shift values of
the bridgehead proton in octahydroindolizine 8 and hexahydro-
1H-pyrrolizine 9 are 2.20 ppm and 2.75 ppm, respectively, imply-
ing that these protons are trans to the nitrogen lone pair.14 More-
over, in the NOESY experiment of compound 9 a strong dipolar
interaction between the proton at the 3-position and the protons
at the 5 and 7a positions was observed, indicating that the phenyl
group and the CH2SePh are in the opposite side of the bridgehead
proton 7a. The stereochemistry of the SePh substituent in the octa-
hydroindolizine 8 was tentatively assigned by the values of the vic-
inal coupling constants of the proton H6 with the protons at the 5
and 7 positions assuming a chair conformation of the six-mem-
bered ring. All these coupling constants are small. The absence of
large axial–axial constants can be taken as an indication that the
SePh group occupies an axial position.
2. Results and discussion
The radical substitution of the phenylseleno group of com-
pounds 5 with an allyl group was affected by treatment with allyl-
tributyltin and AIBN in refluxing benzene. The resulting allylated
product 7 contains a double bond and an internal nitrogen
nucleophile, and it can be subjected to electrophilic cyclization
promoted by N-(phenylseleno)phthalimide in the presence of
BF3. As indicated in Scheme 2, this reaction afforded the
Starting from the allylated product 10, obtained from the pyr-
rolidine 6, the 5-exo trig selenocyclization reaction afforded the
two enantiopure diastereoisomers, hexahydro-1H-pyrrolizines 11
(25%) and 12 (23%), which were separated by column chromato-
graphy (Scheme 3).
3-phenyl-6-[(phenylseleno)methyl]octahydroindolizine
and 3-phenyl-5-[(phenylseleno)methyl]hexahydro-1H-pyrrolizine
(40%). These two compounds were separated by column
chromatography.
8
(7%)
9
2
3
1
H
8a
4
Ph
N
8
7
5
6
SePh
(3S,6S,8aR)-8
SnBu3
N-PSP, BF3Et2O
CH2Cl2, R.T.
SePh
Ph
Ph
AIBN, C6H6, 80°C
N
H
N
H
2
3
1
(2S,5S)-7
H
H
(2S,5R)-5
7a
4
Ph
N
7
6
5
PhSe
H
9
(3S,5R,7aR)-
Scheme 2.
H
2
1
H
7a
3
4
Ph
PhSe
(3S,5R,7aS)-
N
7
6
5
H
11
SnBu3
N-PSP, BF3Et2O
CH2Cl2, r.t..
SePh
Ph
Ph
AIBN, C6H6, 80°C
N
H
N
H
H
1
H
2
3
10
(2R,5S)-
(2S,5S)-6
7a
4
Ph
N
7
5
6
PhSe
H
H
H
12
(3S,5S,7aS)-
Scheme 3.

M. Tiecco et al. / Tetrahedron: Asymmetry 19 (2008) 2411–2416
2413
MgBr
THF, 70 °C
TsCl, Et3N, DMPA
CH2Cl2, r.t.
OH
OTs
O
O
O
N
H
N
H
N
H
(5S)-13
(2S)-14
(5R)-15
Scheme 4.
O
N
H
H
2
1
H
2
1
OH
7a
3
7a
3
4
4
O
O
(5R)-ent-13
N
N
7
6
7
5
5
6
H
H
H
H
PhSe
H
PhSe
H
(5R,7aR)-16
[α]D = +84.9
(5S,7aS)-ent-16
[α]D = - 83.6
O
O
N-PSP, BF3Et2O
CH2Cl2, r.t.
N
H
N-PSP, BF3Et2O
CH2Cl2,r.t.
N
H
H
2
3
1
H
2
3
N
1
7a
7a
4
N
4
O
O
7
7
15
(5R)-
(5S)-ent-15
[α]D = -22.2
5
6
5
6
[α]D = 23.2
PhSe
PhSe
H
H
17
(5S,7aR)-
17
(5R,7aS)-ent-
[α]D = +5.9
[α]D = - 6.9
Scheme 5.
