Organoselenium mediated asymmetric cyclizations. Synthesis of enantiomerically pure 1,6-dioxaspiro[4.4]nonanes

Article abstract of DOI:10.1016/j.tetasy.2006.10.021

The asymmetric cyclization of 1-hydroxyoct-7-en-4-one, promoted by camphorselenenyl tetrafluoroborate, generated from camphor diselenide and silver tetrafluoroborate in dichloromethane at room temperature, afforded a mixture of two diastereoisomeric E- and two diastereoisomeric Z-2-[(camphorseleno)methyl]-1,6-dioxaspiro[4.4]nonanes. These were separated by medium pressure liquid chromatography and then deselenenylated with triphenyltin hydride and AIBN to give enantiomerically pure 2-methyl-1,6-dioxaspiro[4.4]nonanes. The camphorseleno group was also substituted by an allyl function using allyltributyltin in the presence of AIBN.

Full text of DOI:10.1016/j.tetasy.2006.10.021

Tetrahedron: Asymmetry 17 (2006) 2768–2774
Organoselenium mediated asymmetric cyclizations.
Synthesis of enantiomerically pure 1,6-dioxaspiro[4.4]nonanes
Marcello Tiecco,* Lorenzo Testaferri, Luana Bagnoli, Catalina Scarponi,
Andrea Temperini, Francesca Marini and Claudio Santi
`
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universita di Perugia, 06123 Perugia, Italy
Received 28 August 2006; revised 6 October 2006; accepted 17 October 2006
Abstract—The asymmetric cyclization of 1-hydroxyoct-7-en-4-one, promoted by camphorselenenyl tetrafluoroborate, generated from
camphor diselenide and silver tetrafluoroborate in dichloromethane at room temperature, afforded a mixture of two diastereoisomeric
E- and two diastereoisomeric Z-2-[(camphorseleno)methyl]-1,6-dioxaspiro[4.4]nonanes. These were separated by medium pressure liquid
chromatography and then deselenenylated with triphenyltin hydride and AIBN to give enantiomerically pure 2-methyl-1,6-dioxa-
spiro[4.4]nonanes. The camphorseleno group was also substituted by an allyl function using allyltributyltin in the presence of AIBN.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoisomers was obtained. When the reaction was
repeated using the camphorselenenyl sulfate (Scheme 1),
the cyclization reaction was again not stereoselective giving
a mixture of all the four possible diastereoisomers. In this
case however these diastereoisomers could be separated
and the enantiopure perhydrofuro[2,3-b]furans derivatives
could thus be obtained by deselenenylation.12
In recent years, we have described the synthesis of different
types of heterocyclic compounds, in an enantiomerically
enriched or pure form, by means of reagent-controlled or
substrate-controlled cyclizations of alkenes containing
internal nucleophiles, promoted by electrophilic organo-
selenium reagents.1 Several chiral nonracemic selenium
reagents have recently been introduced in the literature to
effect efficient asymmetric reagent-controlled intramolecu-
lar selenocyclization reactions.2–8 In general the electro-
philic selenium reagent is conveniently prepared in situ
starting from the corresponding diselenide. Particular
attention was devoted to the stereoselective synthesis of
substituted cyclic ether derivatives8,9 since these hetero-
cyclic compounds are present in several molecules having
interesting biological properties.10 Of particular impor-
tance are the bicyclic ketal derivatives perhydrofuro[2,3-
b]furans whose skeleton is encountered in many biologi-
cally active natural products.11 In order to synthesize this
kind of substrate we have recently effected the double cycli-
zation of bis-alkenylketones promoted by the electrophilic
reagents deriving from the sulfur containing diselenides in
the presence of water. These experiments, however, gave
unsatisfactory results since an unseparable mixture of
Cf Se+ X-
O
O
CfSe
SeCf
MeCN/ H2O
O
R
R
CfSe
R = Ph, Me
Se
O
Scheme 1.
Herein, we report that by using a similar procedure and
starting from 1-hydroxyoct-7-en-4-one the synthesis of
enantiopure 2-substituted 1,6-dioxaspiro[4.4]nonanes can
easily be effected. The enantioselective synthesis of these
spiroacetals is of considerable importance since these nuclei
are the subunits of many biologically active natural pro-
ducts, for example, insect pheromones, oxygenated terpe-
noids, polyether antibiotics and antiparasitic agents.13,14
This has stimulated considerable interest among synthetic
organic chemists and several methods to obtain different
types of racemic spiroacetals have been reported in the lite-
rature.14–18
*
Corresponding author. Tel.: +39 075 5855100; fax: +39 075 5855116;
e-mail: tiecco@unipg.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.021

M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
2769
2. Results and discussion
Ha
Hb
SePh
O
5
2
O
O
OH
SePh
The starting compound necessary for the present investiga-
tion was easily prepared from the commercially available
ethyl-3-oxobutanoate 1. As indicated in Scheme 2, this
was subjected to two consecutive alkylations to afford ke-
tone 3, which after hydrolysis and simultaneous removal
of the tetrahydropyran-2-yl protecting group gave a 1:2
mixture of hydroxyketone 4 and of hemiacetal 5. This pro-
cedure is shorter than that reported in the literature.14
4
(2R*,5S*)-(Z)-6
Yield 35%
+
N-PSP, CH2Cl2
BF3. Et2O, r.t.