The chemical shift values of the bridgehead proton H7a in the
hexahydro-1H-pyrrolizines 11 and 12 are 3.86 ppm and
3.80 ppm, respectively. These values are characteristic for cis-fused
hexahydro-1H-pyrrolizines in which protons H7a are cis to the
nitrogen lone pair.14 Moreover, the NOESY experiment of com-
pound 11 showed a strong dipolar interaction between the proton
at the 3-position and the proton at the 5-position. In compound 12,
the NOE effect was observed between the proton in the 3-position
and the two protons of CH2SePh group. Further indications for the
proposed structures came from the 13C NMR spectra. The chemical
shift of the carbon C7a in compound 9 appears at 72.2 ppm. Similar
values are reported for trans-fused hexahydro-1H-pyrrolizines. In
compounds 11 and 12, the C7a signals appear at 66.6 ppm and
66.9 ppm, respectively, which is consistent with chemical shifts re-
ported for cis-fused hexahydro-1H-pyrrolizines.14a
power of the nitrogen atom, as previously observed by us11 and by
other research groups.8d Due to the presence of the carbonyl and
phenylselenium groups, these products can be employed for fur-
ther interesting transformations.10a
The enantiomeric purities of the hexahydro-3H-pirrolizin-3-
ones 16, ent-16, 17 and ent-17 were confirmed by HPLC analysis
on chiral column Chiralpak AD-H. The cis fusion of these bicyclic
derivatives was established on the basis of the chemical shift val-
ues of proton and carbon-13 at the 7a positions14a (3.96 ppm and
62.1 ppm for compound 16 and ent-16, and 3.91 ppm and
64.4 ppm for compound 17 and ent-17). Moreover, in the case of
2
2
3
1
1
H
H
7a
7a
3
4
N
4
N
O
O
Bu3SnH, AIBN
C6H6, 80°C
7
6
7
6
Similar cyclization reactions were then carried out on the allyl
derivatives of pyrrolidin-2-ones. The starting product (5R)-5-
but-3-en-1-ylpyrrolidin-2-one15 15 was easily obtained in very
good yields from the commercially available (5S)-5-(hydroxy-
methyl)pyrrolidin-2-one, 13 (ee >99%) (Scheme 4).
5
5
H
H
CH3
H
PhSe
(5S,7aS)-ent-16
H
18
(5R,7aS)-
The 5-exo-trig selenocyclization reaction of 15 gave rise to a
mixture of the two diastereoisomeric 5-[(phenylseleno)methyl]-
hexahydro-3H-pyrrolizin-3-ones 16 (22%) and 17 (54%) (Scheme
5). The two products were obtained in enantiomerically pure form
by medium pressure liquid chromatography.
The same synthetic sequence was then repeated starting
from (5R)-5-(hydroxymethyl)pyrrolidin-2-one, ent-13, to give the
bicyclic products ent-16 (25%) and ent-17 (45%) (Scheme 5).
These cyclization products were formed in higher yields in com-
parison to 9, 11, and 12. The better results observed with 13 and
ent-13 can be probably attributed to a decrease of the nucleophilic
2
3
1
2
3
1
H
H
7a
7a
4
N
4
N
O
O
Bu3SnH, AIBN
C6H6, 80 °C
7
7
5
5
6
6
PhSe
H
H
H3C
17
(5S,7aS)-19
(5R,7aS)-ent-
Scheme 6.

2414
M. Tiecco et al. / Tetrahedron: Asymmetry 19 (2008) 2411–2416
compound 16 a NOESY experiment revealed a strong dipolar inter-
action between the proton in 7a position and the two protons of
the CH2SePh group.
(quint, 1H, J = 7.0 Hz), 2.35–2.13 (m, 4H), 2.07–1.95 (m, 1H),
1.82–1.45 (m, 4H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): d
144.6, 138.7, 128.3 (two carbons), 126.8, 126.6 (two carbons),
114.4, 62.6, 58.8, 35.8, 33.8, 31.5, 31.4; MS (70 eV, EI): m/z (rel.
int.): 201 (<1%), 198 (100), 144 (29), 104 (20), 91 (14), 77 (8). Anal.
Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.49; H,
9.47; N, 7.02.
The proposed structures were further confirmed by converting
hexahydro-3H-pyrrolizin-3-ones ent-16 and ent-17 into the dese-
lenenylated products as previously described in the literature.16
For this purpose, ent-16 and ent-17 were treated with tributyltin
hydride in the presence of a catalytic amount of AIBN in refluxing
benzene to afford 18 (65%) and 19 (70%) (Scheme 6).
4.2.2. (2R,5S)-2-But-3-en-1-yl-5-phenylpyrrolidine, 10
In the 1H NMR, the protons H5 and H7a of compound 18 ap-
peared as a multiplet at 4.00–3.85 ppm [lit.16 d 4.16–3.55 ppm].
On the other hand, in compound 19, these signals were observed
at 3.70 and 3.90 ppm, respectively [lit.16 d 3.55 and 3.95 ppm].
Yield 68%; oil; ½a D23
ꢁ
¼ ꢂ48:9 (c 1.65, CHCl3); 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 7.49–7.20 (m, 5H), 5.78 (ddt, 1H, J = 6.5, 10.0,
16.8 Hz), 5.15–4.90 (m, 2H), 4.30 (dd, 1H, J = 6.7, 6.8 Hz), 3.40
(quint, 1H, J = 7.2 Hz), 2.40–2.02 (m, 4H), 1.90–1.20 (m, 5H); 13C
NMR (100 MHz, CDCl3, 25 °C, TMS): d 145.5, 138.5, 128.3 (two car-
bons), 126.6, 126.3 (two carbons), 114.5, 61.5, 58.3, 36.2, 35.0, 32.4,
31.5; MS (70 eV, EI): m/z (rel. int.): 201 (1), 198 (100), 144 (30), 104
(19), 91 (10), 77 (8). Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N,
6.96. Found: C, 83.51; H, 9.46; N, 6.89.
3. Conclusions
The present method describes a simple synthetic method for
obtaining enantiopure hexahydro-1H-pyrrolizines and octahydro-
indolizines starting from commercially available compounds.
These products can be easily obtained by cyclization reactions pro-
moted by an organoselenium reagent. Similar bicyclic nitrogen
containing heterocycles are widespread in Nature and capable of
effecting a large number of biological processes.1–4
4.3. Synthesis of 3-phenyl-6-[(phenylseleno)methyl]-
octahydroindolizine, 8, 3-phenyl-5-[(phenylseleno)methyl]-
hexahydro-1H-pyrrolizines, 9, 11, 12, and 5-[(phenylseleno)-
methyl]hexahydro-3H-pyrrolizin-3-ones, 16, ent-16, 17, and
ent-17 by selenocyclization
To
a
solution of N-(phenylseleno)phthalimide (0.21 g,
4. Experimental
0.7 mmol) in dichloromethane (6 mL), compounds 7, 10 (0.10 g,
0.5 mmol) or compounds 15 and ent-15 (0.07 g, 0.5 mmol) and a
catalytic amount of BF3ꢀEt2O were added at 0 °C. The temperature
was allowed to raise to room temperature, and the progress of the
reaction was monitored by TLC. The reaction mixture was then
poured into a 5% aqueous solution of NaOH and extracted with
dichloromethane. The organic layer was dried over sodium
sulphate, filtered, and evaporated. 3-Phenyl-5-[(phenylseleno)-
methyl]hexahydro-1H-pyrrolizines, 9, 11, 12, and 3-phenyl-6-
[(phenylseleno)methyl]octahydroindolizine, 8 were separated by
flash chromatography using a mixture of diethyl ether and light
petroleum (from 5:95 to 20:80). In the case of 5-[(phenylsele-
no)methyl]hexahydro-3H-pyrrolizin-3-ones, 16, 17, ent-16 and
ent-17, the reaction mixture was poured into aqueous NaHCO3
solution and extracted with dichloromethane. The combined
organic extracts were washed with brine, dried over sodium
sulfate, filtered, and evaporated. The reaction products were sepa-
rated by medium pressure chromatography on a silica gel column
All new compounds were characterized by MS, 1H, and 13CNMR
spectra. GC analyses and MS spectra were carried out with an HP
6890 gas chromatograph (25 m dimethyl silicone capillary col-
umn) equipped with an HP 5973 Mass Selective Detector; for the
ions containing selenium, only the peaks arising from the sele-
nium-80 isotope are given. 1H and 13C NMR spectra were recorded
at 400 and 100.62 MHz, respectively, on a Bruker DRX 400 instru-
ment; CDCl3 was used as the solvent, and TMS as the standard.
HPLC analyses were performed on an HP 1100 instrument
equipped with a chiral column and an UV detector. Optical rota-
tions were measured with a Jasco DIP-1000 digital polarimeter.
Elemental analyses were carried out on a Carlo Erba 1106 Elemen-
tal Analyzer.
4.1. Starting products
Commercial (R)-(+)-2-phenylglycinol (ee 99%), (5S)-5-(hydroxy-
methyl)pyrrolidin-2-one (ee 99%), and (5R)-5-(hydroxymethyl)
pyrrolidin-2-one (ee 99%) were used without further purification.