column chromatography
Ha
Hb
O
SePh
2
5
O
SePh
OH
O
(2S*,5S*)-(E)-7
5
Yield 35%
In order to dispose of the two racemic geometrical isomers
6 and 7 and of their deselenenylation products, which were
necessary as reference compounds, we carried out the cycli-
zation reaction of the mixture of 4 and 5 with N-(phenyl-
seleno)phthalimide (N-PSP) in the presence of BF3 as the
catalyst at room temperature. This reaction produced a
1:1 mixture of the two isomeric 2-[(phenylseleno)methyl]-
1,6-dioxaspiro[4.4]nonanes 6 and 7, which were separated
by medium pressure liquid chromatography on a silica
gel column. In Scheme 3, the two geometrical isomers are
presented in the order in which they are eluted from the
chromatographic column. This reaction has already been
described in the literature.14 Also in that case a 1:1 mixture
was obtained; however, the two racemic geometrical iso-
mers 6 and 7 could not be separated.
Scheme 3.
Ph3SnH, AIBN
C6H6, 80 °C
O
O
5
2
5
2
O
O
SePh
(2R*,5S*)-(Z)-6
(2S*,5S*)-(Z)-8
O
Ph3SnH, AIBN
C6H6, 80 °C
2
O
5
5
2
O
O
SePh
(2S*,5S*)-(E)-7
(2R*, 5S*)-(E)-9
Scheme 4.
The Z- and E-geometry was attributed to 6 and 7, respec-
respectively. Owing to their volatility13b and to the ten-
dency of the Z-isomer to equilibrate on standing or on pro-
longed contact with silica gel, the benzene was carefully
evaporated under reduced pressure and the deselenenylated
products were isolated by simple filtration of the reaction
mixtures on a deactivated silica gel column.19 The eluate
was carefully evaporated and the resulting crude products
were then directly analyzed by NMR. As anticipated above
1
tively, on the basis of their H and 13C NMR spectra. In
agreement with the data reported in the literature17 (see
below) for similar 2-substituted-1,6-dioxaspiro[4.4]nonanes
the proton at the 2-position is deshielded in the E-isomer in
respect to the corresponding proton in the Z-isomer
(4.35 vs 4.22 ppm). At the same time, the absorption of
carbon-2 is deshielded in the Z-isomer with respect to that
of the E-isomer (78.9 vs 77.1 ppm). These geometrical
attributions were then unambiguously confirmed by the
deselenenylation of 6 and 7 to the corresponding racemic
2-methyl-1,6-dioxaspiro[4.4]nonanes, which are described
in the literature.17 It is also noteworthy that the difference
in chemical shift between the two diastereotopic protons,
Ha and Hb, in the CH2Se group is greater for the Z-isomer
than for the E-isomer (3.25 and 2.97 ppm, Dd = 0.28 for 6
and 3.10 and 2.98 ppm, Dd = 0.12 for 7).
1
the H and 13C NMR data of the racemic Z- and E-2-
methyl-1,6-dioxaspiro[4.4]nonanes 8 and 9 are in good
agreement with those reported in the literature.17
1
These trends of the H and 13C NMR data were particu-
larly useful to confidently assign either the Z- or E-config-
urations to the 1,6-dioxaspiro[4.4]nonanes, which are
described below.
Owing to the presence of the arylseleno group, compounds
6 and 7 can be further functionalized. As an example we re-
port that the PhSe can be substituted by an allyl group by
As illustrated in Scheme 4, the two diastereoisomers 6 and
7 were then submitted to reductive deselenenylation with
Ph3SnH and AIBN and afforded compounds 8 and 9,
COOEt
COOEt
NaH, DMF, BuLi,
NaH, DMF
Br
THP
Br
O
O
O
Yield 65%
Yield 65%
1
2
COOEt
a) NaOH, t = 1 h
b) HCl 7%, t =1 h 30'
O
O
O
Yield 91%
OH
HO
THPO
5
4
3
Scheme 2.

2770
M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
simple treatment with allyltributyltin and AIBN (Scheme
5). In order to minimize the equilibration of the Z-isomer,
the reaction mixtures were worked up as described above
for the deselenenylated products. Z-Isomer 10 (dH2
3.94 ppm, dC2 79.4 ppm) and E-isomer 11 (dH2 4.04 ppm,
dC2 77.6 ppm) were thus obtained in satisfactory yields
from 6 and 7, respectively.
the E-isomer (Dd = 0.25 and 0.27 for 14 and 15 and
Dd = 0.16 and 0.12 for 16 and 17). The enantiopure sele-
nides are presented in Scheme 7 in the same order in which
they are eluted from the chromatographic column. The
geometrical structures of the 2-[(camphorseleno)methyl]-
1,6-dioxaspiro[4.4]nonanes 14–17, assigned on the basis
of their NMR spectra, were also confirmed by the results
obtained from their deselenenylation and allylation reac-
tions, which are described below. The yields of isolated
products are indicated in Scheme 7.
O
, AIBN,C6H6
reflux
5
2
Bu3Sn
SePh
O
5
2
O
O
O
5
2
(2S*,5S*)-(Z)-10
(2R*,5S*)-(Z)-6
Yield 60%
O
SeCf
(2R,5S)-(Z)-14
Yield 18%, [α]D = +73.0
, AIBN,C6H6
reflux
O
Bu3Sn
O
2
5
2
5
5
O
2
O
SeCf
O
O
SePh
(2S*,5S*)-(E)-7
O
SeCf
OH
(2R*,5S*)-(E)-11
4
(2S,5R)-(Z)-15
Yield 65%
Yield 11%, [α]D = -18.2
13 , CH2Cl2, T.A.
Scheme 5.
column chromatography
O
5
O
2
SeCf
With all these data in hand, we then approached the prob-
lem of the asymmetric cyclization reactions of a mixture of
4 and 5 using the camphor diselenide as the precursor of
the chiral nonracemic electrophilic selenenylating agent.
This diselenide can be easily obtained in a one-pot from
(1R)-(+)-camphor and elemental selenium as described by
Back.20
SeCf
(2S,5S)-(E)-16
OH
O
Yield 17%, [α]D = +32.7
5
2
5
O
O
SeCf
(2R,5R)-(E)-17
Yield 22%, [α]D = -20.2
Unsatisfactory results were obtained from some prelimi-
nary experiments carried out with camphorselenenyl
sulfate or triflate, the desired spiro compounds being
obtained in very low yields. Only using camphorselenenyl
tetrafluoroborate 13, generated from the reaction of
camphor diselenide 12 with silver tetrafluoroborate, could
the cyclization products be obtained in a good yield. The
electrophilic reagent was formed in dichloromethane at
ꢀ50 ꢁC, the resulting suspension was stirred at the same
temperature for 30 min21 and then allowed to reach room
temperature before adding the starting compounds
(Scheme 6).
Scheme 7.
These enantiomerically pure diastereoisomers were then
submitted to reductive deselenenylation with Ph3SnH and
AIBN (Scheme 8).
O
O
5
2
5
2
Ph3SnH, AIBN, C6H6
reflux
O
O
SeCf
(2R,5S)-(Z)-14
(2S,5S)-(Z)-8
Ph3SnH, AIBN, C6H6
reflux
5
2
5
2
O
O
O
O
SeCf
AgBF4
(2S,5R)-(Z)-15
(2R,5R)-(Z)-ent-8
CfSeBF4
SeBF4
CH2Cl2
Se)2
O
O
O
O
5
5
O
2
2
12
Scheme 6.
Ph3SnH, AIBN, C6H6
reflux
13
O
SeCf
(2S,5S)-(E)-16
(2R,5S)-(E)-9
As reported in Scheme 7, this reaction afforded a mixture
of the two Z-diastereoisomers 14 (dH2 4.21 ppm, dC2
79.8 ppm) and 15 (dH2 4.21 ppm, dC2 80.3 ppm) and of
the two E-diastereoisomers 16 (dH2 4.34 ppm, dC2
78.4 ppm) and 17 (dH2 4.40 ppm, dC2 77.6 ppm), which
could be separated by medium pressure liquid chromato-
graphy. In agreement with what was already observed for
the corresponding phenylseleno derivatives, the difference
in chemical shift between the two diastereotopic protons
in the CH2Se group is greater for the Z-isomer than for
2
5
5
2
Ph3SnH, AIBN, C6H6
reflux
O
O
O
O
SeCf
(2S,5R)-(E)-ent-9
(2R,5R)-(E)-17
Scheme 8.
The reaction mixtures were carefully worked up as des-
cribed above for the corresponding racemic compounds.
As indicated by the NMR spectra, these products were

M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
2771
slightly contaminated by some unidentified tin compounds
and reaction yields and specific rotations were therefore
not determined. Isomers 8 and ent-8, obtained from 14
and 15, respectively, gave NMR spectra identical to those
of the deselenenylated compound obtained from 6; thus,
they are two enantiomers and have the Z-configurations.