(Merck, LiChroprepÒ Si60, 40–63
lm), using a 70:30 mixture of
ethyl acetate and light petroleum as an eluent. The separation in
a pure form of the two diastereoisomers 16, 17 and ent-16,
ent-17 was carried out by monitoring the different fractions by
GC–MS. Physical and spectral data are reported below. The
enantiomeric purity of compounds 16, ent-16, 17, and ent-17 was
determined by chiral HPLC (Chiralpack AD-H column (250 ꢃ
4.6 mm ID), eluant: hexane/iPrOH 95:5, flow rate 1.0 mL/min, UV
detection at 254 nm.
4.2. Synthesis of compounds 7 and 10 by radical allylation
To a solution of pyrrolidines 5 and 6 (0.27 g, 0.7 mmol) and a
catalytic amount of AIBN in refluxing dry benzene (8 mL) allyltri-
butyltin (1.11 g, 3.5 mmol) was added in 4 h with a syringe pump
under nitrogen. The progress of the reactions was monitored by
TLC. The solvent was then carefully evaporated under vacuum.
The allylated compounds 7 and 10 were isolated in a pure form
after column chromatography on deactivated silica gel using a
20:80 mixture of ethyl acetate and light petroleum. Deactivated
silica gel was prepared by washing silica gel with a 5% suspension
of NaHCO3 in methanol and then by filtering and drying in an oven
at 150 °C.17 Physical and spectral data are reported below.
4.3.1. (3S,6S,8aR)-3-Phenyl-6-[(phenylseleno)methyl]
octahydroindolizine, 8
Yield 7%; oil; 1H NMR (400 MHz, CDCl3, 25 °C, TMS): d 7.52–7.50
(m, 2H), 7.46–7.43 (m, 2H), 7.40–7.32 (m, 2H), 7.29–7.20 (m, 4H),
3.60–3.55 (m, 1H), 3.22 (dd, 1H, J = 7.9, 8.0 Hz), 3.17 (dt, 1H, J = 2.1,
11.5 Hz), 2.37 (dd, 1H, J = 2.4, 11.5 Hz), 2.21–1.58 (m, 9H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): d 143.5, 133.4 (two carbons), 131.8,
128.7 (two carbons), 128.2 (two carbons), 127.5 (two carbons),
126.8, 126.6, 69.2, 64.9, 56.5, 43.7, 32.9, 30.6 29.6, 27.9; MS
(70 eV, EI): m/z (rel. int.): 357 (20), 280 (7), 200 (100), 117 (12),
91 (18), 77 (5). Anal. Calcd for C20H23NSe: C, 67.41; H, 6.51; N,
3.93. Found: C, 67.33; H, 6.45; N, 3.86.
4.2.1. (2S,5S)-2-But-3-en-1-yl-5-phenylpyrrolidine, 7
Yield 65%; oil; ½a D30
ꢁ
¼ ꢂ27:7 (c 2.09, CHCl3); 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 7.49–7.19 (m, 5H), 5.89 (ddt, 1H, J = 6.6, 10.2,
16.8 Hz), 5.08–4.98 (m, 2H), 4.18 (dd, 1H, J = 7.7, 7.9 Hz), 3.22

M. Tiecco et al. / Tetrahedron: Asymmetry 19 (2008) 2411–2416
2415
4.3.2. (3S,5R,7aR)-3-Phenyl-5-[(phenylseleno)methyl]
4.3.7. (5S,7aR)-5-[(Phenylseleno)methyl]hexahydro-3H-
hexahydro-1H-pyrrolizine, 9
pyrrolizin-3-one, 17
Yield 40%; oil; ½a D30
ꢁ
¼ ꢂ11:2 (c 1.05, CHCl3). 1H NMR (400 MHz,
Yield 54%; oil; ½a D21:3
ꢁ
¼ þ5:9 (c 1.27, CHCl3). HPLC analysis: tR
CDCl3, 25 °C, TMS): d 7.45–7.41 (m, 2H), 7.40–7.20 (m, 3H), 7.15–
7.05 (m, 5H), 3.25 (dd, 1H, J = 7.4, 7.6 Hz), 2.82–2.70 (m, 1H),
2.66–2.58 (m, 1H), 2.53 (dq, 1H, J = 8.6, 12.5 Hz), 2.51 (dd, 1H,
J = 3.5, 12.1 Hz), 2.37 (dd, 1H, J = 9.5, 12.1 Hz), 2.36 (dq, 1H,
J = 8.7, 12.5 Hz), 2.15–2.03 (m, 1H), 1.97–1.87 (m, 1H), 1.78–1.65
(m, 2H), 1.66–1.56 (m, 1H), 1.55–1.44 (m, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): d 145.0, 131.6 (two carbons),
131.0, 128.8 (two carbons), 128.2 (two carbons), 127.8 (two car-
bons), 127.1, 126.1, 72.2, 64.7, 59.8, 40.4, 36.7, 33.2, 26.3, 25.5;
MS (70 eV, EI): m/z (rel. int.): 357 (1), 186 (100), 91 (8), 77 (3). Anal.