Isomers 9 and ent-9, obtained from 16 and 17, respectively,
gave NMR spectra, which were identical to those of the
deselenenylated compound obtained from 7; thus, they
are two enantiomers and have E-configurations. Whereas
the Z- and E-configurations indicated in Schemes 7 and 8
are well established the absolute configurations indicated
for compounds 8 and ent-8, and hence 14 and 15, and those
indicated for compounds 9 and ent-9, and hence 16 and 17,
are at present only tentative.
involves intramolecular cyclizations of suitably substituted
hydroxyketones. The considerable advantage of the pres-
ently described cyclizations consists of the use of chiral
nonracemic organoselenium reagents to promote the one-
pot double cyclization reaction and hence to obtain the
1,6-dioxaspiro[4.4]nonane derivatives in an enantiomeri-
cally pure form. As already observed in previous
cases,12,22,23 the use of camphorselenenyl reagents produces
mixtures of diastereoisomers, which are easily separable by
column chromatography. Moreover, the presence of the
organoselenium function in the cyclization products allows
the introduction of several other groups to be easily
effected. The compounds described herein are very similar
to several naturally occurring spiro-ketals.15g,h,24 It can
be anticipated that most of these compounds could be pre-
pared with the presently described method by selecting the
appropriate starting hydroxyketones.
Scheme 9 indicates the products, which are obtained from
the substitution of the camphorselenyl group with the allyl
group. These reactions were carried out and worked up as
described above for the racemic phenylseleno derivatives.
4. Experimental
All new compounds were characterized by MS, 1H and 13
C
, AIBN,C6H6
reflux
Bu3Sn
O
O
NMR. GC analyses and MS spectra were carried out with
an HP 6890 gas chromatograph (25 m dimethyl silicone
capillary column) equipped with an HP 5973 Mass Selec-
tive Detector; for the ions containing selenium only the
5
5
2
2
O
O
SeCf
(2R,5S)-(Z)-14
(2S,5S)-(Z)-10
Yield 80%
1
peaks arising from the selenium-80 isotope are given. H
and 13C NMR spectra were recorded at 400 and
100.62 MHz, respectively, on a Bruker DRX 400 instru-
ment; unless otherwise specified, CDCl3 was used as sol-
vent and TMS as the standard. HPLC analyses were
performed on an HP 1100 instrument equipped with a
Chiracel OD-H column (250 · 4 mm, Daicel), eluent:
i-PrOH–hexane (1:99), flow rate: 1 mL/min, UV detection
at 210 nm. Optical rotations were measured with a Jasco
DIP-1000 digital polarimeter. Elemental analyses were
carried out on a Carlo Erba 1106 Elemental Analyzer.
, AIBN,C6H6
reflux
Bu3Sn
Bu3Sn
5
2
2
5
O
O
O
O
SeCf
(2S,5R)-(Z)-15
(2R,5R)-(Z)-ent-10
Yield 77%
O
5
, AIBN,C6H6
reflux
2
O
2
5
O
SeCf
(2S,5S)-(E)-16
O
(2R,5S)-(E)-11
Yield 68% [α]= +55.3
, AIBN,C6H6
reflux
4.1. Starting products
Bu3Sn
2
5
5
2
O
O
O
O
SeCf
Ethyl-3-oxobutanoate, 2-(2-bromoethoxy) tetrahydro-2H-
pyran, N-(phenylseleno)phthalimide, triphenyltin hydride
and allyltributyltin are commercial products and were used
without further purification.
(2S,5R)-(E)-ent-11
(2R,5R)-(E)-17
Yield 73%, [α]= -57.7
Scheme 9.
The two allylation products deriving from 14 and 15 pre-
sented NMR spectra identical with those of the allylation
product derived from 6, indicating that they are the two
enantiomers 10 and ent-10, having the Z-configuration.
The two diastereoisomers 16 and 17 presented NMR spec-
tra identical to those of the corresponding product
obtained from 7, indicating that they are the two
enantiomers 11 and ent-11, having the E-configuration.
In the latter two cases, the reaction products could be
obtained in a pure form and their specific rotations could
also be measured.
4.2. Synthesis of ethyl 3-oxo-2-[2-(tetrahydro-2H-pyran-2-
yloxy)ethyl]hept-6-enoate, 3
Ethyl-3-oxobutanoate, 1, was submitted to the first alkyl-
ation according to the procedure described in the litera-
ture.25 Ethyl 3-oxohept-6-enoate, 2 was obtained in a
65% yield. The second alkylation was effected adding ethyl
3-oxohept-6-enoate, 2 (2.0 g, 12 mmol) to sodium hydride
(0.31 g, 13 mmol) in DMF at room temperature. After
15 min, 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.45 g,
12 mmol) was added and the mixture warmed up to
70 ꢁC. The progress of the reaction was monitored by
TLC. After 20 h, the reaction mixture was diluted with
water and extracted with diethyl ether. Compound 3 was
isolated in a 65% yield after flash column chromatography
on silica gel using a mixture of diethyl ether and light petro-
leum (from 2:98 to 8:92) as eluant.
3. Conclusions
Although several methods have been described for the
synthesis of spiroacetals, probably the simplest procedure

2772
M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
4.2.1. Ethyl 3-oxo-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-
hept-6-enoate, 3. Oil; 1H NMR: d 5.70 (ddt, 1H, J = 16.7,
10.2, 6.5 Hz), 5.01–4.80 (m, 2H), 4.45–4.41 (m, 1H), 4.09
(q, 2H, J = 7.1 Hz), 3.75–3.57 (m, 3H), 3.42–3.35 (m,
1H), 3.34–3.27 (m, 1H), 2.70–2.50 (m, 2H) 2.29–2.20 (m,
2H), 2.11–2.01 (m, 2H), 1.82–1.28 (m, 6H), 1.17 (t, 3H,
J = 7.1 Hz); 13C NMR: d 204.1, 169.3, 136.6, 115.0, 98.7,
64.6, 62.1, 61.1, 55.8, 41.0, 30.2, 28.0, 27.1, 25.1, 19.3, 13.8.
(dd, 1H, J = 8.0, 12.0 Hz), 2.21–2.13 (m, 1H), 2.07–1.80
(m, 7H); 13C NMR: d 132.4 (two carbons), 130.0, 128.9
(two carbons), 126.6, 114.8, 78.9, 66.8, 35.6, 34.6, 34.4,
31.0, 24.3; MS m/z (rel. int.): 298 (14), 157 (5), 127 (100),
85 (18), 55 (9). Anal. Calcd for C14H18O2Se: C, 56.57; H,
6.10. Found: C, 56.64; H, 6.03.
4.4.2. (2S*,5S*)-2-[(Phenylseleno)methyl]-1,6-dioxa spiro[4.4]-
1
nonane, (E)-7. Yield 35%. Oil; H NMR: d 7.56–7.53 (m,
4.3. Synthesis of 1-hydroxyoct-7-en-4-one, 4, and 2-but-3-
enyltetrahydrofuran-2-ol, 5
2H), 7.22–7.15 (m, 3H), 4.35 (m, 1H), 3.93–3.88 (m, 1H),
3.85–3.80 (m, 1H), 3.10 (dd, 1H, J = 4.7, 12.2 Hz), 2.98
(dd, 1H, J = 7.2, 12.2 Hz), 2.26–2.17 (m, 1H), 2.07–1.95
(m, 4H), 1.91–1.87 (m, 2H) 1.78–1.69 (m, 1H); 13C
NMR: d 132.5 (two carbons), 130.2, 128.9 (two carbons),
126.7, 115.2, 77.1, 67.0, 35.1, 34.5, 33.1, 30.0, 24.5; MS
m/z (rel. int.): 298 (24), 157 (4), 127 (100), 85 (19), 55 (8).
Anal. Calcd for C14H18O2Se: C, 56.57; H, 6.10. Found:
C, 56.53; H, 6.07.
Sodium hydroxide (1.6 g, 40 mmol) was added at room
temperature to a solution (20 mL) of ethyl 3-oxo-2-[2-(tet-
rahydro-2H-pyran-2-yloxy)ethyl]hept-6-enoate,
3 (3.0 g,
10 mmol) in water (20 mL). The mixture was stirred for
1 h and then a 7% solution of hydrochloric acid added.
The reaction was stirred for 1 h and then extracted with
dichloromethane. The organic solution was dried and
evaporated to afford an oil, which was constituted by a
2:1 mixture of hemiacetal 5 and of hydroxyketone, 4
(91% yield), which was sufficiently pure to be directly used
for the cyclization reactions. The physical and spectral data
of compounds 4 and 514 are reported below.
4.5. Cyclization reactions promoted by camphorselenenyl
tetrafluoroborate
Silver tetrafluoroborate (0.44 g, 2.28 mmol) was added to a
solution of (R)-dicamphor diselenide (0.88 g, 1.9 mmol) in
dicholoromethane (5 mL) at ꢀ50 ꢁC. The resulting yellow
suspension was stirred at the same temperature for
30 min. During this time the reaction mixture progressively
turned deep orange.21 The mixture of hydroxyketone 4 and
hemiacetal 5 (0.27 g, 1.90 mmol) was added and the mix-
ture was stirred for 8 h. The reaction mixture was poured
into an aqueous NaHCO3 solution and extracted with
dicholoromethane. After evaporation of the extracts, the
reaction products were separated by medium pressure
chromatography on a silica gel column (Merk, LiChro-
prepꢂSi60, 40–63 lm) using a mixture of diethyl ether
and light petroleum as the eluant (from 10:90 to 20:80).