Calcd for C20H23NSe: C, 67.41; H, 6.51; N, 3.93. Found: C, 67.49; H,
6.58; N, 3.99.
37.44 min. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): d 7.58–7.55
(m, 2 H), 7.30–7.21 (m, 3 H), 4.93 (dq, 1 H, J = 5.4, 10.4 Hz), 3.92–
3.86 (m, 2H), 3.02 (dd, 1H, J = 9.5, 12.8 Hz), 2.67 (ddd, 1H, J = 7.9,
12.5, 16.5 Hz), 2.44 (dd, 1H, J = 8.7, 16.5 Hz), 2.31–2.13 (m, 3H),
1.88 (dt, 1H, J = 5.6, 12.1 Hz), 1.74–1.64 (m, 1H), 1.52 (dq, 1H,
J = 7.2, 12.1 Hz); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): d 172.2,
131.9 (two carbons), 129.8, 129.5 (two carbons), 126.6, 64.4,
53.1, 37.4, 34.4, 29.4, 28.6, 28.2; MS (70 eV, EI) m/z (rel. int.): 295
(26), 138 (57), 124 (100), 80 (15). Anal. Calcd for C14H17NOSe: C,
57.15; H, 5.82; N, 4.76. Found: C, 57.22; H, 5.89; N, 4.80.
4.3.8. (5R,7aS)-5-[(Phenylseleno)methyl]hexahydro-3H-
pyrrolizin-3-one, ent-17
Yield 45%; oil; ½a D22:8
¼ ꢂ6:9 (c 0.68, CHCl3). HPLC analysis: tR
ꢁ
4.3.3. (3S,5R,7aS)-3-Phenyl-5-[(phenylseleno)methyl]
hexahydro-1H-pyrrolizine, 11
27.51 min. NMR and MS spectra are identical to those of compound
17. Anal. Calcd for C14H17NOSe: C, 57.15; H, 5.82; N, 4.76. Found: C,
57.20; H, 5.86; N, 4.81.
Yield 25%; oil; ½a D20:6
ꢁ
¼ ꢂ16:7 (c 0.89, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 7.44–7.38 (m, 2H), 7.36–7.31 (m, 2H), 7.30–
7.22 (m, 4H), 7.18–7.13 (m, 2H), 3.86 (quint, 1H, J = 7.1 Hz), 3.77
(dd, 1H, J = 5.7, 9.5 Hz), 3.15–3.05 (m, 1H), 2.88 (dd, 1H, J = 3.7,
12.1 Hz), 2.70 (dd, 1H, J = 9.7, 12.1 Hz), 2.27–2.15 (m, 2H), 2.12–
1.98 (m, 2H), 1.96–1.82 (m, 1H), 1.80–1.39 (m, 3H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): d 145.2, 131.6, 131.5 (two carbons),
128.8 (two carbons), 128.1 (two carbons), 127.1 (two carbons),
126.7, 126.0, 71.0, 66.6, 66.1, 38.0, 34.0, 33.5, 32.6, 30.0; MS
(70 eV, EI): m/z (rel. int.): 357 (2), 200 (8), 186 (100), 143 (19),
128 (17), 115 (10), 91 (24), 77 (7). Anal. Calcd for C20H23NSe: C,
67.41; H, 6.51; N, 3.93. Found: C, 67.37; H, 6.44; N, 3.90.
4.4. Synthesis of 18 and 19 by reductive deselenenylation
To
a solution of compounds ent-16 and ent-17 (0.10 g,
0.34 mmol) in dry benzene (3 mL), triphenyltin hydride (0.18 g,
0.51 mmol) and a catalytic amount of AIBN were added, and the
mixture was stirred and refluxed for 1 h. The solvent was then
removed under reduced pressure. The deselenenylated products
were separated by chromatography on a silica gel column using
a 70:30 mixture of ethyl acetate and light petroleum as eluent.
Physical and spectral data are reported below.