The separation of compounds 14, 15 and 16, which by
TLC presented the same retention times, was monitored
by HPLC; their tR were 15.6, 16.9 and 20.2 min, respec-
tively. The separation of compound 17 could instead be
easily followed by TLC. Its HPLC tR was 17.5 min. The
products obtained are reported in Scheme 7. The physical
and spectral data are reported below.
1
4.3.1. 1-Hydroxyoct-7-en-4-one, 4. Oil; H NMR: d 5.73
(ddt, 1H, J = 16.9, 10.3, 6.7 Hz), 5.10–4.90 (m, 2H), 3.51
(t, 2H, J = 6.0 Hz), 2.51–2.40 (m, 5H), 2.23 (quart, 2H,
J = 6.5 Hz), 1.75 (quint, 2H, J = 6.7 Hz); 13C NMR: d
210.7, 136.8, 115.0, 61.5, 41.7, 39.4, 27.6, 26.2.
1
4.3.2. 2-But-3-enyltetrahydrofuran-2-ol, 5. Oil; H NMR:
d 5.80 (ddt, 1H, J = 16.9, 10.3, 6.6 Hz), 5.10–4.90 (m,
2H), 3.88–3.80 (m, 1H), 3.41–3.30 (m, 1H), 2.52–2.49 (m,
2H), 2.35–1.61 (m, 7H); 13C NMR: d 138.1, 114.2, 109.0,
67.1, 35.1, 33.2, 28.7, 24.0. Anal. Calcd for C8H14O2: C,
67.57; H, 9.92. Found: C, 67.58; H, 9.91.
4.4. Cyclization reactions promoted by N-(phenylseleno)
phthalimide
To a stirred solution of the mixture of 4 and 5 (0.29 g,
2 mmol) in dichloromethane (6 mL), N-(phenylseleno)-
phthalimide (0.86 g, 2.8 mmol) was added at room temper-
ature. A catalytic amount of BF3ÆEt2O was added dropwise.
The pale yellow solution became orange. The progress of
the reaction was monitored by TLC. After 4 h, 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 liquid chromatography on a sil-
ica gel column (Merck, LiChroprepꢂSi60, 40–63 lm)
using a 1:4 mixture of diethyl ether and light petroleum as
the eluant. The various fractions were analyzed by TLC.
The products obtained are reported in Scheme 3. The phys-
ical and spectral data are reported below.
4.5.1. (2R,5S)-2-[(Camphorseleno)methyl]-1,6-dioxa spiro[4.4]-
17
nonane, (Z)-14. Yield 18%. Oil; ½aꢁD ¼ þ73:0 (c
1
1.95, CHCl3). H NMR: d 4.21 (dq, 1H, J = 7.3, 6.1 Hz),
3.98–3.88 (m, 1H), 3.80–3.70 (m, 2H), 3.05 (dd, 1H,
J = 5.9, 12.3 Hz), 2.80 (dd, 1H, J = 7.3, 12.3 Hz), 2.30–
2.20 (m, 2H), 2.10–1.95 (m, 4H), 1.90–1.85 (m, 2H),
1.84–2.80 (m, 2H), 1.70–1.60 (m, 2H), 1.45–1.37 (m, 1H),
0.96 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H); 13C NMR: d
217.9, 115.0, 79.8, 67.0, 58.1, 48.2, 47.2, 46.7, 35.7, 34.8,
31.2, 30.9, 30.4, 24.4, 23.2, 19.6 (two carbons), 9.6; MS
m/z (rel. int.): 372 (22), 141 (19), 127 (100), 123 (12), 85
(12), 55 (10). Anal. Calcd for C18H28O3Se: C, 58.21; H,
7.60. Found: C, 58.13; H, 7.68.
4.4.1. (2R*,5S*)-2-[(Phenylseleno)methyl]-1,6-dioxa spiro[4.4]-
nonane, (Z)-6. Yield 35%. Oil; H NMR: d 7.56–7.50 (m,
2H), 7.30–7.23 (m, 3H), 4.22 (m, 1H), 3.93–3.88 (m, 1H),
4.5.2. (2S,5R)-2-[(Camphorseleno)methyl]-1,6-dioxa spiro[4.4]-
18
1
nonane, (Z)-15. Yield 11%. Oil; ½aꢁD ¼ ꢀ18:2 (c
1
2.18, CHCl3). H NMR: d 4.21 (dq, 1H, J = 7.0, 6.4 Hz),
3.83–3.78 (m, 1H), 3.25 (dd, 1H, J = 5.7, 12.0 Hz), 2.97
3.90–3.82 (m, 1H), 3.80–3.72 (m, 2H,), 3.08 (dd, 1H,

M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
2773
J = 7.0, 12.2 Hz), 2.81 (dd, 1H, J = 6.4, 12.2 Hz), 2.20–2.10
(m, 2H), 2.02–1.85 (m, 4H), 1.83–1.73 (m, 5H) 1.65–1.58
(m, 1H), 1.41–1.35 (m, 1H), 0.94 (s, 3H), 0.85 (s, 3H),
0.83 (s, 3H); 13C NMR: d 218.1, 114.9, 80.3, 66.9, 58.0,
48.5, 47.1, 46.7, 35.7, 34.7, 31.5, 31.4, 30.4, 24.4, 23.3,
19.6 (two carbons), 9.7; MS m/z (rel. int.): 372 (19), 141
(27), 127 (100), 85 (12), 55 (11). Anal. Calcd for
C18H28O3Se: C, 58.21; H, 7.60. Found: C, 58.28; H, 7.82.
J = 6.1 Hz); 13C NMR: d 114.7, 75.9, 66.9, 36.2, 35.2,
32.7, 24.4, 22.6. Anal. Calcd for C8H14O2: C, 65.57; H,
9.92. Found: 65.48; H, 9.85.
4.6.2. (2R*,5S*)-2-Methyl-1,6-dioxaspiro[4.4]nonane, (E)-
9. 1H NMR: d 4.21 (sex, 1H, J = 6.2 Hz), 3.94–3.89 (m,
1H), 3.87–3.81 (m, 1H), 2.13–1.63 (m, 8H), 1.21 (d, 3H,
J = 6.1 Hz); 13C NMR: d 114.8, 74.1, 66.9, 35.4, 34.9,
32.0, 24.6, 21.2. Anal. Calcd for C8H14O2: C, 65.57; H,
9.92. Found: 65.51; H, 9.98.
4.5.3. (2S,5S)-2-[(Camphorseleno)methyl]-1,6-dioxa spiro[4.4]-
16
nonane, (E)-16. Yield 17%. Oil; ½aꢁD ¼ þ32:7 (c
1
2.57, CHCl3). H NMR: d 4.34 (dq, 1H, J = 7.0, 6.4 Hz),
4.7. Radical allylations. General procedure
3.97–3.89 (m, 2H), 3.87–3.80 (m, 1H), 3.01 (dd, 1H,
J = 5.9, 12.5 Hz), 2.85 (dd, 1H, J = 6.1, 12.5 Hz), 2.30–
2.20 (m, 2H), 2.15–1.95 (m, 4H), 1.93–1.88 (m, 2H),
1.87–1.65 (m, 3H), 1.47–1.38 (m, 2H), 0.95 (s, 3H), 0.86
(s, 3H), 0.83 (s, 3H); 13C NMR: d 218.0, 115.2, 78.4,
67.1, 58.0, 48.4, 47.0, 46.7, 34.8, 34.5, 30.3, 30.2, 29.2,
24.5, 23.0, 19.6 (two carbons), 9.6; MS m/z (rel. int.): 372
(34), 141 (26), 127 (100), 85 (11), 55 (10). Anal. Calcd for
C18H28O3Se: C, 58.21; H, 7.60. Found: C, 58.17; H, 7.50.
Allyltributyltin (0.72 g, 2.3 mmol) and a catalytic amount
of AIBN were added to a solution of compounds 6 and 7
(0.1 g, 0.33 mmol) or 14–17 (0.11 g, 0.33 mmol), in reflux-
ing dry benzene (8 mL) under nitrogen. The progress of
1
the reactions was monitored by TLC and H NMR. After
1 h, a second portion of allyltributyltin (2.3 mmol) and a
catalytic amount of AIBN were added. The reactions were
stirred for 3 h for the compounds 6 and 7, and for 6 h for
compounds 14–17. The solvent was then carefully evapo-
rated under vacuum. The allylated compounds 11 and
ent-11 were isolated in a pure form after column chroma-
tography on silica gel using a mixture of diethyl ether
and light petroleum (from 2:98 to 10:90) as the eluant. Col-
umn chromatography of compounds 10 and ent-10 was
instead carried out on deactivated silica gel. The NMR
spectra of the racemic Z- and E-2-methyl-1,6-dioxa-
spiro[4.4]nonanes 10 and 11 (Scheme 5) are reported below.
The spectral data of compounds 10, ent-10 and 11, ent-11
(Scheme 9) are identical to those of the corresponding race-
mic compounds.