4.3.4. (3S,5S,7aS)-3-Phenyl-5-[(phenylseleno)methyl]-
hexahydro-1H-pyrrolizine, 12
4.4.1. (5R,7aS)-5-Methyl-hexahydro-3H-pyrrolizin-3-one, 1816
Yield 23%; oil; ½a D18:3
ꢁ
¼ ꢂ21:6 (c 0.68, CHCl3). 1H NMR (400 MHz,
Yield 65%; oil; ½a D22:8
ꢁ
¼ ꢂ57:2 (c 2.49, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 7.65–7.01 (m, 10H), 4.09 (dd, 1H, J = 5.6,
9.4 Hz), 3.95–3.75 (m, 1H), 3.49–3.30 (m, 1H), 3.05 (dd, 1H,
J = 4.1, 12.0 Hz), 2.72 (dd, 1H, J = 10.6, 12.0 Hz), 2.42–1.38 (m,
8H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): d 145.0, 131.9 (two
carbons), 131.8, 129.4 (two carbons), 128.7 (two carbons), 127.2
(two carbons), 126.8, 125.9, 66.9, 63.1, 63.0, 39.3, 33.4, 31.8, 31.0,
30.1; MS (70 eV, EI) m/z (rel. int.): 357 (1), 353 (66), 207 (74),
194 (49) 182 (100), 167 (16), 115 (15), 77 (11). Anal. Calcd for
C20H23NSe: C, 67.41; H, 6.51; N, 3.93. Found: C, 67.46; H, 6.48; N,
3.87.
CDCl3, 25 °C, TMS): d 4.00–3.85 (m, 2H), 2.75–2.64 (m, 1H), 2.42–
2.27 (m, 3H), 2.06–2.00 (m, 1H), 1.68–1.61 (m, 2H), 1.31–1.25
(m, 1H), 1.22 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): d 174.6, 61.3, 49.5, 36.2, 35.2, 32.9, 26.9, 20.9; MS (70 eV,
EI) m/z (rel. int.): 139 (62), 124 (100), 11 (45), 83 (40), 68 (26),
55 (20). Anal. Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found:
C, 69.11; H, 9.48; N, 10.12.
4.4.2. (5S,7aS)-5-Methyl-hexahydro-3H-pirrolizin-3-one, 1916
Yield 70%; oil; ½a D22:4
ꢁ
¼ þ4:6 (c 1.71, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 3.90 (dquint, 1H, J = 5.3, 10.3 Hz), 3.70 (quint,
1H, J = 6.8 Hz), 2.68 (ddd, 1H, J = 7.8, 12.5, 16.4 Hz), 2.45 (dd, 1H,
J = 8.8, 16.4 Hz), 2.32–2.22 (m, 1H), 2.18–2.12 (m, 1H), 1.87 (dt,
1H, J = 5.8, 11.7 Hz), 1.78 (dd, 1H, J = 6.8, 12.8 Hz), 1.70–1.59 (m,
1H), 1.51–1.38 (m, 1H), 1.35 (d, 3H, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): d 172.1, 64.5, 48.8, 37.5, 36.6, 29.3,
28.4, 18.8; MS (70 eV, EI) m/z (rel. int.): 139 (71), 124 (100), 11
(44), 83 (45), 68 (29), 55 (24). Anal. Calcd for C8H13NO: C, 69.03;
H, 9.41; N, 10.06. Found: C, 69.08; H, 9.47; N, 10.13.
4.3.5. (5R,7aR)-5-[(Phenylseleno)methyl]hexahydro-3H-
pyrrolizin-3-one, 16
Yield 22%; oil; ½a D26:9
¼ 84:9 (c 2.07, CHCl3) HPLC analysis: tR
ꢁ
29.67 min. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): d 7.57–7.53
(m, 2H), 7.29–7.21 (m, 3H), 4.14 (dq, 1H, J = 4.0, 7.5 Hz), 4.00–
3.93 (m, 1H), 3.26 (dd, 1H, J = 3.9, 12.5 Hz), 3.16 (dd, 1H, J = 5.2,
12.5 Hz), 2.58–2.48 (m, 1H), 2.39–2.30 (m, 2H), 2.26–2.18 (m,
1H), 2.10–2.04 (m, 1H), 2.00–1.83 (m, 1H), 1.72–1.62 (m, 1H),
1.37–1.25 (m, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): d
174.9, 132.0 (two carbons), 130.0, 129.0 (two carbons), 126.7,
62.1, 53.5, 34.9, 34.1, 33.1, 32.4, 27.1; MS (70 eV, EI) m/z (rel.
int.): 295 (22), 207 (6), 138 (42), 124 (100), 80 (16). Anal. Calcd
for C14H17NOSe: C, 57.15; H, 5.82; N, 4.76. Found: C, 57.19; H,
5.88; N, 4.87.
4.5. Synthesis of the (R)- and (S)-5-(but-3-en-1-yl)pyrrolidin-2-
one, 15 and ent-15
The synthesis was carried out according to the literature data15
and started with the conversion of the commercially available (5S)-
5-(hydroxymethyl)pyrrolidin-2-one, 13 (ee >99%) to tosylate 14.
Next, the reaction of allylmagnesium bromide with enantiopure
(2S)-14, under refluxing conditions in THF, furnished (5R)-15 after
chromatography.15 The same sequence was carried out starting
from the commercially available (5R)-5-(hydroxymethyl)pyrroli-
din-2-one, ent-13 (ee >99%), converted in enantiopure tosylate
4.3.6. (5S,7aS)-5-[(Phenylseleno)methyl]hexahydro-3H-
pyrrolizin-3-one, ent-16
Yield 25%; oil; ½a D22:3
¼ ꢂ83:6 (c 1.42, CHCl3). HPLC analysis: tR
ꢁ
31.71 min. NMR and MS spectra are identical to those of compound
16. Anal. Calcd for C14H17NOSe: C, 57.15; H, 5.82; N, 4.76. Found: C,
57.28; H, 5.90; N, 4.87.

2416
M. Tiecco et al. / Tetrahedron: Asymmetry 19 (2008) 2411–2416
2. (a) Watson, A. A.; Fleet, W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265; (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. Tetrahedron: Asymmetry 2000, 11, 164.
(2R)-ent-14, and finally in (5S)-5-but-3-en-1-ylpyrrolidin-2-one
ent-15.
3. (a) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.;
Linney, I. D. Org. Lett. 2008, 10, 3615; (b) Cicchi, S.; Marradi, M.; Vogel, P.; Goti,
A. J. Org. Chem. 2006, 71, 1614; (c) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini,
M.; Goti, A. Tetrahedron Lett. 2003, 44, 2315.
4. Carson, J. R.; Carmosin, R. J.; Vaught, J. L.; Gardocki, J. F.; Costanzo, M. J.; Raffa, R.
B.; Almond, H. R. J. Med. Chem. 1992, 35, 2855.
5. (a) Quiroz, T.; Corona, D.; Covarruvias, A.; Avila-Zarraga, J. G.; Romero-
Ortega, M. Tetrahedron Lett. 2007, 48, 1571 and references cited therein; (b)
Quinet, C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Markò, I. E.
Tetrahedron 2008, 64, 1077; (c) Quinet, C.; Ates, A.; Markò, I. E. Tetrahedron
Lett. 2008, 49, 5032; (d) Coldham, J.; Hufton, R.; Price, K. N.; Rathmell, R. E.;
Snowden, D. J.; Vennal, G. P. Synthesis 2001, 1523; (e) Bowman, W. R.;
Broadhurst, M. J.; Coghlan, D. R.; Lewis, K. A. Tetrahedron Lett. 1997, 38,
6301.
6. (a) Smith, A. B., III.; Kim, D. S. J. Org. Chem. 2006, 71, 2547; (b) Roche, C.;
Kadlecikovà, K.; Veyron, A.; Delair, P.; Philouze, C.; Greene, A. E. J. Org. Chem.
2005, 70, 8352; (c) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802; (d) Park,
S. H.; Kang, H. J.; Ko, S.; Park, S.; Chang, S. Tetrahedron: Asymmetry 2001, 12,
2621; (e) Murray, A.; Proctor, G. R. Tetrahedron Lett. 1995, 36, 291; (f) Holmes,
A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem. 1991, 56, 1393.
4.5.1. [(2S)-5-Oxopyrrolidin-2-yl]methyl 4-methyl
benzenesulfonate, 1415
yield 90%; mp 124–127 °C; ½a D25:3
ꢁ
¼ 18:5 (c 2.05, CHCl3). 1H
NMR: d 7.83–7.78 (m, 2 H), 7.43–7.37 (m, 2H), 5.80 (br s, 1H),
4.09 (dd, 1H, J = 3.7, 9.5 Hz), 4.01–3.92 (m, 1H), 3.88 (dd, 1H,
J = 7.4, 9.5 Hz), 2.49 (s, 3H), 2.37–2.25 (m, 3H), 1.77–1.74 (m,
1H). Anal. Calcd for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found:
C, 53.58; H, 5.69; N, 5.25.