4.5.4. (2R,5R)-2-[(Camphorseleno)methyl]-1,6-dioxa spiro[4.4]-
18
nonane, (E)-17. Yield 22%. Oil; ½aꢁD ¼ ꢀ20:2 (c
1.82, CHCl3). 1H NMR: d 4.40 (dq, 1H, J = 5.95,
5.05 Hz), 3.92–3.89 (m, 1H), 3.88–3.79 (m, 2H), 3.00 (dd,
1H, J = 5.9, 12.5 Hz), 2.88 (dd, 1H, J = 5.05, 12.5 Hz),
2.28–2.18 (m, 2H), 2.10–1.98 (m, 4H), 1.95–1.85 (m, 2H),
1.84–1.62 (m, 4H), 1.48–1.40 (m, 1H), 1.00 (s, 3H), 0.91
(s, 3H), 0.88 (s, 3H); 13C NMR: d 218.0, 115.2, 77.6,
67.0, 58.1, 48.3, 46.8, 46.7, 35.0, 34.6, 30.4, 30.1, 29.5,
24.5, 23.2, 19.6 (two carbons), 9.6; MS m/z (rel. int.): 372
(30), 141 (24), 127 (100), 85 (14), 55 (12). Anal. Calcd for
C18H28O3Se: C, 58.21; H, 7.60. Found: C, 58.11; H, 7.65.
4.7.1.
(2S*,5S*)-2-But-3-enyl-1,6-dioxaspiro[4.4]nonane,
4.6. Reductive deselenenylations. General procedure
(Z)-10. Yield 60%. Oil, 1H NMR d 5.82 (ddt, 1H,
J = 16.8, 10.1, 6.5 Hz), 5.06–4.93 (m, 2H), 3.94 (m, 2H),
3.86–3.76 (m, 1H), 2.26–1.23 (m, 12H); 13C NMR: d
138.5, 114.5, 114.3, 79.4, 66.7, 36.3, 35.7, 34.9, 30.7, 30.2,
24.4. Anal. Calcd for C11H18O2: C, 72.49; H 9.95. Found:
C, 72.55; H, 9.90.
Triphenyltin hydride (0.32 g, 0.9 mmol) and a catalytic
amount of AIBN were added to a solution of compounds
6 and 7 (0.18 g, 0.6 mmol), or 14–17 (0.12 g, 0.32 mmol)
in dry benzene (5 mL) and the mixture was stirred and
refluxed for 1 h. The solvent was then carefully removed
under reduced pressure. The deselenenylated products were
isolated after a simple filtration on a deactivated silica gel
column using a 10:90 mixture of ethyl ether and light petro-
leum as the eluant. Deactivated silica gel was prepared by
flushing with a 10% solution of triethylamine in light petro-
leum and then by washing with light petroleum just before
use.19 The eluate was carefully evaporated and the resulting
products were then directly analyzed by NMR.
4.7.2.
(2R*,5S*)-2-But-3-enyl-1,6-dioxaspiro[4.4]nonane,
(E)-11. Yield 65%. Oil, 1H NMR: d 5.82 (ddt, 1H,
J = 16.8, 10.1, 6.5 Hz), 5.06–4.93 (m, 2H), 4.04 (quint,
1H, J = 6.6 Hz), 3.94–3.89 (m, 1H), 3.87–3.79 (m, 1H),
2.15–1.87 (m, 6H), 1.86–1.81 (m, 2H), 1.64–1.60 (m, 1H),
1.58–1.43 (m, 2H), 1.26–1.17 (m, 1H); 13C NMR: d 138.4,
114.5, 114.4, 77.6, 66.9, 35.2, 34.8, 34.6, 30.1, 30.0, 24.6.
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C,
72.41; H, 9.88.
The NMR spectra of the racemic Z- and E-2-methyl-1,6-
dioxaspiro[4.4]nonanes 8 and 9 (Scheme 4) are reported
below. These data are in very good agreement with those
reported in the literature.11,14,15 The spectral data of the
enantiopure compounds 8, ent-8 and 9, ent-9 (Scheme 8)
are identical to those of the corresponding racemic
compounds.
4.7.3. (2R,5S)-2-But-3-enyl-1,6-dioxaspiro[4.4]nonane, (E)-
16
11. Yield 68%. Oil, ½aꢁD ¼ þ55:3 (c 1.20, CHCl3).
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found:
72.32; H, 9.78.
4.7.4. (2S,5R)-2-But-3-enyl-1,6-dioxaspiro[4.4]nonane, (E)-
16
4.6.1. (2S*,5S*)-2-Methyl-1,6-dioxaspiro[4.4]nonane, (Z)-
8. 1H NMR: d 4.10 (m, 1H), 4.01–3.94 (m, 1H), 3.82–
3.75 (m, 1H), 2.08–1.62 (m, 8H), 1.29 (d, 3H,
ent-11. Yield 73%. Oil, ½aꢁD ¼ ꢀ57:7 (c 1.25, CHCl3).
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found:
72.35; H, 9.03.

2774
M. Tiecco et al. / Tetrahedron: Asymmetry 17 (2006) 2768–2774
9. Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Bagnoli,
Acknowledgements
L.; Santi, C.; Temperini, A. Tetrahedron: Asymmetry 2001,
12, 1493.
Financial support from MIUR, National Projects
PRIN2003 and FIRB2001 and Consorzio CINMPIS is
gratefully acknowledged.
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