4.5.2. [(2R)-5-Oxopyrrolidin-2-yl]methyl 4-methyl
benzenesulfonate, ent-14
yield 95%; mp 119–123 °C; ½a D24:3
ꢁ
¼ ꢂ19:2 (c 1.98, CHCl3). 1H NMR
data are identical to these of compound 14. Anal. Calcd for
C12H15NO4S:C, 53.52; H, 5.61; N,5.20. Found: C, 53.56;H, 5.63; N, 5.28.
7. (a) Tiecco, M. Electrophilic Selenium, Selenocyclizations. In Topics in Current
Chemistry: Organoselenium Chemistry: Modern Developments in Organic
Synthesis; Wirth, T., Ed.; Springer: Berlin, 2000; pp 7–54; (b) Tiecco, M.;
Testaferri, L.; Bagnoli, L.; Marini, F.; Santi, C.; Temperini, A.; Scarponi, G.;
Sternativo, S.; Terlizzi, R.; Tomassini, C. Arkivoc 2006, 186.
8. (a) Jones, A. D.; Redfern, A. L.; Knight, D. W.; Morgan, I. R.; Williams, A. C.
Tetrahedron 2006, 62, 9247 and references cited therein; (b) Clive, D. L. J.;
Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen, S. M. J. Org. Chem. 1980,
45, 2120; (c) Morella, A. M.; Ward, A. D. Aust. J. Chem. 1995, 48, 445; (d) De
Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun. 1993, 916.
4.5.3. (5R)-5-But-3-en-1-ylpyrrolidin-2-one, 1515
Yield 70%; oil; ½a D22:9
ꢁ
¼ þ23:2 (c 1.98, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): d 7.12 (br s, 1H), 5.77 (ddt, 1H, J = 6.6, 10.1,
16.9 Hz), 5.01–4.78 (m, 2H), 3.62 (quint, 1H, J = 6.7 Hz), 2.30–2.24
(m, 2H), 2.09 (q, 2H, J = 6.6 Hz), 1.75–1.49 (m, 4H). Anal. Calcd for
C8H13NO: C, 69.03;H,9.41; N, 10.06. Found: C, 69.06; H, 9.53; N,10.18.
4.5.4. (5S)-5-But-3-en-1-ylpyrrolidin-2-one, ent-15
9. For asymmetric synthesis of the pyrrolidine ring see: (a) Tiecco, M.; Testaferri,
L.; Marini, F.; Sternativo, S.; Bagnoli, L.; Santi, C.; Temperini, A. Tetrahedron:
Asymmetry 2001, 12, 1493; (b) Takada, H.; Nishibayashi, Y.; Uemura, S. J. Chem.
Soc., Perkin Trans. 1 1999, 1511; (c) Nishibayashi, Y.; Srivastava, S. K.; Takada,
H.; Fukuzawa, S.; Uemura, S. J. Chem. Soc., Chem. Commun. 1995, 2321; (d)
Fragale, G.; Wirth, T. Eur. J. Org. Chem. 1998, 1361; (e) Back, T. G.; Dyck, B. P.;
Nan, S. Tetrahedron 1999, 55, 3191.
Yield 68%; oil; ½a D21:5
ꢁ
¼ ꢂ22:2 (c 2.22, CHCl3). 1H NMR data are
identical to those of compound 15. Anal. Calcd for C8H13NO: C,
69.03; H, 9.41; N, 10.06. Found: C, 69.09; H, 9.43; N, 10.08.
Acknowledgments
10. (a) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1986, 51, 1724; (b) Webb,
R. R., II.; Danishefky, S. Tetrahedron Lett. 1983, 24, 1357.
11. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Scarponi, C.; Temperini, A.; Marini, F.;
Santi, C. Tetrahedron: Asymmetry 2007, 18, 2758.
12. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Purgatorio, V.; Temperini, A.; Marini, F.;
Santi, C. Tetrahedron: Asymmetry 2004, 15, 405.
13. Tiecco, M.; Testaferri, L.; Bagnoli, L.; Terlizzi, R.; Temperini, A.; Marini, A.; Santi,
C.; Scarponi, C. Tetrahedron: Asymmetry 2004, 15, 1949.
14. (a) Jones, T. H.; Blum, M. S. J. Org. Chem. 1980, 45, 4778. and references cited
therein; (b) Grigg, R.; Markandu, J.; Perrior, T.; Qiong, Z.; Suzuki, T. J. Chem. Soc.,
Chem. Commun. 1994, 1267.
Financial support from MIUR, National Projects PRIN2005, Con-
sorzio CINMPIS, Bari, and University of Perugia is gratefully
acknowledged.
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